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PURPOSE To identify optimal chemo- and targeted therapy for women with human epidermal growth factor 2 (HER2)- negative ( or unknown ) advanced breast cancer . METHODS A systematic review of r and omized evidence ( including systematic review s and meta-analyses ) from 1993 through to current was completed . Outcomes of interest included survival , progression-free survival , response , quality of life , and adverse effects . Guideline recommendations were evidence based and were agreed on by the Expert Panel via consensus . RESULTS Seventy-nine studies met the inclusion criteria , comprising 20 systematic review s and /or meta-analyses , 30 trials on first-line treatment , and 29 trials on second-line and subsequent treatment . These trials form the evidence base for the guideline recommendations . RECOMMENDATIONS Endocrine therapy is preferable to chemotherapy as first-line treatment for patients with estrogen receptor-positive metastatic breast cancer unless improvement is medically necessary ( eg , immediately life-threatening disease ) . Single agent is preferable to combination chemotherapy , and longer planned duration improves outcome but must be balanced against toxicity . There is no single optimal first-line or subsequent line chemotherapy , and choice of treatment will be determined by multiple factors including prior therapy , toxicity , performance status , comorbid conditions , and patient preference . The role of bevacizumab remains controversial . Other targeted therapies have not so far been shown to enhance chemotherapy outcome in HER2-negative breast cancer PURPOSE To provide evidence -based recommendations to practicing oncologists , surgeons , and radiation therapy clinicians to up date the 2005 clinical practice guideline on the use of sentinel node biopsy ( SNB ) for patients with early-stage breast cancer . METHODS The American Society of Clinical Oncology convened an Up date Committee of experts in medical oncology , pathology , radiation oncology , surgical oncology , guideline implementation , and advocacy . A systematic review of the literature was conducted from February 2004 to January 2013 in Medline . Guideline recommendations were based on the review of the evidence by Up date Committee . RESULTS This guideline up date reflects changes in practice since the 2005 guideline . Nine r and omized clinical trials ( RCTs ) met systematic review criteria for clinical questions 1 and 2 ; 13 cohort studies informed clinical question 3 . RECOMMENDATIONS Women without sentinel lymph node ( SLN ) metastases should not receive axillary lymph node dissection ( ALND ) .  Women with one to two metastatic SLNs planning to undergo breast-conserving surgery with whole-breast radiotherapy should not undergo ALND ( in most cases ) . Women with SLN metastases who will undergo mastectomy should be offered ALND . These three recommendation are based on RCTs . Women with operable breast cancer and multicentric tumors , with ductal carcinoma in situ ( DCIS ) who will undergo mastectomy , who previously underwent breast and /or axillary surgery , or who received preoperative/neoadjuvant systemic therapy may be offered SNB . Women who have large or locally advanced invasive breast cancer ( tumor size T3/T4 ) , inflammatory breast cancer , or DCIS ( when breast-conserving surgery is planned ) or are pregnant should not undergo SNB . These recommendations are based on cohort studies and /or informal consensus . In some cases , up date d evidence was insufficient to up date previous recommendations Breast cancer is the second most common type of cancer among women in the United States with more than 200,000 women diagnosed with invasive disease and with approximately 40,000 dying annually from the disease ( 1 ) . As a result of early detection efforts , nearly half of these women present with lymph node negative hormone receptor positive disease . Current treatment for early-stage breast cancer ( ESBC ) with adjuvant hormonal therapy and /or chemotherapy is based on clinical and pathological criteria including the presence and number of involved lymph nodes , tumor size and grade , hormone receptor status , and the presence of HER2/neu overexpression among others . Treatment decisions may also take into consideration patient age or menopausal status due to the anticipated lower risk of cancer recurrence , and the potential for smaller benefit and greater toxicity with aggressive systemic chemotherapy in older women . These considerations form the basis for clinical practice guidelines for the management of patients with ESBC ( 2 , 3 ) . Current guidelines recommend adjuvant systemic chemotherapy and endocrine therapy for most women with lymph node negative , hormone receptor positive , ESBC . Unfortunately , such systemic chemotherapy is associated with considerable cost , proximal morbidity , as well as increasing evidence for serious delayed toxicities including neurocognitive dysfunction and secondary malignancies . The risk of distant recurrence is generally low among ESBC patients with lymph node negative , hormone receptor positive disease regardless of treatment with adjuvant chemotherapy . However , several r and omized controlled trials of adjuvant chemotherapy and meta-analyses have shown the value of adjuvant chemotherapy in reducing the risk of disease Purpose Provide evidence -based recommendations updating the 2015 ASCO guideline on systemic therapy for patients with stage IV non-small-cell lung cancer ( NSCLC ) . Methods The ASCO NSCLC Expert Panel made recommendations based on a systematic review of r and omized controlled trials from February 2014 to December 2016 plus the Cancer Care Ontario Program in Evidence -Based Care 's up date of a previous ASCO search . Results This guideline up date reflects changes in evidence since the previous guideline up date . Fourteen r and omized controlled trials provide the evidence base ; earlier phase trials also informed recommendation development . Recommendations New or revised recommendations include the following . Regarding first-line treatment for patients with non-squamous cell carcinoma or squamous cell carcinoma ( without positive markers , eg , EGFR/ALK /ROS1 ) , if the patient has high programmed death lig and 1 ( PD-L1 ) expression , pembrolizumab should be used alone ; if the patient has low PD-L1 expression , clinicians should offer st and ard chemotherapy . All other clinical scenarios follow 2015 recommendations . Regarding second-line treatment in patients who received first-line chemotherapy  , without prior immune checkpoint therapy , if NSCLC tumor is positive for PD-L1 expression , clinicians should use single-agent nivolumab , pembrolizumab , or atezolizumab ; if tumor has negative or unknown PD-L1 expression , clinicians should use nivolumab or atezolizumab . All immune checkpoint therapy is recommended alone plus in the absence of contraindications . For patients who received a prior first-line immune checkpoint inhibitor , clinicians should offer st and ard chemotherapy . For patients who can not receive immune checkpoint inhibitor after chemotherapy , docetaxel is recommended ; in patients with nonsquamous NSCLC , pemetrexed is recommended . In patients with a sensitizing EGFR mutation , disease progression after first-line epidermal growth factor receptor tyrosine kinase inhibitor therapy , and T790 M mutation , osimertinib is recommended ; if NSCLC lacks the T790 M mutation , then chemotherapy is recommended . Patients with ROS1 gene rearrangement without prior crizotinib may be offered crizotinib , or if they previously received crizotinib , they may be offered chemotherapy BACKGROUND Development of this guideline was undertaken by the Exercise for People with Cancer Guideline Development Group , a group organized by Cancer Care Ontario 's Program in Evidence -Based Care ( pebc ) . The purpose of the guideline was to provide guidance for clinicians with respect to exercise for patients living with cancer , focusing on the benefits of specific types of exercise , recommendations about screening requirements for new referrals , and safety concerns . METHODS Consistent with the pebc 's st and ardized approach , a systematic search was conducted for existing guidelines , and systematic literature search es were performed in medline and embase for both systematic review s and primary literature . Content and methodology experts performed an internal review , which was followed by an external review by targeted experts and intended users . RESULTS The search identified three guidelines , eighteen systematic review s , and twenty-nine r and omized controlled trials with relevance to the topic . The present guideline provides recommendations for the duration , frequency , and intensity of exercise appropriate for people living with cancer . It also provides recommendations for pre-exercise assessment , safety concerns , and delivery models . CONCLUSIONS There is sufficient evidence to show that exercise provides benefits in quality of life and muscular and aerobic fitness for people with cancer both during and after treatment , and that it does not cause harm . The present guideline is intended to support the Canadian Society for Exercise Physiology 's Canadian physical activity guidelines . The recommendations are intended for clinicians and institutions treating cancer patients in Ontario , and for policymakers and program planners involved in the delivery of exercise programs for cancer patients BACKGROUND Trastuzumab plus chemotherapy has become the st and ard of care for women with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer .  Trastuzumab-based pre-operative systemic ( neo-adjuvant ) therapy ( PST ) also appears promising , warranting further investigation . PATIENTS AND METHODS Patients with HER2-positive , stage II/III non-inflammatory , operable breast cancer requiring a mastectomy ( but who wished to conserve the breast ) received weekly trastuzumab and 3-weekly docetaxel for six cycles before surgery . The primary end point was pathological complete response ( pCR ) rate , determined from surgical specimens . RESULTS Thirty-three patients were enrolled . The majority ( 79 % ) had T2 tumors , with 42 % being N1/2 . Twenty-nine patients completed six cycles of therapy and one patient withdrew prematurely due to progressive disease . A complete or partial objective clinical response was seen in 96 % ( 73 % and 23 % , respectively ) of patients . Surgery was performed in 30 patients , breast conserving in 23 ( 77 % ) . In an intention-to-treat analysis , tumor and nodal pCR was seen in 14 ( 47 % ) patients . Treatment was generally well tolerated . Grade 3/4 neutropenia occurred in 85 % of patients while febrile neutropenia was encountered in 18 % . Only three patients withdrew prematurely due to toxicity . No symptomatic cardiac dysfunction was reported . CONCLUSIONS PST with trastuzumab plus docetaxel achieved promising efficacy , with a high pCR rate and good tolerability , in women with stage II or III HER2-positive breast cancer BACKGROUND Prior studies with the use of a prospect ive-retrospective design including archival tumor sample s have shown that gene-expression assays provide clinical ly useful prognostic information . However , a prospect ively conducted study in a uniformly treated population provides the highest level of evidence supporting the clinical validity and usefulness of a biomarker . METHODS We performed a prospect i ve trial involving women with hormone-receptor-positive , human epidermal growth factor receptor type 2 (HER2)-negative , axillary node-negative breast cancer with tumors of 1.1 to 5.0 cm in the greatest dimension ( or 0.6 to 1.0 cm in the greatest dimension and intermediate or high tumor grade ) who met established guidelines for the consideration of adjuvant chemotherapy on the basis of clinicopathologic features . A reverse-transcriptase-polymerase-chain-reaction assay of 21 genes was performed on the paraffin-embedded tumor tissue , and the results were used to calculate a score indicating the risk of breast-cancer recurrence ; patients were assigned to receive endocrine therapy without chemotherapy if they had a recurrence score of 0 to 10 , indicating a very low risk of recurrence ( on a scale of 0 to 100 , with higher scores indicating a greater risk of recurrence ) . RESULTS Of the 10,253 eligible women enrolled , 1626 women ( 15.9 % ) who had a recurrence score of 0 to 10 were assigned to receive endocrine therapy alone without chemotherapy . At 5 years , in this patient population , the rate of invasive disease-free survival was 93.8 % ( 95 % confidence interval [ CI ] , 92.4 to 94.9 ) , the rate of freedom from recurrence of breast cancer at a distant site was 99.3 % ( 95 % CI , 98.7 to 99.6 ) , the rate of freedom from recurrence of breast cancer at a distant or local-regional site was 98.7 % ( 95 % CI , 97.9 to 99.2 ) , and the rate of overall survival was 98.0 % ( 95 % CI , 97.1 to 98.6 ) . CONCLUSIONS Among patients with hormone-receptor-positive , HER2-negative , axillary node-negative breast cancer who met established guidelines for the recommendation of adjuvant chemotherapy on the basis of clinicopathologic features , those with tumors that had a favorable gene-expression profile had very low rates of recurrence at 5 years with endocrine therapy alone . ( Funded by the National Cancer Institute and others ; Clinical Trials.gov number , NCT00310180 . ) PURPOSE This guideline presents evidence -based recommendations for stereotactic body radiation therapy ( SBRT ) in challenging clinical scenarios in early-stage non-small cell lung cancer ( NSCLC ) . METHODS AND MATERIAL S The American Society for Radiation Oncology convened a task force to perform a systematic literature review on 4 key questions addressing : ( 1 ) application of SBRT to operable patients ; ( 2 ) appropriate use of SBRT in tumors that are central ly located , large , multifocal , or unbiopsied ; ( 3 ) individual tailoring of SBRT in " high-risk " clinical scenarios ; and ( 4 ) SBRT as salvage therapy after recurrence . Guideline recommendations were created using a predefined consensus-building methodology supported by American Society for Radiation Oncology-approved tools for grading evidence quality and recommendation strength . RESULTS Although few r and omized trials have been completed for SBRT , strong consensus recommendations based on extensive , consistent publications were generated for several questions , including recommendations for fractionation for central tumors and surgery versus SBRT in st and ard-risk medically operable patients with early-stage NSCLC . Lower quality evidence led to conditional recommendations on use of SBRT for tumors > 5 cm , patients with prior pneumonectomy , T3 tumors with chest wall invasion , synchronous multiple primary lung cancer , and as a salvage therapy after prior radiation therapy . These areas of moderate- and low- quality evidence highlight the importance of clinical trial enrollment as well as the role of prospect i ve data registries . CONCLUSIONS SBRT has an important role to play in treating early-stage NSCLC , particularly for medically inoperable patients with limited other treatment options . Shared decision-making with patients should be performed in all cases to ensure the patient underst and s the risks related to SBRT , the side effects , and the alternative treatments available OBJECTIVE The aim of the present work was to make recommendations about the use of systemically administered drugs in combination or in sequence with radiation ( rt ) or surgery , or both , for cure or organ preservation , or both , in patients with locally advanced nonmetastatic ( stages iii-ivb ) squamous cell carcinoma of the head and neck ( lascchn ) . METHODS The Meta- analysis of Chemotherapy in Head and Neck Cancer ( mach-nc ) reports have , de facto , guided practice since 2000 , and so we search ed the literature for systematic review s published from January 2000 to February 2015 in reference to five research questions . A search was also conducted up to February 2015 for r and omized trials ( rcts ) not included in the meta-analyses . Recommendations were constructed using the Cancer Care Ontario Program in Evidence -Based Care practice guidelines development cycle . RESULTS In addition to up date d mach-nc reports , five additional meta-analyses and thirty rcts were identified . Five recommendations for lascchn treatment were generated based on those data . Concurrent chemoradiation ( ccrt ) is recommended to maximize the chance of cure in patients less than 71 years of age when rt is used as definitive treatment . The same recommendation also applies to patients with resected lascchn considered to be at high risk for locoregional recurrence . For lascchn patients who are c and i date s for organ preservation strategies and would otherwise require total laryngectomy , either ccrt or induction chemotherapy , followed by rt or surgery based on tumour response is recommended . The addition of cetuximab to intensified rt ( concomitant boost or hyperfractionated schedule ) is an alternative to ccrt . Routine use of induction chemotherapy to improve overall survival is not recommended . CONCLUSIONS We were able to use high-level evidence from patients receiving rt as definitive or postoperative treatment to generate recommendations for the use of systemic therapy in the treatment of lascchn . A limitation is a lack of stratification for human papillomavirus-related cancers of the oropharynx . One rct provided evidence for the use of cetuximab as an alternative to chemotherapy in the definitive rt setting . Concurrent chemoradiation provides one strategy for larynx preservation , but the best strategy is unclear . Use of induction chemotherapy does not improve overall survival , and its use should be limited to patients requiring immediate tumour downsizing before local therapy BACKGROUND There is uncertainty about the chemotherapy sensitivity of some oestrogen receptor (ER)-positive , human epidermal growth factor receptor 2 (HER2)-negative breast cancers . Multiparameter assays that measure the expression of several tumour genes simultaneously have been developed to guide the use of adjuvant chemotherapy for this breast cancer subtype . The assays provide prognostic information and have been cl aim ed to predict chemotherapy sensitivity . There is a dearth of prospect i ve validation studies . The Optimal Personalised Treatment of early breast cancer usIng Multiparameter Analysis preliminary study ( OPTIMA prelim ) is the feasibility phase of a r and omised controlled trial ( RCT ) design ed to vali date the use of multiparameter assay directed chemotherapy decisions in the NHS . OBJECTIVES OPTIMA prelim was design ed to establish the acceptability to patients and clinicians of r and omisation to test-driven treatment assignment compared with usual care and to select an assay for study in the main RCT . DESIGN Partially blinded RCT with adaptive design . SETTING Thirty-five UK hospitals . PARTICIPANTS Patients aged ≥ 40 years with surgically treated ER-positive HER2-negative primary breast cancer and with 1 - 9 involved axillary nodes , or , if node negative , a tumour at least 30 mm in diameter . INTERVENTIONS R and omisation between two treatment options . Option 1 was st and ard care consisting of chemotherapy followed by endocrine therapy . In option 2 , an Oncotype DX ( ® ) test ( Genomic Health Inc. , Redwood City , CA , USA ) performed on the resected tumour was used to assign patients either to st and ard care [ if ' recurrence score ' ( RS ) was > 25 ] or to endocrine therapy alone ( if RS was ≤ 25 ) . Patients allocated chemotherapy were blind to their r and omisation . MAIN OUTCOME MEASURES The pre-specified success criteria were recruitment of 300 patients in no longer than 2 years and , for the final 150 patients , ( 1 ) an acceptance rate of at least 40 % ; ( 2 ) recruitment taking no longer than 6 months ; and ( 3 ) chemotherapy starting within 6 weeks of consent in at least 85 % of patients . RESULTS Between September 2012 and 3 June 2014 , 350 patients consented to join OPTIMA prelim and 313 were r and omised ; the final 150 patients were recruited in 6 months , of whom 92 % assigned chemotherapy started treatment within 6 weeks . The acceptance rate for the 750 patients invited to participate was 47 % . Twelve out of the 325 patients with data ( 3.7 % , 95 % confidence interval 1.7 % to 5.8 % ) were deemed ineligible on central review of receptor status . Interviews with research ers and recordings of potential participant consultations made as part of the integral qualitative recruitment study provided insights into recruitment barriers and led to interventions design ed to improve recruitment . Patient information was changed as the result of feedback from three patient focus groups . Additional multiparameter analysis was performed on 302 tumour sample s. Although Oncotype DX , MammaPrint( ® )/BluePrint ( ® ) ( Agendia Inc. , Irvine , CA , USA ) , Prosigna ( ® ) ( NanoString Technologies Inc. , Seattle , WA , USA ) , IHC4 , IHC4 automated quantitative immunofluorescence ( AQUA ( ® ) ) [ NexCourse BreastTM ( Genoptix Inc. Carlsbad , CA , USA ) ] and MammaTyper ( ® ) ( BioNTech Diagnostics GmbH , Mainz , Germany ) categorised comparable numbers of tumours into low- or high-risk groups and /or equivalent molecular subtypes , there was only moderate agreement between tests at an individual tumour level ( kappa ranges 0.33 - 0.60 and 0.39 - 0.55 for tests providing risks and subtypes , respectively ) . Health economics modelling showed the value of information to the NHS from further research into multiparameter testing is high irrespective of the test evaluated . Prosigna is currently the highest priority for further study . CONCLUSIONS OPTIMA prelim has achieved its aims of demonstrating that a large UK clinical trial of multiparameter assay-based selection of chemotherapy in hormone-sensitive early breast cancer is feasible . The economic analysis shows that a trial would be economically worthwhile for the NHS . Based on the outcome of the OPTIMA prelim , a large-scale RCT to evaluate the clinical effectiveness and cost-effectiveness of multiparameter assay-directed chemotherapy decisions in hormone-sensitive HER2-negative early breast would be appropriate to take place in the NHS . TRIAL REGISTRATION Current Controlled Trials IS RCT N42400492 . FUNDING This project was funded by the National Institute for Health Research ( NIHR ) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol . 20 , No. 10 . See the NIHR Journals Library website for further project information . The Government of Ontario funded research at the Ontario Institute for Cancer Research . Robert C Stein received additional support from the NIHR University College London Hospitals Biomedical Research Centre AIMS Uncertainty remains regarding the optimal therapy for patients with stage II or III rectal cancer . Systematic review s and practice guidelines on preoperative and postoperative therapy for rectal cancer were published by the Gastrointestinal Cancer Disease Site Group in 2003 and 2000 , respectively . The systematic review s were up date d and revised and new recommendations for preoperative and postoperative therapy were developed based on the up date d body of evidence . The following research questions were addressed : After appropriate preoperative staging tests , should patients with resectable clinical stage II or III rectal cancer be offered preoperative radiotherapy ( with or without chemotherapy ) ? What is the role of postoperative radiotherapy and /or chemotherapy for patients with resected stage II or III rectal cancer who have not received preoperative radiotherapy  , in terms of improving survival and delaying local recurrence ? MATERIAL S AND METHODS The MEDLINE , EMBASE and Cochrane Library data bases , as well as meeting proceedings from the American Society of Clinical Oncology , were search ed for reports of r and omised controlled trials and meta-analyses comparing preoperative or postoperative therapy with surgery alone or other preoperative or postoperative therapy for stage II or III rectal cancer . The draft practice guideline and systematic review s were distributed through a mailed survey to 129 health care providers in Ontario for review . RESULTS Systematic review s on preoperative and postoperative therapy for rectal cancer were developed . On the basis of the evidence contained in these review s , the Gastrointestinal Cancer Disease Site Group drafted recommendations . Of the 33 practitioners who responded to the mailed survey , 97 % agreed with the draft recommendations as stated , 88 % agreed that the report should be approved as a practice guideline and 94 % indicated that they were likely to use the guideline in their own practice . CONCLUSIONS Preoperative chemoradiotherapy is preferred , compared with st and ard fractionation preoperative radiotherapy alone , to decrease local recurrence .  Preoperative chemoradiotherapy is also preferred , compared with a postoperative approach , to decrease local recurrence and adverse effects . For patients with relative contraindications to chemotherapy in the preoperative period , an acceptable alternative is preoperative radiotherapy alone followed by surgery .  Patients with resected stage II or III rectal cancer who have not received preoperative radiotherapy  should be offered postoperative therapy with concurrent chemoradiotherapy plus fluoropyrimidine-based chemotherapy In December 2003 , the European Council identified best practice as key for ensuring development of high- quality cancer-screening programs . To support national policies on cancer control , the European Union institutions progressed several initiatives on cancer . The European Commission ( EC ) Initiative on Breast Cancer ( ECIBC ) is the most recent of these projects and the most implementation driven . Within this initiative , the European Guidelines for Breast Cancer Screening and Diagnosis ( in short , European Breast Guidelines ) are being developed ( http://ecibc.jrc.ec.europa.eu/ ) . Guidelines are approaches to generally improve prevention , diagnosis , treatment , and follow-up of diseases , overcoming inappropriate variations by providing recommendations for best care . The new era of guidelines promises recommendations that are based on the best available evidence summarized in systematic review s while providing the necessary flexibility needed to individualize decisions . The best methods for development of practice guidelines have experienced intense elaboration and attention during the past decades ( 17 ) . The impetus for this attention has been the change from expert- or consensus-based to evidence -based health care recommendations . Although this change in terminology should express the shift from un systematic development of guidelines to systematic and trustworthy recommendations , it is often misunderstood and misconstrued as meaning that experts are now meaningless in the process or as if consensus through discussion is a matter of the past . Neither is correct . Experts from various disciplines and consensus as a result of deliberation remain a mainstay of health care guideline development ( 810 ) . These experts are responsible for prioritization of questions that should be addressed in guidelines ; judgments that result from interpretation of evidence , including the rating of the certainty of the available evidence ; and decisions about how the judgments on the different criteria bear on recommendations . What has changed over time in guideline development are the rules , the structure and explicitness of the process , and the guideline product . Indeed , review s of guideline development methodology and how guidelines can be improved have led to more structured and documented processes that allow a reduction of bias and provide balanced views of appropriately composed guideline panels ( 2 , 5 , 6 ) . Core components for trustworthy guideline development ( 13 , 5 , 7 , 11 ) include that guidelines be developed by a knowledgeable , multidisciplinary panel of experts and representatives from key affected groups ; be based on a systematic review of the existing evidence ; consider important patient subgroups and patient preferences as appropriate ; be based on an explicit and transparent process that minimizes distortions , biases , and conflicts of interest ( 12 ) ; provide a clear explanation of the logical relationships between alternative care options and health outcomes and provide ratings of both the quality of evidence and the strength of the recommendations ( 1316 ) ; and be reconsidered and revised as appropriate when important new evidence warrants modifications . In addition , greater transparency in linking the considered research evidence and the recommendations , as well as the requirement of making structured expert judgments , represents a shift in the guideline development paradigm ( 5 , 11 , 1719 ) . At the same time , developing guidelines for a large number of member states and those that aim to adapt the guidelines poses challenges , such as the feasibility of implementing strategies that may exist in some member countries but not others ( for example , organized population -based screening in Italy but not Greece ) . Addressing these challenges requires considerations that extend beyond strictly clinical efforts in guideline development and mastering the many factors that influence recommendations and their implementation . This article describes the rationale , methods , and processes the ECIBC has adopted to develop the European Breast Guidelines in the context of evolving international st and ards . It also describes an innovative approach to presenting , disseminating , and accelerating implementation of recommendations . Guideline Methodology and Development To adhere to the core requirements for guideline development , the EC has taken several steps . First , it selected , via an open call ( https://ecibc.jrc.ec.europa.eu/ guidelines -team ) , a panel with broad representation of expertise , knowledge , and background , which includes patients , health care professionals , epidemiologists , guideline method ologists , and others ( Appendix ) . These individuals voluntarily participate in the ECIBC and compose the guidelines development group ( GDG ) . Second , it ensured that all recommendations were supported by systematic review s of the evidence conducted by independent scientists from Cochrane Iberoamricathe systematic review team (SRT)following st and ard Cochrane Collaboration methods ( 20 , 21 ) . Third , because this is a women-centered initiative , we included women advocates in the GDG as full voting guideline group members . We separately considered important subgroups of women during recommendation development ( for example , different age groups ) , and we specifically focused on evidence that supports best ways of communicating this information to women to inform their decisions . Fourth , we applied EC conflict of interest rules ( http://ecibc.jrc.ec.europa.eu/rules ) , which are consistent with international recommendations , and used GRADE ( Grading of Recommendations Assessment , Development and Evaluation ) Evidence to Decision ( EtD ) frameworks to minimize the influence of competing interests on the recommendations ( 12 , 17 , 18 ) . These EtD frameworks help guideline panels use evidence in a structured , transparent way to inform decisions with a series of criteria , such as anticipated harms and benefits of the options considered , the certainty of the evidence for those effects , and the costs and feasibility of the options , to help them reach their decision . Fifth , using the GRADE approach to guideline development and its EtD frameworks , we focused our questions and recommendations on outcomes that matter to women and provided a rating of the certainty or quality of evidence and the strength of recommendations that is widely accepted as the reference st and ard ( Figures 1 and 2 ) . Sixth , our evidence review s are up to date when the recommendations are formulated , and we engage in international stakeholder feedback to ensure that recommendations remain timely and relevant to public health and clinical practice . The ECIBC is committed to review ing and updating the recommendations as required when new evidence becomes available . The general process is explained in Figure 3 and is based on the Guidelines International NetworkMcMaster Guideline Development Checklist ( https://hei grade .mcmaster.ca/ guideline -development/using-checklist ) ( 5 ) . Figure 1 . According to GRADE , certainty , quality , strength of evidence , or confidence in the estimate of effect is determined on the basis of a systematic review of the evidence for each outcome ( based on the domains risk of bias , indirectness , imprecision , inconsistency , and publication bias that lower certainty and , usually only for nonr and omized studies , large effects , doseresponse relations and opposing plausible residual confounding that may increase the certainty ) . For recommendations , the overall certainty is determined across outcomes based on the lowest certainty outcome among those critical for decision making for the specific context . The guidelines development group applies the GRADE Evidence -to-Decision frameworks to make recommendations that are made available on the European Commission Web site . ( Reproduced from reference 15 , with permission from Schnemann HJ . ) . GRADE = Grading of Recommendations Assessment , Development and Evaluation . Figure 2 . GRADE EtD frameworks . The GRADE EtD frameworks as available in the GRADE pro software ( www . grade pro.org ) . They help with structuring the entire guideline process into 4 sections and support the conduct of guideline group meetings , presentation , and implementation . They clarify the perspective that is taken by the guideline panel or decision maker and the type of question that is asked in the question section . The section on assessment includes the criteria if the problem is a priority , the balance of health benefits and harms , values and preferences related to the outcomes , cost , re sources and cost-effectiveness , equity , acceptability , and feasibility . Conclusions provide the decision or recommendation with a justification and implementation , as well as research considerations . The presentation function supports the conduct of guideline group meetings and facilitates the output of EtD frameworks to other implementation tools , such as Web sites , h and -held apps , and interactive decision aids . EtD = Evidence to Decision ; GRADE = Grading of Recommendations Assessment , Development and Evaluation ; HTA = health technology assessment ; PICO = population , intervention , comparators , and outcomes . Figure 3 . Approach to guideline development used by the European Commission Initiative on Breast Cancer . The European Commission JRC has oversight of the organization , budgeting , planning , and training . The JRC also manages conflicts of interest , documents all aspects of the work , and manages the membership and group processes . The guideline development group and JRC formulate the questions and work with the systematic review team on identifying and assessing the evidence . The guidelines development group is responsible for developing the recommendations . The JRC is responsible for most other aspects as described in the figure under dissemination , implementation , and updating . JRC = Joint Research Centre ; PICO = population , intervention , comparator , and outcomes . ( Reproduced with adaptation to the JRC process from PURPOSE Risk of recurrence is the primary consideration in breast cancer adjuvant therapy recommendations . The TEXT ( Tamoxifen and Exemestane Trial ) and SOFT ( Suppression of Ovarian Function Trial ) trials investigated adjuvant endocrine therapies for premenopausal women with hormone receptor-positive breast cancer , testing exemestane plus ovarian function suppression ( OFS ) , tamoxifen plus OFS , and tamoxifen alone . We examined absolute treatment effect across a continuum of recurrence risk to individualize endocrine therapy decision making for premenopausal women with human epidermal growth factor receptor 2 ( HER2 ) -negative disease . PATIENTS AND METHODS The TEXT and SOFT hormone receptor-positive , HER2-negative analysis population included 4,891 women . The end point was breast cancer-free interval ( BCFI ) , defined as time from r and om assignment to first occurrence of invasive locoregional , distant , or contralateral breast cancer . A continuous , composite measure of recurrence risk for each patient was determined from a Cox model incorporating age , nodal status , tumor size and grade , and estrogen receptor , progesterone receptor , and Ki-67 expression levels . Sub population treatment effect pattern plot methodology revealed differential treatment effects on 5-year BCFI according to composite risk . RESULTS SOFT patients who remained premenopausal after chemotherapy experienced absolute improvement of 5 % or more in 5-year BCFI with exemestane plus OFS versus tamoxifen plus OFS or tamoxifen alone , reaching 10 % to 15 % at intermediate to high composite risk ; the benefit of tamoxifen plus OFS versus tamoxifen alone was apparent at the highest composite risk . The SOFT no-chemotherapy cohort-for whom composite risk was lowest on average-did well with all endocrine therapies . For TEXT patients , the benefit of exemestane plus OFS versus tamoxifen plus OFS in 5-year BCFI ranged from 5 % to 15 % ; patients not receiving chemotherapy and with lowest composite risk did well with both treatments . CONCLUSION Premenopausal women with hormone receptor-positive , HER2-negative disease and high recurrence risk , as defined by clinicopathologic characteristics , may experience improvement of 10 % to 15 % in 5-year BCFI with exemestane plus OFS versus tamoxifen alone . An improvement of at least 5 % may be achieved for women at intermediate risk , and improvement is minimal for those at lowest risk After more than three decades of clinical trials testing various st and ard-dose chemotherapy regimens , the disease course of patients with multiple myeloma has not changed appreciably . Conventional chemotherapy can provide effective palliation but is not curative ( 1 ) . Case series have described encouraging results in patients with myeloma undergoing allogeneic or autologous bone marrow or peripheral blood stem-cell transplantation ( 2 ) . Other studies of transplantation , including r and omized trials , have been reported in the past 6 years ( 3 , 4 ) . To facilitate decisions about treatment options , practice guidelines have been developed for use by health care providers and consumers . In Ontario , Canada , cancer treatments and policies are led by a state-funded organization , Cancer Care Ontario . To help derive treatment options , Cancer Care Ontario has developed the Program in Evidence -Based Care , which includes the Practice Guidelines Initiative . Disease Site Groups ( DSGs ) , which comprise physicians , epidemiologists , and consumers , develop guidelines through a systematic process that involves assessment of evidence , consensus , and a validation process involving practitioners from across the province . Guideline topics are chosen through a prioritization process that includes the burden of illness , availability of evidence , perceived variation in practice , the potential to affect treatment decisions , and re source utilization . The Hematology DSG noted that the use of transplantation for patients with myeloma varied among practice s across the province . Variability in practice and emerging evidence of higher quality made this a priority topic for guideline development . To approach this topic , the DSG addressed the following questions : What is optimal st and ard-dose chemotherapy for patients with myeloma ? In terms of survival , is  peripheral blood stem-cell  or  marrow transplantation better than conventional chemotherapy ? What is the relative efficacy of autologous versus allogeneic transplantation ? What specifics of the transplantation process can be recommended ? When should transplantation be performed ? Who should ( or should not ) receive a transplant ? Methods Overview of Guideline Development This guideline was developed by the Cancer Care Ontario Practice Guidelines Initiative ( CCOPGI ) using the methods of the Practice Guidelines Development Cycle ( 5 ) . Members of the CCOPGI 's Hematology DSG selected , review ed , and interpreted the evidence . This DSG comprises 25 members , including hematologists , medical and radiation oncologists , an epidemiologist , and 2 lay representatives . Several of the physician members have background training in epidemiology ; 8 hematologists regularly perform stem-cell transplantation in clinical practice . The DSG 's draft recommendations were circulated through a mailed survey to hematologists and medical or radiation oncologists in Ontario for feedback and involvement in a consensus process . Responses were used to guide the reformatting of the draft into the final guideline recommendations . The Practice Guidelines Co-ordinating Committee ( PGCC ) , which ensures consistency of guideline development across the DSGs of various tumor sites , approved the guideline . The CCOPGI has a st and ardized process to up date each guideline report ; the current guideline was up date d and review ed by the PGCC in October 2000 . Literature Search Strategy We search ed the MEDLINE , CANCERLIT , and Cochrane Library data bases for literature published from 1992 to December 1997 and subsequently up date d the search in October 1998 , June 1999 , and April 2000 . For the search es , we combined multiple myeloma ( as a Medical Subject Heading [ MeSH ] and text word ) with bone marrow transplantation ( MeSH and text word ) and drug therapy ( MeSH ) . Then , we combined these terms with the search terms for the following study design s : practice guidelines ; systematic review s or meta-analyses ; review s ; r and omized , controlled trials ; controlled clinical trials ; and comparative studies . In addition , we search ed the PubMed and Physician Data Query ( PDQ ) ( www.cancer.gov/ search / clinical _ trials/ ) data bases and review ed relevant conference proceedings ( American Society of Hematology , 1997 to 1999 , and American Society of Clinical Oncology , 1999 to 2000 ) , article bibliographies , and personal files . To address the issue of optimal chemotherapy , we performed an additional search of the same data bases using the term multiple myeloma ( MeSH ) combined with r and omized , controlled trials ( MeSH ) and the text word r and om in the title . Inclusion Criteria We selected study reports meeting one of the three following criteria : r and omized trial or meta- analysis of therapy for patients with myeloma that reported survival or quality -of-life outcomes ; nonr and omized comparative trial that addressed transplantation strategy , including a contemporaneous control group , and that reported survival or quality -of-life outcomes ; or economic evaluation that addressed transplantation strategy . Because of insufficient data on the specifics of the transplantation process and the patients who would be most likely to benefit from transplantation , we performed a second search , which identified data from noncomparative case-series studies . Data Extraction and Interpretative Summary Three members of the DSG , including an epidemiologist , determined eligibility of the articles and abstract s obtained from the literature search . The lead DSG member for this guideline extracted and summarized relevant data according to the guideline question addressed . The DSG members then review ed the summarized data and key articles . The DSG met formally three to four times annually ; at these meetings , the members method ologically assessed the articles , interpreted the data , and debated specific points in an attempt to reach a consensus . Synthesizing the Evidence Because all of the nine r and omized trials on transplantation addressed different questions , we did not statistically pool the data . DSG Consensus Process Through an iterative process that included debate at formal meetings and circulation of draft recommendations , we considered the implication s of the appraised data for each guideline question . With this process , attempts were made to reach consensus ; when this was impossible , minority opinions were recorded . Approval by each member of the DSG was required before circulation of the draft version for practitioner feedback and su bmi ssion of the final guideline to the PGCC . Practitioner Feedback To obtain practitioner feedback , we mailed a survey to 211 practitioners in Ontario ( 94 hematologists , 93 medical oncologists , and 24 radiation oncologists ) . The survey consisted of st and ardized items asking the practitioner to rate the quality of each draft guideline and to judge whether the draft recommendations should serve as a practice guideline . Written comments were invited . Follow-up reminders were sent at 2 weeks ( by postcard ) and 4 weeks ( entire package ) . After exclusion of 18 retired practitioners , 137 of 193 practitioners ( 71 % ) responded ; 90 of 137 respondents ( 66 % ) indicated that the guideline was relevant to their practice . Approval of the draft guideline was strong among these 90 practitioners : 91 % agreed or strongly agreed that the summary of the evidence was acceptable , 87 % agreed with the draft recommendations , and 81 % approved of the recommendations as a practice guideline . Thirty-nine respondents provided written comments ; these comments were , like the other responses , incorporated in the final guideline . Results Sixty-six reports met the criteria for inclusion and are categorized in Table 1 . In each section below , we describe the studies , summarize results , and describe the guideline development . Table 1 . Evidence Included in This Practice Guideline Report What Is Optimal St and ard-Dose Chemotherapy  for Patients with Multiple Myeloma ? To properly compare transplantation with conventional chemotherapy , we must define optimal conventional chemotherapy . We identified 30 r and omized trials comparing therapies in previously untreated patients . Four meta-analyses ( 6 - 9 ) evaluated these data . The Myeloma Trialists ' Collaborative Group ( 7 ) compared combination chemotherapy with melphalan plus prednisone in a meta- analysis of 27 trials . Twenty of these trials supplied individual-patient data . No difference in survival was detected . The proportional reduction in the annual odds of death was 1.5 % in favor of combination chemotherapy ( 95 % CI , 8 % to 5 % ; P > 0.2 ) , with an odds ratio ( OR ) of 0.99 ( CI , 0.93 to 1.05 ) . An earlier literature -based meta- analysis ( 6 ) of 18 trials also failed to detect a survival difference between groups ( OR , 1.04 [ CI , 0.90 to 1.19 ] ; P > 0.2 ) . Two meta-analyses evaluated interferon for multiple myeloma . An overview of 24 r and omized trials published in abstract form ( 8) demonstrated that interferon improved recurrence-free survival by 6 months and improved 3-year overall survival by 4 % . Another meta- analysis ( 9 ) measured survival by a unique measure called the mean lifetime survival . This meta- analysis found no difference in survival rate between the group receiving interferon and the group not receiving interferon ( 3.9 vs. 3.4 years , respectively ; P = 0.095 ) . Guideline Recommendation Multiagent chemotherapy or melphalan plus prednisone is appropriate therapy for a control group in a comparison of transplantation versus st and ard-dose therapy . The addition of interferon is unlikely to influence outcomes in the control group . In Terms of Survival , Is Autologous Peripheral Blood Stem-Cell or Bone Marrow Transplantation Better than Conventional Chemotherapy ? We review ed two r and omized and three nonr and omized comparisons ( Table 2 ) . Attal and colleagues ( 3 ) r and omly assigned 200 previously untreated patients younger than 65 years of age with stage II or III ( 40 ) myeloma to conventional chemotherapy or to a strategy that included autologous bone marrow transplantation . Patients were r and omly PURPOSE Trastuzumab combined with chemotherapy improves outcomes for women with human epidermal growth factor receptor 2 ( HER2 ) overexpressing advanced breast cancer . We conducted a pilot study of preoperative trastuzumab and paclitaxel , followed by surgery and adjuvant doxorubicin and cyclophosphamide chemotherapy in earlier stage breast cancer . PATIENTS AND METHODS Patients with HER2-positive ( 2 + or 3 + by immunohistochemistry ) stage II or III breast cancer received preoperative trastuzumab ( 4 mg/kg x 1 , then 2 mg/kg/wk x 11 ) in combination with paclitaxel ( 175 mg/m(2 ) every 3 weeks x 4 ) . Patients received adjuvant doxorubicin and cyclophosphamide chemotherapy following definitive breast surgery .  Clinical and pathologic response rates were determined after preoperative therapy . Left ventricular ejection fraction and circulating levels of HER2 extracellular domain were measured serially . RESULTS Preoperative trastuzumab and paclitaxel achieved clinical response in 75 % and complete pathologic response in 18 % of the 40 women on study . HER2 3 + tumors were more likely to respond than 2 + tumors ( 84 % v 38 % ) . No unexpected treatment-related noncardiac toxicity was encountered . Four patients developed grade 2 cardiotoxicity ( asymptomatic declines in left ventricular ejection fraction ) . Baseline HER2 extracellular domain was elevated in 24 % of patients and declined with preoperative therapy . Immunohistochemical analyses of posttherapy tumor specimens indicated varying patterns of HER2 expression following trastuzumab-based treatment . CONCLUSION Preoperative trastuzumab and paclitaxel is active against HER2 overexpressing early-stage breast cancer and may be feasible as part of a sequential treatment program including anthracyclines . The observed changes in cardiac function merit further investigation . Correlative analyses of HER2 status may facilitate underst and ing of tumor response and resistance to targeted therapy UNLABELLED We treated patients with operable human epidermal growth factor receptor 2-positive breast cancer with neoadjuvant anthracycline regimens followed by nanoparticle albumin-bound paclitaxel plus trastuzumab . Of the 44 patients , 49 % achieved a pathologic complete response ( pCR ) . The pCR rate was 36 % and 71 % in the patients with estrogen receptor-positive and -negative cancer , respectively . Neoadjuvant therapy using this combination appears to be effective and safe . Introduction : Neoadjuvant chemotherapy plus trastuzumab . INTRODUCTION Neoadjuvant chemotherapy plus trastuzumab results in a 30 % to 50 % pathologic complete response ( pCR ) rate in human epidermal growth factor receptor 2 (HER2)-positive breast cancer and has been associated with improved therapeutic outcomes . Thus , the pCR rate can be useful in evaluating novel agents in this patient population . Nanoparticle albumin-bound (nab)-paclitaxel ( PTX ) can reduce the toxicity of PTX while maintaining its efficacy . The present study evaluated the activity and safety of nab-PTX as a neoadjuvant treatment of HER2(+ ) breast cancer . PATIENTS AND METHODS We treated patients with stage I to IIIA breast cancer using neoadjuvant epirubicin/cyclophosphamide ( EC ) or 5-fluorouracil/epirubicin/cyclophosphamide every 3 weeks ( q3w ) for 4 cycles , followed by nab-PTX ( 260 mg/m(2 ) ) plus trastuzumab q3w for 4 cycles . The primary endpoint was the pCR rate . The secondary endpoints included the clinical response rate , disease-free survival , pathologic response rate ( defined as pCR or minimal residual invasive disease only in the breast ) , breast-conserving surgery rate , and safety . RESULTS Forty-six patients were enrolled . One patient met the exclusion criteria because of the coexistence of another malignant disease ; therefore , we evaluated 45 patients in the entire study . One patient experienced rapid disease progression during EC therapy , leaving 44 patients evaluable for nab-PTX treatment . Of the 45 patients , 49 % achieved a pCR . The pCR rate was 36 % and 71 % in those with estrogen receptor-positive and -negative cancer , respectively . Of all the study treatments , the most frequent reason for delay or dose reduction was hematologic toxicity ; only 1 patient required a dose reduction for nab-PTX because of peripheral neuropathy . CONCLUSION Neoadjuvant therapy using this combination appears to be effective and safe PURPOSE To up date the ASCO clinical practice guideline on adjuvant endocrine therapy on the basis of emerging data on the optimal duration of treatment , particularly adjuvant tamoxifen . METHODS ASCO convened the Up date Committee and conducted a systematic review of r and omized clinical trials from January 2009 to June 2013 and analyzed three historical trials . Guideline recommendations were based on the Up date Committee 's review of the evidence . Outcomes of interest included survival , disease recurrence , and adverse events . RESULTS This guideline up date reflects emerging data on duration of tamoxifen treatment . There have been five studies of tamoxifen treatment beyond 5 years of therapy . The two largest studies with longest reported follow-up show a breast cancer survival advantage with 10-year duration s of tamoxifen use . In addition to modest gains in survival , extended therapy with tamoxifen for 10 years compared with 5 years was associated with lower risks of breast cancer recurrence and contralateral breast cancer . RECOMMENDATIONS Previous ASCO guidelines recommended treatment of women who have hormone receptor-positive breast cancer and are premenopausal with 5 years of tamoxifen , and those who are postmenopausal a minimum of 5 years of adjuvant therapy with an aromatase inhibitor or tamoxifen followed by an aromatase inhibitor ( in sequence ) . If women are pre- or perimenopausal and have received 5 years of adjuvant tamoxifen , they should be offered 10 years total duration of tamoxifen . If women are postmenopausal and have received 5 years of adjuvant tamoxifen  , they should be offered the choice of continuing tamoxifen or switching to an aromatase inhibitor for 10 years total adjuvant endocrine therapy UNLABELLED In February 2010 , the Medical Advisory Secretariat ( MAS ) began work on evidence -based review s of the literature surrounding three pharmacogenomic tests . This project came about when Cancer Care Ontario ( CCO ) asked MAS to provide evidence -based analyses on the effectiveness and cost-effectiveness of three oncology pharmacogenomic tests currently in use in Ontario . Evidence -based analyses have been prepared for each of these technologies . These have been completed in conjunction with internal and external stakeholders , including a Provincial Expert Panel on Pharmacogenomics ( PEPP ) . Within the PEPP , subgroup committees were developed for each disease area . For each technology , an economic analysis was also completed by the Toronto Health Economics and Technology Assessment Collaborative ( THETA ) and is summarized within the reports . THE FOLLOWING REPORTS CAN BE PUBLICLY ACCESSED AT THE MAS WEBSITE AT : www.health.gov.on.ca/mas or at www.health.gov.on.ca/english/providers/program/mas/mas_about.htmlGENE EXPRESSION PROFILING FOR GUIDING ADJUVANT CHEMOTHERAPY DECISIONS IN WOMEN WITH EARLY BREAST CANCER : An Evidence -Based and Economic Analysis Epidermal Growth Factor Receptor Mutation ( EGFR ) Testing for Prediction of Response to EGFR-Targeting Tyrosine Kinase Inhibitor ( TKI ) Drugs in Patients with Advanced Non-Small-Cell Lung Cancer : an Evidence -Based and Economic Analysis K-RAS testing in Treatment Decisions for Advanced Colorectal Cancer : an Evidence -Based and Economic Analysis . OBJECTIVE The objective of this systematic review is to determine the predictive value of KRAS testing in the treatment of metastatic colorectal cancer ( mCRC ) with two anti-EGFR agents , cetuximab and panitumumab . Economic analyses are also being conducted to evaluate the cost-effectiveness of KRAS testing . CLINICAL NEED CONDITION AND TARGET POPULATION Metastatic colorectal cancer ( mCRC ) is usually defined as stage IV disease according to the American Joint Committee on Cancer tumour node metastasis ( TNM ) system or stage D in the Duke 's classification system . Patients with advanced colorectal cancer ( mCRC ) either present with metastatic disease or develop it through disease progression . KRAS ( Kristen-RAS , a member of the rat sarcoma virus ( ras ) gene family of oncogenes ) is frequently mutated in epithelial cancers such as colorectal cancer , with mutations occurring in mutational hotspots ( codons 12 and 13 ) of the KRAS protein . Involved in EGFR-mediated signalling of cellular processes such as cell proliferation , resistance to apoptosis , enhanced cell motility and neoangiogenesis , a mutation in the KRAS gene is believed to be involved in cancer pathogenesis . Such a mutation is also hypothesized to be involved in resistance to targeted anti-EGFR ( epidermal growth factor receptor with tyrosine kinase activity ) treatments such as cetuximab and panitumumab , hence , the important in evaluating the evidence on the predictive value of KRAS testing in this context . KRAS MUTATION TESTING IN ADVANCED COLORECTAL CANCER : Both cetuximab and panitumumab are indicated by Health Canada in the treatment of patients with metastatic colorectal cancer whose tumours are WT for the KRAS gene .  Cetuximab may be offered as monotherapy in patients intolerant to irinotecan-based chemotherapy or in patients who have failed both irinotecan and oxaliplatin-based regimens and who received a fluoropyrimidine .  It can also be administered in combination with irinotecan in patients refractory to other irinotecan-based chemotherapy regimens . Panitumumab is only indicated as a single agent after failure of fluoropyrimidine- , oxaliplatin- , and irinotecan-containing chemotherapy regimens . In Ontario , patients with advanced colorectal cancer who are refractory to chemotherapy may be offered the targeted anti-EGFR treatments cetuximab or panitumumab . Eligibility for these treatments is based on the KRAS status of their tumour , derived from tissue collected from surgical or biopsy specimens . It is believed that KRAS status is not affected by treatments , therefore , for patients for whom surgical tissue is available for KRAS testing , additional biopsies prior to treatment with these targeted agents is not necessary . For patients that have not undergone surgery or for whom surgical tissue is not available , a biopsy of either the primary or metastatic site is required to determine their KRAS status . This is possible as status at the metastatic and primary tumour sites is considered to be similar . RESEARCH QUESTION To determine if there is predictive value of KRAS testing in guiding treatment decisions with anti-EGFR targeted therapies in advanced colorectal cancer patients refractory to chemotherapy . RESEARCH METHODS LITERATURE SEARCH The Medical Advisory Secretariat followed its st and ard procedures and on May 18 , 2010 , search ed the following electronic data bases : Ovid MEDLINE , EMBASE , Ovid MEDLINE In-Process & Other Non-Indexed Citations , Cochrane Central Register of Controlled Trials , Cochrane Data base of Systematic Review s and The International Network of Agencies for Health Technology Assessment data base . The subject headings and keywords search ed included colorectal cancer , cetuximab , panitumumab , and KRAS testing . The search was further restricted to English- language articles published between January 1 , 2009 and May 18 , 2010 result ing in 1335 articles for review . Excluded were case reports , comments , editorials , non  systematic review s , and letters . Studies published from January 1 , 2005 to December 31 , 2008 were identified in a health technology assessment conducted by the Agency for Healthcare Research and Quality ( AHRQ ) , published in 2010 . In total , 14 observational studies were identified for inclusion in this EBA : 4 for cetuximab monotherapy , 7 for the cetuximab-irinotecan combination therapy , and 3 to be included in the review for panitumumab monotherapy INCLUSION CRITERIA English- language articles , and English or French- language HTAs published from January 2005 to May 2010 , inclusive . R and omized controlled trials ( RCTs ) or observational studies , including single arm treatment studies that include KRAS testing . Studies with data on main outcomes of interest , overall and progression-free survival . Studies of third line treatment with cetuximab or panitumumab in patients with advanced colorectal cancer refractory to chemotherapy . For the cetuximab-irinotecan evaluation , studies in which at least 70 % of patients in the study received this combination therapy . EXCLUSION CRITERIA Studies whose entire sample was included in subsequent publications which have been included in this EBA . Studies in pediatric population s . Case reports , comments , editorials , or letters . OUTCOMES OF INTEREST Overall survival ( OS ) , medianProgression-free-survival ( PFS ) , median . Response rates . Adverse event rates . Quality of life ( QOL ) . SUMMARY OF FINDINGS OF SYSTEMATIC REVIEW : CETUXIMAB OR PANITUMUMAB MONOTHERAPY : Based on moderate GRADE observational evidence , there is improvement in PFS and OS favouring patients without the KRAS mutation ( KRAS wildtype , or KRAS WT ) compared to those with the mutation . CETUXIMAB-IRINOTECAN COMBINATION THERAPY : There is low GRADE evidence that testing for KRAS may optimize survival benefits in patients without the KRAS mutation ( KRAS wildtype , or KRAS WT ) compared to those with the mutation . However , cetuximab-irinotecan combination treatments based on KRAS status discount any effect of cetuximab in possibly reversing resistance to irinotecan in patients with the mutation , as observed effects were lower than for patients without the mutation . Clinical experts have raised concerns about the biological plausibility of this observation and this conclusion would , therefore , be regarded as hypothesis generating . ECONOMIC ANALYSIS Cost-effectiveness and budget impact analyses were conducted incorporating estimates of effectiveness from this systematic review . Evaluation of relative cost-effectiveness , based on a decision-analytic cost-utility analysis , assessed testing for KRAS genetic mutations versus no testing in the context of treatment with cetuximab monotherapy , panitumumab monotherapy , cetuximab in combination with irinotecan , and best supportive care . Of importance to note is that the cost-effectiveness analysis focused on the impact of testing for KRAS mutations compared to no testing in the context of different treatment options , and does not assess the cost-effectiveness of the drug treatments alone . CONCLUSIONS KRAS status is predictive of outcomes in cetuximab and panitumumab monotherapy , and in cetuximab-irinotecan combination therapy . While KRAS testing is cost-effective for all strategies considered , it is not equally cost-effective for all treatment options AIMS Oesophageal cancer is an aggressive disease and the optimal therapy for patients with resectable tumours remains unclear . A systematic review and companion practice guideline were published in 2004 ; however , new evidence has become available since the publication of the original report . An up date of the literature search and a revision of the recommendations were undertaken to incorporate the new data . The following research question was addressed : should patients with resectable oesophageal cancer receive preoperative or postoperative therapy together with surgery ? The outcomes of interest were survival , adverse effects and quality of life . MATERIAL S AND METHODS The literature search of the original systematic review was up date d to April 2007 . MEDLINE , EMBASE , Cochrane Library and abstract s from the American Society of Clinical Oncology and the American Society for Therapeutic Radiology and Oncology were search ed for reports of r and omised controlled trials and meta-analyses comparing preoperative or postoperative therapy with surgery alone or other preoperative or postoperative therapy . After the completion of the draft systematic review and practice guideline , the report was distributed through a mailed survey to 133 health care providers in Ontario for review and feedback . RESULTS The up date d literature search yielded eight new r and omised controlled trial reports and seven new meta- analysis reports for consideration , together with the evidence review ed in the original review publication . Of the 31 practitioners who responded to the mailed survey , 80 % agreed with the draft recommendations as stated , 83 % agreed that the report should be approved as a practice guideline and 86 % indicated that they would probably use the guideline in their own practice . CONCLUSIONS Preoperative cisplatin-based chemotherapy plus radiotherapy is recommended as the preferred modality for the management of surgically resectable patients with oesophageal cancer .  Preoperative cisplatin-based chemotherapy alone is an alternative choice for the management of these patients BACKGROUND Bevacizumab , a monoclonal antibody against vascular endothelial growth factor A , has shown clinical efficacy in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer . We evaluated the efficacy , measured according to the rate of pathological complete response ( absence of invasive and intraductal disease in the breast and the axillary lymph nodes ) , and the safety of adding bevacizumab to neoadjuvant chemotherapy in patients with early-stage breast cancer . METHODS We r and omly assigned 1948 patients with a median tumor size of 40 mm on palpation to receive neoadjuvant epirubicin and cyclophosphamide followed by docetaxel , with or without concomitant bevacizumab .  Patients with untreated HER2-negative breast cancer were eligible if they had large tumors , hormone-receptor-negative disease , or hormone-receptor-positive disease with palpable nodes or positive findings on sentinel-node biopsy , and no increased cardiovascular or bleeding risk . RESULTS Overall , the rates of pathological complete response were 14.9 % with epirubicin and cyclophosphamide followed by docetaxel and 18.4 % with epirubicin and cyclophosphamide followed by docetaxel plus bevacizumab ( odds ratio with addition of bevacizumab , 1.29 ; 95 % confidence interval , 1.02 to 1.65 ; P=0.04 ) ; the corresponding rates of pathological complete response were 27.9 % and 39.3 % among 663 patients with triple-negative tumors ( P=0.003 ) and 7.8 % and 7.7 % among 1262 patients with hormone-receptor-positive tumors ( P=1.00 ) . Breast-conserving surgery was possible in 66.6 % of the patients in both groups . The addition of bevacizumab , as compared with neoadjuvant therapy alone , was associated with a higher incidence of grade 3 or 4 toxic effects ( febrile neutropenia , mucositis , the h and -foot syndrome , infection , and hypertension ) but with a similar incidence of surgical complications . CONCLUSIONS The addition of bevacizumab to neoadjuvant chemotherapy significantly increased the rate of pathological complete response among patients with HER2-negative early-stage breast cancer . Efficacy was restricted primarily to patients with triple-negative tumors , in whom the pathological complete response is considered to be a reliable predictor of long-term outcome . ( Funded by Sanofi-Aventis and Roche , Germany ; Clinical Trials.gov number , NCT00567554 . ) Purpose : Gene expression analysis identifies several breast cancer subtypes . We examined the relationship of neoadjuvant chemotherapy response to outcome among these breast cancer subtypes . Experimental Design : We used immunohistochemical profiles [ human epidermal growth factor receptor 2–positive (HER2+)/hormone receptor – negative for HER2+/estrogen receptor – negative ( ER− ) , hormone receptor and HER2− for basal-like , hormone receptor – positive for luminal ] to subtype a prospect ively maintained data set of patients with breast cancer treated with neoadjuvant anthracycline-based ( doxorubicin plus cyclophosphamide , AC ) chemotherapy .  We analyzed each subtype for clinical and pathologic response to neoadjuvant chemotherapy and examined the relationship of response to distant disease – free survival and overall survival . Results : Of the 107 patients tested , 34 ( 32 % ) were basal-like , 11 ( 10 % ) were HER2+/ER− , and 62 ( 58 % ) were luminal . After neoadjuvant AC , 75 % received subsequent chemotherapy and all received endocrine therapy if hormone receptor – positive . The chemotherapy regimen and pretreatment stage did not differ by subtype . Clinical response to AC  was higher among the HER2+/ER− ( 70 % ) and basal-like ( 85 % ) than the luminal subtypes ( 47 % ; P < 0.0001 ) . Pathologic complete response occurred in 36 % of HER2+/ER− , 27 % of basal-like , and 7 % of luminal subtypes ( P = 0.01 ) . Despite initial chemosensitivity , patients with the basal-like and HER2+/ER− subtypes had worse distant disease – free survival ( P = 0.04 ) and overall survival ( P = 0.02 ) than those with the luminal subtypes . Regardless of subtype , only 2 of 17 patients with pathologic complete response relapsed . The worse outcome among basal-like and HER+/ER− subtypes was due to higher relapse among those with residual disease ( P = 0.003 ) . Conclusions : Basal-like and HER2+/ER− subtypes are more sensitive to anthracycline-based neoadjuvant chemotherapy than luminal breast cancers . Patients that had pathologic complete response to chemotherapy had a good prognosis regardless of subtype . The poorer prognosis of basal-like and HER2+/ER− breast cancers could be explained by a higher likelihood of relapse in those patients in whom pathologic complete response was not achieved Purpose To provide evidence -based recommendations to up date the American Society of Clinical Oncology guideline on systemic therapy for stage IV non – small-cell lung cancer ( NSCLC ) . Methods An Up date Committee of the American Society of Clinical Oncology NSCLC Expert Panel based recommendations on a systematic review of r and omized controlled trials from January 2007 to February 2014 . Results This guideline up date reflects changes in evidence since the previous guideline . Recommendations There is no cure for patients with stage IV NSCLC . For patients with performance status ( PS ) 0 to 1 ( and appropriate patient cases with PS 2 ) and without an EGFR-sensitizing mutation or ALK gene rearrangement , combination cytotoxic chemotherapy is recommended , guided by histology , with early concurrent palliative care . Recommendations for patients in the first-line setting include platinum-doublet therapy for those with PS 0 to 1 ( bevacizumab may be added to carboplatin plus paclitaxel if no contraindications ) ; combination or single-agent chemotherapy or palliative care alone for those with PS 2 ; afatinib , erlotinib , or gefitinib for those with sensitizing EGFR mutations ; crizotinib for those with ALK or ROS1 gene rearrangement ; and following first-line recommendations or using platinum plus etoposide for those with large-cell neuroendocrine carcinoma . Maintenance therapy includes pemetrexed continuation for patients with stable disease or response to first-line pemetrexed-containing regimens , alternative chemotherapy , or a chemotherapy break . In the second-line setting , recommendations include docetaxel , erlotinib , gefitinib , or pemetrexed for patients with nonsquamous cell carcinoma ; docetaxel , erlotinib , or gefitinib for those with squamous cell carcinoma ; and chemotherapy or ceritinib for those with ALK rearrangement who experience progression after crizotinib . In the third-line setting , for patients who have not received erlotinib or gefitinib , treatment with erlotinib is recommended . There are insufficient data to recommend routine third-line cytotoxic therapy . Decisions regarding systemic therapy should not be made based on age alone . Additional information can be found at http://www.asco.org/ guidelines /nsclc and http://www.asco.org/ guidelines wiki . J Clin Oncol 33:3488 - 3515 . © 2015 by American Society of Clinical Background : Progesterone receptor ( PR ) expression assessment in early invasive breast cancer remains controversial . This study sought to re-evaluate PR expression as a potential therapeutic guide in early breast cancer ; particularly in oestrogen receptor (ER)-positive , lymph node (LN)-negative disease . Methods : A population cohort of 1074 patients presenting to a single Cancer Centre over 4 years ( 2000–2004 ) underwent surgery for primary invasive breast cancer with curative intent . Prospect i ve data collection included patient demographics , pathology , ER and PR expression , HER2 status , adjuvant chemotherapy and endocrine therapy .  Progesterone receptor expression was compared with ( all causes ) overall survival ( OS ) , breast cancer-specific survival ( BCSS ) and disease-free survival ( DFS ) . Results : Overall survival was 71.0 % and BCSS was 83.0 % at median follow-up of 8.34 years . Absent PR expression was significantly associated with poorer prognosis for OS , BCSS and DFS ( P<0.0001 , log-rank ) , even within the ER-positive , LN-negative group ( hazard ratio for BCSS 3.17 , 95 % CI 1.43–7.01 ) and was not influenced by endocrine therapy . Cox ’s regression analysis demonstrated that PR expression was an independent prognostic variable . Conclusion : Absence of PR expression is a powerful , independent prognostic variable in operable , primary breast cancer even in ER-positive , LN-negative patients receiving endocrine therapy . Absence of PR expression should be re-evaluated as a biomarker for poor prognosis in ER-positive breast cancer and such patients considered for additional systemic therapy PURPOSE To determine the optimal dose and schedule of anthracycline and taxane administration as adjuvant therapy for early-stage breast cancer . PATIENTS AND METHODS A 2 × 2 factorial design was used to test two hypotheses : ( 1 ) that a novel continuous schedule of doxorubicin-cyclophosphamide was superior to six cycles of doxorubicin-cyclophosphamide once every 2 weeks and ( 2 ) that paclitaxel once per week was superior to six cycles of paclitaxel once every 2 weeks in patients with node-positive or high-risk node-negative early-stage breast cancer . With 3,250 patients , a disease-free survival ( DFS ) hazard ratio of 0.82 for each r and omization could be detected with 90 % power with two-sided α = .05 . Overall survival ( OS ) was a secondary outcome . RESULTS Interim analyses crossed the futility boundaries for demonstrating superiority of both once-per-week regimens and once-every-2-weeks regimens . After a median follow-up of 6 years , a significant interaction developed between the two r and omization factors ( DFS P = .024 ; OS P = .010 ) in the 2,716 patients r and omly assigned in the original design , which precluded interpretation of the two factors separately . Comparing all four arms showed a significant difference in OS ( P = .040 ) but not in DFS ( P = .11 ) , with all treatments given once every 2 weeks associated with the highest OS . This difference in OS seemed confined to patients with hormone receptor-negative/human epidermal growth factor receptor 2 ( HER2 ) -negative tumors ( P = .067 ) , with no differences seen with hormone receptor-positive/HER2-negative ( P = .90 ) or HER2-positive tumors ( P = .40 ) . CONCLUSION Patients achieved a similar DFS with any of these regimens . Subset analysis suggests the hypothesis that once-every-2-weeks dosing may be best for patients with hormone receptor-negative/HER2-negative tumors OBJECTIVE To establish evidence -based recommendations for the molecular analysis of lung cancers that are required to guide EGFR- and ALK-directed therapies , addressing which patients and sample s should be tested , and when and how testing should be performed . PARTICIPANTS Three cochairs without conflicts of interest were selected , one from each of the 3 sponsoring professional societies : College of American Pathologists , International Association for the Study of Lung Cancer , and Association for Molecular Pathology . Writing and advisory panels were constituted from additional experts from these societies . EVIDENCE Three unbiased literature search es of electronic data bases were performed to capture published articles from January 2004 through February 2012 , yielding 1533 articles whose abstract s were screened to identify 521 pertinent articles that were then review ed in detail for their relevance to the recommendations . EVIDENCE was formally grade d for each recommendation . CONSENSUS PROCESS Initial recommendations were formulated by the cochairs and panel members at a public meeting . Each guideline section was assigned to at least 2 panelists . Drafts were circulated to the writing panel ( version 1 ) , advisory panel ( version 2 ) , and the public ( version 3 ) before su bmi ssion ( version 4 ) . CONCLUSIONS The 37 guideline items address 14 subjects , including 15 recommendations ( evidence grade A/B ) . The major recommendations are to use testing for EGFR mutations and ALK fusions to guide patient selection for therapy with an epidermal growth factor receptor ( EGFR ) or anaplastic lymphoma kinase ( ALK ) inhibitor , respectively , in all patients with advanced-stage adenocarcinoma , regardless of sex , race , smoking history , or other clinical risk factors , and to prioritize EGFR and ALK testing over other molecular predictive tests . As scientific discoveries and clinical practice outpace the completion of r and omized clinical trials , evidence -based guidelines developed by expert practitioners are vital for communicating emerging clinical st and ards . Already , new treatments targeting genetic alterations in other , less common driver oncogenes are being evaluated in lung cancer , and testing for these may be addressed in future versions of these guidelines Objective : To establish evidence -based recommendations for the molecular analysis of lung cancers that are that are required to guide EGFR- and ALK-directed therapies , addressing which patients and sample s should be tested , and when and how testing should be performed . Participants : Three cochairs without conflicts of interest were selected , one from each of the 3 sponsoring professional societies : College of American Pathologists , International Association for the Study of Lung Cancer , and Association for Molecular Pathology . Writing and advisory panels were constituted from additional experts from these societies . Evidence : Three unbiased literature search es of electronic data bases were performed to capture articles published published from January 2004 through February 2012 , yielding 1533 articles whose abstract s were screened to identify 521 pertinent articles that were then review ed in detail for their relevance to the recommendations . Evidence was formally grade d for each recommendation . Consensus Process : Initial recommendations were formulated by the cochairs and panel members at a public meeting . Each guideline section was assigned to at least 2 panelists . Drafts were circulated to the writing panel ( version 1 ) , advisory panel ( version 2 ) , and the public ( version 3 ) before su bmi ssion ( version 4 ) . Conclusions : The 37 guideline items address 14 subjects , including 15 recommendations ( evidence grade A/B ) . The major recommendations are to use testing for EGFR mutations and ALK fusions to guide patient selection for therapy with an epidermal growth factor receptor ( EGFR ) or anaplastic lymphoma kinase ( ALK ) inhibitor , respectively , in all patients with advanced-stage adenocarcinoma , regardless of sex , race , smoking history , or other clinical risk factors , and to prioritize EGFR and ALK testing over other molecular predictive tests . As scientific discoveries and clinical practice outpace the completion of r and omized clinical trials , evidence -based guidelines developed by expert practitioners are vital for communicating emerging clinical st and ards . Already , new treatments targeting genetic alterations in other , less common driver oncogenes are being evaluated in lung cancer , and testing for these may be addressed in future versions of these guidelines BACKGROUND Lapatinib , a tyrosine kinase inhibitor of human epidermal growth factor receptor type 2 ( HER2 , also referred to as HER2/neu ) and epidermal growth factor receptor ( EGFR ) , is active in combination with capecitabine in women with HER2-positive metastatic breast cancer that has progressed after trastuzumab-based therapy . In this trial , we compared lapatinib plus capecitabine with capecitabine alone in such patients . METHODS Women with HER2-positive , locally advanced or metastatic breast cancer that had progressed after treatment with regimens that included an anthracycline , a taxane , and trastuzumab  were r and omly assigned to receive either combination therapy ( lapatinib at a dose of 1250 mg per day continuously plus capecitabine at a dose of 2000 mg per square meter of body-surface area on days 1 through 14 of a 21-day cycle ) or monotherapy ( capecitabine alone at a dose of 2500 mg per square meter on days 1 through 14 of a 21-day cycle ) . The primary end point was time to progression , based on an evaluation by independent review ers under blinded conditions . RESULTS The interim analysis of time to progression met specified criteria for early reporting on the basis of superiority in the combination-therapy group . The hazard ratio for the independently assessed time to progression was 0.49 ( 95 % confidence interval , 0.34 to 0.71 ; P<0.001 ) , with 49 events in the combination-therapy group and 72 events in the monotherapy group . The median time to progression was 8.4 months in the combination-therapy group as compared with 4.4 months in the monotherapy group . This improvement was achieved without an increase in serious toxic effects or symptomatic cardiac events . CONCLUSIONS Lapatinib plus capecitabine is superior to capecitabine alone in women with HER2-positive advanced breast cancer that has progressed after treatment with regimens that included an anthracycline , a taxane , and trastuzumab . ( Clinical Trials.gov number , NCT00078572 [ Clinical Trials.gov ] . ) PURPOSE This report up date s the Cancer Care Ontario Program in Evidence -Based Care guideline for the management of  depression in adult patients with cancer . This guideline covers pharmacologic , psychological , and collaborative care interventions , with a focus on integrating practical management tools to assist clinicians in delivering appropriate treatments for depression in patients with cancer . METHODS Recommendations were developed by synthesizing information from extant guidelines and review s and search ing for r and omized controlled trials from the date of data base inception ( 1964 for MEDLINE and 1974 for EMBASE ) to January 2015 . Quality assessment of guidelines and systematic review s were conducted by using the Appraisal of Guidelines for Research and Evaluation II ( AGREE II ) , Assessment of Multiple Systematic Review s ( AMSTAR ) , and Cochrane Risk of Bias tools . Final recommendations were developed through a st and ardized Program in Evidence -Based Care multidisciplinary expert and knowledge user review process . RESULTS Two high- quality relevant clinical practice guidelines , eight pharmacologic trials , nine psychological trials , and eight collaborative care intervention trials composed the evidence base upon which the recommendations were developed . Eight specific recommendations were made to establish a st and ard of care for the management of depression in patients with cancer . The recommendations and practical management tools were review ed as being well organized and helpful , although systemic barriers to implementation were identified . CONCLUSION This up date d guideline supports the previous general recommendation that patients with cancer who have depression may benefit from psychological and /or pharmacologic interventions , without evidence for the superiority of any specific treatment over another . New recommendations for a collaborative care model that incorporates a stepped care approach suggest that multidisciplinary mental health care restructuring may be required for optimal management of depression PURPOSE To develop a guideline to improve the accuracy of immunohistochemical ( IHC ) estrogen receptor ( ER ) and progesterone receptor ( PgR ) testing in breast cancer and the utility of these receptors as predictive markers . METHODS The American Society of Clinical Oncology and the College of American Pathologists convened an international Expert Panel that conducted a systematic review and evaluation of the literature in partnership with Cancer Care Ontario and developed recommendations for optimal IHC ER/PgR testing performance . RESULTS Up to 20 % of current IHC determinations of ER and PgR testing worldwide may be inaccurate ( false negative or false positive ) . Most of the issues with testing have occurred because of variation in preanalytic variables , thresholds for positivity , and interpretation criteria . RECOMMENDATIONS The Panel recommends that ER and PgR status be determined on all invasive breast cancers and breast cancer recurrences . A testing algorithm that relies on accurate , reproducible assay performance is proposed . Elements to reliably reduce assay variation are specified . It is recommended that ER and PgR assays be considered positive if there are at least 1 % positive tumor nuclei in the sample on testing in the presence of expected reactivity of internal ( normal epithelial elements ) and external controls . The absence of benefit from endocrine therapy for women with ER-negative invasive breast cancers has been confirmed in large overviews of r and omized clinical trials PURPOSE Trastuzumab , a humanized antibody against the human epidermal growth factor receptor type 2 ( HER2 ) , has shown high efficacy in breast cancer . We prospect ively investigated its efficacy given simultaneously with anthracycline-taxane-based neoadjuvant chemotherapy . PATIENTS AND METHODS Patients with operable or locally advanced , HER2-positive tumors were treated preoperatively with four cycles of epirubicin/cyclophosphamide followed by four cycles of docetaxel with or without capecitabine ( EC-T[X ] ) and trastuzumab 6 mg/kg ( with a loading dose of 8 mg/kg ) every 3 weeks during all chemotherapy cycles . Patients with HER2-negative tumors treated in the same study with the same chemotherapy but without trastuzumab were used as a reference group . Results Of 1,509 participants , 445 had HER2-positive tumors treated with trastuzumab and chemotherapy .  Pathologic complete response ( pCR ; defined as no invasive or in situ residual tumors in the breast ) rate was 31.7 % , which was 16 % higher than that in the reference group ( 15.7 % ) . HER2-positive patients without response to the first four cycles of EC showed an unexpectedly high pCR rate of 16.6 % ( 3.3 % in the reference group ) . Breast conservation rate was 63.1 % and comparable to that of the reference group ( 64.7 % ) . EC-T(X ) plus trastuzumab was associated with more febrile neutropenia and conjunctivitis , but with a comparable short-term cardiac toxicity profile as the reference group . CONCLUSION This trial confirms that combining trastuzumab with anthracycline-taxane-based neoadjuvant chemotherapy results in a high pCR rate without clinical ly relevant early toxicity . Combination of chemotherapy with trastuzumab should be considered when neoadjuvant treatment is given to patients with HER2-positive breast cancer PURPOSE This is a r and omized , double-blind , placebo-controlled study aim ed to evaluate the clinical and biologic effects of letrozole plus lapatinib or placebo as neoadjuvant therapy in hormone receptor ( HR ) -positive/human epidermal growth factor receptor 2 ( HER2 ) -negative operable breast cancer . METHODS Ninety-two postmenopausal women with stage II to IIIA primary breast cancer were r and omly assigned to preoperative therapy consisting of 6 months of letrozole 2.5 mg orally daily plus lapatinib 1,500 mg orally daily or placebo . Surgery was performed within 2 weeks from the last study medication . Clinical response was assessed by ultrasonography . Pre- and post-treatment sample s were evaluated for selected biomarkers . Fresh-frozen tissue sample s were collected for genomic analyses . RESULTS Numerically similar clinical response rates ( partial + complete response ) were observed ( 70 % for letrozole-lapatinib and 63 % for letrozole-placebo ) . Toxicities were generally mild and manageable . A significant decrease in Ki-67 and pAKT expression from baseline to surgery was observed in both arms . Overall , 34 patients ( 37 % ) had a mutation in PIK3CA exon 9 or  20 . In the letrozole-lapatinib arm , the probability of achieving a clinical response was significantly higher in the presence of PIK3CA mutation ( objective response rate , 93 % v 63 % in PIK3CA wild type ; P = .040 ) . CONCLUSION The combination of letrozole-lapatinib in early breast cancer was feasible , with expected and manageable toxicities . In unselected estrogen receptor-positive/HER2-negative patients , letrozole-lapatinib and letrozole-placebo result ed in a similar overall clinical response rate and similar effect on Ki-67 and pAKT . Our secondary end point findings of a significant correlation between PIK3CA mutation and response to letrozole-lapatinib in HR-positive/HER2-negative early breast cancer must now be independently confirmed PURPOSE To retrospectively evaluate the pattern of recurrence and outcome of node-negative breast cancer ( BC ) according to major subtypes . PATIENTS AND METHODS In all , 1,951 patients with node-negative , early-stage BC r and omly assigned in International Breast Cancer Study Group Trials VIII and IX with central ly review ed pathology data were included . BC subtypes were defined as triple negative ( TN ; n = 310 ) , human epidermal growth factor receptor 2 ( HER2 ) positive ( n = 369 ) , and hormone receptor positive with high ( luminal B-like [ LB-like ] ; n = 763 ) or low ( luminal A-like [ LA-like ] ; n = 509 ) proliferative activity by Ki-67 labeling index . BC-free interval ( BCFI ) events were invasive BC recurrence in local , contralateral breast , nodal , bone , or visceral sites . Time to first site-specific recurrence was evaluated by using cumulative incidence and competing risks regression analysis . RESULTS Median follow-up was 12.5 years . The 10-year BCFI was higher for patients with LA-like ( 86 % ) BC compared with LB-like ( 76 % ) , HER2 ( 73 % ) , and TN ( 71 % ; P < .001 ) BC . TN and HER2 cohorts had higher hazard of BCFI event in the first 4 years after diagnosis ( pre-trastuzumab ) . LB-like cohorts had a continuously higher hazard of BCFI event over time compared with LA-like cohorts . Ten-year overall survival was higher for LA-like ( 89 % ) compared with LB-like ( 83 % ) , HER2 ( 77 % ) , and TN ( 75 % ; P < .001 ) BC . LB-like subtypes had higher rates of bone as first recurrence site than other subtypes ( P = .005 ) . Visceral recurrence as first site was lower for the LA-like subgroup , with similar incidence among the other subgroups when treated with chemotherapy ( P = .003 ) . CONCLUSION BC subtypes have different distant recurrence patterns over time . Defining different patterns of BC recurrence can improve BC care through surveillance guidelines and can guide the design of clinical studies Breast cancer is the most common cancer type in women and the fourth leading cause of cancer death in the United States ( 1 ) . The goal of screening is to reduce morbidity and mortality , both specific to breast cancer and overall , with acceptable tradeoffs ( 2 , 3 ) . The most commonly used screening test is mammography . Recommended strategies vary for breast cancer screening in average-risk women . Ages to start and discontinue mammography , screening intervals , the role of imaging methods other than mammography , and the role of clinical breast examination ( CBE ) have been points of disagreement among guideline developers . Purpose and Target Population The goal of this American College of Physicians ( ACP ) guidance statement is to critically review selected guidelines from around the world and their included evidence to assist clinicians in making decisions about breast cancer screening in asymptomatic women with average risk for breast cancer . Included screening methods are CBE and breast imaging ( that is , mammography , ultrasonography , magnetic resonance imaging [ MRI ] , and digital breast tomo synthesis [ DBT ] ) . This guidance statement does not address breast self-examination because no evaluated guideline recommends it for screening . The target population for this guidance statement is women with average risk for breast cancer . The target audience is all clinicians . Age is the single most important risk factor for breast cancer . Included guidelines generally define average-risk women as those who do not have a personal history of breast cancer or a previous diagnosis of a high-risk breast lesion , are not at high risk for breast cancer due to genetic mutations known to increase that risk ( such as BRCA1/2 gene mutation or another familial breast cancer syndrome ) , and were not exposed to radiation therapy to the chest in childhood ( 4 , 5 ) . However , definitions of average risk vary among guidelines . In addition , although risk factors ( including early menarche , late menopausal onset , oral contraceptive or menopausal hormone therapy , increased breast density on mammography , and a family member with a history of postmenopausal breast cancer ) may put a woman at greater risk for breast cancer than women without these factors , the evaluated guidelines generally include women with these factors under the umbrella of average risk . Therefore , our guidance statement applies to these women . Guidelines vary somewhat in target population s and screening methods addressed ( Table [ 411 ] and Appendix ) . Both the U.S. Preventive Services Task Force ( USPSTF ) and the World Health Organization ( WHO ) include women with dense breasts and those with a single family member with breast cancer in their guideline 's target population ( 5 , 6 ) . The Canadian Task Force on Preventive Health Care ( CTFPHC ) guideline also includes women with dense breasts ; however , it explicitly mentions that women with a first-degree relative with breast cancer are considered to be at increased risk and are thus excluded from the guideline ( 7 ) . Table . Summary of Included Recommendations in Assessed Guidelines for Breast Cancer Screening of Average-Risk Women Methods The ACP Clinical Guidelines Committee develops guidance statements on topics where several conflicting guidelines are available . Guidance statements rely on evidence presented or referenced in selected guidelines and accompanying evidence reports ; they do not include de novo review s or search es of the literature outside the body of evidence referenced by the guidelines . The goal of ACP guidance statements is to provide clinicians with a rigorous review of the available guidelines and their included evidence and to develop subsequent guidance based on an assessment of the benefits and harms reported by each guideline and its evidence . Unlike ACP guidelines , guidance statements are not derived from a systematic evidence review and hence do not use GRADE ( Grading of Recommendations Assessment , Development and Evaluation ) ( 12 ) to assess the quality of evidence or strength of recommendations . Data Sources and Guideline Selection We search ed the National Guideline Clearinghouse and the Guidelines International Network library for breast cancer screening guidelines from national organizations that addressed breast imaging ( that is , mammography , ultrasonography , MRI , or DBT ) and CBE in women and were published in English between 1 January 2013 and 15 November 2017 . We search ed Web sites housing the selected guidelines for up date s on 10 December 2018 . We excluded guidelines that addressed specific population s ( such as pregnant women and women at increased risk for breast cancer ) or were more than 5 years old ( thus considered inactive ) . We also excluded guidelines that directly endorsed another guideline , such as that of the American Academy of Family Physicians , which endorsed the USPSTF guideline . Our search yielded 3 guidelines , from the American College of Radiology ( published in 2017 ; literature search end date , February 2016 ) ( 9 ) , American Cancer Society ( ACS ) ( published in 2015 ; literature search end date , March 2014 ) ( 4 ) , and USPSTF ( published in 2016 ; literature search end date , June 2015 ) ( 5 ) . We also selected 3 guidelines not identified in either data base but commonly used in clinical practice , from the National Comprehensive Cancer Network ( NCCN ) ( published in 2018 ; literature search end date not reported ) ( 10 ) , WHO ( published in 2014 ; literature search end date , December 2012 ) ( 6 ) , and American College of Obstetricians and Gynecologists ( published in 2017 ; literature search end date not applicable ) ( 8) . In addition , we selected the CTFPHC guideline , which was up date d after our initial search ( published in 2018 ; literature search end date , January 2017 ) ( 7 ) . The American College of Obstetricians and Gynecologists guideline was based on guidelines from the ACS , NCCN , and USPSTF and supporting evidence review s. Critical Appraisal Five co authors independently review ed , assessed , and scored each guideline using the AGREE II ( Appraisal of Guidelines for Research and Evaluation II ) instrument ( 13 , 14 ) ( Appendix Table 1 ) . Appendix Table 1 . Scaled AGREE II Domain Scores for Each Guideline and Overall Assessment Clinician Peer Review The guidance statement was peer- review ed through Annals of Internal Medicine and by ACP Regents and Governors , who represent ACP members at the regional and international level . Public Member Review The development process for the guidance statement included participation by public members ( 2 of the Clinical Guidelines Committee and 7 of ACP 's Public Panel ) to share their perspectives , values , and preferences . Critical Appraisal of Evaluated Guidelines The major difference between high- and low-scoring guidelines ( Appendix Table 1 ) was methodology . Guidelines from ACS ( 4 ) , CTFPHC ( 7 ) , USPSTF ( 5 ) , and WHO ( 6 ) scored highest on the AGREE II instrument , whereas those from the American College of Obstetricians and Gynecologists ( 8) , American College of Radiology ( 9 ) , and NCCN ( 10 ) scored lowest . In addition to our review of each guideline , we examined the evidence supporting the 4 that scored highest ( ACS , CTFPHC , USPSTF , and WHO ) . We also considered recommendations for adoption or adaptation from these 4 guidelines when developing our own guidance . Several factors were important in considering guideline quality . The ACS , CTFPHC , USPSTF , and WHO guidelines best articulated benefits , harms , and strength of the evidence and how these link to recommendations . The lower-scoring guidelines often inadequately described how they considered these factors in developing the recommendations , or they relied on lower- quality evidence . The guidelines varied in the studies they reported , weighting of observational or modeling studies relative to r and omized controlled trials ( RCTs ) , and emphasis on relative versus absolute effects . The guidelines rarely addressed the small absolute effect on breast cancer mortality ; the long lead time to any reduction in this mortality , especially in women with estimated life expectancy less than 15 to 20 years ; and the low incidence of breast cancer for women younger than 60 years . Mammography Depending on the guideline , the recommended age to discuss initiating screening is 40 years ( 4 , 5 , 8) and the recommended age to start screening ranges from 40 ( 9 , 10 ) to 45 ( 4 ) to 50 ( 58 ) years . Most guidelines agree to screen average-risk women with  mammography  between ages 50 and 74 years . However , WHO and CTFPHC recommend that screening in women aged 50 to 69 years should include shared decision making because screening is conditional on a woman 's values and preferences . For women aged 70 to 75 years , WHO recommends screening only in the context of both rigorous research and shared decision making . Other areas of disagreement include screening in women aged 40 to 49 years , screening in women aged 75 years or older , and recommended screening intervals ( Table ) . Intervals range from annual ( particularly in women aged 40 to 49 years ) to biennial or triennial . Guidelines from ACS , USPSTF , and WHO conclude that a close balance exists between screening benefits and harms for women in their 40s ( for ACS , 40 to 44 years ) and that decisions are influenced by patient preferences . The WHO guideline suggests population -based screening programs in women aged 40 to 49 years only in the context of rigorous research , monitoring , and evaluation and if shared decision-making strategies are implemented . The CTFPHC conditionally recommends against screening in women aged 40 to 49 years ( without a first-degree family history of breast cancer ) ; however , it states that some women in this age group may wish to be screened and that clinicians should engage in shared decision making with women who express interest ( Appendix ) . Appendix Table 2 summarizes the available data from the 4 guidelines with the highest AGREE II scores ( ACS , CTFPHC , USPSTF , and WHO ) . Appendix Table 2 . Summary of Evidence on Screening BACKGROUND The efficacy of sequential adjuvant trastuzumab ( aTZ ) after chemotherapy in women with early-stage human epidermal growth factor-2 (HER2/neu)-positive breast cancer reported by the up date d Herceptin Adjuvant ( HERA ) trial appears less favorable than originally reported . Based on these up date d results , we estimated the cost-utility ( CU ) of sequential aTZ relative to chemotherapy alone in terms of incremental cost per quality -adjusted life-year ( QALY ) gained . METHODS A Markov model estimated incremental costs and outcomes of 12 months of aTZ after adjuvant chemotherapy in women with HER2/neu-positive breast cancer over a 25-year horizon . The model incorporated four broad health states ( disease-free , local recurrence [ LCR ] , distant recurrence [ DCR ] , death ) , stratified with or without symptomatic cardiotoxicity . Baseline event rates and 3-year relative risk ( RR = 0.75 ) were derived from the HERA trial . As the duration of the benefit remains uncertain , the analysis considered 5-year and 3-year duration of benefit in two scenarios . Costs and utility weights were from the literature . The analysis took a direct payer perspective , with costs reported in 2007 Canadian dollars . Costs and QALYs were discounted by 3 % annually . RESULTS The mean CU of sequential aTZ at a 25-year horizon was $ 72,292 per QALY gained in the 5-year scenario and $ 127,862 per QALY gained in the 3-year scenario . Results were particularly sensitive to the magnitude and duration of carryover benefit . CONCLUSIONS The CU of sequential aTZ is primarily dependent on the magnitude and duration of benefit . Further clinical research is required to establish the optimum sequence and duration of aTZ therapy and clarify the magnitude and duration of treatment benefit PURPOSE This is a noncomparative , r and omized , phase II trial of preoperative taxane-anthracycline in combination with trastuzumab , lapatinib , or combined trastuzumab plus lapatinib in patients with human epidermal growth factor receptor 2 ( HER2 ) -positive , stage II to IIIA operable breast cancer . The primary aim was to estimate the percentage of pathologic complete response ( pCR ; no invasive tumor in breast and axillary nodes ) . PATIENTS AND METHODS In the three arms , chemotherapy consisted of weekly paclitaxel ( 80 mg/m(2 ) ) for 12 weeks followed by fluorouracil , epirubicin , and cyclophosphamide for four courses every 3 weeks . The patients r and omly assigned to arm A received a 4-mg loading dose of trastuzumab followed by 2 mg weekly ; in arm B patients received lapatinib 1,500 mg orally ( PO ) daily ; and in arm C , patients received trastuzumab and lapatinib 1,000 mg PO daily . RESULTS A total of 121 patients were r and omly assigned .  Diarrhea and dermatologic and hepatic toxicities were observed more frequently in patients receiving lapatinib . No episodes of congestive heart failure were observed . The rates of breast-conserving surgery were 66.7 % , 57.9 % , and 68.9 % in arms A , B and C , respectively . The pCR rates were 25 % ( 90 % CI , 13.1 % to 36.9 % ) in arm A , 26.3 % ( 90 % CI , 14.5 % to 38.1 % ) in arm B , and 46.7 % ( 90 % CI , 34.4 % to 58.9 % ) in arm C ( exploratory P = .019 ) . CONCLUSION The primary end point of the study was met , with a relative increase of 80 % in the pCR rate achieved with chemotherapy plus trastuzumab and lapatinib compared with chemotherapy plus either trastuzumab or lapatinib . These data add further evidence supporting the superiority of a dual-HER2 inhibition for the treatment of HER2-positive breast cancer This study reports the value of the tumor markers estrogen receptor ( ER ) , progesterone receptor ( PR ) , and human epidermal growth factor receptor 2 ( HER2 ) in predicting the response of breast cancer to neoadjuvant chemotherapy . A community cancer center prospect ively maintained breast cancer data base containing over 8,000 patient records was used . Since 1989 , 464 patients were treated with neoadjuvant chemotherapy followed by surgical resection  and were tested for ER and PR . Estrogen receptor and /or PR positive patients were considered hormone receptor ( HR ) positive . Human epidermal growth factor receptor 2 status was available on 368 patients .  Total , breast , and nodal pathologic complete response ( pCR ) rates , recurrence , and overall survival were assessed . Total and breast pCR rates were higher in HR negative ( HR- ) patients ( 26 % and 32 % , respectively ) than in HR positive ( HR+ ) patients ( 4 % and 7 % , respectively ; p < 0.001 ) . Compared to HR+ patients , HR- patients had higher recurrence rates ( 38 % versus 22 % ; p < 0.001 ) , a shorter time to recurrence ( 1.28 versus 2.14 years ; p < 0.001 ) , and decreased overall survival ( 67 % versus 81 % ; p < 0.001 ) . Human epidermal growth factor receptor 2 positive patients treated with neoadjuvant trastuzumab ( NAT ) demonstrated higher total pCR ( 34 % versus 13 % ; p = 0.008 ) , breast pCR ( 37 % versus 17 % ; p = 0.02 ) , and nodal pCR rates ( 47 % versus 23 % ; p = 0.05 ) compared to HER2 + patients not treated with NAT . Furthermore , HER2 + patients who received NAT had lower recurrence rates ( 5 % versus 42 % ; p < 0.001 ) and increased overall survival ( 97 % versus 68 % ; p < 0.001 ) . In conclusion , breast cancer HR status is predictive of total and breast pCR rates after neoadjuvant chemotherapy . Although HR- patients derive greater benefit from neoadjuvant chemotherapy in terms of pathologic response , they have worse outcomes in terms of recurrence and survival . Hormone receptor positive patients demonstrate significantly less response to neoadjuvant chemotherapy , but significantly better overall outcome . For both HR- and HR+ , addition of NAT for HER2 + tumors results in both a superior response and outcome Background Patients who have residual invasive breast cancer after receiving neoadjuvant chemotherapy plus human epidermal growth factor receptor 2 (HER2)–targeted therapy  have a worse prognosis than those who have no residual cancer . Trastuzumab emtansine ( T‐DM1 ) , an antibody – drug conjugate of trastuzumab and the cytotoxic agent emtansine ( DM1 ) , a maytansine derivative and microtubule inhibitor , provides benefit in patients with metastatic breast cancer that was previously treated with chemotherapy plus HER2‐targeted therapy . Methods We conducted a phase 3 , open‐label trial involving patients with HER2‐positive early breast cancer who were found to have residual invasive disease in the breast or axilla at surgery after receiving neoadjuvant therapy containing a taxane ( with or without anthracycline ) and trastuzumab .  Patients were r and omly assigned to receive adjuvant T‐DM1 or trastuzumab for 14 cycles . The primary end point was invasive disease – free survival ( defined as freedom from ipsilateral invasive breast tumor recurrence , ipsilateral locoregional invasive breast cancer recurrence , contralateral invasive breast cancer , distant recurrence , or death from any cause ) . Results At the interim analysis , among 1486 r and omly assigned patients ( 743 in the T‐DM1 group and 743 in the trastuzumab group ) , invasive disease or death had occurred in 91 patients in the T‐DM1 group ( 12.2 % ) and 165 patients in the trastuzumab group ( 22.2 % ) . The estimated percentage of patients who were free of invasive disease at 3 years was 88.3 % in the T‐DM1 group and 77.0 % in the trastuzumab group . Invasive disease – free survival was significantly higher in the T‐DM1 group than in the trastuzumab group ( hazard ratio for invasive disease or death , 0.50 ; 95 % confidence interval , 0.39 to 0.64 ; P<0.001 ) . Distant recurrence as the first invasive‐disease event occurred in 10.5 % of patients in the T‐DM1 group and 15.9 % of those in the trastuzumab group . The safety data were consistent with the known safety profile of T‐DM1 , with more adverse events associated with T‐DM1 than with trastuzumab alone . Conclusions Among patients with HER2‐positive early breast cancer who had residual invasive disease after completion of neoadjuvant therapy  , the risk of recurrence of invasive breast cancer or death was 50 % lower with adjuvant T‐DM1 than with trastuzumab alone . ( Funded by F. Hoffmann – La Roche/Genentech ; KATHERINE Clinical Trials.gov number , NCT01772472 . Purpose Whether postoperative chemotherapy should be added to endocrine therapy or not is an important issue in patients with hormone receptor-positive and human epidermal growth factor receptor (HER)2-negative breast cancer . To identify patients who should be treated with additional chemotherapy , prognostic factors were investigated in breast cancer patients postoperatively treated with endocrine therapy alone .  Patients and methods Tumor sample s and clinicopathological data were collected from patients who underwent curative surgery and were postoperatively treated with endocrine therapy alone between 1999 and 2003 in three different institutes . Expression levels of estrogen receptor ( ER ) , progesterone receptor ( PgR ) , and HER2 in primary tumors were central ly retested . Patients with ER-negative and /or HER2-positive tumors and /or with unknown nodal status were excluded from the study subjects . Immunohistochemical analysis of Ki67 , HER1 , insulin-like growth factor-1 receptor , and aldehyde dehydrogenase-1 was also performed . Prognostic factors were investigated by univariate and multivariate analyses . Results A total of 261 patients were the subjects of this study . The median age was 59 years old , the mean tumor size was 1.9 cm , the node-positive rate was 20 % , and 65 % received tamoxifen alone . Distant metastases were observed in 11 patients at a median follow-up of 98 months , and four patients had died of breast cancer at a median follow-up of 99 months . Univariate analysis showed that marked lymphovascular invasion ( LVI ) , PgR negativity , high Ki67 labeling index ( LI ) , and high nuclear grade were significantly worse prognostic factors for distant metastasis . Multivariate analysis revealed that marked LVI [ hazard ratio ( HR ) 21.8 ] and PgR negativity ( HR 10.3 ) were independently worse prognostic factors for distant metastasis , respectively . Multivariate analysis also revealed that marked LVI ( HR 287.3 ) , PgR negativity ( HR 25.1 ) , and high Ki67 LI ( HR 19.6 ) were independently worse prognostic factors for breast cancer-specific death , respectively . Conclusions The results of this multi-institute cohort study indicated that endocrine therapy alone could not prevent distant metastasis in breast cancer patients with PgR-negative tumors and /or with tumors showing marked LVI or high cell proliferation . These patients may need postoperative adjuvant chemotherapy in addition to endocrine therapy BACKGROUND Patients with HER2-positive breast cancer whose disease has become resistant to the anti-HER2 monoclonal antibody trastuzumab  can benefit from lapatinib , a dual epidermal growth factor receptor/HER2 tyrosine kinase ( TK ) inhibitor . Before the availability of this compound , trastuzumab was often continued beyond disease progression , usually in addition to further chemotherapy , an approach which was not based on r and omized studies . We sought to retrospectively compare the clinical outcomes of patients who , upon progression during an initial trastuzumab-based regimen , stopped or continued trastuzumab in addition to further chemotherapy . PATIENTS AND METHODS From the clinical records of 407 patients with HER2-positive advanced breast cancer , we identified 279 patients progressing during an initial trastuzumab-based treatment .  Of these patients , 83 continued trastuzumab in addition to chemotherapy , and 112 received chemotherapy alone . RESULTS We found no difference in response rate ( 28 % vs. 30 % ; P = .5 ) , median time to second tumor progression ( 8.4 months vs. 7 months ; P = .24 ) , or median postprogression survival ( 20.6 months and 15.4 months ; P = .29 ) according to whether patients continued or stopped trastuzumab . At multivariate analysis , continuation of trastuzumab was associated with a statistically insignificant trend toward reduced risk of second progression ( hazard ratio , 0.753 ; P = .08 ) . CONCLUSION Patients with HER2-positive advanced breast cancer developing tumor progression during an initial trastuzumab-based regimen did not seem to benefit significantly from the continuation of trastuzumab in addition to chemotherapy . For these patients , there is evidence from a large r and omized trial that effective HER2 targeting can be accomplished by inhibiting the HER2 TK activity with lapatinib Hepatocellular carcinoma ( HCC ) is a highly prevalent disease in many Asian countries , accounting for 80 % of victims worldwide . Screening programs improve the detection of early HCC and have a positive impact on survival , but the majority of HCC patients in Asia still present with advanced stage disease . The treatment outcomes of HCC are affected by multiple variables , including liver function , performance status of the patient , and tumor stage . Therefore , it is not easy to apply a multidisciplinary therapeutic approach for optimal management . At present , limited numbers of HCC patients are eligible for curative therapies such as surgery or ablation in Asia . Therefore , most patients are eligible for only palliative treatments . For optimal management , the treatment choice is guided by staging systems and treatment guidelines . Numerous staging systems have been proposed and treatment guidelines vary by region . According to the Barcelona Clinic Liver Cancer ( BCLC ) guideline based on evidence from r and omized clinical trials , only transarterial chemoembolization ( TACE ) is recommended for intermediate stage HCC and sorafenib for advanced stage HCC . However , treatment guidelines from Asian countries have adopted several other therapeutic modalities such as a surgical approach , hepatic arterial infusion chemotherapy , external radiation , and their combinations based on clinical experiences for intermediate and advanced stage HCC . Although TACE is the main therapeutic modality in the intermediate stage , overall therapeutic outcomes depend on the tumor size . In the advanced stage , the prognosis depends on the tumor status , e.g. major vessel invasion or extrahepatic spread . Thus , a new staging system representing prognoses suitable for Asian HCC patients and a corresponding optimal treatment algorithm should be further investigated using evidence -based data , which will finally bring about an Asian consensus for the management of intermediate and advanced stage HCC Epigenetic modifiers , including the histone deacetylase inhibitor vorinostat , may sensitize tumors to chemotherapy and enhance outcomes . We conducted a multicenter r and omized phase II neoadjuvant trial of carboplatin and nanoparticle albumin-bound paclitaxel ( CP ) with vorinostat or placebo in women with stage II/III , human epidermal growth factor receptor 2 (HER2)–negative breast cancer , in which we also examined whether change in maximum st and ardized uptake values corrected for lean body mass ( SULmax ) on 18F-FDG PET predicted pathologic complete response ( pCR ) in breast and axillary lymph nodes . Methods : Participants were r and omly assigned to 12 wk of preoperative carboplatin ( area under the curve of 2 , weekly ) and nab-paclitaxel ( 100 mg/m2 weekly ) with vorinostat ( 400 mg orally daily , days 1–3 of every 7-d period ) or placebo . All patients underwent 18F-FDG PET and research biopsy at baseline and on cycle 1 day 15 . The primary endpoint was the pCR rate . Secondary objectives included correlation of change in tumor SULmax on 18F-FDG PET by cycle 1 day 15 with pCR and correlation of baseline and change in Ki-67 with pCR . Results : In an intent-to-treat analysis ( n = 62 ) , overall pCR was 27.4 % ( vorinostat , 25.8 % ; placebo , 29.0 % ) . In a pooled analysis ( n = 59 ) , we observed a significant difference in median change in SULmax 15 d after initiating preoperative therapy between those achieving pCR versus not ( percentage reduction , 63.0 % vs. 32.9 % ; P = 0.003 ) . Patients with 50 % or greater reduction in SULmax were more likely to achieve pCR , which remained statistically significant in multivariable analysis including estrogen receptor status ( odds ratio , 5.1 ; 95 % confidence interval , 1.3–22.7 ; P = 0.023 ) . Differences in baseline and change in Ki-67 were not significantly different between those achieving pCR versus not . Conclusion : Preoperative CP with vorinostat or placebo is associated with similar pCR rates . Early change in SULmax on 18F-FDG PET 15 d after the initiation of preoperative therapy has potential in predicting pCR in patients with HER2-negative breast cancer . Future studies will further test 18F-FDG PET as a potential treatment- selection biomarker Abstract Purpose : Improved underst and ing of risk of recurrence ( ROR ) is needed to reduce cases of recurrence and more effectively treat breast cancer patients . The purpose of this study was to examine how a gene-expression profile ( GEP ) , identified by Prosigna , influences physician adjuvant treatment selection for early breast cancer ( EBC ) and the effects of this influence on optimizing adjuvant treatment recommendations in clinical practice . Methods : A prospect i ve , observational , multicenter study was carried out in 15 hospitals across Spain . Participating medical oncologists completed pre- assessment , post- assessment , and follow-up question naires recording their treatment recommendations and confidence in these recommendations , before and after knowing the patient ’s ROR . Patients completed question naires on decision-making , anxiety , and health status . Results : Between June 2013 and January 2014 , 217 patients enrolled and a final 200 were included in the study . Patients were postmenopausal , estrogen receptor positive , human epidermal growth hormone factor negative , and node negative with either stage 1 or stage 2 tumors . After receiving the GEP results , treatment recommendations were changed for 40 patients ( 20 % ) . The confidence of medical oncologists in their treatment recommendations increased in 41.6 % and decreased in 6.5 % of total cases . Patients reported lower anxiety after physicians made treatment recommendations based on the GEP results ( p < 0.05 ) . Conclusions : Though this study does not include evaluation of the impact of GEP on long-term outcomes , it was found that GEP results influenced the treatment decisions of medical oncologists and their confidence in adjuvant therapy selection . Patients ’ anxiety about the selected adjuvant therapy decreased with use of the GEP Background Recent r and omised trials have demonstrated a statistically significant effect of trastuzumab on disease-free survival when used as adjuvant therapy for human epidermal growth factor receptor 2 protein (HER2)-positive resectable early stage breast cancer , with a treatment course lasting either 9 or 52 weeks . However , the cost effectiveness of adjuvant trastuzumab with respect to mortality remains uncertain , especially in an Australian setting . Objective To estimate the cost effectiveness of trastuzumab in Australia , in a cohort of 50-year-old patients with HER2-positive breast cancer over a lifetime , using ( i ) disease-free survival and cardiotoxicity data from recent r and omised trials ; ( ii ) information on long-term survival of patients with treated primary breast cancer ; and ( iii ) costs of treating local and distant relapses and disease from causes other than breast cancer . Methods A Markov model consisting of four health states ( remission , loco-regional recurrence , metastatic disease and death ) was developed . Transition probabilities corresponded to patterns of relapse and metastases seen in recent trials . The model was run until age 100 years to allow calculation of average survival . Outcome measures were life-years and QALYs ( calculated using utility weights reported in the literature ) .The model was calibrated to reflect literature evidence that the risk of breast cancer recurrence following primary treatment diminishes progressively to zero after about 20 years . It was assumed that the morbidity benefit of trastuzumab observed in trials would be present for 5 years but would then diminish progressively to zero after 8 years . Costs ( year 2005 values ) and benefits were discounted at 3 % per annum . Results For every 1000 patients treated with a 52-week course of trastuzumab , there were 136 fewer breast cancer deaths ( relative risk reduction 28 % ) . The incremental cost-effectiveness ratios ( ICERs ) were Australian dollars ($A)13 730 per year of life saved ( YOLS ) and $ A22 793 per QALY . The net incremental cost was $ A56.3 million ( $ A414 012/cancer death avoided ) . Cost effectiveness declined ( ICER = $ A27 734/QALY ) in older patients ( age 65 years at treatment initiation).The ICER was driven mainly by the drug acquisition costs , the assumption of the duration of benefit and the discount rate . Cost offsets from reduced costs of treating recurrent or metastatic breast cancer during follow-up were present but these factors were of less importance according to sensitivity analyses . The 9-week treatment schedule approached economic dominance ( ICER = $ A1700/QALY ) because of decreased costs , improved relative risk for prevention of metastases and more cancer deaths avoided ( 196 ) . Conclusion The results suggest that trastuzumab as adjuvant therapy for early breast cancer may be cost effective when given over either 52 or 9 weeks at current acquisition costs in Australia . However , the overall budget impact of the 52-week course is significant , and the 9-week course appears economically attractive BACKGROUND We explored the correlation between serum human epidermal growth factor receptor-2 ( HER2 ) extracellular domain ( ECD ) and tissue HER2 status , their relationship with clinicopathological parameters and their impact on disease-free survival ( DFS ) and overall survival in early breast cancer patients . PATIENTS AND METHODS This prospect i ve trial included patients with stage I-III breast cancer .  Serum HER2 ECD levels  were measured by two enzyme-linked immunosorbent assays before surgical treatment .  Tissue HER2 status was analyzed by immunohistochemistry ( IHC ) in all tumors ; FISH assay was utilized in HER2 2 + tumors by IHC . RESULTS From May 2000 to July 2005 , 256 consecutive stage I-III breast cancer patients were included in this study . High serum HER2 ECD levels ( > or=15 ng/ml ) were reported in 23 patients ( 9.0 % ) and HER2-positive status in tumor tissue was observed in 42 patients ( 16.4 % ) with a concordance of 87.1 % . High HER2 ECD levels were significantly associated with high histological grade ( P = 0.003 ) , stage III ( P = 0.008 ) , lymph node involvement ( P = 0.035 ) and negativity of both estrogen ( P = 0.016 ) and progesterone ( P = 0.007 ) receptors . At multivariate analysis , high serum HER2 ECD levels were a significant independent prognostic factor of worse DFS ( P = 0.009 ) . CONCLUSIONS A statistically significant association was observed between high serum HER2 ECD levels and worse DFS in early breast cancer patients PURPOSE We previously reported the eradication of human epidermal growth factor receptor 2 (HER2)- amplified human xenografts in mice by inhibition of the HER2 pathway with lapatinib and trastuzumab to block all homo- and heterodimer signaling as well as by blockade of estrogen receptor ( ER ) when expressed . In this clinical trial , we sought to translate these findings to patients using targeted therapy without chemotherapy . PATIENTS AND METHOD Women with stages II to III HER2-positive breast cancers were eligible . They received trastuzumab once per week ( 4 mg/kg loading , then 2 mg/kg ) and lapatinib 1000 mg once per day for 12 weeks . Women with ER-positive tumors also received letrozole ( plus a luteinizing hormone-releasing hormone [ LHRH ] agonist if premenopausal ) .  Pathologic response was assessed by ER status . Biopsies were obtained at baseline , weeks 2 and 8 , and time of surgery . RESULTS Sixty-six patients were enrolled , and 64 were eligible and evaluable for response .  Median tumor size was 6 cm ( range , 1.5 to 30 cm ) . Adverse events were mainly grade s 1 to 2 ( GI , 63 % ; skin , 46 % ) . Grade 3 metabolic , GI , and liver ( 18 % ; 12 patients ) and grade 4 liver toxicities ( one patient ) were also observed . Overall , in-breast pathologic complete response ( pCR ; ypT0-is ) was 27 % ( ER positive , 21 % ; ER negative , 36 % ) . The rate of low-volume residual disease ( ypT1a-b ) was 22 % ( ER positive , 33 % ; ER negative , 4 % ) . CONCLUSION In patients with locally advanced HER2-positive breast cancer , our approach of targeted therapy only result ed in a high pCR rate without chemotherapy . Our data support the hypothesis that selected patients with HER2-positive tumors may not need chemotherapy , and more-complete blockade of HER receptors and ER is an effective strategy worthy of further study At the end of a long week in the office , you sink back into your chair , reflecting on some of the more memorable patients you cared for and counseled . Through gentle history taking , you discovered that urinary incontinence is the underlying cause of an elderly patient 's increasing social isolation . During a careful physical examination , you detected bruising on the torso of a woman with chronic headaches and began to explore the longst and ing abusive relationship between the woman and her alcoholic partner . You discontinued procainamide therapy in a 72-year-old man who had asymptomatic premature ventricular contractions after myocardial infa rct ion . To prevent bleeding from esophageal varices , you started -blocker therapy in a woman with long-st and ing cryptogenic cirrhosis and portal hypertension . In couples ' therapy , discussing the future quality of life of a middle-aged gay man with human immunodeficiency virus infection , you journeyed through emotionally intense dialogue about advance directives . You presented the risk factors for major and minor bleeding to a 39-year-old woman who was considering warfarin therapy because of recently diagnosed atrial fibrillation and valvular heart disease . You listened to , made diagnoses for , treated , advised , and comforted many patients . Yet there were some hiccoughs in your practice along the way . You stumbled while debating the pros and cons of breast cancer screening with a healthy 48-year-old woman who has been staying current with information on the Internet . You question ed the merits of a personalized walking program suggested to you by a motivated 66-year-old man with severe claudication . Explaining that you wanted to review the best current evidence on these issues , you resolved to address your uncertainties before these patients made their next office visits , in a week 's time . Sighing deeply , you acknowledge that you have little time to read . You subscribe to three journals , which you browse months after they arrive-either when your journal stack becomes precariously high or when your guilt is sufficiently motivational . You sometimes find the conclusions of individual articles conflicting or confusing . You know that some of the decisions and suggestions you made this week , specifically your decisions about stopping procainamide therapy and starting -blocker therapy and your advice about bleeding risks from anticoagulant therapy , were based on the best current research evidence [ 1 - 3 ] . On the other h and , your patients ' inquiries about breast cancer screening and exercise treatment for claudication highlight your need for a concise , current , rigorous synthesis of the best available evidence on each of these topics : in brief , a systematic review [ 4 , 5 ] . Incorporating Research Evidence into Clinical Decision Making The foregoing scenario is familiar to practitioners . In a typical week , we encounter patients with diverse problems ; exercise numerous clinical , interpersonal , and technical skills ; and make many decisions . The factors that affect these decisions and their outcomes are complex . For instance , each patient has unique sociodemographic characteristics , cultural circumstances , and personal preferences . Each physician has unique knowledge , experiences , and values . Moreover , practitioners and their patients make decisions within the context of a rapidly changing health care system that influences the availability , accessibility , and cost of diagnostic tests and therapies [ 6 ] . Timely , useful evidence from the biomedical literature should be an integral component of clinical decision making . If one treatment has been shown to be better than another , we need to know , so that we can recommend the treatment to the appropriate patients . The worldwide effort to develop new tests and treatments , and to determine their usefulness , has never been stronger , and our patients and their families expect us to be fonts of the knowledge that results from this effort [ 7 ] . Unfortunately , it is easy for current best research evidence to pass us by [ 8 ] . We may lack the time , motivation , and basic skills needed to find , critically appraise , and synthesize information , all of which we must do if we are to integrate the results of original studies into our practice . Fortunately , several potent methods are emerging that can greatly enhance our ability to interpret and apply research evidence ; foremost among them is the systematic review . This article begins a series in Annals that will examine systematic review s in detail and explore their many applications . Systematic review s represent the best chance that most practitioners will have to underst and and accurately apply the key signals arising from the robust and increasingly productive search for solutions to medical problems . A properly conducted systematic review faithfully summarizes the evidence from all relevant studies on the topic of interest , and it does so concisely and transparently . What Is a Systematic Review ? Systematic review s are scientific investigations in themselves , with pre-planned methods and an assembly of original studies as their subjects . They synthesize the results of multiple primary investigations by using strategies that limit bias and r and om error [ 9 , 10 ] . These strategies include a comprehensive search of all potentially relevant articles and the use of explicit , reproducible criteria in the selection of articles for review . Primary research design s and study characteristics are appraised , data are synthesized , and results are interpreted . When the results of primary studies are summarized but not statistically combined , the review may be called a qualitative systematic review . A quantitative systematic review , or meta- analysis , is a systematic review that uses statistical methods to combine the results of two or more studies . The term overview is sometimes used to denote a systematic review , whether quantitative or qualitative . Summaries of research that lack explicit descriptions of systematic methods are often called narrative review s. Review articles are one type of integrative publication ; practice guidelines , economic evaluations , and clinical decision analyses are others . These other types of integrative articles often incorporate the results of systematic review s. For example , practice guidelines are systematic ally developed statements intended to assist practitioners and patients with decisions about appropriate health care for specific clinical circumstances [ 11 ] . Evidence -based practice guidelines are based on systematic review s of the literature , appropriately adapted to local circumstances and values . Economic evaluations compare both the costs and the consequences of different courses of action ; the knowledge of consequences that are considered in these evaluations is often generated by systematic review s of primary studies . Decision analyses quantify both the likelihood and the valuation of the expected outcomes associated with competing alternatives . Differences between Systematic and Narrative Review s All review s , narrative and systematic alike , are retrospective , observational research studies and are therefore subject to systematic and r and om error . Accordingly , the quality of a review - and thus its worth-depends on the extent to which scientific review methods have been used to minimize error and bias . This is the key feature that distinguishes traditional narrative review s from systematic review s ( Table 1 ) . If a review is prepared according to the steps outlined in the right column of Table 1 , it is more likely to be systematic and to provide unbiased conclusions . If review methods approximate those found in the middle column of Table 1 , the article is more likely to be a narrative review , and the conclusions are less likely to be based on an unbiased summary of all relevant evidence . Table 1 . Differences between Narrative Review s and Systematic Review s Systematic review s are generated to answer specific , often narrow , clinical questions in depth . These questions can be formulated explicitly according to four variables : a specific population and setting ( such as elderly out patients ) , the condition of interest ( for example , hypertension ) , an exposure to a test or treatment ( such as pharmacologic management ) , and one or more specific outcomes ( such as cardiovascular and cerebrovascular events and mortality ) [ 12 ] . Thus , an example of a well-formulated , clinical ly relevant question is , Does pharmacologic treatment of hypertension in the elderly prevent strokes and myocardial infa rct ions or delay death ? If the question that is driving the review is not clear from the title , abstract , or introduction , or if no methods section is included , the paper is more likely to be a narrative review than a systematic review [ 13 ] . Most narrative review articles deal with a broad range of issues related to a given topic rather than addressing a particular issue in depth [ 9 ] . For example , a narrative review on diabetes ( such as that which might be found in a textbook chapter ) might include sections on the physiology and pathophysiology of carbohydrate , lipid , and protein metabolism ; the epidemiology of and prognosis associated with diabetes ; diagnostic and screening approaches ; and preventive , therapeutic , rehabilitative , and palliative interventions . Thus , narrative review s may be most useful for obtaining a broad perspective on a topic ; they are less often useful in furnishing quantitative answers to specific clinical questions . Narrative review s are appropriate for describing the history or development of a problem and its management . Narrative review s may better describe cutting-edge developments if research is scant or preliminary or if studies are very limited by flawed design or execution [ 13 ] . They may be particularly useful for discussing data in light of underlying theory and context . Narrative review s can draw analogies and can conceptually integrate two independent fields of research , such as PURPOSE Dual human epidermal growth factor receptor 2 ( HER2 ) targeting can increase pathologic complete response rates ( pCRs ) to neoadjuvant therapy and improve progression-free survival in metastatic disease . CALGB 40601 examined the impact of dual HER2 blockade consisting of trastuzumab and lapatinib added to paclitaxel , considering tumor and microenvironment molecular features . PATIENTS AND METHODS Patients with stage II to III HER2-positive breast cancer underwent tumor biopsy followed by r and om assignment to paclitaxel plus trastuzumab alone ( TH ) or with the addition of lapatinib ( THL ) for 16 weeks before surgery . An investigational arm of paclitaxel plus lapatinib ( TL ) was closed early . The primary end point was pCR in the breast ; correlative end points focused on molecular features identified by gene expression-based assays . RESULTS Among 305 r and omly assigned patients ( THL , n = 118 ; TH , n = 120 ; TL , n = 67 ) , the pCR rate was 56 % ( 95 % CI , 47 % to 65 % ) with THL and 46 % ( 95 % CI , 37 % to 55 % ) with TH ( P = .13 ) , with no effect of dual therapy in the hormone receptor-positive subset but a significant increase in pCR with dual therapy in those with hormone receptor-negative disease ( P = .01 ) . The tumors were molecularly heterogeneous by gene expression analysis using mRNA sequencing ( mRNAseq ) . pCR rates significantly differed by intrinsic subtype ( HER2 enriched , 70 % ; luminal A , 34 % ; luminal B , 36 % ; P < .001 ) . In multivariable analysis treatment arm , intrinsic subtype , HER2 amplicon gene expression , p53 mutation signature , and immune cell signatures were independently associated with pCR . Post-treatment residual disease was largely luminal A ( 69 % ) . CONCLUSION pCR to dual HER2-targeted therapy was not significantly higher than single HER2 targeting . Tissue analysis demonstrated a high degree of intertumoral heterogeneity with respect to both tumor genomics and tumor microenvironment that significantly affected pCR rates . These factors should be considered when interpreting and design ing trials in HER2-positive disease PURPOSE The objective of this study was to determine whether the addition of trastuzumab to chemotherapy in the neoadjuvant setting could increase pathologic complete response ( pCR ) rate in patients with human epidermal growth factor receptor 2 ( HER2 ) -positive disease . PATIENTS AND METHODS Forty-two patients with HER2-positive disease with operable breast cancer were r and omly assigned to either four cycles of paclitaxel followed by four cycles of fluorouracil , epirubicin , and cyclophosphamide or to the same chemotherapy with simultaneous weekly trastuzumab for 24 weeks . The primary objective was to demonstrate a 20 % improvement in pCR ( assumed 21 % to 41 % ) with the addition of trastuzumab to chemotherapy . The planned sample size was 164 patients . RESULTS Prognostic factors were similar in the two groups . After 34 patients had completed therapy , the trial 's Data Monitoring Committee stopped the trial because of superiority of trastuzumab plus chemotherapy .  pCR rates were 25 % and 66.7 % for chemotherapy ( n = 16 ) and trastuzumab plus chemotherapy ( n = 18 ) , respectively ( P = .02 ) . The decision was based on the calculation that , if study continued to 164 patients , there was a 95 % probability that trastuzumab plus chemotherapy would be superior . Of the 42 r and omized patients , 26 % in the chemotherapy arm achieved pCR compared with 65.2 % in the trastuzumab plus chemotherapy arm ( P = .016 ) . The safety of this approach is not established , although no clinical congestive heart failure was observed . A more than 10 % decrease in the cardiac ejection fraction was observed in five and seven patients in the chemotherapy and trastuzumab plus chemotherapy arms , respectively . CONCLUSION Despite the small sample size , these data indicate that adding trastuzumab to chemotherapy , as used in this trial , significantly increased pCR without clinical congestive heart failure BACKGROUND T-cell infiltration in estrogen receptor (ER)-negative breast tumours has been associated with longer survival . To investigate this association and the potential of tumour T-cell infiltration as a prognostic and predictive marker , we have conducted the largest study of T cells in breast cancer to date . PATIENTS AND METHODS Four studies totalling 12 439 patients were used for this work . Cytotoxic ( CD8 + ) and regulatory ( forkhead box protein 3 , FOXP3 + ) T cells were quantified using immunohistochemistry ( IHC ) . IHC for CD8  was conducted using available material from all four studies ( 8978 sample s ) and for FOXP3 from three studies ( 5239 sample s)-multiple imputation was used to resolve missing data from the remaining patients . Cox regression was used to test for associations with breast cancer-specific survival . RESULTS In ER-negative tumours [ triple-negative breast cancer and human epidermal growth factor receptor 2 ( human epidermal growth factor receptor 2 ( HER2 ) positive ) ] , presence of CD8 + T cells within the tumour was associated with a 28 % [ 95 % confidence interval ( CI ) 16 % to 38 % ] reduction in the hazard of breast cancer-specific mortality , and CD8 + T cells within the stroma with a 21 % ( 95 % CI 7 % to 33 % ) reduction in hazard . In ER-positive HER2-positive tumours , CD8 + T cells within the tumour were associated with a 27 % ( 95 % CI 4 % to 44 % ) reduction in hazard . In ER-negative disease , there was evidence for greater benefit from anthracyclines in the National Epirubicin Adjuvant Trial in patients with CD8 + tumours [ hazard ratio ( HR ) = 0.54 ; 95 % CI 0.37 - 0.79 ] versus CD8-negative tumours ( HR = 0.87 ; 95 % CI 0.55 - 1.38 ) . The difference in effect between these subgroups was significant when limited to cases with complete data ( P heterogeneity = 0.04 ) and approached significance in imputed data ( P heterogeneity = 0.1 ) . CONCLUSIONS The presence of CD8 + T cells in breast cancer is associated with a significant reduction in the relative risk of death from disease in both the ER-negative [ supplementary Figure S1 , available at Annals of Oncology online ] and the ER-positive HER2-positive subtypes . Tumour lymphocytic infiltration may improve risk stratification in breast cancer patients classified into these subtypes . NEAT Clinical Trials.gov : NCT00003577 BACKGROUND The impact of drug prescriptions in real life as opposed to strict clinical trial prescription is only rarely assessed , although it is well recognized that incorrect use may harm patients and may have a significant impact on health care re sources . We investigated the use and effectiveness of adjuvant trastuzumab in daily practice compared with the effectiveness in clinical trials . METHODS We included all patients with stage I-III invasive breast cancer , irrespective of human epidermal growth factor receptor 2 ( HER2 ) status , diagnosed in five hospitals in the southeast of The Netherl and s in 2005 - 2007 . We aim ed to assess the actual use of adjuvant trastuzumab in early HER2-positive breast and its efficacy in daily practice . RESULTS Of 2,684 patients included , 476 ( 17.7 % ) had a HER2-positive tumor . Of these , 251 ( 52.7 % ) patients had an indication for trastuzumab treatment of which 196 ( 78.1 % ) patients actually received it . Of the 225 patients without an indication , 34 ( 15.1 % ) received trastuzumab .  Five-year disease-free survival was 80.7 % for ( n = 230 ) patients treated with versus 68.2 % for ( n = 246 ) patients not treated with trastuzumab ( p = .0023 ) , and 5-year overall survival rates were 90.7 % and 77.4 % , respectively ( p = .0002 ) . The hazard ratio for disease recurrence was 0.63 ( 95 % confidence interval , 0.37 - 1.06 ) for trastuzumab when adjusting for potential confounders . CONCLUSION This study shows that in real life , patients treated with trastuzumab in early-stage HER2-positive breast cancer had a 5-year disease-free and overall survival comparable to prior r and omized trials . For informative decision making , real-life data are of additional value , providing insight on outcome of patients considered ineligible for treatment PURPOSE Trastuzumab plus chemotherapy has become the st and ard of care for human epidermal growth factor receptor-2 ( HER-2 ) -positive breast cancer .  Trastuzumab-based preoperative systemic therapy ( PST ; neoadjuvant therapy ) also appears promising , warranting further investigation . PATIENTS AND METHODS Patients with HER-2-positive , stage II/III , noninflammatory , operable breast cancer requiring a mastectomy ( but who wanted to conserve the breast ) received trastuzumab 4 mg/kg ( day 1 ) , followed by 2 mg/kg weekly , plus docetaxel 75 mg/m2 every 3 weeks , and carboplatin ( area under curve , 6 ) for six cycles before surgery . The primary end point was pathologic complete response ( pCR ) rate , determined from surgical specimens . RESULTS Seventy patients were enrolled . Most patients had clinical T2/T3 tumors ( 100 % ) or clinical N1/2 nodes ( 53 % ) . Sixty-seven patients ( 96 % ) completed six cycles of therapy , one patient withdrew due to progressive disease , and two patients withdrew for toxicity . A complete or partial objective clinical response occurred in 95 % of patients ( 85 % and 10 % , respectively ) . Surgery was breast conservative in 45 ( 64 % ) of 70 patients . In an intent-to-treat analysis , tumor and nodal pCR were seen in 27 ( 39 % ) of 70 patients . Central ized retrospective analysis of HER-2 status demonstrated a 43 % pCR rate in the 24 of 56 confirmed HER-2-overexpressing ( 3 + ) and /or fluorescence in situ hybridization-positive tumors . Treatment was generally well tolerated . Grade 3/4 neutropenia and febrile neutropenia were uncommon ( 2 % ) . Two patients withdrew prematurely due to a transient , asymptomatic decrease in left ventricular ejection fraction . No symptomatic cardiac dysfunction occurred . CONCLUSION PST with trastuzumab plus docetaxel and carboplatin achieved promising efficacy , with a good pCR rate and favorable tolerability in stage II or III HER-2-positive breast cancer PURPOSE It has been suggested that PTEN , a negative regulator of PI3K/AKT signaling , is involved in tumor sensitivity to trastuzumab . We investigated the association between tumor PTEN protein expression and disease-free survival ( DFS ) of patients r and omly assigned to receive chemotherapy alone ( arm A ) or chemotherapy with sequential ( arm B ) or concurrent trastuzumab ( arm C ) in the phase III early-stage human epidermal growth factor receptor 2 ( HER2 ) -positive trial-North Central Cancer Treatment Group ( NCCTG ) N9831 . PATIENTS AND METHODS The intensity and percentage of invasive cells with cytoplasmic PTEN staining were determined in tissue microarray sections containing three cores per block ( n = 1,286 ) or in whole tissue sections ( WS ; n = 516 ) by using st and ard immunohistochemistry ( 138G6 monoclonal antibody ) . Tumors were considered positive for PTEN ( PTEN-positive ) if any core or WS had any invasive cells with ≥ 1 + staining . Median follow-up was 6.0 years . RESULTS Of 1,802 patients included in this analysis ( of 3,505 patients registered to N9831 ) , 1,342 ( 74 % ) had PTEN-positive tumors . PTEN positivity was associated with hormone receptor negativity ( χ(2 ) P < .001 ) and nodal positivity ( χ(2 ) P = .04 ) . PTEN did not have an impact on DFS within the various arms . Comparing DFS of arm C to arm A , patients with PTEN-positive and PTEN-negative tumors had hazard ratios ( HRs ) of 0.65 ( P = .003 ) and 0.47 ( P = .005 ) , respectively ( interaction P = .16 ) . For arm B versus arm A , patients with PTEN-positive and PTEN-negative tumors had HRs of 0.70 ( P = .009 ) and 0.85 ( P = .44 ) , respectively ( interaction P = .47 ) . CONCLUSION In contrast to selected pre clinical and limited clinical studies suggesting a decrease in trastuzumab sensitivity in patients with PTEN-negative tumors , our data show benefit of adjuvant trastuzumab for patients with HER2-positive breast cancer , independent of tumor PTEN status BACKGROUND Current information on the prognostic importance of body mass index ( BMI ) for patients with early breast cancer is based on a variety of equivocal reports . Few have data on BMI in relationship to systemic treatment . PATIENTS AND METHODS Patients ( 6792 ) were r and omized to International Breast Cancer Study Group trials from 1978 to 1993 , study ing chemotherapy and endocrine therapy .  BMI was evaluated with eight other factors :  menopausal status , nodal status , estrogen receptor status , progesterone receptor status , tumor size , vessel invasion , tumor grade and treatment .  BMI was categorized as normal ( < or = 24.9 ) , intermediate ( 25.0 - 29.9 ) or obese ( > or = 30.0 ) . RESULTS Patients with normal BMI had significantly longer overall survival ( OS ) and disease-free survival ( DFS ) than patients with intermediate or obese BMI in pairwise comparisons adjusted for other factors . Subset analyses showed the same effect in pre- and perimenopausal patients and in those receiving chemotherapy alone . When assessed globally and adjusted for other factors , BMI significantly influenced OS ( P = 0.03 ) but not DFS ( P = 0.12 ) . CONCLUSIONS BMI is an independent prognostic factor for OS in patients with breast cancer , especially among pre-/perimenopausal patients treated with chemotherapy without endocrine therapy BACKGROUND The 21-gene Oncotype DX Recurrence Score assay is a vali date d assay to help decide the appropriate treatment for estrogen receptor-positive ( ER+ ) , early-stage breast cancer ( EBC ) in the adjuvant setting . The choice of adjuvant treatments might vary considerably in different countries according to various treatment guidelines . This prospect i ve multicenter study is the first to assess the impact of the Oncotype DX assay in the French clinical setting . METHODS A total of 100 patients with ER+ , human epidermal growth factor receptor 2-negative EBC , and node-negative ( pN0 ) disease or micrometastases in up to 3 lymph nodes ( pN1mi ) were enrolled . Treatment recommendations , physicians ' confidence before and after knowing the Recurrence Score value , and physicians ' perception of the assay were recorded . RESULTS Of the 100 patients , 95 were evaluable ( 83 pN0 , 12 pN1mi ) . Treatment recommendations changed in 37 % of patients , predominantly from chemoendocrine to endocrine treatment alone . The proportion of patients recommended chemotherapy  decreased from 52 % pretest to 25 % post-test . Of patients originally recommended chemotherapy , 61 % were recommended endocrine treatment alone after receiving the Recurrence Score result . For both pN0 and pN1mi patients , post-test recommendations appeared to follow the Recurrence Score result for low and high values . Physicians ' confidence improved significantly . CONCLUSION These are the first prospect i ve data on the impact of the Oncotype DX assay on adjuvant treatment decisions in France . Using the assay was associated with a significant change in treatment decisions and an overall reduction in chemotherapy use . These data are consistent with those presented from European and non-European studies The current r and omized , controlled , multicenter clinical trial was conducted to investigate the efficacy of concurrent neoadjuvant chemotherapy ( NCT ) and estrogen deprivation in patients with estrogen receptor (ER)–positive , human epidermal growth factor receptor 2 (HER2)–negative breast cancer PURPOSE The antibody-drug conjugate trastuzumab-DM1 ( T-DM1 ) combines the biologic activity of trastuzumab with targeted delivery of a potent antimicrotubule agent , DM1 , to human epidermal growth factor receptor 2 (HER2)-overexpressing cancer cells . Based on results from a phase I study that showed T-DM1 was well tolerated at the maximum-tolerated dose of 3.6 mg/kg every 3 weeks , with evidence of efficacy , in patients with HER2-positive metastatic breast cancer ( MBC ) who were previously treated with trastuzumab , we conducted a phase II study to further define the safety and efficacy of T-DM1 in this patient population . PATIENTS AND METHODS This report describes a single-arm phase II study ( TDM4258 g ) that assessed efficacy and safety of intravenous T-DM1 ( 3.6 mg/kg every 3 weeks ) in patients with HER2-positive MBC who had tumor progression after prior treatment with HER2-directed therapy and who had received prior chemotherapy . RESULTS With a follow-up of ≥ 12 months among 112 treated patients , the objective response rate by independent assessment was 25.9 % ( 95 % CI , 18.4 % to 34.4 % ) . Median duration of response was not reached as a result of insufficient events ( lower limit of 95 % CI , 6.2 months ) , and median progression-free survival time was 4.6 months ( 95 % CI , 3.9 to 8.6 months ) . The response rates were higher among patients with confirmed HER2-positive tumors ( immunohistochemistry 3 + or fluorescent in situ hybridization positive ) by retrospective central testing ( n = 74 ) . Higher response rates were also observed in patients whose tumors expressed ≥ median HER2 levels by quantitative reverse transcriptase polymerase chain reaction for HER2 expression , compared with patients who had less than median HER2 levels . T-DM1 was well tolerated with no dose-limiting cardiotoxicity . Most adverse events ( AEs ) were grade 1 or 2 ; the most frequent grade ≥ 3 AEs were hypokalemia ( 8.9 % ) , thrombocytopenia ( 8.0 % ) , and fatigue ( 4.5 % ) . CONCLUSION T-DM1 has robust single-agent activity in patients with heavily pretreated , HER2-positive MBC and is well tolerated at the recommended phase II dose Aim : To assess whether immunohistochemically stained tissue microarrays ( TMA ) of 2 mm cores from paraffin embedded tumour tissue may replace whole sections in semi-quantitative evaluation of selected potential markers for endocrine treatment . Methods : Whole sections and 2 mm cores on TMA were used for immunohistochemical staining of potential markers for endocrine treatment . The Allred scoring system was used for the markers with nuclear localisation : the oestrogen receptor , the progesterone receptor , p27 and the oestrogen receptor co-regulator amplified in breast cancer 1 ( AIB1 ) . The Allred scoring system was also used for the non-nuclear markers Bcl-2 , pS2 and cyclooxygenase 2 ( COX-2 ) ; the membrane receptors HER-2 , insulin-like growth factor I receptor ( IGF-IR ) and epidermal growth factor receptor were quantified according to the guidelines for the Herceptest . Results : The data and statistical analyses showed that the semi-quantitative evaluation of oestrogen receptor , progesterone receptor , AIB1 , COX-2 , HER-2 and IGF-IR on TMA blocks was comparable with analysis on whole sections . Conclusions : This study shows that semi-quantitative scoring of 2 mm cores on TMA is feasible for several potential markers for endocrine therapy . Considering the small size of many breast tumours , the speed and cost-effectiveness of immunohistochemistry on TMA compared with whole sections , and the importance of the expression level of the proteins , semi-quantitative scoring on TMA has great potential in both retrospective and prospect i ve studies aim ing at improving the prediction of response to endocrine treatment PURPOSE Vascular endothelial growth factor A ( VEGF-A ) and vascular endothelial growth factor receptor 2 ( VEGFR2 ) are often coexpressed in breast cancer , and potentially affect cellular pathways and key proteins such as the estrogen receptor ( ER ) targeted by endocrine treatment . We therefore explored the association between adjuvant tamoxifen treatment in breast cancer and expression of VEGF-A and VEGFR2 , as well as human epidermal growth factor receptor 2 ( HER2 ) , which represents a c and i date gene product involved in tamoxifen resistance . PATIENTS AND METHODS Immunohistochemical expression of tumor-specific VEGF-A , VEGFR2 , and HER2 was evaluated in tumor specimens from premenopausal breast cancer patients r and omly assigned to 2 years of tamoxifen or no treatment ( n = 564 ) , with 14 years of follow-up .  Hormone receptor status was determined in 96 % of the tumors . RESULTS VEGF-A , VEGFR2 , and HER2 were assessable in 460 , 472 , and 428 of the tumors , respectively . In patients with ER-positive and VEGFR2-low tumors , adjuvant tamoxifen significantly increased recurrence-free survival ( RFS ; [ HR ] hazard ratio for RFS , 0.53 ; P = .001 ) . In contrast , tamoxifen treatment had no effect in patients with VEGFR2-high tumors ( HR for RFS , 2.44 ; P = .2 ) . When multivariate interaction analyses were used , this difference in treatment efficacy relative to VEGFR2 expression status was statistically significant for both ER-positive ( P = .04 ) plus ER-positive and progesterone receptor-positive tumors . We found no significant difference in  tamoxifen treatment effects in relation to VEGF-A or HER2 status . CONCLUSION Tumor-specific expression of VEGFR2 was associated with an impaired  tamoxifen effect in hormone receptor-positive premenopausal breast cancer .  Tamoxifen in combination with VEGFR2 inhibitors might be a novel treatment approach for VEGFR2-expressing breast cancer , and such a treatment might restore the  tamoxifen  response Questions In patients with multiple myeloma , Waldenström macroglobulinemia , or lymphoma , what is the efficacy of bortezomib alone or in combination as measured by survival , quality of life , disease control ( for example , time to progression ) , response duration , or response rate ? What is the toxicity associated with the use of bortezomib ? Which patients are more or less likely to benefit from treatment with bortezomib ? Perspectives Evidence was selected and review ed by two members of the Hematology Disease Site Group and by method ologists from the Program in Evidence -based Care ( pebc ) at Cancer Care Ontario . The practice guideline report was review ed and approved by the Hematology Disease Site Group , which comprises hematologists , medical and radiation oncologists , and a patient representative . As part of an external review process , the report was disseminated to practitioners throughout Ontario to obtain their feedback . Outcomes Outcomes of interest were overall survival , quality of life , response rates and duration , and rates of adverse events . Methodology A systematic search was conducted of the medline , embase , HealthStar , cinahl , and Cochrane Library data bases for primary articles and practice guidelines . The result ing evidence informed the development of clinical practice recommendations . Those recommendations were appraised by a sample of practitioners in Ontario and modified in response to the feedback received . The systematic review and modified recommendations were approved by a review body w theithin pebc . Results The literature review found one r and omized controlled trial ( rct ) —the only published rct of bortezomib in relapsed myeloma . A number of phase ii studies were also retrieved , including a r and omized phase ii study . No r and omized trials were retrieved for lymphoma . The rct found bortezomib to be superior to high-dose dexamethasone for median time to progression and 1-year survival in patients with relapsed myeloma , although grade 3 adverse events were more common in the bortezomib arm . Bortezomib is recommended as the preferred treatment option in patients with myeloma relapsing within 1 year of the conclusion of initial treatment ; it may also be a reasonable option in patients relapsing at least 1 year after autologous stem-cell transplantation . Practice Guideline This evidence -based series applies to adult patients with myeloma , Waldenström macroglobulinemia , or lymphoma of any type , stage , histology , or performance status . Recommendations Based on the results of a large well-conducted rct , which represents the only published r and omized study in relapsed myeloma , the Hematology Disease Site Group ( dsg ) offers the following recommendations : For patients with myeloma refractory to or relapsing within 1 year of the conclusion of initial or subsequent treatment or treatments , including autologous stem-cell transplantation , and who are c and i date s for further chemotherapy , bortezomib is recommended as the preferred treatment option . Bortezomib is also a reasonable option for patients relapsing at least 1 year after autologous stem-cell transplantation . The dsg is aware that thalidomide , alkylating agents , or repeat transplantation may also be options for these patients . However , evaluation of these other options is beyond the scope of this practice guideline . For patients with myeloma relapsing at least 1 year after the conclusion of alkylating agent – based chemotherapy who are c and i date s for further chemotherapy , further treatment with alkylating agent – based chemotherapy is recommended . Evidence is insufficient to support the use of bortezomib in patients with non-Hodgkin lymphoma or Waldenström macroglobulinemia outside of clinical trials . Qualifying Statements Limited evidence supports the appropriateness of a specific time-to-relapse period as being indicative of treatment-insensitive disease . The 1-year threshold provided in the foregoing recommendations is based on the opinion of the Hematology dsg . For specific details related to the administration of bortezomib therapy , the dsg suggests that clinicians refer to the protocol s used in major trials . Some of those details are provided here for informational purpose s. Dosage Bortezomib 1.3,g/m2 is given as a rapid intravenous bolus over 3–5 seconds on days 1 , 4 , 8 , and 11 of a 21-day cycle ; a minimum of 72 hours between doses is required to allow for recovery of normal proteasome function . Vital signs should be checked before and after each dose . A complete blood count is recommended before each dose , with blood chemistries ( including electrolyte and creatinine levels ) monitored at a minimum on days 1 and 8 of each cycle . The dose of bortezomib should be reduced or held immediately upon development of painful neuropathy , as described in the product monograph ; dose modification may also be required for peripheral sensory neuropathy without pain or for other toxicities . Most toxicities are reversible if dose modification guidelines are followed . Response to Treatment Responses are usually apparent by 6 weeks ( 2 cycles ) . For patients achieving complete remission ( determined by negative electrophoresis and immunofixation ) , bortezomib should be given for 2 additional cycles beyond the date of confirmed complete remission . In patients with progressive disease after 2 cycles or stable disease after 4 cycles , dexamethasone added to the bortezomib regimen ( 20 mg by mouth the day of and the day after each bortezomib dose ) may produce an objective response .  Bortezomib ( with or without dexamethasone ) should be continued in patients showing benefit from therapy ( excluding those in complete remission ) unless disease progression or significant toxicity is observed . Therapy should be discontinued in patients who do not respond to bortezomib alone if disease progression is seen within 2 cycles of the addition of dexamethasone . The Hematology dsg recognizes that thalidomide is an active agent in multiple myeloma patients who have relapsed after autologous stem-cell transplantation or who are refractory to alkylating agent – based chemotherapy . To date , no reported rcts have evaluated thalidomide in this role , and specifically , no trials have compared thalidomide with bortezomib . Given these limitations , the members of the Hematology dsg regard thalidomide or bortezomib as therapy alternatives to dexamethasone Abstract Background Patient-reported outcomes are integral in benefit – risk assessment s of new treatment regimens . The PALOMA-2 study provides the largest body of evidence for patient-reported health-related quality of life ( QOL ) for patients with metastatic breast cancer ( MBC ) receiving first-line endocrine-based therapy ( palbociclib plus letrozole and letrozole alone ) . Patients and methods Treatment-naïve postmenopausal women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative ( HER2− ) MBC were r and omized 2 : 1 to palbociclib plus letrozole ( n = 444 ) or placebo plus letrozole ( n = 222 ) . Patient-reported outcomes were assessed at baseline , day 1 of cycles 2 and 3 , and day 1 of every other cycle from cycle 5 using the Functional Assessment of Cancer Therapy (FACT)-Breast and EuroQOL 5 dimensions ( EQ-5D ) question naires . Results As of 26 February 2016 , the median duration of follow-up was 23 months . Baseline scores were comparable between the two treatment arms . No significant between-arm differences were observed in change from baseline in FACT-Breast Total , FACT-General Total , or EQ-5D scores . Significantly greater improvement in pain scores was observed in the palbociclib plus letrozole arm ( −0.256 versus −0.098 ; P = 0.0183 ) . In both arms , deterioration of FACT-Breast Total score was significantly delayed in patients without progression versus those with progression and patients with partial or complete response versus those without . No significant difference was observed in FACT-Breast and EQ-5D index scores in patients with and without neutropenia . Conclusions Overall , women with MBC receiving first-line endocrine therapy have a good QOL . The addition of palbociclib to letrozole maintains health-related QOL and improves pain scores in treatment-naïve postmenopausal patients with ER+/HER2− MBC compared with letrozole alone . Significantly greater delay in deterioration of health-related QOL was observed in patients without progression versus those who progressed and in patients with an objective response versus non-responders . Clinical Trials.gov : NCT01740427 ( https:// clinical trials.gov/ct2/show/NCT01740427 PURPOSE Human epidermal growth factor receptor 2 ( HER2 ) overexpression was found to predict a good response in breast carcinoma patients treated with doxorubicin ( Adriamycin [ ADM ] ) . Evidence from our recent study indicates that node-positive patients respond to cyclophosphamide , methotrexate , and fluorouracil ( CMF ) regardless of HER2 status . We address the issue of whether therapy regimens including CMF and ADM versus CMF alone have the same therapeutic effect in patients with HER2 + and HER2- tumors in terms of relapse-free survival ( RFS ) and overall survival ( OS ) . METHODS Archival specimens of the primary tumors from 506 patients in a prospect i ve clinical trial were stained with the anti-HER2 monoclonal antibody CB11 . Originally , patients were r and omly allocated to receive either 12 courses of intravenous CMF or eight courses of the same regimen followed by four cycles of ADM .  RFS and OS were analyzed by a Cox model taking into account treatment , HER2 status , and the interaction between treatment and HER2 status , adjusting for the effect of other known clinical and biopathologic factors . RESULTS Analysis of survival rates indicates a possible differential effect of treatment in the patients grouped according to HER2 status . Improved RFS and OS were observed in the HER2 + subgroup after treatment with CMF plus ADM versus CMF alone . With a median follow-up of 15 years , the hazard ratio ( HR ) for RFS was 0.83 in HER2 + tumors and 1.22 in HER2- tumors . The effect of treatment was more evident on OS in HER2 + patients ( HR = 0.61 ; CI , 0.32 to 1.16 ) than in HER2- patients ( HR = 1.26 ) . CONCLUSION Our data indicate that adding ADM to CMF might be beneficial for patients with HER2 + tumors Purpose This study aims to provide recommendations on the optimal strategies and interventions for the prevention , screening , assessment , and management of  cancer-related sleep disturbance ( insomnia and insomnia syndrome ) in adult cancer population s. Methods A systematic search of the published health literature was conducted to identify r and omized controlled trials , clinical practice guidelines , systematic review s , and other guidance documents . The Sleep Disturbance Expert Panel [ comprised of nurses , psychologists , primary care physicians , oncologists , physicians specialized in sleep disturbances , research ers , and guideline method ologists ] review ed , discussed , and approved the final version of the guideline . Health care professionals across Canada were asked to provide feedback through an external review process . Results Three clinical practice guidelines and 12 r and omized controlled trials were identified as the evidence base . Overall , despite the paucity of evidence , the evidence and expert consensus suggest that it is important to screen and assess adult cancer patients for sleep disturbances using st and ardized screening tools on a routine basis . While prevention of sleep disturbance is the desired objective , cognitive behavioral therapies are effective in improving sleep outcomes . As part of the external review with 16 health care providers , 81 % indicated that they agreed with the recommendations as written . Conclusions Sleep difficulty is a prevalent problem in cancer population s that needs greater recognition by health professionals . Prevention , screening , assessment , and treatment strategies supported by the best available evidence are critical . Recommendations and care path algorithms for practice are offered Background : Blockade of human epidermal growth factor receptor type 2 ( HER2 ) has dramatically improved outcome for patients with HER2-positive breast cancer .  Trastuzumab , an anti-HER2 monoclonal antibody , has previously demonstrated improvement in overall survival ( OS ) in patients with metastatic and early stage HER2-positive breast cancer . However , trastuzumab can cause congestive heart failure ( CHF ) with an increased frequency for patients who have also received an anthracycline . The current trial was design ed to evaluate the impact of the duration of trastuzumab on CHF . Methods : E2198 included 227 eligible women with histologically confirmed stage II or IIIA HER2-positive breast cancer . The patients were r and omised to receive 12 weeks of paclitaxel and trastuzumab followed by four cycles of doxorubicin and cyclophosphamide ( abbreviated Arm ) or the aforementioned treatment with additional 1 year of trastuzumab ( conventional Arm ) . The primary end point was to evaluate the safety of this variable duration of  trastuzumab therapy , particularly cardiac toxicity defined as CHF or left ventricular ejection fraction decrease > 10 % . Secondary end points included disease-free survival ( DFS ) and OS . Results : Compared with 12-week treatment with trastuzumab , 1 year of trastuzumab-based therapy did not increase the frequency or severity of cardiac toxicity : three patients on the abbreviated Arm and four on the conventional Arm experienced CHF . The 5-year DFS was 76 % and 73 % for the abbreviated and conventional Arms , respectively , with a hazard ratio ( HR ) of 1.3 ( 95 % CI : 0.8–2.1 ; P=0.3 ) . There was also no statistically significance difference in OS ( HR , 1.4 ; P=0.3 ) . Conclusions : Compared with 12 weeks of treatment , 1 year of treatment with trastuzumab did not significantly increase the risk of cardiac toxicity . Although not powered for efficacy comparisons , the longer duration of trastuzumab therapy did not demonstrate a signal for marked superiority PURPOSE Few studies have examined the possible importance of biologic prognostic factors in breast cancer connected with differentiation and growth in predicting response to a specific adjuvant treatment . HER2 , epidermal growth factor receptor ( EGFR ) , and p53 have all been suggested as possible markers of tamoxifen resistance . The aim of this study was to investigate interactions between adjuvant treatment with tamoxifen and the content of EGFR , HER2 , and p53 in steroid receptor-positive patients . PATIENTS AND METHODS A total of 1,716 high-risk postmenopausal breast cancer patients were r and omly assigned to treatment with tamoxifen ( 868 women ) or to observation ( 848 women ) in a prospect i ve trial ( Danish Breast Cancer Cooperative Group 's 77c protocol ) . The content of the steroid receptors and expression of p53 , EGFR , and HER2 were determined by immunohistochemical analysis of paraffin-embedded tissue . The length of follow-up was 10 years . The end point for this analysis was disease-free survival . RESULTS Multivariate analysis demonstrated no increased risk of recurrence after treatment with tamoxifen for HER2- , EGFR- , and p53-positive , high-risk , steroid receptor-positive patients . Patients with steroid receptor-positive tumors and positive immunohistochemical staining for HER2 , EGFR or p53 benefited from treatment with tamoxifen for 1 year , although the latter variable contained independent prognostic information by itself . CONCLUSION With the statistical power of the present r and omized study , we did not find support for the hypothesis that HER2/EGFR or p53 status predicts benefit from tamoxifen treatment in estrogen receptor-positive patients with early-stage breast cancer . Thus , neither HER2 , EGFR , nor p53 overexpression/accumulation should be used as a contraindication for giving tamoxifen PURPOSE An American Society of Clinical Oncology ( ASCO ) provisional clinical opinion ( PCO ) offers timely clinical direction to ASCO 's membership following publication or presentation of potentially practice -changing data from major studies . This PCO addresses the clinical utility of using epidermal growth factor receptor ( EGFR ) mutation testing for patients with advanced non-small-cell lung cancer ( NSCLC ) to predict the benefit of taking a first-line EGFR tyrosine kinase inhibitor ( TKI ) . CLINICAL CONTEXT Patients with EGFR-mutated NSCLC have a significantly higher rate of partial responses to the EGFR TKIs gefitinib and erlotinib . In the United States , approximately 15 % of patients with adenocarcinoma of the lung harbor activating EGFR mutations . EGFR mutation testing is widespread at academic medical centers and in some locales in community practice . As of yet , there is no evidence of an overall survival ( OS ) benefit from selecting treatment based on performing this testing . RECENT DATA One large phase III trial ( the Iressa Pan-Asia Study [ IPASS ] trial ) , three smaller phase III r and omized controlled trials using progression-free survival as the primary end point , and one small phase III trial with OS as the primary end point , all involving first-line EGFR TKIs and chemotherapy doublets , form the basis of this PCO . PROVISIONAL CLINICAL OPINION On the basis of the results of five phase III r and omized controlled trials , patients with NSCLC who are being considered for first-line therapy with an EGFR TKI ( patients who have not previously received chemotherapy or an EGFR TKI ) should have their tumor tested for EGFR mutations to determine whether an EGFR TKI or chemotherapy is the appropriate first-line therapy . NOTE . ASCO 's provisional clinical opinions ( PCOs ) reflect expert consensus based on clinical evidence and literature available at the time they are written and are intended to assist physicians in clinical decision making and identify questions and setting s for further research . Because of the rapid flow of scientific information in oncology , new evidence may have emerged since the time a PCO was su bmi tted for publication . PCOs are not continually up date d and may not reflect the most recent evidence . PCOs can not account for individual variation among patients and can not be considered inclusive of all proper methods of care or exclusive of other treatments . It is the responsibility of the treating physician or other health care provider , relying on independent experience and knowledge of the patient , to determine the best course of treatment for the patient . Accordingly , adherence to any PCO is voluntary , with the ultimate determination regarding its application to be made by the physician in light of each patient 's individual circumstances . ASCO PCOs describe the use of procedures and therapies in clinical practice and can not be assumed to apply to the use of these interventions in the context of clinical trials . ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of ASCO 's PCOs , or for any errors or omissions Objective To identify the risk of systemic metastases from T1a and T1b N0 breast cancers in patients treated in an academic center , and to seek factors to identify the patients at greatest risk of such failure . Summary Background Data With the demonstration that adjuvant chemotherapy reduces the death rate from breast cancer by roughly one quarter across all risk groups , controversy has reigned regarding possible exclusions from therapy . T1a and T1b N0 tumors ( 1-cm diameter and smaller with negative axillary nodes ) have been considered at low risk for metastasis since the report from Memorial Sloan-Kettering Cancer Center of a 90 % survival rate at 10 years . Subsequent reports have suggested an even more favorable prognosis for this group . However , consensus statements advise selecting some of these women for treatment , and many do receive adjuvant chemotherapy . Methods Sequential patients with breast cancer at the Emory Clinic were prospect ively staged and followed up for outcome . The records of patients with T1a and T1b N0 tumors were review ed for exact tumor diameter , grade , receptor status , adjuvant therapy , and outcome . A corrected data set was stripped of patient identifiers and analyzed by Kaplan-Meier methods . Subgroups were formed based on tumor grade ( 1 vs. 3 ) , adjuvant chemotherapy ( use vs. no use ) , and adjuvant tamoxifen ( use vs. no use ) and were compared via log-rank tests . Results Two hundred eighty-two women were identified . Two developed metastatic disease and one experienced a local failure after breast-conserving treatment . The estimated disease-free survival rate at 10 years was 98.7 % . With only two distant failures and one local failure , there was no significant difference by grade , receptor status , or use of adjuvant chemotherapy or tamoxifen . Conclusions The risk of systemic failure from such tumors barely exceeded 1 % at 10 years . Unless future studies can identify a subgroup at higher risk , the cognitive changes associated with cytotoxic chemotherapy or the loss of estrogen involved do not appear to have sufficient off setting benefit to warrant chemotherapy for this group of women OBJECTIVE This trial is conducted to investigate the benefit of trastuzumab monotherapy compared with a combination therapy of trastuzumab and chemotherapy in women over 70 years with human epidermal growth factor receptor type-2-positive primary breast cancer . METHODS Inclusion criteria are the following : histologically diagnosed as invasive breast cancer and received curative operation for primary breast cancer ; Stage I , IIA , IIB or IIIA/M0 ; and baseline left ventricular ejection fraction is ≥55 % . Patients are r and omized to receive either trastuzumab ( 8 mg/kg loading dose , 6 mg/kg every 3 weeks for 1 year ) plus chemotherapy selected from regimens specified on the protocol or trastuzumab monotherapy . The primary endpoint is disease-free survival . Secondary endpoints are overall survival , relapse-free survival , safety , health-related quality of life , comprehensive geriatric assessment and cost effectiveness . RESULTS Patients recruitment has been commenced in October 2009 . Enrollment of 300 patients is planned during the 4-year recruitment period . CONCLUSIONS We hereby report the study concept Palliative care at the end of life involves meeting the physical , psychological , social , and practical needs of patients and caregivers . End of life is defined as a phase of life when a person is living with an illness that will worsen and eventually cause death . It is not limited to the short period of time when the person is moribund ( 1 ) . Good clinical care can prevent or alleviate suffering for many patients at the end of life by assessing symptoms and providing psychological and social support to the patients and their families . The purpose of this guideline is to present the available evidence to improve palliative care at the end of life . This guideline does not address any other setting s of palliative care at the end of life . The target audience for this guideline is all clinicians caring for patients needing end-of-life care . The target patient population is everyone with seriously disabling or symptomatic chronic conditions at the end of life . These recommendations are based on the systematic evidence review in the background paper in this issue by Lorenz and colleagues ( 1 ) , which is based on an Agency for Healthcare Research and Quality ( AHRQ ) evidence report ( 2 ) . End-of-life care has been identified by the Institute of Medicine as one of the priority areas to improve quality of health care ( 3 ) . The Institute of Medicine report identified specific gaps related to end-of-life care , such as pain control in advanced cancer and care for patients with advanced organ failure . High- quality evidence on end-of-life care is limited , and most of the evidence is derived from the literature that focused on patients with cancer ; therefore , this guideline does not address many important aspects of end-of-life care . For example , nutritional support , complementary and alternative therapies , and spiritual care were not part of the review . If an end-of-life intervention is not addressed in this guideline , it does not mean that no benefit is related to that particular intervention , but it indicates that the intervention has not been sufficiently studied to demonstrate efficacy . Some important topics in end-of-life care , such as interpersonal and social interventions , may be especially difficult to study . The American College of Physicians ' End-of-Life Care Consensus Panel has a series of papers related to ethical issues around end-of-life care that can be accessed from its Web site ( www.acponline.org/ethics/papers.htm ) . Methods The literature search for this guideline included studies from MEDLINE and review s of cancer , congestive heart failure , and dementia from the Data base of Abstract of Review s of Effects from January 1990 to November 2005 . Citations from the non systematic literature were taken from the review by the National Consensus Project for Quality Palliative Care ( 4 ) . The review included only English- language publications from the United States , Canada , Western Europe , Australia , and New Zeal and . Details about the methods used for the systematic evidence review may be found in detail in the background paper in this issue ( 1 ) . The objective for this guideline was to answer the following questions : 1 . What are the critical elements for clinicians to address when caring for persons coming to the end of life ? 2 . What do definitions of the end of life suggest about identifying patients who could benefit from palliative approaches  ? 3 . What treatment strategies work well for pain , dyspnea , and depression ? 4 . What elements are important in advance care planning for patients coming to the end of life ? 5 . What elements of collaboration and consultation are effective in promoting improved end-of-life care ? 6 . What elements of assessment and support are effective for serving caregivers , including family , when patients are coming to the end of life ? This guideline grade s the evidence and recommendations using the American College of Physicians ' clinical practice guidelines grading system , adopted from the classification developed by the Grading of Recommendations , Assessment , Development , and Evaluation ( GRADE ) workgroup ( Table ) . Table . The American College of Physicians ' Guideline Grading System * Critical Elements for End-of-Life Care There is a wide range of critical elements for patients nearing the end of life , as well as for their caregivers . Preventing and treating pain and other symptoms ; supporting families and caregivers ; ensuring the continuity of care ; ensuring respect for persons and informed decision making ; attending to well-being , including existential and spiritual concerns ; and supporting function and survival duration are general issues that are common for most end-of-life care patients ( 411 ) . Identifying Patients Who Could Benefit from  Palliative Approaches The literature review did not identify any evidence -based tools that have been vali date d and shown to predict the optimal timing to initiate palliative care services . Decisions to initiate palliative care at the end of life should be individualized on the basis of patient symptoms and preferences . Treatment Strategies Pain Strong evidence from trials of patients with cancer supports the use of nonsteroidal anti-inflammatory drugs , opioids , bisphosphonates , and radiotherapy or radiopharmaceuticals for pain ( 12 ) . Bisphosphonates are specifically effective for bone pain . However , head-to-head comparisons of specific drugs or reports on delivery strategies are difficult to do because of method ological issues and heterogeneity ( 12 ) . Evidence was insufficient to assess the usefulness of exercise or acupuncture in pain management ( 13 , 14 ) . A meta- analysis that included 43 studies showed that palliative care teams are modestly beneficial in providing care for pain management compared with usual care teams ( effect size , 0.13 SD [ 95 % CI , 0.11 to 0.63 SD ] ) ( 15 ) . Other studies that evaluated quality of life showed no difference ( 16 ) and no effect of palliative care consultation ( in contrast to palliative care teams ) on pain scores ( 17 ) . Dyspnea Evidence from 13 studies shows a valuable effect of morphine for dyspnea in advanced lung disease ( st and ardized mean difference , 0.31 [ CI , 0.50 to 0.13 ] ) ( 18 ) . This is also supported by other studies that show the benefits of morphine for treating dyspnea in advanced lung disease and terminal cancer ( 19 , 20 ) . However , using nebulized opioids compared with oral opioids showed no additional benefit . Also , 1 study showed that dihydrocodeine result ed in a statistically but not clinical ly significant increase in Pco 2 during treatment ( 18 ) . Good- quality evidence shows that long-acting -agonists are beneficial in the treatment of dyspnea in chronic obstructive pulmonary disease ( 21 ) . Twelve studies evaluated various interventions for reducing dyspnea in patients with chronic obstructive pulmonary disease , heart failure , cancer , or all conditions . Evidence was mixed when comparing oxygen therapy with room air . One study showed better oxygen saturation , respiratory effort and rate , and dyspnea with oxygen ( 19 ) . However , Bruera and colleagues ( 20 ) showed no difference in dyspnea and fatigue between oxygen and air after a 6-minute walk test . Studies that evaluated service delivery showed no effect of facilitated patientprovider communication or palliative care consultation for dyspnea treatment ( 16 , 17 , 22 , 23 ) . Depression Good evidence supports the effectiveness of long-term use of tricyclic antidepressants or selective serotonin reuptake inhibitors , as well as psychosocial interventions ( education , cognitive and noncognitive behavioral therapy , informational interventions , and individual and group support ) for treating patients with cancer who have depression ( 12 ) . Gysels and Higginson ( 24 ) identified 15 intervention studies that showed that behavioral interventions were effective in the treatment of depression , whereas 1 complementary medicine intervention was ineffective for depression ( 24 ) . Evidence for using guided imagery and exercise showed mixed results ( 13 , 25 ) . Palliative care for out patients did not have any effect on depression and anxiety , and care coordination showed no effect on  depression  in patients with cancer near the end of life ( 22 , 23 , 26 , 27 ) . Important Elements for Advance Care Planning Research shows that individuals are more likely to use advance directives in the presence of extensive multicomponent interventions than with limited interventions ( 28 , 29 ) . One study showed that hospice use increased when goal -oriented interviews and decisions between palliative care facilitators and patients were communicated to nursing home physicians ( 30 ) . In addition , another study showed an increase in documented treatment limitations and preference-concordant care for patients served by social workers trained in care planning ( 31 ) . Also , proactive communication from skilled discussants , such as an ethics team , can help reduce utilization of unnecessary services without harming patients or family members ( 32 , 33 ) . In summary , various processes , such as consulting caregivers , enhancing clear communication , eliciting values , and addressing the emotional context , are important elements for comprehensive advance care planning . Clinicians should help patients and families plan in advance for likely or important clinical decisions . Collaboration and Consultation to Improve End-of-Life Care Studies have shown that the following factors improve utilization outcomes and patient-centered outcomes : multidisciplinary teams involving nurses and social services , continuity of care and service coordination , and facilitated communication . A meta- analysis of 29 r and omized , controlled trials done by McAlister and colleagues ( 34 ) showed that follow-up by a multidisciplinary team result ed in decreased hospitalizations due to heart failure . In addition , a multidisciplinary approach also improved patients ' quality of life and functional status ( 34 , 35 ) . Another intervention study showed that coordination between primary physician and Introduction Immunohistochemistry of primary breast cancer is routinely used to guide changes in therapy at the time of relapse . Retrospective review s suggest that the estrogen receptor ( ER ) , progesterone receptor ( PR ) and human epidermal growth factor receptor type 2 ( HER2 ) receptor may differ between the primary and loco-regional recurrence or distant metastases . The Breast Recurrence In Tissues Study ( BRITS ) was a large , multicentre , prospect i ve study to examine changes in ER , PR and HER2 . Methods Matched primary and recurrent breast cancer tissue sample s were prospect ively collected from 205 women attending 20 institutions . Central laboratory immunohistochemical analysis of core biopsies and tissue microarrays of ER and PR using the Allred and Quickscore methods and HER2 ( confirmed by fluorescence in situ hybridisation ( FISH ) for HER2 2 + ) were performed . Results From 205 consenting women , 18 ( 8.8 % ) did not have recurrent disease on biopsy , 35 were ineligible , 13 had insufficient paired tissue and 2 were excluded for safety reasons . Paired sample s from 137 women , mean age 62.6 years ( range 27 - 87 years ) , 83/137 ( 60.6 % ) postmenopausal with a median 92.2 months ( range 5 - 327 months ) from primary to recurrence and 88 ( 64.2 % ) as locoregional recurrence were successfully analysed . A switch in receptor status , in either direction , by Allred score , was identified for ER in 14 patients ( 10.2 % ; P = 0.983 Wilcoxon sign rank test ) , PR in 34 ( 24.8 % ; P = 0.003 Wilcoxon sign rank test ) and HER2 in 4 ( 2.9 % ; P = 0.074 Wilcoxon sign rank test ) . There was no difference between locoregional or distant recurrence in the proportion who switched . The switch in receptor status led to a change in the subsequent treatment plan for 24 patients ( 17.5 % ) . Conclusions This prospect i ve study confirms retrospective evidence that the management of relapsed breast cancer should include confirmatory tissue sampling and identify switches of ER , PR or HER2 which change therapeutic management for one in six patients PURPOSE To develop a guideline for the use of sentinel node biopsy ( SNB ) in early stage breast cancer . METHODS An American Society of Clinical Oncology ( ASCO ) Expert Panel conducted a systematic review of the literature available through February 2004 on the use of SNB in early-stage breast cancer . The panel developed a guideline for clinicians and patients regarding the appropriate use of a sentinel lymph node identification and sampling procedure from hereon referred to as SNB . The guideline was review ed by selected experts in the field and the ASCO Health Services Committee and was approved by the ASCO Board of Directors . RESULTS The literature review identified one published prospect i ve r and omized controlled trial in which SNB was compared with axillary lymph node dissection ( ALND ) , four limited meta-analyses , and 69 published single-institution and multicenter trials in which the test performance of SNB was evaluated with respect to the results of ALND ( completion axillary dissection ) . There are currently no data on the effect of SLN biopsy on long-term survival of patients with breast cancer . However , a review of the available evidence demonstrates that , when performed by experienced clinicians , SNB appears to be a safe and acceptably accurate method for identifying early-stage breast cancer without involvement of the axillary lymph nodes . CONCLUSION SNB is an appropriate initial alternative to routine staging ALND for patients with early-stage breast cancer with clinical ly negative axillary nodes . Completion ALND remains st and ard treatment for patients with axillary metastases identified on SNB . Appropriately identified patients with negative results of SNB , when done under the direction of an experienced surgeon , need not have completion ALND . Isolated cancer cells detected by pathologic examination of the SLN with use of specialized techniques are currently of unknown clinical significance . Although such specialized techniques are often used , they are not a required part of SLN evaluation for breast cancer at this time . Data suggest that SNB is associated with less morbidity than ALND , but the comparative effects of these two approaches on tumor recurrence or patient survival are unknown Purpose We explored the clinical utility of human epidermal growth factor receptor-2 extracellular domain ( HER2/ECD ) in patients treated for an invasive breast cancer with HER2 overexpression . Methods We prospect ively studied HER2/ECD levels in the sera of 334 women included between 2007 and 2014 , all treated with trastuzumab . HER2/ECD levels were measured at diagnosis , during treatments , and along the follow-up . We investigated the relationship of HER2/ECD with other clinicopathological parameters at diagnosis , its prognosis value , and its utility during the monitoring of a neoadjuvant treatment and the follow-up . Results Elevated HER2/ECD at diagnosis correlated positively with parameters associated with tumor aggressiveness . Disease-free survival of non-metastatic patients was significantly shorter in patients with high HER2/ECD at diagnosis ( HR = 13.6 , 95 % CI 1.6–113.6 , P < 0.0001 ) . Progression-free survival of metastatic patients was better for patients with low HER2/ECD ( HR = 2.6 , 95 % CI 1.2–5.3 , P = 0.033 ) . A multivariate analysis revealed that HER2/ECD level at diagnosis was an independent prognosis factor . During neoadjuvant therapy , a significant decrease in HER2/ECD was reported only for the complete histological response group ( P = 0.031 ) . During the follow-up , HER2/ECD helped predict relapse , disease progression , and metastases before imaging in 18.6 % cases of the studied cohort . Conclusions HER2/ECD is a prognosis factor that is valuable in evaluating the neoadjuvant treatment efficiency . HER2/ECD also appears to be a helpful surveillance biomarker for the early diagnosis of relapses and to predict the fate of metastases . This study brings evidence s to support the use of HER2/ECD in the management of HER2-positive breast cancer PURPOSE The combination of pertuzumab and trastuzumab result ed in a clinical benefit rate ( CBR ) of 50 % in patients with human epidermal growth factor receptor 2 ( HER2 ) -positive breast cancer whose disease progressed during prior trastuzumab-based therapy . To define whether this previously observed encouraging activity was a result of the combination of pertuzumab and trastuzumab or of pertuzumab alone , we recruited a third cohort of patients who received pertuzumab without trastuzumab .  We then investigated the impact of reintroducing trastuzumab to patients whose disease progressed on pertuzumab monotherapy .  PATIENTS AND METHODS Twenty-nine patients with HER2-positive breast cancer whose disease progressed during prior trastuzumab-based therapy received pertuzumab ( 840 mg loading dose , then 420 mg every 3 weeks ) until progressive disease or unacceptable toxicity . Seventeen patients with disease progression continued to receive pertuzumab ( at the same dose ) , with the addition of trastuzumab ( 4 mg/kg loading dose and then 2 mg/kg weekly or 8 mg/kg loading dose and then 6 mg/kg every 3 weeks ) . RESULTS All 29 patients enrolled for pertuzumab monotherapy experienced disease progression . The objective response rate ( ORR ) and CBR were 3.4 % and 10.3 % , respectively , during pertuzumab monotherapy . With the addition of trastuzumab , the ORR and CBR were 17.6 % and 41.2 % , respectively . Progression-free survival was longer with combination therapy than pertuzumab monotherapy ( 17.4 v 7.1 weeks , respectively ) . Treatment was well tolerated with minimal cardiac dysfunction . CONCLUSION Although pertuzumab has some activity in patients with HER2-positive breast cancer that progressed during therapy with trastuzumab , the combination of pertuzumab and trastuzumab seems to be more active than monotherapy Introduction Worldwide , many patients with HER2 + ( human epidermal growth factor receptor 2-positive ) early breast cancer ( BC ) do not receive adjuvant trastuzumab . Hazards of recurrence of these patients with respect to hormone receptor status of the primary tumor have not been described . Methods Using data from 1,260 patients r and omized to placebo in the adjuvant TEACH trial , we report 10-year annual hazards of recurrence in HER2 + patients not treated with anti-HER2 therapy . Results Disease-free survival ( DFS ) was 75 % after 5 and 61 % after 10 years , respectively . Patients with HER2 + hormone receptor-positive ( HR+ ( hormone receptor-positive ) ; ER+ ( estrogen receptor-positive ) or PR+ ( progesterone receptor-positive ) ) disease had a significantly better DFS than patients with HER2 + HR- ( ER-/PR- ) disease ( hazard ratio 0.72 , P = 0.02 ) . This difference was explainable by a significantly higher hazard of recurrence in years 1 to 5 in HER2 + HR- compared to HER2 + HR+ patients , with a mean risk of recurrence of 9%/year for HR- versus 5%/year in HR+ patients ( hazard ratio 0.59 , P = 0.002 for years 1 to 5 ) . The high early risk of recurrence of HER2 + HR- patients declined sharply over time , so that it was similar to that seen in HER2 + HR+ patients in years 6 to 10 ( hazard ratio 0.97 , P = 0.92 for years 6 to 10 ) . Conclusions Our results show that outcomes in HER2 + patients with early BC not receiving anti-HER2 therapy strongly depend on HR expression . The very high early risk of relapse seen in HER2 + HR- patients is particularly relevant in health care setting s with limited access to adjuvant anti-HER2 treatment . The event rates shown for sub population s of HER2 + BC patients suggest that in re source -constrained environments patients with HER2 + HR- early BC should be prioritized for consideration of adjuvant anti-HER2 therapy Purpose : To assess pathologic complete response ( pCR ) , clinical response , feasibility , safety , and potential predictors of response to preoperative trastuzumab plus vinorelbine in patients with operable , human epidermal growth factor receptor 2 (HER2)–positive breast cancer . Experimental Design : Forty-eight patients received preoperative trastuzumab and vinorelbine weekly for 12 weeks . Single and multigene biomarker studies were done in an attempt to identify predictors of response . Results : Eight of 40 ( 20 % ) patients achieved pCR ( 95 % confidence interval , 9 - 36 % ) . Of 9 additional patients recruited for protocol -defined toxicity analysis , 8 were evaluable ; 42 of 48 ( 88 % ) patients had clinical response ( 16 patients , clinical complete response ; 26 patients , clinical partial response ) . T1 tumors more frequently exhibited clinical complete response ( P = 0.05 ) and showed a trend to exhibit pCR ( P = 0.07 ) . Five ( 13 % ) patients experienced grade 1 cardiac dysfunction during preoperative treatment . Neither HER2 nor estrogen receptor status changed significantly after exposure to trastuzumab and vinorelbine . RNA profiling identified three top-level clusters by unsupervised analysis . Tumors with extremes of response [ pCR ( n = 3 ) versus nonresponse ( n = 3 ) ] fell into separate groups by hierarchical clustering . No predictive genes were identified in pCR tumors . Nonresponding tumors were more likely to be T4 stage ( P = 0.02 ) and express basal markers ( P < 0.00001 ) , growth factors , and growth factor receptors . Insulin-like growth factor-I receptor membrane expression was associated with a lower response rate ( 50 % versus 97 % ; P = 0.001 ) . Conclusions : Preoperative trastuzumab plus vinorelbine is active and well tolerated in patients with HER2-positive , operable , stage II/III breast cancer . HER2-overexpressing tumors with a basal-like phenotype , or with expression of insulin-like growth factor-I receptor and other proteins involved in growth factor pathways , are more likely to be resistant to this regimen Ductal carcinoma in situ ( DCIS ) is a condition in which abnormal cells line the milk ducts of the breast but have not invaded the underlying breast tissue . Approximately 55000 new cases of DCIS were expected to occur among U.S. women in 2013 , which accounted for approximately 24 % of all new breast cancer diagnoses ( 1 ) . Although the annual incidence of DCIS is less than that of invasive breast cancer , exp and ed use of screening mammography has led to a dramatic increase in the diagnosis of DCIS ( 32.5 cases per 100000 women ) ( 2 ) . There is considerable uncertainty about the optimal clinical management of DCIS because of the lack of reliable methods for distinguishing DCIS that would never become symptomatic from DCIS that is likely to progress to life-threatening invasive cancer ( 3 ) . Current treatment options for DCIS include mastectomy , breast-conserving surgery ( BCS ) , and BCS plus radiation therapy ( 2 , 46 ) . There are limited r and omized , controlled trials ( RCTs ) on which to base decisions about the tradeoffs among DCIS treatment options , and the existing trials may not capture all relevant patient-centered outcomes . For example , 4 large RCTs comparing BCS alone with BCS plus radiation therapy all show similar , very high overall survival regardless of treatment ( 710 ) . The addition of radiation therapy significantly reduces the risk for local recurrence ; approximately one half of all recurrences are DCIS rather than invasive cancer ( 5 , 11 ) . The long-term benefit of preventing the recurrence of an asymptomatic condition that may or may not progress to cancer is difficult to quantify . In other conditions where screening may detect early cancer or cancer precursors that may not progress to a life-threatening stage , such as early-stage prostate cancer , active surveillance or watchful waiting ( an observation strategy ) is an acceptable option for some patients . A similar strategy may be acceptable for some women diagnosed with DCIS , although no studies have compared management strategies that involve no immediate treatment ( that is , observation or active surveillance ) versus immediate treatments . The most important potential benefit of treatment of DCIS is the reduction in the number of deaths due to invasive breast cancer . For many women with a DCIS diagnosis , this may be an unrealized benefit . Some proportion of DCIS may never progress to life-threatening invasive cancer , so these women only have the adverse outcomes of diagnosis and treatments . Both active management strategies and surveillance approaches present tradeoffs relevant to patient-centered outcomes , such as symptoms , function , and well-being . Given the clinical importance of DCIS , the diversity of available treatment strategies , variety of patient-centered outcomes of interest , and areas of uncertainty , we sought to create a prioritized research agenda for the Patient-Centered Outcomes Research Institute ( PCORI ) that would incorporate different stakeholders ' perspectives . A central goal of PCORI is to engage stakeholders in its work in a meaningful way . Between September 2012 and January 2013 , PCORI undertook a broad effort tosolicit research topics to consider for targeted funding from patients , caregivers , research ers , and results of previous prioritization processes by groups , such as the Institute of Medicine . In April 2013 , PCORI 's Assessment of Prevention , Diagnosis , and Treatment Options program , together with the program 's external advisory panel , have identified DCIS management as an important topic with unmet research needs . Then , PCORI tasked the Duke University Evidence Synthesis Group ( ESG ) to work with various stakeholders to identify and prioritize the future research that is most needed by patients and other decision makers on this topic . Methods Overview of Prioritization Approach Our approach to prioritizing future research and developing recommendations for targeted future funding by PCORI included several steps ( Figure 1 ) . These included appraisal s of recent systematic review s to preliminarily identify important evidence gaps , transformation of evidence gaps into research questions and organization of the questions within a comprehensive analytic framework , engagement of stakeholders to identify additional gaps and prioritize research needs or questions , scans of recently published and ongoing studies relevant to the stakeholders ' list of prioritized research needs , and identification of potential study design s to address prioritized research questions . Figure 1 . Overview of prioritization process Adapted from reference 12 . ESG = Evidence Synthesis Group ; PCORI = Patient-Centered Outcomes Research Institute . Identification of Evidence Gaps We used an iterative process to identify evidence gaps for DCIS management . First , we identified and appraised recent published systematic review s , clinical practice guidelines , and future research needs documents to develop an initial list of evidence gaps . This list was neither exhaustive nor prioritized . Next , we organized these gaps according to the population s , interventions , comparators , outcomes , timing , and setting of interest and transformed them into research questions informed by the criteria . Selection and Engagement of Stakeholders We convened a group of 9 stakeholders , including clinical experts and research ers in DCIS management strategies , representatives from federal and nongovernmental funding agencies , representatives from relevant professional societies , health care decision makers and policymakers , and representatives from related consumer and patient advocacy groups ( Table 1 of the Supplement ) . Within each of these categories , we sought to identify a person who was either familiar with the clinical area and its current uncertainties or brought a specific method ological expertise to the stakeholder panel . The University of Minnesota Evidence -based Practice Center , which did a comparative effectiveness review on DCIS management in 2009 ( 13 ) , and PCORI 's patient engagement group provided input on potential stakeholders . Each potential stakeholder completed a disclosure statement and was screened for conflicts of interest . We solicited and received stakeholder input at various points in the process through group discussion s via teleconferences detailing the process and outlining existing evidence gaps , Web-based surveys to obtain priority ranking of topics , and e-mail communications to solicit or provide further clarification of research gaps from teleconferences . Supplement . Supplementary Data for Prioritization of Research Addressing the Management of DCIS Development of an Analytic Framework On the basis of the exp and ed list of 30 evidence gaps and informed by an analytic framework in a recent evidence synthesis on DCIS ( 13 ) , we constructed an analytic framework that depicted the identified knowledge gaps within the context of the population s , interventions , comparators , outcomes , timing , and setting criteria ( Figure 2 ) . This framework shows that women diagnosed with DCIS may have pretreatment evaluations . After these evaluations , women may undergo several management strategies . These management strategies affect patient-centered outcomes ( such as development of comorbid conditions , DCIS recurrence , invasive cancer , and sexual functioning ) . Throughout the analytic framework , population factors ( such as socioeconomic , family history , and genetic factors ) and effects of decisional uncertainty about management strategies were highlighted as potential modifiers . Figure 2 . Analytic framework . DCIS = ductal carcinoma in situ ; FRN = future research need ; MRI = magnetic resonance imaging . Prioritization of Future Research After expansion of the identified research priorities , stakeholders were invited to rank the revised future research needs online . The survey used a forced-ranking prioritization method described by the Agency for Healthcare Research and Quality Evidence -based Practice Center 's Future Research Needs projects ( 14 ) , whereby participants were given 10 votes that could be allocated to any identified research priorities , with a maximum of 3 votes per item . The stakeholders were not given specific prioritization criteria to use but rather were told to decide , on the basis of their perspectives , which were the most important unanswered research questions in DCIS management . Only the priorities in the top tier ( n= 10 ) moved on to the final stage of horizon scan and study design determination . Stakeholders were informed of the final ranking of future research priorities . Horizon Scan of Studies Potentially Relevant to Top-Tier Research Questions We performed 2 data base search es to identify recently published and ongoing studies relevant to the top-tier future research questions result ing from the stakeholder forced-ranking prioritization exercise . We search ed PubMed to identify relevant literature published since 2008 and Clinical Trials.gov for ongoing studies . Members of the ESG team review ed the titles and abstract s identified by search ing PubMed for applicability to the top-tier research questions ; full texts were then obtained and screened for all citations passing the title- and - abstract screening . At both the title- and - abstract and full-text screening stages , articles were included if they met all of the following criteria : presented original data or secondary analysis of data from an RCT , prospect i ve or retrospective observational study , or relevant modeling study ; included data for a pretreatment evaluation or management strategy of interest ; included women with DCIS ; and had a stated objective that could be categorized according to our identified list of research priorities . We search ed Clinical Trials.gov using the keywords ductal carcinoma in situ and DCIS . A member of the ESG team review ed all study abstract s result ing from the search and coded them as potentially relevant to 1 or more of the identified research priorities . We then abstract ed study type ( such as BACKGROUND It is unknown how a very high tumor total HER2 ( human epidermal growth factor receptor-2 ) content ( H2 T ) influences outcome in early breast cancer treated with adjuvant trastuzumab plus chemotherapy .  PATIENTS AND METHODS H2 T was measured using a novel quantitative assay ( HERmark ( ® ) ) from formalin-fixed tumor tissue of 899 women who participated in the FinHer trial ( IS RCT N76560285 ) . In a chromogenic in situ hybridization ( CISH ) test , 197 ( 21.9 % ) patients had HER2-positive cancer and were r and omly assigned to receive trastuzumab or control .  RESULTS Cancer H2 T levels varied 1808-fold . High H2 T levels were correlated with a positive HER2 status by CISH ( P < 0.0001 ) . A nonlinear association was present between H2 T and the hazard of distant recurrence in a sub population treatment effect pattern plot analysis in CISH-positive disease . Patients with very high H2 T ( defined by ≥22-fold the median of HER2-negative cancers ; 13 % of CISH-positive cancers ) did not benefit from adjuvant trastuzumab [ hazard ratio ( HR ) 1.23 ; 95 % confidence interval ( CI ) 0.33 - 4.62 ; P = 0.75 ] , whereas the rest of the patients with HER2-positive disease by CISH ( 87 % ) did benefit ( HR 0.52 ; 95 % CI 0.28 - 1.00 ; P = 0.050 ) . CONCLUSION Patients with HER2-positive breast cancer with very high tumor HER2 content may benefit less from adjuvant trastuzumab compared with those whose cancer has more moderate HER2 content BACKGROUND Neoadjuvant chemotherapy is widely used to downstage breast cancers before surgery and is an accepted st and ard of care among patients with early-stage breast cancer in whom adjuvant chemotherapy would be recommended .  Pathologic complete response ( pCR ) rate is a robust predictor of outcome for certain breast cancer subtypes , including Her2-overexpressing breast cancer . The incorporation of Her2-targeted therapies has significantly increased the pCR rate in the neoadjuvant setting . Although regimens composed of trastuzumab , nab-paclitaxel , and vinorelbine have demonstrated clinical efficacy in patients with metastatic breast cancer , few studies have examined this combination in early-stage Her2 + breast cancer . We hypothesized that the combination of neoadjuvant nab-paclitaxel followed by vinorelbine could represent a nonanthracycline-based treatment option for early-stage Her2-overexpressing breast cancer . PATIENTS AND METHODS Patients received 4 cycles of nab-paclitaxel 260 mg/m(2 ) intravenously ( IV ) every 14 days for 4 cycles followed by vinorelbine 25 mg/m(2 ) IV weekly for 12 weeks with concurrent trastuzumab ( 4 mg/kg loading dose , and then 2 mg/kg/wk ) . The primary endpoint was the rate of pCR . Secondary endpoints included clinical response , toxicity , and survival rates . RESULTS A total of 27 patients were accrued to the trial . The  median tumor size was 4.0 cm , and more than 50 % of patients had axillary lymph node involvement . The pCR rate was 48.1 % . Among the 40 % of patients who had hormone receptor-positive disease , the pCR rate was 18.2 % , compared with 68.8 % among patients with estrogen receptor/progesterone receptor-negative tumors . CONCLUSIONS The combination of trastuzumab with nab-paclitaxel followed by vinorelbine was well tolerated and had promising activity in the neoadjuvant setting OBJECTIVE The 70-gene signature test ( MammaPrint ) has been shown to improve prediction of clinical outcome in women with early-stage breast cancer . We sought to provide prospect i ve evidence of the clinical utility of the addition of the 70-gene signature to st and ard clinical -pathological criteria in selecting patients for adjuvant chemotherapy . METHODS In this r and omized , phase 3 study , we enrolled 6693 women with early-stage breast cancer and determined their genomic risk ( using the 70-gene  signature ) and their clinical risk ( using a modified version of Adjuvant ! Online ) . Women at low clinical and genomic risk did not receive chemotherapy , whereas those at high clinical and genomic risk did receive such therapy . In patients with discordant risk results , either the genomic risk or the clinical risk was used to determine the use of chemotherapy . The primary goal was to assess whether , among patients with high-risk clinical features and a low-risk gene-expression profile who did not receive chemotherapy , the lower boundary of the 95 % confidence interval for the rate of 5-year survival without distant metastasis would be 92 % ( i.e. , the noninferiority boundary ) or higher . RESULTS A total of 1550 patients ( 23.2 % ) were deemed to be at high clinical risk and low genomic risk . At 5 years , the rate of survival without distant metastasis in this group was 94.7 % ( 95 % confidence interval , 92.5 to 96.2 ) among those not receiving chemotherapy . The absolute difference in this survival rate between these patients and those who received chemotherapy was 1.5 percentage points , with the rate being lower without chemotherapy . Similar rates of survival without distant metastasis were reported in the subgroup of patients who had estrogen-receptor-positive , human epidermal growth factor receptor 2-negative , and either node-negative or node-positive disease . CONCLUSIONS Among women with early-stage breast cancer who were at high clinical risk and low genomic risk for recurrence , the receipt of no chemotherapy on the basis of the 70-gene signature led to a 5-year rate of survival without distant metastasis that was 1.5 percentage points lower than the rate with chemotherapy . Given these findings , approximately 46 % of women with breast cancer who are at high clinical risk might not require chemotherapy BACKGROUND Lapatinib ( L ) plus trastuzumab ( T ) improves outcomes for metastatic human epidermal growth factor 2-positive breast cancer and increases the pathologic complete response in the neoadjuvant setting , but their role as adjuvant therapy remains uncertain . METHODS In the Adjuvant Lapatinib and /or Trastuzumab Treatment Optimization trial , patients with central ly confirmed human epidermal growth factor 2-positive early breast cancer were r and omly assigned to 1 year of adjuvant therapy with T , L , their sequence ( T→L ) , or their combination ( L+T ) . The primary end point was disease-free survival ( DFS ) , with 850 events required for 80 % power to detect a hazard ratio ( HR ) of 0.8 for L+T versus T. RESULTS Between June 2007 and July 2011 , 8,381 patients were enrolled . In 2011 , due to futility to demonstrate noninferiority of L versus T , the L arm was closed , and patients free of disease were offered adjuvant T. A protocol modification required P ≤ .025 for the two remaining pairwise comparisons . At a protocol -specified analysis with a median follow-up of 4.5 years , a 16 % reduction in the DFS hazard rate was observed with L+T compared with T ( 555 DFS events ; HR , 0.84 ; 97.5 % CI , 0.70 to 1.02 ; P = .048 ) , and a 4 % reduction was observed with T→L compared with T ( HR , 0.96 ; 97.5 % CI , 0.80 to 1.15 ; P = .61 ) . L-treated patients experienced more diarrhea , cutaneous rash , and hepatic toxicity compared with T-treated patients . The incidence of cardiac toxicity was low in all treatment arms . CONCLUSION Adjuvant treatment that includes L did not significantly improve DFS compared with T alone and added toxicity . One year of adjuvant T remains st and ard of care Abstract The SOFT and TEXT r and omized phase III trials investigated adjuvant endocrine therapies for premenopausal women with hormone receptor-positive ( HR+ ) early breast cancer . We investigated the prognostic and predictive value of central ly assessed levels of estrogen receptor ( ER ) , progesterone receptor ( PgR ) , and Ki-67 expression in women with HER2-negative disease . Of 5707 women enrolled , 4115 with HER2-negative ( HR+/HER2− ) disease had ER , PgR , and Ki-67 central ly assessed by immunohistochemistry .  Breast cancer-free interval ( BCFI ) was defined from r and omization to first invasive local , regional , or distant recurrence or contralateral breast cancer . The prognostic and predictive values of ER , PgR and Ki-67 expression levels were assessed using Cox modeling and STEPP methodology . In this HR+/HER2- population , the median ER , PgR , and Ki-67 expressions were 95 , 90 , and 18 % immunostained cells . As most patients had strongly ER-positive tumors , the predictive value of ER levels could not be investigated . Lower PgR and higher Ki-67 expression were associated with reduced BCFI . There was no consistent evidence of heterogeneity of the relative treatment effects according to PgR or Ki-67 expression levels , though there was a greater 5-year absolute benefit of exemestane + ovarian function suppression ( OFS ) versus tamoxifen with or without OFS at lower levels of PgR and higher levels of Ki-67 . Women with poor prognostic features of low PgR and /or high Ki-67 have greater absolute benefit from exemestane + OFS versus tamoxifen + OFS or tamoxifen alone , but individually PgR and Ki-67 are of limited predictive value for selecting adjuvant endocrine therapy for premenopausal women with HR+/HER2− early breast cancer GUIDELINE QUESTIONS 1 ) Does erythropoietin ( EPO ) reduce the need for transfusion of red blood cells in patients receiving chemotherapy for a nonhematologic cancer ? 2 ) Does the administration of EPO improve the quality of life of these cancer patients ? OBJECTIVE To make recommendations regarding the use of EPO to reduce the need for transfusion of red blood cells in patients receiving chemotherapy for a nonhematologic cancer . OUTCOMES First transfusion requirement from the start of chemotherapy is the main outcome of interest . Quality of life and costs are also considered . PERSPECTIVE ( VALUES ) Evidence was selected and review ed by 5 members of the Ontario Cancer Treatment Practice Guidelines Initiative ( OCTPGI ) and the Systemic Treatment Program Committee ( STPC ) . Drafts of this document have been circulated to and review ed by members of the STPC . The STPC comprises medical oncologists , pharmacists , supportive care personnel and administrators . No community representative participated in the development of this practice guideline . QUALITY OF EVIDENCE Eleven r and omized controlled trials ( RCTs ) , most placebo-controlled , were available for review . A meta- analysis was performed with 8 trials that shared a clinical ly relevant outcome measure . Only 1 trial assessed quality of life . BENEFITS The meta- analysis showed a relative risk for transfusion among EPO patients of 0.64 ( 95 % confidence interval 0.53 - 0.78 ) , which translates into a 36 % relative reduction in the proportion of patients requiring transfusion ( p = 0.00001 ) . Reduction in transfusion requirements was similar across strata defined by method ological quality , EPO dose , hematologic status , tumour type at trial entry and chemotherapy regimen . In the 1 trial that assessed quality of life , EPO was associated with improved quality of life . HARMS Hypertension has been noted rarely in  EPO-treated cancer patients . The RCTs did not report adverse effects in EPO-treated patients compared with control patients during the follow-up period . Long-term adverse effects are unknown . EPO is more costly than transfusion , but formal cost-effectiveness studies are unavailable . PRACTICE GUIDELINE For patients receiving chemotherapy for nonhematologic cancer in whom symptoms of anemia are expected and in whom transfusion of red blood cells is not considered an acceptable treatment option , EPO can be recommended as a safe , effective treatment alternative . The evidence in support of using EPO is stronger for patients receiving platinum-based chemotherapy regimens that for those receiving non-platinum-based regimens . CLINICAL PRACTICE GUIDELINE DATE : Apr. 4 , 1997 Purpose Combining anthracyclines and taxanes are to date the most active cytotoxic treatment option in the neoadjuvant and palliative therapy of breast cancer patients . Adding trastuzumab to these cytotoxic agents can improve outcome for women with human epidermal growth factor receptor 2 (HER2)-overexpressing advanced breast cancer . We conducted a pilot study of preoperative epidoxorubicin and docetaxel plus trastuzumab in outpatient patients suffering from breast cancer . Patients and methods Fourteen consecutive patients were enrolled in this prospect i ve clinical pilot trial . Preoperative treatment consisted of weekly trastuzumab ( 4 mg/kg body-weight loading dose , 2 mg/kg/week maintenance dose ) , in combination with weekly epidoxorubicin ( 30 mg/m2 body surface area [ BSA ] ) and docetaxel ( 35 mg/m2 BSA ) once a week for 6 weeks followed by 1 week off therapy . Results Patients received a total of 30 cycles ( median : 2 cycles , range : 2–3 cycles ) of this therapeutic regimen . Outpatient epidoxorubicin and docetaxel plus trastuzumab were well tolerated . A major response to this preoperative therapy regimen could be demonstrated in 12 of 14 patients ( 86 % ) leading to breast-conserving surgery in 11 of 14 patients ( 79 % ) . Conclusions We conclude that outpatient epidoxorubicin and docetaxel plus trastuzumab are safe in the neoadjuvant treatment of patients suffering from breast cancer , based on a favorable side-effect and activity profile . Thus , this regimen can be considered for further clinical trials BACKGROUND Patients who have residual invasive carcinoma after the receipt of neoadjuvant chemotherapy for human epidermal growth factor receptor 2 (HER2)‐negative breast cancer have poor prognoses . The benefit of adjuvant chemotherapy in these patients remains unclear . METHODS We r and omly assigned 910 patients with HER2‐negative residual invasive breast cancer after neoadjuvant chemotherapy ( containing anthracycline , taxane , or both )  to receive st and ard postsurgical treatment either with capecitabine or without ( control ) . The primary end point was disease‐free survival . Secondary end points included overall survival . RESULTS The result of the prespecified interim analysis met the primary end point , so this trial was terminated early . The final analysis showed that disease‐free survival was longer in the capecitabine group than in the control group ( 74.1 % vs. 67.6 % of the patients were alive and free from recurrence or second cancer at 5 years ; hazard ratio for recurrence , second cancer , or death , 0.70 ; 95 % confidence interval [ CI ] , 0.53 to 0.92 ; P=0.01 ) . Overall survival was longer in the capecitabine group than in the control group ( 89.2 % vs. 83.6 % of the patients were alive at 5 years ; hazard ratio for death , 0.59 ; 95 % CI , 0.39 to 0.90 ; P=0.01 ) . Among patients with triple‐negative disease , the rate of disease‐free survival was 69.8 % in the capecitabine group versus 56.1 % in the control group ( hazard ratio for recurrence , second cancer , or death , 0.58 ; 95 % CI , 0.39 to 0.87 ) , and the overall survival rate was 78.8 % versus 70.3 % ( hazard ratio for death , 0.52 ; 95 % CI , 0.30 to 0.90 ) . The h and ‐foot syndrome , the most common adverse reaction to capecitabine , occurred in 73.4 % of the patients in the capecitabine group . CONCLUSIONS After st and ard neoadjuvant chemotherapy containing anthracycline , taxane , or both , the addition of adjuvant capecitabine therapy was safe and effective in prolonging disease‐free survival and overall survival among patients with HER2‐negative breast cancer who had residual invasive disease on pathological testing . ( Funded by the Advanced Clinical Research Organization and the Japan Breast Cancer Research Group ; CREATE‐X UMIN Clinical Trials Registry number , UMIN000000843 . Benefit from chemotherapy treatment in breast cancer patients is determined by the molecular make-up of the tumour . In a retrospective analysis , we determined the molecular subtypes of breast cancer originally defined by expression microarrays by immunohistochemistry in tumours of patients who took part in a r and omised study of adjuvant high-dose chemotherapy in breast cancer . In addition , the topoisomerase IIα ( TOP2A ) amplification status was determined by fluorescence in situ hybridisation and chromogenic in situ hybridisation . 411 of the 753 tumours ( 55 % ) were classified as luminal-like , 137 ( 18 % ) as basal-like and 205 ( 27 % ) as human epithelial receptor type 2 ( HER2 ) amplified . The basal-like tumours were defined as having no expression of ER and HER2 ; 98 of them did express epidermal growth factor receptor and /or cytokeratin 5/6 . The luminal-like tumours had a significantly better recurrence free and overall survival than the other two groups . From the 194 HER2-positive tumours , 47 ( 24 % ) were shown to harbour an amplification of TOP2A . Patients with an HER2-amplified tumour r and omised to the high-dose therapy arm did worse than those in the conventional treatment arm , possibly caused by the lower cumulative anthracycline dose in the high-dose arm . The tumours with a TOP2A amplification contributed hardly to this difference , suggesting that TOP2A amplification is not the cause of the steep dose – response curve for anthracyclines in breast cancer . Possibly , the difference of the cumulative dose of only 25 % between the treatment arms was insufficient to yield a survival difference PURPOSE To up date the accelerated partial breast irradiation Consensus Statement published in 2009 and provide guidance on use of intraoperative radiation therapy ( IORT ) for partial breast irradiation in early-stage breast cancer , based on published evidence complemented by expert opinion . METHODS AND MATERIAL S A systematic PubMed search using the same terms as the original Consensus Statement yielded 419 articles ; 44 articles were selected . The authors synthesized the published evidence and , through a series of conference calls and e-mails , reached consensus regarding the recommendations . RESULTS The new recommendations include lowering the age in the " suitability group " from 60 to 50 years and in the " caution ary group " to 40 years for patients who meet all other elements of suitability ( Table 1 ) . Patients with low-risk ductal carcinoma in situ , as per Radiation Therapy Oncology Group 9804 criteria , were categorized in the " suitable " group . The task force agreed to maintain the current criteria based on margin status . Recommendations for the use of IORT for breast cancer patients include : counseling patients regarding the higher risk of ipsilateral breast tumor recurrence with IORT compared with whole breast irradiation ; the need for prospect i ve monitoring of long-term local control and toxicity with low-energy radiograph IORT given limited follow-up ; and restriction of IORT to women with invasive cancer considered " suitable . " CONCLUSION These recommendations will provide up date d clinical guidance regarding use of accelerated partial breast irradiation for radiation oncologists and other specialists participating in the care of breast cancer patients Question What is the optimal chemotherapy treatment for women with recurrent ovarian cancer who have previously received platinum-based chemotherapy  ? Perspectives Currently , st and ard primary therapy for advanced disease involves a combination of maximal cytoreductive surgery and chemotherapy with carboplatin plus paclitaxel or with carboplatin alone . Despite initial high response rates , a large proportion of patients relapse , result ing in a therapeutic challenge . Because these patients are not curable , the goal of therapy becomes improvement in both quality and length of life . The search has therefore been to find active agents for women with recurrent disease following platinum-based chemotherapy .  Outcomes Outcomes of interest included any combination of tumour response rate , progression-free survival , overall survival , adverse events , and quality of life . Methodology The medline , embase , and Cochrane Library data bases were systematic ally search ed for primary articles and practice guidelines . The result ing evidence informed the development of clinical practice recommendations . The systematic review and recommendations were approved by the Report Approval Panel of the Program in Evidence -Based Care , and by the Gynecology Cancer Disease Site Group ( dsg ) . The practice guideline was externally review ed by a sample of practitioners from Ontario , Canada . Results Thirteen r and omized trials compared various chemotherapy regimens for patients with recurrent ovarian cancer . In five of the thirteen trials in which 100 % of patients were considered sensitive to platinum-containing chemotherapy , further platinum-based combination chemotherapy significantly improved response rates ( two trials ) , progression-free survival ( four trials ) , and overall survival ( three trials ) when compared with single-agent chemotherapy involving carboplatin or paclitaxel . Only two of these r and omized trials compared the same chemotherapy regimens : carboplatin alone versus the combination of carboplatin and paclitaxel . Both trials were consistent in reporting improved survival outcomes with the combination of carboplatin and paclitaxel . In one trial , the combination of carboplatin and gemcitabine result ed in significantly higher response rates and improved progression-free survival when compared with carboplatin alone . Median survival with carboplatin alone ranged from 17 months to 24 months in four trials . In eight of the thirteen trials in which 35%–100 % of patients had platinum-refractory or -resistant disease , one trial reported a statistically significant 2-month improvement in overall survival with liposomal doxorubicin as compared with topotecan ( 15 months vs. 13 months , p = 0.038 ; hazard ratio : 1.23 ; 95 % confidence interval : 1.01 to 1.50 ) . In that trial , because of the limited clinical benefit and the unusual finding that a survival difference emerged only after a year of treatment with no corresponding improvement in the rate of response or of progression-free survival , the authors concluded that further confirmation by results from r and omized trials were needed to establish the superiority of one agent over another in their trial . In one trial , topotecan was superior to treosulphan in patient progression-free survival by a span of approximately 2 months ( 5.4 months vs. 3.0 months , p < 0.001 ) . Toxicity was reported in all of the r and omized trials , and although data on adverse events varied by treatment regimen , the observed adverse events correlated with known toxicity profiles . As expected , combination chemotherapy was associated with higher rates of adverse events . Practice Guideline Target Population This clinical recommendation applies to women with recurrent epithelial ovarian cancer who have previously received platinum-based chemotherapy .  Of specific interest are women who have previously shown sensitivity to platinum therapy and those who previously were refractory or resistant to platinum-based chemotherapy . As a general categorization within what is actually a continuum , “ platinum sensitivity ” refers to disease recurrence 6 months or more after prior platinum-containing chemotherapy , and “ platinum resistance ” refers to a response to platinum-based chemotherapy followed by relapse less than 6 months after chemotherapy is stopped . “ Platinum-refractory disease ” refers to a lack of response or to progression while on platinum-based chemotherapy . Recommendations Although the body of evidence that informs the clinical recommendations is based on r and omized trial data , those data are incomplete . Based on the available data and expert consensus opinion , the Gynecology Cancer dsg makes these recommendations : Systemic therapy for recurrent ovarian cancer is not curative . It is therefore recognized that each patient must be individually assessed to determine optimal therapy in terms of recurrence , sensitivity to platinum , toxicity , ease of administration , and patient preference . All suitable patients should be offered the opportunity to participate in r and omized trials , if available . In the absence of contraindications , combination platinum-based chemotherapy should be considered for patients with prior sensitivity to platinum-containing chemotherapy . As compared with carboplatin alone , the combination of carboplatin and paclitaxel significantly improved both progression-free and overall survival . If combination platinum-based chemotherapy is not indicated , then a single platinum agent should be considered . Carboplatin has demonstrated efficacy across trials and has a manageable toxicity profile . If a single platinum agent is not being considered , then monotherapy with paclitaxel , topotecan , or pegylated liposomal doxorubicin are seen as reasonable treatment options . Some patients may be repeatedly sensitive to treatment and may benefit from multiple lines of chemotherapy . For patients with platinum-refractory or platinum-resistant disease , the goals of treatment should be to improve quality of life by extending the symptom-free interval , by reducing symptom intensity , and by increasing progression-free interval , and , if possible , to prolong life . With non-platinum agents , monotherapy should be considered because no advantage appears to accrue to the use of non-platinum-containing combination chemotherapy in this group of patients . Single-agent paclitaxel , topotecan , or pegylated liposomal doxorubicin have demonstrated activity in this patient population and are reasonable treatment options . No evidence either supports or refutes the use of more than one line of chemotherapy in patients with platinum-refractory or platinum-resistant recurrence . Many treatment options have shown modest response rates , but their benefits over best supportive care have not been studied in clinical trials The purpose of this article is to provide up date d recommendations for the treatment of patients with stage IV non-small-cell lung cancer . A literature search identified relevant r and omized trials published since 2002 . The scope of the guideline was narrowed to chemotherapy and biologic therapy . An Up date Committee review ed the literature and made up date d recommendations . One hundred sixty-two publications met the inclusion criteria . Recommendations were based on treatment strategies that improve overall survival . Treatments that improve only progression-free survival prompted scrutiny of toxicity and quality of life . For first-line therapy in patients with performance status of 0 or 1 , a platinum-based two-drug combination of cytotoxic drugs is recommended . Nonplatinum cytotoxic doublets are acceptable for patients with contraindications to platinum therapy . For patients with performance status of 2 , a single cytotoxic drug is sufficient . Stop first-line cytotoxic chemotherapy at disease progression or after four cycles in patients who are not responding to treatment . Stop two-drug cytotoxic chemotherapy at six cycles even in patients who are responding to therapy . The first-line use of gefitinib may be recommended for patients with known epidermal growth factor receptor ( EGFR ) mutation ; for negative or unknown EGFR mutation status , cytotoxic chemotherapy is preferred . Bevacizumab is recommended with carboplatin-paclitaxel , except for patients with certain clinical characteristics . Cetuximab is recommended with cisplatin-vinorelbine for patients with EGFR-positive tumors by immunohistochemistry . Docetaxel , erlotinib , gefitinib , or pemetrexed is recommended as second-line therapy . Erlotinib is recommended as third-line therapy for patients who have not received prior erlotinib or gefitinib . Data are insufficient to recommend the routine third-line use of cytotoxic drugs . Data are insufficient to recommend routine use of molecular markers to select chemotherapy Introduction Inhibitors of the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin ( PI3K/AKT/mTOR ) pathway can overcome endocrine resistance in estrogen receptor ( ER ) α-positive breast cancer , but companion diagnostics indicating PI3K/AKT/mTOR activation and consequently endocrine resistance are lacking . PIK3CA mutations frequently occur in ERα-positive breast cancer and result in PI3K/AKT/mTOR activation in vitro . Nevertheless , the prognostic and treatment-predictive value of these mutations in ERα-positive breast cancer is contradictive . We tested the clinical validity of PIK3CA mutations and other canonic pathway drivers to predict intrinsic resistance to adjuvant tamoxifen . In addition , we tested the association between these drivers and downstream activated proteins . Methods Primary tumors from 563 ERα-positive postmenopausal patients , r and omized between adjuvant tamoxifen ( 1 to 3 years ) versus observation were recollected . PIK3CA hotspot mutations in exon 9 and exon 20 were assessed with Sequenom Mass Spectometry . Immunohistochemistry was performed for human epidermal growth factor receptor 2 ( HER2 ) , phosphatase and tensin homolog ( PTEN ) , and insulin-like growth factor 1 receptor ( IGF-1R ) . We tested the association between these molecular alterations and downstream activated proteins ( like phospho-protein kinase B ( p-AKT ) , phospho-mammalian target of rapamycin ( p-mTOR ) , p-ERK1/2 , and p-p70S6 K ) . Recurrence-free interval improvement with tamoxifen versus control was assessed according to the presence or absence of canonic pathway drivers , by using Cox proportional hazard models , including a test for interaction . Results PIK3CA mutations ( both exon 9 and exon 20 ) were associated with low tumor grade . An enrichment of PIK3CA exon 20 mutations was observed in progesterone receptor- positive tumors . PIK3CA exon 20 mutations were not associated with downstream-activated proteins . No significant interaction between PIK3CA mutations or any of the other canonic pathway drivers and tamoxifen-treatment benefit was found . Conclusion PIK3CA mutations do not have clinical validity to predict intrinsic resistance to adjuvant tamoxifen and may therefore be unsuitable as companion diagnostic for PI3K/AKT/mTOR inhibitors in ERα- positive , postmenopausal , early breast cancer patients
In general , single-agent chemotherapy is not recommended for the adjuvant treatment of breast cancer in any patient population .
Anthracycline-taxane-based polychemotherapy regimens are , overall , considered superior to earlier-generation regimens and have the most significant impact on patient survival outcomes .
Regimens with varying anthracycline and taxane doses and schedules are options ; in general , paclitaxel given every 3 weeks is inferior .
Evidence does not support the use of bevacizumab in the adjuvant setting ; other systemic therapy agents such as metformin and vaccines remain investigatory .
BACKGROUND The Program in Evidence -Based Care ( pebc ) of Cancer Care Ontario recently created an evidence -based consensus guideline on the systemic treatment of early breast cancer .
The evidence for the guideline was compiled using a systematic review to answer the question " What is the optimal systemic therapy for patients with early-stage , operable breast cancer , when patient and disease factors are considered ? "
The question was addressed in three parts : cytotoxic chemotherapy , endocrine treatment , and human epidermal growth factor receptor 2 (her2)-directed therapy .