Longer-term assessment of trastuzumab-related cardiac adverse events in the Herceptin Adjuvant (HERA) trial. Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy. [Efficacy and safety assessment of neoadjuvant paclitaxel and trastuzumab in Chinese women with Her-2 positive operable breast cancer]. A multicenter randomized phase II study of sequential epirubicin/cyclophosphamide followed by docetaxel with or without celecoxib or trastuzumab according to HER2 status, as primary chemotherapy for localized invasive breast cancer patients Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. A phase II study of neoadjuvant docetaxel/carboplatin with or without trastuzumab in locally advanced breast cancer: Response and cardiotoxicity. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. Neoadjuvant treatment with trastuzumab in HER2-positive breast cancer: results from the GeparQuattro study.
PURPOSE We investigated the incidence of cardiac adverse events in patients with early breast cancer in the Herceptin Adjuvant ( HERA ) trial who were treated with 1 year of trastuzumab after completion of (neo)adjuvant chemotherapy . PATIENTS AND METHODS The HERA trial is a three-group , r and omized trial that compared 1 year or 2 years of trastuzumab with observation in women with human epidermal growth factor receptor-2 ( HER2 ) -positive early breast cancer . Eligible patients had normal left ventricular ejection fraction ( LVEF ; > or= 55 % ) after completion of (neo)adjuvant chemotherapy with or without radiotherapy .  Cardiac function was monitored throughout the trial . This analysis considers patients r and omly assigned to 1 year of trastuzumab treatment or observation . RESULTS There were 1,698 patients r and omly assigned to observation and 1,703 r and omly assigned to 1 year of trastuzumab treatment ; 94.1 % of patients had been treated with anthracyclines . The incidence of discontinuation of trastuzumab because of cardiac disorders was low ( 5.1 % ) . At a median follow-up of 3.6 years , the incidence of cardiac end points remained low , though it was higher in the trastuzumab group than in the observation group ( severe CHF , 0.8 % v 0.0 % ; confirmed significant LVEF decreases , 3.6 % v 0.6 % ) In the trastuzumab group , 59 of 73 patients with a cardiac end point reached acute recovery ; of these 59 patients , 52 were considered by the cardiac advisory board ( CAB ) to have a favorable outcome from the cardiac end point . CONCLUSION The incidence of cardiac end points remains low even after longer-term follow-up . The cumulative incidence of any type of cardiac end point increases during the scheduled treatment period of 1 year , but it remains relatively constant thereafter PURPOSE To assess patient and tumor characteristics associated with a complete pathologic response ( pCR ) in both the breast and axillary lymph node specimens and the outcome of patients found to have a pCR after neoadjuvant chemotherapy for locally advanced breast cancer ( LABC ) . PATIENTS AND METHODS Three hundred seventy-two LABC patients received treatment in two prospect i ve neoadjuvant trials using four cycles of doxorubicin-containing chemotherapy .  Patients had a total mastectomy with axillary dissection or segmental mastectomy and axillary dissection followed by four or more cycles of additional chemotherapy .  Patients then received irradiation treatment of the chest-wall or breast and regional lymphatics . Median follow-up was 58 months ( range , 8 to 99 months ) . RESULTS The initial nodal status , age , and stage distribution of patients with a pCR were not significantly different from those of patients with less than a pCR ( P>.05 ) . Patients with a pCR had initial tumors that were more likely to be estrogen receptor (ER)-negative ( P<.01 ) , and anaplastic ( P = .01 ) but of smaller size ( P<.01 ) than those of patients with less than a pCR . Upon multivariate analysis , the effects of ER status and nuclear grade were independent of initial tumor size . Sixteen percent of the patients in this study ( n = 60 ) had a pathologic complete primary tumor response . Twelve percent of patients ( n = 43 ) had no microscopic evidence of invasive cancer in their breast and axillary specimens . A pathologic complete primary tumor response was predictive of a complete axillary lymph node response ( P<.01 ) . The 5-year overall and disease-free survival rates were significantly higher in the group who had a pCR ( 89 % and 87 % , respectively ) than in the group who had less than a pCR ( 64 % and 58 % , respectively ; P<.01 ) . CONCLUSION Neoadjuvant chemotherapy has the capacity to completely clear the breast and axillary lymph nodes of invasive tumor before surgery . Patients with LABC who have a pCR in the breast and axillary nodes have a significantly improved disease-free survival rate . However , a pCR does not entirely eliminate recurrence . Further efforts should focus on elucidating the molecular mechanisms associated with this response OBJECTIVE To assess the efficacy and safety of neoadjuvant 3-weekly paclitaxel plus trastuzumab ( TH ) in Chinese women with Her-2 overexpressing operable breast cancer . METHODS This is a single center open-label phase II clinical trial . The included patients underwent 4 cycles of neoadjuvant 3-weekly TH before surgery . The primary endpoint was pathologic complete response rate ( pCR rate ) and the secondary endpoint was overall response rate ( OR rate ) . Patients were also stratified according to hormone receptor status , and pCR rate and OR rate were compared between subgroups . Adverse events were grade d according to CTCAE v3.0 . RESULTS There were 40 eligible patients entering this study with median age of 49 years . All patients completed 4 cycles of neoadjuvant treatment . pCR rate was 52.5 % and OR rate was 87.5 % . The differences of pCR and OR rates between subgroups were of no statistical significance . No cardiac toxicity event severer than grade 2 was recorded . CONCLUSION 3-weekly TH regimen has satisfactory pCR rate and OR rate in Chinese patients with Her-2 overexpressing operable breast cancer and reliable safety To assess anti-tumor activity of sequential epirubicin/cyclophosphamide followed by docetaxel with the r and omized addition of celecoxib in HER2 negative patients or trastuzumab in HER2 positive patients . From May 2004 till October 2007 , 340 patients with stage II and III breast adenocarcinoma , ineligible for breast conserving surgery , received eight sequential three weekly cycles of EC-D [ epirubicin ( 75 mg/m2)–cyclophosphamide ( 750 mg/m2 ) for four cycles followed by docetaxel ( 100 mg/m2 ) for four cycles ] . HER2-negative patients ( N = 220 ) were r and omized to receive concomitantly with docetaxel celecoxib 800 mg/day during cycles 5–8 or no additional treatment , while HER2-positive patients confirmed by FISH ( N = 120 ) were r and omized to trastuzumab concomitant to docetaxel ( 8 mg/kg then 6 mg/kg IV every 3 weeks ) or no additional preoperative treatment . In the HER2 negative group , pCR ( grade 1 and 2 of Chevallier ’s classification ) was observed in 11.5 and 13 % of patients treated without and with neoadjuvant Celecoxib , respectively . In the HER2 positive group , pCR rate reached 26 % in those who received neoadjuvant trastuzumab versus 19 % in the others . There was no unexpected toxicity , no cardiac toxicity , and no toxic death . Triple negative breast cancers experience the highest pCR rate of 30 % . Celecoxib is not likely to improve pCR rates in addition to EC-D in patients with HER2-negative tumor . In HER2-positive tumor patients , trastuzumab added to ECD leads to increased pCR rates . It was the only combination to deserve further study according to the two-stage Fleming ’s design used in this trial National Surgical Adjuvant Breast and Bowel Project ( NSABP ) Protocol B-18 was initiated in 1988 to determine whether four cycles of doxorubicin/cyclophosphamide given preoperatively improve survival and disease-free survival ( DFS ) when compared with the same chemotherapy given postoperatively . Secondary aims included the evaluation of preoperative chemotherapy in downstaging the primary breast tumor and involved axillary lymph nodes , the comparison of lumpectomy rates and rates of ipsilateral breast tumor recurrence ( IBTR ) in the two treatment groups , and the assessment of the correlation between primary tumor response and outcome . Initially published findings were based on a follow-up of 5 years ; this report up date s results through 9 years of follow-up . There continue to be no statistically significant overall differences in survival or DFS between the two treatment groups . Survival at 9 years is 70 % in the postoperative group and 69 % in the preoperative group ( P = .80 ) . DFS is 53 % in postoperative patients and 55 % in preoperative patients ( P = .50 ) . A statistically significant correlation persists between primary tumor response and outcome , and this correlation has become statistically stronger with longer follow-up . Patients assigned to preoperative chemotherapy  received notably more lumpectomies than postoperative patients , especially among patients with tumors greater than 5 cm at study entry . Although the rate of IBTR was slightly higher in the preoperative group ( 10.7 % versus 7.6 % ) , this difference was not statistically significant . Marginally statistically significant treatment-by-age interactions appear to be emerging for survival and DFS , suggesting that younger patients may benefit from preoperative therapy , whereas the reverse may be true for older patients PURPOSE To determine , in women with primary operable breast cancer , if preoperative doxorubicin ( Adriamycin ) and cyclophosphamide ( Cytoxan ; AC ) therapy yields a better outcome than postoperative AC therapy , if a relationship exists between outcome and tumor response to preoperative chemotherapy , and if such therapy results in the performance of more lumpectomies . PATIENTS AND METHODS Women ( 1,523 ) enrolled onto National Surgical Adjuvant Breast and Bowel Project ( NSABP ) B-18 were r and omly assigned to preoperative or postoperative AC therapy . Clinical tumor response to preoperative therapy was grade d as complete ( cCR ) , partial ( cPR ) , or no response ( cNR ) . Tumors with a cCR were further categorized as either pathologic complete response ( pCR ) or invasive cells ( pINV ) . Disease-free survival ( DFS ) , distant disease-free survival ( DDFS ) , and survival were estimated through 5 years and compared between treatment groups . In the preoperative arm , proportional-hazards models were used to investigate the relationship between outcome and tumor response . RESULTS There was no significant difference in DFS , DDFS , or survival ( P = .99 , .70 , and .83 , respectively ) among patients in either group . More patients treated preoperatively than postoperatively underwent lumpectomy and radiation therapy ( 67.8 % v 59.8 % , respectively ) . Rates of ipsilateral breast tumor recurrence ( IBTR ) after lumpectomy were similar in both groups ( 7.9 % and 5.8 % , respectively ; P = .23 ) . Outcome was better in women whose tumors showed a pCR than in those with a pINV , cPR , or cNR ( relapse-free survival [ RFS ] rates , 85.7 % , 76.9 % , 68.1 % , and 63.9 % , respectively ; P < .0001 ) , even when baseline prognostic variables were controlled . When prognostic models were compared for each treatment group , the preoperative model , which included breast tumor response as a variable , discriminated outcome among patients to about the same degree as the postoperative model . CONCLUSION Preoperative chemotherapy is as effective as postoperative chemotherapy , permits more lumpectomies , is appropriate for the treatment of certain patients with stages I and II disease , and can be used to study breast cancer biology . Tumor response to preoperative chemotherapy correlates with outcome and could be a surrogate for evaluating the effect of chemotherapy on micrometastases ; however , knowledge of such a response provided little prognostic information beyond that which result ed from postoperative therapy 10515 Background : A phase II clinical trial was conducted to study the safety and efficacy of neoadjuvant docetaxel/carboplatin ( T/C ) with or without trastuzumab ( H ) in women with stage III breast cancer . METHODS Forty-eight of 75 planned primary breast cancer patients ( T3 or T4 , any N , M0 ) , age between 18 and 80 have been enrolled . Four cycles of T ( 75 mg/m2 ) + C ( AUC 6 ) were given every 3 weeks preoperatively . Patients with HER-2 amplified tumors ( FISH + ) were r and omized to receive either weekly concurrent H or T/C alone preoperatively and T/C plus H postoperatively . Tumors were assessed clinical ly at baseline and after neoadjuvant therapy . Cardiac assessment consisted of medical history , EKG and LVEF ( by echocardiogram or MUGA ) at baseline and at the end of neoadjuvant chemotherapy . RESULTS Available data from 45 of 48 enrolled patients showed 49 % ( 22 cases ) with complete clinical response , with 54.5 % being HER-2 ( + ) ( 12 cases ) . Stable disease was seen in one patient who was HER-2 ( - ) ( 2.2 % ) . Of 37 with complete pathology verification , 11 ( 29.7 % ) showed pathologic complete response ( pCR ) of the primary tumor with 5 cases being HER-2 ( + ) . Of the 22 HER-2 ( + ) cases that completed neoadjuvant treatment , 11 received T/C/H and 11 received T/C. pCR was noted in 36.4 % of the T/C/H group and 9 % of the T/C  group . LVEF data is available from 43 patients during the neoadjuvant phase , showing 18.6 % ( 8 cases ) with decrease of ≥ 10 % ( 5 patients in the T/C arm and 3 patients in the T/C/H arm ) , although none had cardiac symptoms or LVEF below the normal limit . CONCLUSIONS T/C ± H is clinical ly active in patients with locally advanced breast cancer including a 30 % pCR rate . The cardiotoxicity rates were comparable between patients who received T/C and T/C/H. No significant financial relationships to disclose BACKGROUND The monoclonal antibody trastuzumab has survival benefit when given with chemotherapy to patients with early , operable , and metastatic breast cancer that has HER2 ( also known as ERBB2 ) overexpression or amplification . We aim ed to assess event-free survival in patients with HER2-positive locally advanced or inflammatory breast cancer receiving neoadjuvant chemotherapy with or without 1 year of trastuzumab .  METHODS We compared 1 year of treatment with trastuzumab ( given as neoadjuvant and adjuvant treatment ; n=117 ) with no trastuzumab ( 118 ) , in women with HER2-positive locally advanced or inflammatory breast cancer treated with a neoadjuvant chemotherapy regimen consisting of doxorubicin , paclitaxel , cyclophosphamide , methotrexate , and fluorouracil . R and omisation was done with a computer program and minimisation technique , taking account of geographical area , disease stage , and hormone receptor status . Investigators were informed of treatment allocation . A parallel cohort of 99 patients with HER2-negative disease was included and treated with the same chemotherapy regimen . Primary endpoint was event-free survival . Analysis was by intention to treat . This study is registered , number IS RCT N86043495 . FINDINGS Trastuzumab significantly improved event-free survival in patients with HER2-positive breast cancer ( 3-year event-free survival , 71 % [ 95 % CI 61 - 78 ; n=36 events ] with trastuzumab , vs 56 % [ 46 - 65 ; n=51 events ] without ; hazard ratio 0.59 [ 95 % CI 0.38 - 0.90 ] ; p=0.013 ) . Trastuzumab was well tolerated and , despite concurrent administration with doxorubicin , only two patients ( 2 % ) developed symptomatic cardiac failure . Both responded to cardiac drugs . INTERPRETATION The addition of neoadjuvant and adjuvant trastuzumab to neoadjuvant chemotherapy should be considered for women with HER2-positive locally advanced or inflammatory breast cancer to improve event-free survival , survival , and clinical and pathological tumour responses . FUNDING F Hoffmann-La Roche 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 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 To perform a meta- analysis in order to quantify the actual cumulative r and omized evidence for the benefit and toxicity of trastuzumab combined with neoadjuvant chemotherapy in HER2-positive breast cancer .