Differential Response to Neoadjuvant Chemotherapy Among 7 Triple-Negative Breast Cancer Molecular Subtypes Ki67 levels as predictive and prognostic parameters in pretherapeutic breast cancer core biopsies: a translational investigation in the neoadjuvant GeparTrio trial. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. The Triple Negative Paradox: Primary Tumor Chemosensitivity of Breast Cancer Subtypes A phase II study of sequential neoadjuvant gemcitabine plus doxorubicin followed by gemcitabine plus cisplatin in patients with operable breast cancer: prediction of response using molecular profiling Tailored preoperative treatment of locally advanced triple negative (hormone receptor negative and HER2 negative) breast cancer with epirubicin, cisplatin, and infusional fluorouracil followed by weekly paclitaxel The use of neoadjuvant platinum-based chemotherapy in locally advanced breast cancer that is triple negative: retrospective analysis of 144 patients Weekly paclitaxel plus carboplatin is an effective nonanthracycline-containing regimen as neoadjuvant chemotherapy for breast cancer. Neoadjuvant bevacizumab and anthracycline-taxane-based chemotherapy in 678 triple-negative primary breast cancers; results from the geparquinto study (GBG 44). Effect of adding gefitinib to neoadjuvant chemotherapy in estrogen receptor negative early breast cancer in a randomized phase II trial Triple-Negative Breast Cancer: Early Assessment with 18F-FDG PET/CT During Neoadjuvant Chemotherapy Identifies Patients Who Are Unlikely to Achieve a Pathologic Complete Response and Are at a High Risk of Early Relapse Effect of neoadjuvant anthracycline–taxane-based chemotherapy in different biological breast cancer phenotypes: overall results from the GeparTrio study A randomized phase II trial of platinum salts in basal-like breast cancer patients in the neoadjuvant setting. Results from the GEICAM/2006-03, multicenter study CK5/6, EGFR, Ki-67, cyclin D1, and nm23-H1 protein expressions as predictors of pathological complete response to neoadjuvant chemotherapy in triple-negative breast cancer patients Multicentre phase II trial of bevacizumab combined with docetaxel-carboplatin for the neoadjuvant treatment of triple-negative breast cancer (KCSG BR-0905). Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. A Phase II Trial of Docetaxel and Carboplatin Administered Every 2 Weeks as Preoperative Therapy for Stage II or III Breast Cancer: NCCTG Study N0338 A phase II trial of a neoadjuvant platinum regimen for locally advanced breast cancer: pathologic response, long-term follow-up, and correlation with biomarkers. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. Frequent pathologic complete responses in aggressive stages II to III breast cancers with every-4-week carboplatin and weekly paclitaxel with or without trastuzumab: a Brown University Oncology Group Study. A phase II study of the combination of gemcitabine plus carboplatin as the neoadjuvant treatment in locally advanced breast cancer.
Purpose : The clinical relevancy of the 7-subtype classification of triple-negative breast cancer ( TNBC ) reported by Lehmann and colleagues is unknown . We investigated the clinical relevancy of TNBC heterogeneity by determining pathologic complete response ( pCR ) rates after neoadjuvant chemotherapy , based on TNBC subtypes . Experimental Design : We revali date d the Lehmann and colleagues experiments using Affymetrix CEL files from public data sets . We applied these methods to 146 patients with TNBC with gene expression microarrays obtained from June 2000 to March 2010 at our institution . Of those , 130 had received st and ard neoadjuvant chemotherapy and had evaluable pathologic response data . We classified the TNBC sample s by subtype and then correlated subtype and pCR status using Fisher exact test and a logistic regression model . We also assessed survival and compared the subtypes with PAM50 intrinsic subtypes and residual cancer burden ( RCB ) index . Results : TNBC subtype and pCR status were significantly associated ( P = 0.04379 ) . The basal-like 1 ( BL1 ) subtype had the highest pCR rate ( 52 % ) ; basal-like 2 ( BL2 ) and luminal and rogen receptor had the lowest ( 0 % and 10 % , respectively ) . TNBC subtype was an independent predictor of pCR status ( P = 0.022 ) by a likelihood ratio test . The subtypes better predicted pCR status than did the PAM50 intrinsic subtypes ( basal-like vs. non basal-like ) . Conclusions : Classifying TNBC by 7 subtypes predicts high versus low pCR rate . We confirm the clinical relevancy of the 7 subtypes of TNBC . We need to prospect ively vali date whether the pCR rate differences translate into long-term outcome differences . The 7-subtype classification may spur innovative personalized medicine strategies for patients with TNBC . Clin Cancer Res ; 19(19 ) ; 5533–40 . © 2013 AACR 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 BACKGROUND Studies with pertuzumab , a novel anti-HER2 antibody , show improved efficacy when combined with the established HER2-directed antibody trastuzumab in breast cancer therapy . We investigated the combination of pertuzumab or trastuzumab , or both , with docetaxel and the combination of pertuzumab and trastuzumab without chemotherapy in the neoadjuvant setting . METHODS In this multicentre , open-label , phase 2 study , treatment-naive women with HER2-positive breast cancer were r and omly assigned ( 1:1:1:1 ) central ly and stratified by operable , locally advanced , and inflammatory breast cancer , and by hormone receptor expression to receive four neoadjuvant cycles of : trastuzumab ( 8 mg/kg loading dose , followed by 6 mg/kg every 3 weeks ) plus docetaxel ( 75 mg/m(2 ) , escalating , if tolerated , to 100 mg/m(2 ) every 3 weeks ; group A ) or pertuzumab ( loading dose 840 mg , followed by 420 mg every 3 weeks ) and trastuzumab plus docetaxel ( group B ) or pertuzumab and trastuzumab ( group C ) or pertuzumab plus docetaxel ( group D ) . The primary endpoint , examined in the intention-to-treat population , was pathological complete response in the breast . Neither patients nor investigators were masked to treatment . This study is registered with Clinical Trials.gov , number NCT00545688 . FINDINGS Of 417 eligible patients , 107 were r and omly assigned to group A , 107 to group B , 107 to group C , and 96 to group D. Patients given pertuzumab and trastuzumab plus docetaxel ( group B ) had a significantly improved pathological complete response rate ( 49 of 107 patients ; 45·8 % [ 95 % CI 36·1 - 55·7 ] ) compared with those given trastuzumab plus docetaxel ( group A ; 31 of 107 ; 29·0 % [ 20·6 - 38·5 ] ; p=0·0141 ) . 23 of 96 ( 24·0 % [ 15·8 - 33·7 ] ) women given pertuzumab plus docetaxel ( group D ) had a pathological complete response , as did 18 of 107 ( 16·8 % [ 10·3 - 25·3 ] ) given pertuzumab and trastuzumab ( group C ) . The most common adverse events of grade 3 or higher were neutropenia ( 61 of 107 women in group A , 48 of 107 in group B , one of 108 in group C , and 52 of 94 in group D ) , febrile neutropenia ( eight , nine , none , and seven , respectively ) , and leucopenia ( 13 , five , none , and seven , respectively ) . The number of serious adverse events was similar in groups A , B , and D ( 15 - 20 serious adverse events per group in 10 - 17 % of patients ) but lower in group C ( four serious adverse events in 4 % of patients ) . INTERPRETATION Patients given pertuzumab and trastuzumab plus docetaxel ( group B ) had a significantly improved pathological complete response rate compared with those given trastuzumab plus docetaxel , without substantial differences in tolerability .  Pertuzumab and trastuzumab without chemotherapy eradicated tumours in a proportion of women and showed a favourable safety profile . These findings justify further exploration in adjuvant trials and support the neoadjuvant approach for accelerating drug assessment in early breast cancer . FUNDING F Hoffmann-La Roche 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 This study examined the pathological complete response ( pCR ) rate and safety of sequential gemcitabine-based combinations in breast cancer . We also examined gene expression profiles from tumour biopsies to identify biomarkers predictive of response . Indian women with large or locally advanced breast cancer received 4 cycles of gemcitabine 1200 mg m−2 plus doxorubicin 60 mg m−2 ( Gem+Dox ) , then 4 cycles of gemcitabine 1000 mg m−2 plus cisplatin 70 mg m−2 ( Gem+Cis ) , and surgery . Three alternate dosing sequences were used during cycle 1 to examine dynamic changes in molecular profiles . Of 65 women treated , 13 ( 24.5 % of 53 patients with surgery ) had a pCR and 22 ( 33.8 % ) had a complete clinical response . Patients administered Gem d1 , 8 and Dox d2 in cycle 1 ( 20 of 65 ) reported more toxicities , with G3/4 neutropenic infection/febrile neutropenia ( 7 of 20 ) as the most common cycle-1 event . Four drug-related deaths occurred . In 46 of 65 patients , 10-fold cross vali date d supervised analyses identified gene expression patterns that predicted with ⩾73 % accuracy ( 1 ) clinical complete response after eight cycles , ( 2 ) overall clinical complete response , and ( 3 ) pCR . This regimen shows strong activity . Patients receiving Gem d1 , 8 and Dox d2  experienced unacceptable toxicity , whereas patients on other sequences had manageable safety profiles . Gene expression patterns may predict benefit from gemcitabine-containing neoadjuvant therapy Background No specific treatment guidelines are available for triple-negative breast cancers , defined by a lack of expression of estrogen ( ER ) , progesterone ( PgR ) , and HER2 receptors . Patients and methods We investigated in patients with T2–T3 N0 - 3 ER , PgR < 10 % and HER2 negative breast cancers the activity both in terms of pathological ( pCR ) and objective responses of four courses of cisplatin containing chemotherapy ( ECF , epirubicin , cisplatin , and fluorouracil as continuous infusion ) followed by three courses of weekly paclitaxel . Adjuvant metronomic chemotherapy including cyclophosphamide and methotrexate for 4–6 months was administered . Results Thirty patients are evaluable . Median age was 41 years ( 28–64 years ) . Twenty-three of 25 evaluable tumors stained positively for epidermal growth factor receptor . An objective response , either complete and partial , was observed in 26 patients ( 86 , 95 % CI 69.3–96.2 % ) . and a pCR was obtained in 12 patients ( 40 , 95 % CI 22.7–59.4 % ) . Two patients progressed during paclitaxel . Negative axillary nodes were found in 80 % ( 95 % CI 61.4–92.3 % ) of patients at surgery . Twenty-six patients ( 86 , 95 % CI 61.4–92.3 % ) underwent breast conserving surgery . Grade > 2 non-hematological toxicity was observed in three and two patients during ECF and paclitaxel , respectively . The 2-year disease free survival ( DFS ) was 87.5 % ( 95 % CI 74.7–100 % ) . No significant correlation was observed between EGFR staining and either pCR or DFS . Conclusions Preoperative cisplatin containing chemotherapy followed by paclitaxel induced an high pCR rate in a population of triple-negative breast cancer . The impact of this schedule on long-term outcome should be investigated in larger series Triple-negative breast cancers comprise about 20 % of breast cancers . They have poor prognosis and have no st and ard therapy . The aim of this study was to evaluate pathologic complete response ( pCR ) , progression-free survival ( PFS ) , and overall survival ( OS ) in patients with TNBC treated with neoadjuvant platinum-based chemotherapy .  This is a retrospective study of one hundred and forty-four women with TNBC treated with neoadjuvant platinum-containing chemotherapy for locally advanced breast cancer at the University of Miami between January 1 , 1999 , and January 1 , 2011 . The medical record was review ed to obtain data on clinical characteristics , including ethnicity , race , age , clinical stage , treatment regimen , and vital status . This study was approved by the University of Miami IRB . All patients had locally advanced breast cancer with at least one of the following features at presentation : T3 , T4 , N2 , and N3 . The mean tumor size by palpation was 9.4 cm . The clinical T-stage at presentation was 1.4 % T1 , 8.3 % T2 , 52.8 % T3 , and 37.5 % T4 ( 19.4 % T4d ) . The nodal status by physical exam at presentation was 23 % N0 , 37.5 % N1 , 34 % N2 , and 5.5 % N3 . pCR in breast and axilla was seen in 31 % . PFS and OS were 55 and 59 % , respectively , at 7 years . Cisplatin offered a survival advantage over carboplatin in both PFS ( P = 0.007 ) and OS ( P = 0.018 ) . Node positivity was the most important predictor of survival  . Cisplatin/docetaxel neoadjuvant therapy was well tolerated and an effective therapy in locally advanced TNB BACKGROUND To evaluate the activity and safety of nonanthracycline-containing weekly PCb [ paclitaxel ( Taxol ) plus carboplatin ] regimen in neoadjuvant treatment of breast cancer . PATIENTS AND METHODS Eligible patients were assigned to receive four cycles of PCb with dose of paclitaxel 80 mg/m(2 ) and carboplatin at an area under the curve of 2 mg x min/ml , given day 1 , day 8 and day 15 of every 4 weeks . Pathological complete remission ( pCR ) was defined as no invasive cancer in breast and axillary sample s. RESULTS Overall , 107 consecutive patients received weekly PCb treatment from December 2007 to December 2008 , and one was diagnosed with bilateral breast cancer . A total of 85.2 % of patients were initially diagnosed with stage III diseases . Clinical response rate was 86.1 % with complete remission rate 32.4 % . Twenty-one patients achieved pCR after neoadjuvant treatment , with pCR rate 19.4 % . The incidence of grade 3 - 4 neutropenia was 40.2 % and only one patient was reported with febrile neutropenia . Severe anemia and thrombocytopenia occurred in 4.7 % and 0.9 % , respectively , of patients . Peripheral neuropathy was frequent but never severe . Patients with estrogen receptor-negative , progesterone receptor-negative , triple-negative or human epidermal growth factor receptor 2 (Her2)-positive subtype disease had higher pCR . CONCLUSIONS Weekly PCb regimen was very active and tolerable as neoadjuvant treatment of breast cancer . This weekly PCb regimen should consider as a reasonable nonanthracycline-containing option in the neoadjuvant treatment of breast cancer BACKGROUND We evaluated the pathological complete response ( pCR ) rate after neoadjuvant epirubicin , ( E ) cyclophosphamide ( C ) and docetaxel containing chemotherapy with and without the addition of bevacizumab in patients with triple-negative breast cancer ( TNBC ) . PATIENTS AND METHODS Patients with untreated cT1c-4d TNBC represented a stratified subset of the 1948 participants of the HER2-negative part of the GeparQuinto trial . Patients were r and omized to receive four cycles EC ( 90/600 mg/m(2 ) ; q3w ) followed by four cycles docetaxel ( 100 mg/m(2 ) ; q3w ) each with or without bevacizumab ( 15 mg/kg ; q3w ) added to chemotherapy . RESULTS TNBC patients were r and omized to chemotherapy without ( n = 340 ) or with bevacizumab ( n = 323 ) . pCR ( ypT0 ypN0 , primary end point ) rates were 27.9 % without and 39.3 % with bevacizumab ( P = 0.003 ) . According to other pCR definitions , the addition of bevacizumab increased the pCR rate from 30.9 % to 41.8 % ( ypT0 ypN0/+ ; P = 0.004 ) , 36.2 % to 46.4 % ( ypT0/is ypN0/+ ; P = 0.009 ) and 32.9 % to 43.3 % ( ypT0/is ypN0 ; P = 0.007 ) .  Bevacizumab  treatment [ OR 1.73 , 95 % confidence interval ( CI ) 1.23 - 2.42 ; P = 0.002 ] , lower tumor stage ( OR 2.38 , 95 % CI 1.24 - 4.54 ; P = 0.009 ) and grade 3 tumors ( OR 1.68 , 95 % CI 1.14 - 2.48 ; P = 0.009 ) were confirmed as independent predictors of higher pCR in multivariate logistic regression analysis . CONCLUSIONS The addition of bevacizumab to chemotherapy in TNBC significantly increases pCR rates Gefitinib , an epidermal growth factor receptor tyrosine kinase inhibitor , has shown both anti-proliferative and anti-tumoral activity in breast cancer . This study was design ed to determine the effect of adding gefitinib to neoadjuvant epirubicin and cyclophosphamide ( EC ) on tumor response rates . Women with unilateral , primary operable , estrogen receptor negative invasive breast cancer ≥ 2 cm were eligible for inclusion . R and omized patients were to receive four cycles of neoadjuvant EC plus 12 weeks of either gefitinib ( 250 mg daily ) or placebo . Primary endpoint was pathologic complete response ( pCR ) , and secondary endpoints were complete response ( CR ) and overall objective response ( OR ) . 181 patients were r and omized .  A pCR was observed in 17 % ( 12/71 ) of patients treated with gefitinib and in 12 % ( 9/73 ) of patients treated with placebo ( 4.57 % difference , 95 % CI −7.19 to 6.33 ; P = 0.44 ) . CR was observed in 10 % of patients in both the gefitinib ( 7/71 ) and the placebo group ( 7/73 ) ( 0.27 % difference , 95 % CI −9.6 to 10.2 ; P = 0.96 ) . There was no significant difference in OR ( 5.96 % ; 95 % CI −9.9 to 21.9 ; P = 0.45 ) between the two groups . Post hoc subgroup analysis showed a significant difference in pCR between triple negative breast cancer ( TNBC ) and non-TNBC tumors ( P = 0.03 ) . More patients in the gefitinib arm had hematological toxicity ( P = 0.15 ) and discontinued treatment ( 9/94 vs. 2/86 ) because of adverse events ( AE ) . Tumor response rates were similar in the two groups . A significantly higher pCR rate was observed post hoc in TNBC versus non-TNBC independent of treatment . More patients in the gefitinib group discontinued treatment because of AE Triple-negative breast cancer , an aggressive subtype , represents 15 % of invasive breast tumors . This prospect i ve study investigated whether early changes in 18F-FDG tumor uptake during neoadjuvant chemotherapy ( NAC ) can predict outcomes . Methods : Twenty ( M0 ) patients underwent 18F-FDG PET/CT at baseline and after the second cycle . NAC was continued irrespective of PET results . Results : At surgery , 6 patients had a pathologic complete response , whereas 14 had residual tumor . Four patients showed early relapse ( in the 2 y after surgery ) . There were 11 metabolic responders and 9 nonresponders using a 42 % decrease in maximum st and ardized uptake value as a cutoff . In nonresponding patients , the risk of residual tumor at surgery was 100 % ( vs. 45 % in responders ; P = 0.014 ) , and the risk of early relapse was 44 % ( vs. 0 % ; P = 0.024 ) . Conclusion : A less than 42 % decrease in 18F-FDG uptake at 2 cycles means residual tumor at the end of NAC and a high risk of early relapse In order to explore the effect of neoadjuvant chemotherapy ( NACT ) on clinical mid-course and pathological complete response ( pCR ) at surgery in different biological breast cancer subtypes . The GeparTrio study included 2,072 patients with operable or locally advanced breast cancer . After two cycles with docetaxel , doxorubicin and cyclophosphamide ( TAC ) patients were r and omized according to their clinical response . Clinical and biological factors were assessed for predicting clinical ly mid-course response and pCR at surgery . The overall pCR rate , defined as no invasive residuals in breast and axilla , was 20.5 % . The highest pCR rate of 57 % was observed in patients below 40 years of age with triple negative or grade 3 tumors . Independent factors for mid-course response and pCR were : young age , non-T4 tumors , high grade , and hormone receptor status , the strongest single predictive factor . Within the biological subtypes , grading was an independent factor to predict pCR for luminal tumors , clinical tumor stage for the HER2 like tumors and age for the triple negative ones . Grading gave independent information for mid-course response within the triple negative group . No factor predicted mid-course response within the other groups . Grading and age can identify subgroups within the luminal and triple negative patients who have an increased benefit from NACT Chemotherapy remains as the only systemic treatment option available for basal-like breast cancer ( BC ) patients . Pre clinical models and several phase II studies suggested that platinum salts are active drugs in this BC subtype though there is no r and omized study supporting this hypothesis . This study investigates if the addition of carboplatin to a combination of an alkylating agent together with anthracyclines and taxanes is able to increase the efficacy in the neoadjuvant treatment context . Patients with operable breast cancer and immunophenotypically defined basal-like disease ( ER-/PR-/HER2- and cytokeratin 5/6 + or EGFR+ ) were recruited . Patients were r and omized to receive EC ( epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 for 4 cycles ) followed either by D ( docetaxel 100 mg/m2 × 4 cycles ; EC – D ) or DCb ( docetaxel 75 mg/m2 plus carboplatin AUC 6 × 4 cycles ; EC – DCb ) . The primary end point was pathological complete response ( pCR ) in the breast following the Miller and Payne criteria . Ninety-four patients were r and omized ( 46 EC – D , 48 EC – DCb ) . pCR rate in the breast was seen in 16 patients ( 35 % ) with EC – D and 14 patients ( 30 % ) with EC – DCb ( P value = 0.61 ) . pCR in the breast and axilla was seen in 30 % of patients in both arms . The overall clinical response rate was 70 % ( 95 % CI 56–83 ) in the EC – D arm and 77 % ( 95 % CI 65–87 ) in the EC – DCb arm . Grade 3/4 toxicity was similar in both arms . The addition of carboplatin to conventional chemotherapy with EC – D in basal-like breast cancer patients did not improve the efficacy probably because they had already received an alkylating agent . These findings should be taken into consideration when developing new agents for this disease The purpose of this study was to evaluate the importance of biological markers to predict pathologic complete response ( pCR ) to neoadjuvant chemotherapy ( NCT ) in patients with locally advanced triple-negative breast cancers ( TNBCs ) . Forty-one patients ( 18.6 % ) among 220 breast cancer patients were identified as TNBCs from March 2006 to 2009 were included in this prospect i ve study . The pre-NCT treatment  expression levels of Ki-67 proliferation index , estrogen receptor ( ER ) , progesterone receptor ( PgR ) , epidermal growth factor receptor 2 ( HER-2 ) , CK5/6 , epidermal growth factor receptor ( EGFR ) , cyclin D1 , and nm23-H1 were detected by immunohistochemistry ( IHC ) . A total of 180 cycles were administered with the median number of four cycles per patient ( range , 4–6 ) . The pCR rate was 34.1 % ( 95 % CI , 19.6–48.6 % ) . In univariate analysis , early T stage , clinical response after 2 cycles , negative basal-like , negative EGFR , high Ki-67 proliferation index , and positive nm23-H1 were found to be significantly predictive of a pCR ( P = 0.010 , 0.040 , 0.007 , 0.001 , 0.019 , and 0.010 , respectively ) . Basal-like status and nm23-H1 status were significant for pCR on multivariate analysis ( P = 0.004 and 0.031 , respectively ) . Basal-like status and nm23-H1 are independent predictive factors of pCR to neoadjuvant docetaxel plus epirubicin combination chemotherapy in patients with TNBCs BACKGROUND This phase II neoadjuvant trial evaluated bevacizumab-docetaxel and carboplatin in triple-negative breast cancer . PATIENTS AND METHODS Women with hormone receptor- and human epidermal growth factor receptor 2 (HER2)-negative , stage II/III breast cancer received six cycles of 75 mg/m(2 ) docetaxel , carboplatin ( AUC = 5 ) and 15 mg/kg bevacizumab every 21 days . The primary end point was pathological complete response ( pCR ) in breasts and axillary lymph nodes ( ALN ) . RESULTS Forty-five patients were recruited from the Korean Cancer Study Group . The median age was 45 ( range 30 - 72 ) years .  ALNs were positive in 80 % of patients ( n = 36 ) at diagnosis . Overall , 98 % of patients ( n = 44 ) completed therapy and underwent surgery . The pCR rate was 42 % ( n = 19 ) ; clinical response rate 96 % ( n = 43 ) ; complete 13 % ( n = 6 ) ; partial 82 % ( n = 37 ) ; stable disease 2 % ( n = 1 ) . Breast-conserving surgery was undertaken in 78 % of patients ( n = 35 ) . Most frequent grade 3/4 adverse events were neutropenia ( 84 % , n = 38 ) and febrile neutropenia ( 9 % , n = 4 ) . One patient experienced delayed wound healing after surgery . CONCLUSIONS Neoadjuvant bevacizumab , docetaxel and carboplatin result ed in an encouraging pCR rate and negligible wound healing problems after surgery PURPOSE The exact definition of pathologic complete response ( pCR ) and its prognostic impact on survival in intrinsic breast cancer subtypes is uncertain . METHODS Tumor response at surgery and its association with long-term outcome of 6,377 patients with primary breast cancer receiving neoadjuvant anthracycline-taxane-based chemotherapy in seven r and omized trials were analyzed . RESULTS Disease-free survival ( DFS ) was significantly superior in patients with no invasive and no in situ residuals in breast or nodes ( n = 955 ) compared with patients with residual ductal carcinoma in situ only ( n = 309 ) , no invasive residuals in breast but involved nodes ( n = 186 ) , only focal-invasive disease in the breast ( n = 478 ) , and gross invasive residual disease ( n = 4,449 ; P < .001 ) . Hazard ratios for DFS comparing patients with or without pCR were lowest when defined as no invasive and no in situ residuals ( 0.446 ) and increased monotonously when in situ residuals ( 0.523 ) , no invasive breast residuals but involved nodes ( 0.623 ) , and focal-invasive disease ( 0.727 ) were included in the definition . pCR was associated with improved DFS in luminal B/human epidermal growth factor receptor 2 ( HER2 ) -negative ( P = .005 ) , HER2-positive/nonluminal ( P < .001 ) , and triple-negative ( P < .001 ) tumors but not in luminal A ( P = .39 ) or luminal B/HER2-positive ( P = .45 ) breast cancer . pCR in HER2-positive ( nonluminal ) and triple-negative tumors was associated with excellent prognosis . CONCLUSION pCR defined as no invasive and no in situ residuals in breast and nodes can best discriminate between patients with favorable and unfavorable outcomes . Patients with noninvasive or focal-invasive residues or involved lymph nodes should not be considered as having achieved pCR . pCR is a suitable surrogate end point for patients with luminal B/HER2-negative , HER2-positive ( nonluminal ) , and triple-negative disease but not for those with luminal B/HER2-positive or luminal A tumors Objective : We conducted a multicenter phase II trial to assess the efficacy and toxicity of docetaxel and carboplatin combination as neoadjuvant therapy for stage II or III breast cancer ( BC ) . Methods : Patients received 75 mg/m2 of docetaxel and AUC 6 of carboplatin on day 1 followed by pegfilgrastim on day 2 , every 14 days for 4 cycles , followed by definitive breast surgery . The primary endpoint was the proportion of patients achieving pathologic complete remission ( pCR ) , defined as disappearance of all invasive and in situ tumors in the breast and axilla after chemotherapy . Results : A total of 57 women ( median age , 53 y ) were enrolled . Thirty-eight ( 67 % ) had ER+ , 31 ( 54 % ) PR+ , and 6 ( 11 % ) HER2 + disease ; 9 had triple negative BC ( TNBC ) . Forty-three ( 75 % ; 95 % confidence interval , 62%-86 % ) of 57 eligible patients had clinical response ( 15 clinical complete response , 28 clinical partial response ) . Nine ( 16 % ; 90 % confidence interval , 10%-28 % ) patients achieved pCR . Four of 9 ( 44 % ) patients with TNBC achieved pCR . Thrombocytopenia ( 5 % ) was the only grade 4 adverse event . The most common grade 3 adverse events were thrombocytopenia ( 19 % ) , fatigue ( 12 % ) , and anemia ( 9 % ) . Conclusions : Four cycles of 2-weekly Docetaxel and Carboplatin are feasible with acceptable toxicity and a pCR rate of 16 % . This regimen can be considered for neoadjuvant therapy of BC , particularly for patients not eligible for anthracycline therapy . A high pCR rate of 44 % noted in a subset of patients with TNBC is encouraging and needs to be vali date d in large prospect i ve trials PURPOSE The purpose of this study is to determine the response , tolerability , and long-term outcome of a neoadjuvant platinum-containing regimen for locally advanced breast cancer ( LABC ) and to search for a correlation between pathologic complete response ( pCR ) and predefined biomarkers in this cohort . PATIENTS AND METHODS Patients with LABC received 8 cycles of either sequence A or B. Sequence A was doxorubicin 60 mg/m(2 ) and paclitaxel 175 mg/m(2 ) ( AT ) every 3 weeks x 4 followed by cisplatin ( C ) 60 mg/m(2 ) and paclitaxel 90 mg/m(2 ) ( CT ) every 2 weeks x 4 . Sequence B was CT x 4 ( with paclitaxel dose escalation ) followed by AT x 4 . In addition to estrogen receptor ( ER ) and HER2 , immunohistochemistry for MDR-1 , MRP-1 , topoisomerase IIalpha ( topo IIalpha ) , and p53 was performed . RESULTS A total of 88 patients were evaluable for response and toxicity . Median follow-up was 97 months . The overall pCR rate was 21.5 % . For subgroups ER+/HER2- , HER2 + and double negative ( ER-/HER2- ) disease , the pCR rates were 5.9 % , 23.3 % , and 35 % , respectively ( P = .006 ) . Five-year overall survival for the entire cohort was 71.1 % . Five-year overall survival was 88.1 % ( 95 % CI , 77.1%-99.1 % ) for the ER+/HER2- group compared with 68.5 % ( 95 % CI , 51.3%-85.7 % ) and 49.5 % ( 95 % CI , 27.4%-71.6 % ) in the HER2 + and " double-negative " group , respectively ( P = .0077 ) . Overexpression of topo IIalpha was correlated with pCR ( P < .001 ) . There were no toxic deaths . CONCLUSION A platinum-containing neoadjuvant regimen was well tolerated and achieved a pCR comparable to other recent studies of multiagent chemotherapy . Further studies tailored for specific breast cancer subtypes are required 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 To evaluate the efficacy and safety of neoadjuvant carboplatin and weekly paclitaxel + /- weekly trastuzumab in resectable and locally advanced breast cancer . PATIENTS AND METHODS Women with stages IIA to IIIB disease received carboplatin dosed by six times the area under the curve every 4 weeks and paclitaxel 80 mg/m(2 ) weekly for 16 weeks , and weekly trastuzumab was added for human epidermal growth factor receptor 2 ( HER2 ) -positive status . The primary end point was the pathologic complete response ( pCR ) rate , defined as the absence of invasive disease in the breast and axillary nodes . Postoperative therapies were at the discretion of the treating physicians . RESULTS Fifty-five patients were enrolled , and of these 43 had resectable disease . The median age was 54 years ( range , 31 to 74 years ) . Treatment was well tolerated ; there were no episodes of febrile neutropenia or grade 4 thrombocytopenia , and there were only two instances of grade 3 peripheral neuropathy . Overall , the pCR rate was 45 % . The pCR rate was 43 % ( 95 % CI , 28 % to 58 % ) in patients with resectable disease . Higher pCR rates occurred in patients with HER2-positive tumors ( 76 % v 31 % for HER2-negative tumors ; P = .003 ) , with estrogen receptor ( ER ) -negative tumors ( 75 % v 27 % for ER-positive tumors ; P = .001 ) , or with triple-negative tumors ( 67 % v 12 % ER-positive and HER2-negative tumors ; P = .002 ) . At a median of 28 months postoperation , recurrence-free survival ( RFS ) was 88.7 % . If patients with ER-positive and HER2-negative tumors are excluded from analysis , patients who achieved a pCR were less likely to experience disease recurrence ( RFS , 86 % ) than those who did not achieve a pCR ( RFS , 75 % ) . CONCLUSION Neoadjuvant carboplatin and weekly paclitaxel + /- trastuzumab achieve high pCR rates in patients with HER2-positive and triple-negative disease without exposure to an anthracycline . Preliminary RFS results are encouraging but are likely influenced by adjuvant therapy received . Additional study of this regimen in high-risk patients is warranted OBJECTIVE Although anthracycline-based regimen is st and ard neoadjuvant chemotherapy ( NAC ) for locally advanced breast cancer ( LABC ) , there is some concern over its toxicities such as alopecia and cardiotoxicity .  Gemcitabine is another active agent in metastatic breast cancer after failure to anthracycline with less toxicity . The objective of the present study is to evaluate the efficacy and safety of the combination of gemcitabine and carboplatin as NAC in LABC . MATERIAL AND METHOD Patients with histologically confirmed LABC ( T3 , T4 or N2 and M0 ) were included . Patients were scheduled to receive 3 cycles of neoadjuvant GC ( gemcitabine 1,000 mg/m2 D1 , D8 and carboplatin AUC x 5 D1 ) every 21 days . Patients with clinical response underwent surgery and additional 3 cycles of adjuvant GC . Primary endpoint was clinical response rate whereas secondary endpoints included pathological response , DFS , OS and toxicity . RESULTS Between 2004 and 2007 , 40 LABC patients were enrolled . Of 40 patients , 35 were evaluable for efficacy and 40 for toxicity . Twenty-three out of 35 patients ( 65 % ) obtained cPR . Among 22 patients who had clinical response and who underwent surgery , overall pathological response rate was 51.5 % with 1-pCR ( 2.9 % ) and 17-pPR ( 48.5 % ) . All 7 triple-negative patients had pathological response ( 1-pCR , 6-pPR ) . At median follow-up of 59 months , median DFS and OS were not reached . Five-year OS and DFS were 67 % and 62 % , respectively Major adverse effect was myelosuppression without fatal complications . CONCLUSION The combination GC was feasible and well-tolerated for LABC in neoadjuvant setting . Triple-negative subgroup seems to have high response to GC
Platinum agents such as cisplatin and carboplatin are DNA-damaging agents with activity in breast cancer ( BC ) , particularly in the triple negative ( TN ) subgroup .
The utility of platinum agents , in addition to st and ard neoadjuvant chemotherapy ( NAC ) , is controversial .