Ki67 levels as predictive and prognostic parameters in pretherapeutic breast cancer core biopsies: a translational investigation in the neoadjuvant GeparTrio trial. Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. The Triple Negative Paradox: Primary Tumor Chemosensitivity of Breast Cancer Subtypes Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. Prospective Validation of Immunological Infiltrate for Prediction of Response to Neoadjuvant Chemotherapy in HER2-Negative Breast Cancer – A Substudy of the Neoadjuvant GeparQuinto Trial Randomized trial of preoperative docetaxel with or without capecitabine after 4 cycles of 5-fluorouracil–epirubicin–cyclophosphamide (FEC) in early-stage breast cancer: exploratory analyses identify Ki67 as a predictive biomarker for response to neoadjuvant chemotherapy Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. Neoadjuvant Chemotherapy Is Associated with Improved Survival Compared with Adjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer Only after Complete Pathologic Response Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial. Preoperative chemotherapy in primary operable breast cancer: results from the European Organization for Research and Treatment of Cancer trial 10902. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18.
BACKGROUND The proliferation marker Ki67 has been suggested as a promising cancer biomarker . As Ki67 needs an exact quantification , this marker is a prototype of a new generation of tissue-based biomarkers . In this study , we have systematic ally evaluated different cut points for Ki67 using three different clinical end points in a large neoadjuvant study cohort . PATIENTS AND METHODS We have evaluated pretherapeutic Ki67 levels by immunohistochemistry in 1166 breast cancer core biopsies from the neoadjuvant GeparTrio trial . We used the st and ardized cutoff-finder algorithm for three end points [ response to neoadjuvant chemotherapy ( pCR ) , disease-free ( DFS ) and overall-survival ( OS ) ] . The analyses were stratified for hormone receptor ( HR ) and HER2 status by molecular subtype radar diagrams ( MSRDs ) . RESULTS A wide range of Ki67 cut points between 3%-94 % ( for pCR ) , 6%-46 % ( for DFS ) and 4%-58 % ( for OS ) were significant . The three groups of Ki67 ≤ 15 % versus 15.1%-35 % versus > 35 % had pCR-rates of 4.2 % , 12.8 % , and 29.0 % ( P < 0.0005 ) , this effect was also present in six of eight molecular subtypes . In MSRD , Ki67 was significantly linked to prognosis in uni- and multivariate analysis in the complete cohort and in HR-positive , but not triple-negative tumors . CONCLUSIONS Ki67 is a significant predictive and prognostic marker over a wide range of cut points suggesting that data -derived cut point optimization might not be possible . Ki67 could be used as a continuous marker ; in addition , the scientific community could define st and ardized cut points for Ki67 . Our analysis explains the variability observed for Ki67 cut points in previous studies ; however , this should not be seen as weakness , but as strength of this marker . MSRDs are an easy new approach for visualization of biomarker effects on outcome across molecular subtypes in breast cancer . The experience with Ki67 could provide important information regarding the development and implementation of other quantitative biomarkers PURPOSE Pre clinical data suggest a contribution of the immune system to chemotherapy response . In this study , we investigated the prespecified hypothesis that the presence of a lymphocytic infiltrate in cancer tissue predicts the response to neoadjuvant chemotherapy . METHODS We investigated intratumoral and stromal lymphocytes in a total of 1,058 pretherapeutic breast cancer core biopsies from two neoadjuvant anthracycline/taxane-based studies ( GeparDuo , n = 218 , training cohort ; and GeparTrio , n = 840 , validation cohort ) . Molecular parameters of lymphocyte recruitment and activation were evaluated by kinetic polymerase chain reaction in 134 formalin-fixed , paraffin-embedded tumor sample s. Results In a multivariate regression analysis including all known predictive clinicopathologic factors , the percentage of intratumoral lymphocytes was a significant independent parameter for pathologic complete response ( pCR ) in both cohorts ( training cohort : P = .012 ; validation cohort : P = .001 ) . Lymphocyte-predominant breast cancer responded , with pCR rates of 42 % ( training cohort ) and 40 % ( validation cohort ) . In contrast , those tumors without any infiltrating lymphocytes had pCR rates of 3 % ( training cohort ) and 7 % ( validation cohort ) . The expression of inflammatory marker genes and proteins was linked to the histopathologic infiltrate , and logistic regression showed a significant association of the T-cell-related markers CD3D and CXCL9 with pCR . CONCLUSION The presence of tumor-associated lymphocytes in breast cancer is a new independent predictor of response to anthracycline/taxane neoadjuvant chemotherapy and provides useful information for oncologists to identify a subgroup of patients with a high benefit from this type of chemotherapy 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 Breast carcinomas are often infiltrated by inflammatory cells , particularly macrophages and T lymphocytes , but the significance of these cells remains unclear . One possible role of these inflammatory cells is that they represent a cell-mediated immune response against the carcinoma . CD8(+ ) lymphocytes are a known crucial component of cell-mediated immunity . The purpose of this study was to explore the prognostic value of tumor-infiltrating CD8(+ ) cytotoxic lymphocytes in breast cancer .  Tumor-infiltrating CD8(+ ) lymphocytes were assessed by immunohistochemical staining of tissue microarray cores from 1,334 unselected breast tumors from patients with long-term follow-up . The number of CD8(+ ) T cells was counted in tumor nests ( intratumoral ) , in stroma adjacent to tumor cells , and in stroma distant to tumor cells , and their relationship with clinical outcome was determined . The total number of CD8(+ ) cells was positively correlated with tumor grade ( r(s ) = 0.20 ; P < .001 ) and inversely correlated with patient 's age at diagnosis , estrogen receptor-alpha ( ER-α ) , and progesterone receptor ( PgR ) expression ( Mann-Whitney U test , P < .001 ) . The total patient cohort was r and omly divided into two separate training and validation sets before performing univariate survival analysis . Total number and distant stromal CD8(+ ) lymphocytes were associated with better patient survival ( P = .041 and P < .001 , respectively ) in the training set . In multivariate analysis , total CD8(+ ) T-cell count was an independent prognostic factor in both training and validation sets . These results suggest that tumor-infiltrating CD8(+ ) T lymphocytes have antitumor activity as judged by their favorable effect on patients ' survival and could potentially be exploited in the treatment of breast cancer Introduction We have recently described an increased lymphocytic infiltration rate in breast carcinoma tissue is a significant response predictor for anthracycline/taxane-based neoadjuvant chemotherapy ( NACT ) . The aim of this study was to prospect ively vali date the tumor-associated lymphocyte infiltrate as predictive marker for response to anthracycline/taxane-based NACT . Patients and Methods The immunological infiltrate was prospect ively evaluated in a total of 313 core biopsies from HER2 negative patients of the multicenter PREDICT study , a sub study of the neoadjuvant GeparQuinto study .  Intratumoral lymphocytes ( iTuLy ) , stromal lymphocytes ( strLy ) as well as lymphocyte-predominant breast cancer ( LPBC ) were evaluated by histopathological assessment . Pathological complete response ( pCR ) rates were analyzed and compared between the defined subgroups using the exact test of Fisher . Results Patients with lymphocyte-predominant breast cancer ( LPBC ) had a significantly increased pCR rate of 36.6 % , compared to non-LPBC patients ( 14.3 % , p<0.001 ) . LPBC and stromal lymphocytes were significantly independent predictors for pCR in multivariate analysis ( LPBC : OR 2.7 , p = 0.003 , strLy : OR 1.2 , p = 0.01 ) . The amount of intratumoral lymphocytes was significantly predictive for pCR in univariate ( OR 1.2 , p = 0.01 ) but not in multivariate logistic regression analysis ( OR 1.2 , p = 0.11 ) . Conclusion Confirming previous investigations of our group , we have prospect ively vali date d in an independent cohort that an increased immunological infiltrate in breast tumor tissue is predictive for response to anthracycline/taxane-based NACT .  Patients with LPBC and increased stromal lymphocyte infiltration have significantly increased pCR rates . The lymphocytic infiltrate is a promising additional parameter for histopathological evaluation of breast cancer core biopsies Abstract This r and omized , multicenter study compared the efficacy of docetaxel with or without capecitabine following fluorouracil/epirubicin/cyclophosphamide ( FEC ) therapy in operable breast cancer and investigated the role of Ki67 as a predictive biomarker . Patients were r and omized to 4 cycles of docetaxel/capecitabine ( docetaxel : 75 mg/m2 on day 1 ; capecitabine : 1,650 mg/m2 on days 1–14 every 3 weeks ) or docetaxel alone ( 75 mg/m2 on day 1 every 3 weeks ) after completion of 4 cycles of FEC ( 5-fluorouracil 500 mg/m2 , epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 on day 1 every 3 weeks ) . The primary endpoint was the pathological complete response ( pCR ) rate . Predictive factor analysis was conducted using clinicopathological markers , including hormone receptors and Ki67 labeling index ( Ki67LI ) . A total of 477 patients were r and omized ; the overall response in the docetaxel/capecitabine and docetaxel groups was 88.3 and 87.4 % , respectively . There were no significant differences in the pCR rate  ( docetaxel/capecitabine : 23 % ; docetaxel : 24 % ; p = 0.748 ) , disease-free survival , or overall survival . However , patients with mid-range Ki67LI ( 10–20 % ) showed a trend towards improved pCR rate with docetaxel/capecitabine compared to docetaxel alone . Furthermore , multivariate logistic regression analysis showed pre-treatment Ki67LI ( odds ratio 1.031 ; 95 % CI 1.014–1.048 ; p = 0.0004 ) to be a significant predictor of pCR in this neoadjuvant treatment setting . Docetaxel/capecitabine ( after 4 cycles of FEC ) did not generate significant improvement in pCR compared to docetaxel alone . However , exploratory analyses suggested that assessment of pre-treatment Ki67LI may be a useful tool in the identification of responders to preoperative docetaxel/capecitabine in early-stage breast cancer BACKGROUND We have previously shown the prognostic importance of tumor-infiltrating  lymphocytes ( TILs ) in newly diagnosed triple-negative breast cancer ( TNBC ) using tumor sample s from a large clinical trial cohort . In this study , we aim ed to vali date these findings and also investigate associations with trastuzumab benefit in HER2-overexpressing disease ( HER2 + ) . PATIENTS AND METHODS A prospect ive-retrospective study was conducted using sample s from the FinHER adjuvant , phase III trial that enrolled 1010 early-stage BC patients , 778 of whom were HER2-nonamplified . Those with HER2 + disease ( n = 232 ) were r and omized to 9 weeks of trastuzumab or no trastuzumab in addition to chemotherapy . Two pathologists independently quantified stromal TILs in 935 ( 92.6 % ) available slides . The primary end point of distant disease-free survival ( DDFS ) and interactions with trastuzumab  were studied in Cox regression models . RESULTS Confirming our previous findings , in TNBC ( n = 134 ) each 10 % increase in TILs was significantly associated with decreased distant recurrence in TNBC ; for DDFS the hazard ratio adjusted for clinicopathological factors : 0.77 ; 95 % confidence interval ( CI ) 0.61 - 0.98 , P = 0.02 . In HER2 + BC ( n = 209 ) , each 10 % increase in lymphocytic infiltration was significantly associated with decreased distant recurrence in patients r and omized to the trastuzumab arm ( DDFS P interaction = 0.025 ) . CONCLUSIONS Higher levels of TILs present at diagnosis were significantly associated with decreased distant recurrence rates in primary TNBC . These results confirm our previous data and further support that TILs should be considered as a robust prognostic factor in this BC subtype . We also report for the first time an association between higher levels of TILs and increased  trastuzumab  benefit in HER2 + disease . Further research into why some TN and HER2 + BCs can or can not generate a host antitumor immune response and how trastuzumab can favorably alter the immune microenvironment is warranted 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 Introduction Triple-negative breast cancer ( TNBC ) is an aggressive subtype of breast cancer that is known to be chemosensitive . In patients with TNBC , we sought to compare survival outcomes between patients receiving neoadjuvant chemotherapy , with and without complete pathologic response ( pCR ) , and those receiving adjuvant chemotherapy . Methods We performed a retrospective chart review and identified 385 patients with stage I – III TNBC who were treated with neoadjuvant or adjuvant chemotherapy between 2000 and 2008 . Patients were divided according to receipt of neoadjuvant chemotherapy with pCR , neoadjuvant chemotherapy without pCR , and adjuvant chemotherapy . Data were compared using Fisher ’s exact test and analysis of variance ( ANOVA ) . Kaplan – Meier curves were generated . Results Of 385 patients , 151 ( 39 % ) received neoadjuvant chemotherapy and 234 ( 61 % ) received adjuvant chemotherapy . Twenty-six ( 17 % ) of those patients receiving neoadjuvant chemotherapy had pCR . After controlling for covariates associated with survival in unadjusted tests , patients undergoing neoadjuvant chemotherapy with residual tumor had significantly worse survival compared with patients receiving adjuvant therapy [ hazard ratio ( HR ) = 0.51 , P = 0.007 ] and a trend towards worse survival compared with patients receiving neoadjuvant therapy with pCR ( HR = 0.19 , P = 0.10 ) . Conclusions Although previous clinical trials have not demonstrated a survival difference between patients receiving neoadjuvant versus adjuvant chemotherapy for breast cancer , our study suggests an overall survival benefit in patients with pCR following neoadjuvant chemotherapy compared with patients receiving adjuvant therapy . It is clear that a prospect i ve study needs to be carried out to better eluci date the timing of chemotherapy in patients with TNBC PURPOSE Previous pre clinical and clinical data suggest that the immune system influences prognosis and response to chemotherapy ( CT ) ; however , clinical relevance has yet to be established in breast cancer ( BC ) . We hypothesized that increased lymphocytic infiltration would be associated with good prognosis and benefit from immunogenic CT-in this case , anthracycline-only CT-in  selected BC subtypes . PATIENTS AND METHODS We investigated the relationship between quantity and location of lymphocytic infiltrate at diagnosis with clinical outcome in 2009 node-positive BC sample s from the BIG 02 - 98 adjuvant phase III trial comparing anthracycline-only CT ( doxorubicin followed by cyclophosphamide , methotrexate , and fluorouracil [ CMF ] or doxorubicin plus cyclophosphamide followed by CMF ) versus CT combining doxorubicin and docetaxel ( doxorubicin plus docetaxel followed by CMF or doxorubicin followed by docetaxel followed by CMF ) . Readings were independently performed by two pathologists . Disease-free survival ( DFS ) , overall survival ( OS ) , and interaction with type of CT associations were studied . Median follow-up was 8 years . RESULTS There was no significant prognostic association in the global nor estrogen receptor ( ER ) -positive/human epidermal growth factor receptor 2 ( HER2 ) -negative population . However , each 10 % increase in intratumoral and stromal lymphocytic infiltrations was associated with 17 % and 15 % reduced risk of relapse ( adjusted P = .1 and P = .025 ) , respectively , and 27 % and 17 % reduced risk of death in ER-negative/HER2-negative BC regardless of CT type ( adjusted P = .035 and P = .023 ) , respectively . In HER2-positive BC , there was a significant interaction between increasing stromal lymphocytic infiltration ( 10 % increments ) and benefit with anthracycline-only CT ( DFS , interaction P = .042 ; OS , P = .018 ) . CONCLUSION In node-positive , ER-negative/HER2-negative BC , increasing lymphocytic infiltration was associated with excellent prognosis . Further validation of the clinical utility of tumor-infiltrating lymphocytes in this context is warranted . Our data also support the evaluation of immunotherapeutic approaches in selected BC subtypes BACKGROUND A subcutaneous formulation of trastuzumab has been developed , offering potential improvements in patient convenience and re source use compared with the st and ard intravenous infusion of the drug . We compared the pharmacokinetic profile , efficacy , and safety of the subcutaneous and intravenous formulations in patients with HER2-positive early breast cancer . METHODS The HannaH study was a phase 3 , r and omised , international , open-label , trial in the (neo)adjuvant setting . Patients with HER2-positive , operable , locally advanced or inflammatory breast cancer were r and omly assigned to eight cycles of neoadjuvant chemotherapy administered concurrently with trastuzumab every 3 weeks either intravenously ( 8 mg/kg loading dose , 6 mg/kg maintenance dose ) or subcutaneously ( fixed dose of 600 mg ) ; 1:1 ratio . Chemotherapy consisted of four cycles of docetaxel ( 75 mg/m(2 ) ) followed by four cycles of fluorouracil ( 500 mg/m(2 ) ) , epirubicin ( 75 mg/m(2 ) ) , and cyclophosphamide ( 500 mg/m(2 ) ) , every 3 weeks . After surgery , patients continued trastuzumab to complete 1 year of treatment . Co primary endpoints were serum trough concentration ( C(trough ) ) at pre-dose cycle 8 before surgery ( non-inferiority margin for the ratio between groups of 0·80 ) and pathological complete response ( pCR ; non-inferiority margin for the difference between groups of -12·5 % ) , analysed in the per- protocol population . This study is registered with Clinical Trials.gov , number NCT00950300 . FINDINGS 299 patients were r and omly assigned to receive intravenous trastuzumab and 297 to receive subcutaneous trastuzumab .  The geometric mean presurgery C(trough ) was 51·8 μg/mL ( coefficient of variation 52·5 % ) in the intravenous group and 69·0 μg/mL ( 55·8 % ) in the subcutaneous group . The geometric mean ratio of C(trough ) subcutaneous to C(trough ) intravenous was 1·33 ( 90 % CI 1·24 - 1·44 ) . 107 ( 40·7 % ) of 263 patients in the intravenous group and 118 ( 45·4 % ) of 260 in the subcutaneous group achieved a pCR . The difference between groups in pCR was 4·7 % ( 95 % CI -4·0 to 13·4 ) . Thus subcutaneous trastuzumab was non-inferior to intravenous trastuzumab for both co primary endpoints . The incidence of grade 3 - 5 adverse events was similar between groups . The most common of these adverse events were neutropenia ( 99 [ 33·2 % ] of 298 patients in the intravenous group vs 86 [ 29·0 % ] of 297 in the subcutaneous group ) , leucopenia ( 17 [ 5·7 % ] vs 12 [ 4·0 % ] ) , and febrile neutropenia ( 10 [ 3·4 % ] vs 17 [ 5·7 % ] ) . However , more patients had serious adverse events in the subcutaneous group ( 62 [ 21 % ] of 297 patients ) than in the intravenous group ( 37 [ 12 % ] of 298 ) ; the difference was mainly attributable to infections and infestations ( 24 [ 8·1 % ] in the subcutaneous group vs 13 [ 4·4 % ] in the intravenous group ) . Four adverse events led to death ( one in the intravenous group and three in the subcutaneous group ) , all of which occurred during the neoadjuvant phase . Of these , two -- both in the subcutaneous group -- were deemed to be treatment related . INTERPRETATION Subcutaneous trastuzumab , administered over about 5 min , has a pharmacokinetic profile and efficacy non-inferior to st and ard intravenous administration , with a similar safety profile to intravenous trastuzumab , and therefore offers a valid treatment alternative . FUNDING F Hoffmann-La Roche PURPOSE To evaluate whether preoperative neoadjuvant chemotherapy in patients with primary operable breast cancer results in better overall survival ( OS ) and relapse-free survival rates and whether preoperative chemotherapy permits more breast-conserving surgery procedures than postoperative chemotherapy . PATIENTS AND METHODS Six hundred ninety-eight breast cancer patients ( T1c , T2 , T3 , T4b , N0 to 1 , and M0 ) were enrolled onto a r and omized phase III trial that compared four cycles of fluorouracil , epirubicin , and cyclophosphamide administered preoperatively versus the same regimen administered postoperatively ( the first cycle administered within 36 hours after surgery ) . Patients were followed up for OS , progression-free survival ( PFS ) , and locoregional recurrence ( LRR ) . RESULTS At a median follow-up of 56 months , there was no significant difference in terms of OS ( hazards ratio , 1.16 ; P = .38 ) , PFS ( hazards ratio , 1.15 ; P = .27 ) , and time to LRR ( hazards ratio , 1.13 ; P = .61 ) . Fifty-seven patients ( 23 % ) were downstaged by the preoperative chemotherapy , whereas 14 patients ( 18 % ) underwent mastectomy and not the planned breast-conserving therapy . CONCLUSION The use of preoperative chemotherapy yields similar results in terms of PFS , OS , and locoregional control compared with conventional postoperative chemotherapy . In addition , preoperative chemotherapy enables more patients to be treated with breast-conserving surgery . Because preoperative chemotherapy does not improve disease outcome compared with postoperative chemotherapy , future trials should involve quality -of-life studies to investigate whether patients will benefit from this treatment modality PURPOSE Triple-negative breast cancer ( TNBC ) is defined by the lack of estrogen receptor ( ER ) , progesterone receptor ( PR ) , and human epidermal growth factor receptor 2 ( HER-2 ) expression . In this study , we compared response to neoadjuvant chemotherapy and survival between patients with TNBC and non-TNBC . PATIENTS AND METHODS Analysis of a prospect ively collected clinical data base was performed . We included 1,118 patients who received neoadjuvant chemotherapy at M.D. And erson Cancer Center for stage I-III breast cancer from 1985 to 2004 and for whom complete receptor information were available .  Clinical and pathologic parameters , pathologic complete response rates ( pCR ) , survival measurements , and organ-specific relapse rates were compared between patients with TNBC and non-TNBC . RESULTS Two hundred fifty-five patients ( 23 % ) had TNBC . Patients with TNBC compared with non-TNBC had significantly higher pCR rates ( 22 % v 11 % ; P = .034 ) , but decreased 3-year progression-free survival rates ( P < .0001 ) and 3-year overall survival ( OS ) rates ( P < .0001 ) . TNBC was associated with increased risk for visceral metastases ( P = .0005 ) , lower risk for bone recurrence ( P = .027 ) , and shorter postrecurrence survival ( P < .0001 ) . Recurrence and death rates were higher for TNBC only in the first 3 years . If pCR was achieved , patients with TNBC and non-TNBC had similar survival ( P = .24 ) . In contrast , patients with residual disease ( RD ) had worse OS if they had TNBC compared with non-TNBC ( P < .0001 ) . CONCLUSION Patients with TNBC have increased pCR rates compared with non-TNBC , and those with pCR have excellent survival . However , patients with RD after neoadjuvant chemotherapy have significantly worse survival if they have TNBC compared with non-TNBC , particularly in the first 3 years PURPOSE The National Surgical Adjuvant Breast and Bowel Project Protocol B-27 was design ed to determine the effect of adding docetaxel after four cycles of preoperative doxorubicin and cyclophosphamide ( AC ) on clinical and pathological response rates and on disease-free and overall survival of women with operable breast cancer . PATIENTS AND METHODS Women ( N = 2,411 ) with operable primary breast cancer were r and omly assigned to receive either four cycles of preoperative AC followed by surgery ( group I ) , or four cycles of AC followed by four cycles of docetaxel , followed by surgery ( group II ) , or four cycles of AC followed by surgery and then four cycles of docetaxel ( group III ) . Clinical and pathologic tumor responses to preoperative therapy were assessed . RESULTS Mean tumor size ( 4.5 cm ) and other key characteristics were evenly balanced among the three treatment arms . Grade 4 toxicity was observed in 10.3 % of 2,400 patients during AC treatment , and in 23.4 % of 1584 patients during docetaxel treatment . Compared to preoperative AC alone , preoperative AC followed by docetaxel increased the clinical complete response rate ( 40.1 % v 63.6 % ; P < .001 ) , the overall clinical response rate ( 85.5 % v 90.7 % ; P < .001 ) , the pathologic complete response rate ( 13.7 % v 26.1 % ; P < .001 ) , and the proportion of patients with negative nodes ( 50.8 % v 58.2 % ; P < .001 ) . Pathologic primary breast tumor response was a significant predictor of pathologic nodal status ( P < .001 ) . CONCLUSION The addition of four cycles of preoperative docetaxel after four cycles of preoperative AC significantly increased clinical and pathologic response rates for operable breast cancer PURPOSE To determine whether preoperative doxorubicin and cyclophosphamide ( AC ) permits more lumpectomies to be performed and decreases the incidence of positive nodes in women with primary breast cancer . PATIENTS AND METHODS Women ( n = 1,523 ) were r and omized to National Surgical Adjuvant Breast and Bowel Project ( NSABP ) B-18 ; 759 eligible patients received postoperative AC and 747 , preoperative AC . The clinical size of breast and axillary tumors was determined before each of four cycles of AC and before surgery . Tumor response to preoperative therapy was clinical ly complete ( cCR ) , partial ( cPR ) , stable ( cSD ) , or progressive disease ( cPD ) . Tissue from patients with a cCR was evaluated for a pathologic complete response ( pCR ) . RESULTS Breast tumor size was reduced in 80 % of patients after preoperative therapy ; 36 % had a cCR . Tumor size and clinical nodal status were independent predictors of cCR . Twenty-six percent of women with a cCR had a pCR . Clinical nodal response occurred in 89 % of node-positive patients : 73 % had a cCR and 44 % of those had a pCR . There was a 37 % increase in the incidence of pathologically negative nodes . Before r and omization ,  lumpectomy  was proposed for 86 % of women with tumors < or = 2 cm , 70 % with tumors 2.1 to 5.0 cm , and 3 % with tumors > or = 5.1 cm . Clinical tumor size and nodal status influenced the physician 's decision . Overall , 12 % more lumpectomies were performed in the preoperative group ; in women with tumors > or = 5.1 cm , there was a 175 % increase . CONCLUSION Preoperative therapy reduced the size of most breast tumors and decreased the incidence of positive nodes . The greatest increase in lumpectomy after preoperative therapy occurred in women with tumors > or = 5 cm , since women with tumors less than 5 cm were already lumpectomy c and i date s. Preoperative therapy should be considered for the initial management of breast tumors judged too large for lumpectomy
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