Comparison of Neoadjuvant Nab-Paclitaxel+Carboplatin vs Nab-Paclitaxel+Gemcitabine in Triple-Negative Breast Cancer: Randomized WSG-ADAPT-TN Trial Results Better pathologic complete response and relapse-free survival after carboplatin plus paclitaxel compared with epirubicin plus paclitaxel as neoadjuvant chemotherapy for locally advanced triple-negative breast cancer: a randomized phase 2 trial The Triple Negative Paradox: Primary Tumor Chemosensitivity of Breast Cancer Subtypes Germline Mutation Status, Pathological Complete Response, and Disease-Free Survival in Triple-Negative Breast Cancer: Secondary Analysis of the GeparSixto Randomized Clinical Trial Pathologic complete response to neoadjuvant cisplatin in BRCA1-positive breast cancer patients Germline BRCA mutation evaluation in a prospective triple-negative breast cancer registry: implications for hereditary breast and/or ovarian cancer syndrome testing Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial 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 Randomized phase II study of weekly paclitaxel with and without carboplatin followed by cyclophosphamide/epirubicin/5-fluorouracil as neoadjuvant chemotherapy for stage II/IIIA breast cancer without HER2 overexpression Homologous Recombination Deficiency (HRD) Score Predicts Response to Platinum-Containing Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). Carboplatin plus paclitaxel once a week versus every 3 weeks in patients with advanced ovarian cancer (MITO-7): a randomised, multicentre, open-label, phase 3 trial. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial.
Background Pathological complete response ( pCR ) is associated with improved prognosis in triple-negative breast cancer ( TNBC ) . The optimal chemotherapy regimen is unclear . Weekly nab-paclitaxel vs conventional paclitaxel or addition of carboplatin to anthracycline-taxane results in higher pCR rates with uncertain survival impact . We evaluated carboplatin vs gemcitabine with a nab-paclitaxel backbone as a short 12-week A-free regimen with a focus on early response . Methods Patients with TNBC ( estrogen receptor/progesterone receptor < 1 % , human epidermal growth factor receptor 2-negative , cT1c-cT4c , cN0/+ ) were r and omly assigned to A : nab-paclitaxel 125 mg/m2/gemcitabine 1000 mg/m2 d1,8 three times weekly ( q3w ) ; vs B : nab-paclitaxel 125 mg/m2/carboplatin AUC2 day 1,8 q3w . The trial was powered for a pCR ( ypT0/is ypN0 ) comparison by therapy arm and early response ( defined as Ki-67 decrease > 30 % or < 500 invasive tumor cells in the three-week serial biopsy ) . All statistical tests were two-sided . Results A total of 336 patients were enrolled ( 48 centers , arms A/B : n = 182/154 ) . The median age was 50 years . At baseline ( A vs B ) , 62.6 % and 62.9 % had cT2 - 4c tumors ; 86.8 % and 90.9 % completed therapy per protocol , respectively . pCR favored arm B ( 28.7 % , 95 % CI = 0.22 to 0.36 , vs 45.9 % , 95 % CI = 0.38 to 0.54 ; 95 % CI(dBA ) = 6.2 % to 27.9 % , P = .002 ) and was lower in nonresponders than in early responders ( 19.5 % vs 44.4 % , P < .001 ) or in patients with unclassifiable early response ( 50.0 % ) . The nab-paclitaxel/gemcitabine was associated with more frequent dose reductions ( 20.6 % vs 11.9 % , P = .04 ) , treatment-related serious adverse events ( 11.1 % vs 5.3 % , P = .07 ) , grade 3 - 4 infections ( 7.2 % vs 2.6 % , P = .07 ) , and grade 3 - 4 ALAT elevations ( 11.7 vs 3.3 % , P = .01 ) . Conclusions This first large r and omized trial suggests high efficacy and excellent tolerability of a neoadjuvant nab-paclitaxel/carboplatin regimen , superior to nab-paclitaxel/gemcitabine in TNBC . De-escalation of further chemotherapy in patients with early pCR after a short anthracycline-free regimen is a promising field of future research . Early necrotic morphological changes and /or proliferation decrease after the first therapy cycle seem to be associated with subsequent pCR Background : No st and ard chemotherapy is used as neoadjuvant therapy in triple negative breast cancer ( TNBC ) . This study has compared carboplatin plus paclitaxel with commonly used epirubicin plus paclitaxel as neoadjuvant chemotherapy ( NAC ) in TNBC . Results : 91 patients with a median age of 47 years ( PC 47 patients , EP 44 patients ) were enrolled . 65 % of the patients were premenopausal . While the objective response rate was similar in the PC and EP arm ( 89.4 % vs. 79.5 % , P = 0.195 ) , the pCR rate in the PC arm was significantly higher ( 38.6 % vs. 14.0 % , P = 0.014 ) . The median follow-up time was 55.0 months . 5-year RFS were 77.6 % and 56.2 % , significantly higher in the PC arm , P = 0.043 . No significant difference in OS was observed between the two arms ( P = 0.350 ) . Adverse events were similar , except for more thrombocytopenia in the PC arm ( P = 0.001 ) . Methods : Patients with stage II/III TNBC were r and omized to receive either paclitaxel ( 175 mg/m2 , day1 ) plus carboplatin ( Area Under the Curve = 5 , day2 ) ( PC ) or epirubicin ( 75mg/m2 , day1 ) plus paclitaxel ( 175 mg/m2 , day2 ) ( EP ) as NAC every three weeks for 4 - 6 cycles . The primary endpoint was rate of pathologic complete response (pCR).The secondary endpoints included relapse-free survival ( RFS ) , overall survival ( OS ) and safety . Conclusions : This study suggested that the addition of carboplatin to paclitaxel was superior to the regimen of epirubicin plus paclitaxel as NAC for TNBC in terms of improving pCR rate and RFS . Further phase 3 study has already started 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 Importance The GeparSixto trial provided evidence that the addition of neoadjuvant carboplatin to a regimen consisting of anthracycline , taxane , and bevacizumab increases pathological complete response ( pCR ) rates in patients with triple-negative breast cancer ( TNBC ) . Whether BRCA1 and BRCA2 germline mutation status affects treatment outcome remains elusive . Objective To determine whether BRCA1 and BRCA2 germline mutation status affects therapy response in patients with TNBC . Design , Setting , and Participants This secondary analysis of a r and omized clinical trial used archived DNA sample s and cancer family history of 315 patients with TNBC enrolled between August 1 , 2011 , and December 31 , 2012 , in the GeparSixto trial . In all , 291 participants ( 92.4 % ) were included in this multicenter prospect i ve investigation . DNA sample s were analyzed for germline mutations in BRCA1 , BRCA2 , and 16 other cancer predisposition genes . The pCR rates between the carboplatin and noncarboplatin arms were compared . Genetic analyses were performed at the Center for Familial Breast and Ovarian Cancer in Cologne , Germany ; data analysis , November 1 through December 31 , 2015 . Main Outcomes and Measures Proportion of patients who achieved pCR and disease-free survival after neoadjuvant treatment according to BRCA1 and BRCA2 germline mutation status . For pCR rates , the ypT0/is ypN0 definition was used as a primary end point . Results Of the 291 patients with TNBC , all were women ; the mean ( SD ) age was 48 ( 11 ) years . The pCR rate in the carboplatin group was 56.8 % ( 83 of 146 ) and 41.4 % ( 60 of 145 ) in the noncarboplatin group ( odds ratio [ OR ] , 1.87 ; 95 % CI , 1.17 - 2.97 ; P = .009 ) . Pathogenic BRCA1 and BRCA2 germline mutations were present in 50 of the 291 patients ( 17.2 % ) . In the noncarboplatin arm , the pCR rate was 66.7 % ( 16 of 24 ) for patients with BRCA1 and BRCA2 mutations and 36.4 % ( 44 of 121 ) for patients without ( OR , 3.50 ; 95 % CI , 1.39 - 8.84 ; P = .008 ) . The high pCR rate observed in BRCA1 and BRCA2 mutation carriers ( 16 of 24 [ 66.7 % ] ) was not increased further by adding carboplatin ( 17 of 26 [ 65.4 % ] ) . In contrast , carboplatin increased response rates in patients without BRCA1 and BRCA2 mutations : 66 of the 120 patients ( 55 % ) without BRCA1 and BRCA2 mutations achieved pCR in the carboplatin arm vs 44 of the 121 patients ( 36.4 % ) in the noncarboplatin arm ( OR , 2.14 ; 95 % CI , 1.28 - 3.58 ; P = .004 ) . Patients without pathogenic BRCA1 and BRCA2 alterations showed elevated disease-free survival rates when carboplatin was added ( without carboplatin , 73.5 % ; 95 % CI , 64.1%-80.8 % vs with carboplatin , 85.3 % ; 95 % CI , 77.0%-90.8 % ; hazard ratio , 0.53 ; 95 % CI , 0.29 - 0.96 ; P = .04 ) . Conclusions and Relevance Under the nonst and ard GeparSixto polychemotherapy regimen , patients without BRCA1 and BRCA2 germline mutations benefited from the addition of carboplatin and those with BRCA1 and BRCA2 mutations showed superior response rates without additive effects observed for carboplatin . Trial Registration clinical trials.gov Identifier : The aim of this study is to estimate the frequency of pathologic complete response ( pCR ) after neoadjuvant treatment with cisplatin chemotherapy in women with breast cancer and a BRCA1 mutation . One hundred and seven women with breast cancer and a BRCA1 mutation , who were diagnosed with stage I to III breast cancer between December 2006 and June 2014 , were treated with cisplatin 75 mg/m2 every 3 weeks for four cycles , followed by mastectomy and conventional chemotherapy . Information was collected on clinical stage , grade , hormone receptor status , and Her2neu status prior to treatment . pCR was determined by review of surgical specimens . One hundred and seven patients were enrolled in the study , including 93 patients who were treated for first primary breast cancer and 14 patients who had previously received treatment for a prior cancer .  A pCR was observed in 65 of the 107 patients ( 61 % ) . Platinum-based chemotherapy is effective in a high proportion of patients with BRCA1-associated breast cancer NCCN guidelines recommend genetic testing for all triple-negative breast cancer ( TNBC ) patients aged ≤60 years . However , due to the lack of prospect i ve information in unselected patients , these guidelines are not uniformly adopted by clinicians and insurance carriers . The aim of this study was to determine the prevalence of BRCA mutations and evaluate the utility of NCCN guidelines in unselected TNBC population . Stage I – IV TNBC patients were enrolled on a prospect i ve registry at academic and community practice s. All patients underwent BRCA1/2 testing . Significant family history ( SFH ) was defined > 1 relative with breast cancer at age ≤50 or ≥1 relative with ovarian cancer . Mutation prevalence in the entire cohort and subgroups was calculated . 207 TNBC patients were enrolled between 2011 and 2013 . Racial/ethnic distribution : Caucasian ( 80 % ) , African – American ( 14 % ) , Ashkenazi ( 1 % ) . Deleterious BRCA1/2 mutations were identified in 15.4 % ( 32/207 ) of patients ( BRCA1:11.1 % , BRCA2:4.3 % ) . SFH reported by 36 % of patients . Mutation prevalence in patients with and without SFH was 31.6 and 6.1 % , respectively . When assessed by age at TNBC diagnosis , the mutation prevalences were 27.6 % ( ≤50 years ) , 11.4 % ( 51–60 years ) , and 4.9 % ( ≥61 years ) . Using SFH or age ≤50 as criteria , 25 and 34 % of mutations , respectively , were missed . Mutation prevalence in patients meeting NCCN guidelines was 18.3 % ( 32/175 ) and 0 % ( 0/32 ) in patients who did not meet guidelines ( p = .0059 ) . In this unselected academic and community population with negligible Ashkenazi representation , we observed an overall BRCA mutation prevalence rate of 15.4 % . BRCA testing based on NCCN guidelines identified all carriers supporting its routine application in clinical practice for TNBC Germline mutations in BRCA1/2 predispose individuals to breast cancer ( termed germline-mutated BRCA1/2 breast cancer , gBRCA-BC ) by impairing homologous recombination ( HR ) and causing genomic instability . HR also repairs DNA lesions caused by platinum agents and PARP inhibitors . Triple-negative breast cancers ( TNBCs ) harbor sub population s with BRCA1/2 mutations , hypothesized to be especially platinum-sensitive . Cancers in putative ‘ BRCAness ’ subgroups — tumors with BRCA1 methylation ; low levels of BRCA1 mRNA ( BRCA1 mRNA-low ) ; or mutational signatures for HR deficiency and those with basal phenotypes — may also be sensitive to platinum . We assessed the efficacy of carboplatin and another mechanistically distinct therapy , docetaxel , in a phase 3 trial in subjects with unselected advanced TNBC . A prespecified protocol enabled biomarker – treatment interaction analyses in gBRCA-BC and BRCAness subgroups . The primary endpoint was objective response rate ( ORR ) . In the unselected population ( 376 subjects ; 188 carboplatin  , 188 docetaxel )  , carboplatin was not more active than docetaxel ( ORR , 31.4 % versus 34.0 % , respectively ; P = 0.66 ) . In contrast , in subjects with gBRCA-BC , carboplatin had double the ORR of docetaxel ( 68 % versus 33 % , respectively ; biomarker , treatment interaction P = 0.01 ) . Such benefit was not observed for subjects with BRCA1 methylation , BRCA1 mRNA-low tumors or a high score in a Myriad HRD assay . Significant interaction between treatment and the basal-like subtype was driven by high docetaxel response in the nonbasal subgroup . We conclude that patients with advanced TNBC benefit from characterization of BRCA1/2 mutations , but not BRCA1 methylation or Myriad HRD analyses , to inform choices on platinum-based chemotherapy . Additionally , gene expression analysis of basal-like cancers may also influence treatment selection .The phase 3 TNT Trial in subjects with triple-negative breast cancer supports the superiority of carboplatin over docetaxel in BRCA1/2-mutated tumors and a greater response to taxanes in the nonbasal subtype 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 Abstract Addition of carboplatin to neoadjuvant chemotherapy in HER2-negative breast cancer may improve pathological complete response ( pCR ) rates . We evaluated the efficacy and safety of carboplatin and weekly paclitaxel ( wPTX ) followed by cyclophosphamide , epirubicin , and 5-fluorouracil ( CEF ) as neoadjuvant chemotherapy for HER2-negative breast cancer . Patients with stage II/IIIA HER2-negative breast cancer were r and omly assigned to preoperatively receive CP-CEF ( four 3-week cycles of carboplatin [ area under the curve 5 mg/mL/min , day 1 ] and wPTX [ 80 mg/m2 , day 1 , 8 , 15 ] followed by four 3-week cycles of CEF [ 500/100/500 mg/m2 ] or P-CEF ( four cycles of wPTX followed by four cycles of CEF ) . The primary objective was pCR rate .  Of 181 eligible patients , 89 were r and omly assigned to the  CP-CEF  and 92 to the P-CEF . Two patients in each arm refused to receive neoadjuvant chemotherapy . Overall 88 patients in the CP-CEF and 91 patients in the P-CEF were assessable for efficacy and safety . The pCR rate in the CP-CEF was significantly higher than that in the P-CEF ( 31.8 vs. 17.6 % , one-sided P = 0.01 ) . Among patients with triple-negative breast cancer , the pCR rate in the CP-CEF was significantly higher than that in the P-CEF [ 61.2 ( 23/37 ) vs. 26.3 % ( 10/38 ) , P = 0.003 ] . Grade 3–4 neutropenia was observed in the CP-CEF more frequently than in the P-CEF ( 65.9 vs. 38.5 % ) . Adding carboplatin to neoadjuvant wPTX followed by CEF for HER2-negative breast cancer improved the pCR rate and exacerbated hematotoxicity Purpose : BRCA1/2-mutated and some sporadic triple-negative breast cancers ( TNBC ) have DNA repair defects and are sensitive to DNA-damaging therapeutics . Recently , three independent DNA-based measures of genomic instability were developed on the basis of loss of heterozygosity ( LOH ) , telomeric allelic imbalance ( TAI ) , and large-scale state transitions ( LST ) . Experimental Design : We assessed a combined homologous recombination deficiency ( HRD ) score , an unweighted sum of LOH , TAI , and LST scores , in three neoadjuvant TNBC trials of platinum-containing therapy .  We then tested the association of HR deficiency , defined as HRD score ≥42 or BRCA1/2 mutation , with response to platinum-based therapy . Results : In a trial of neoadjuvant platinum , gemcitabine , and iniparib , HR deficiency predicted residual cancer burden score of 0 or I ( RCB 0/I ) and pathologic complete response ( pCR ; OR = 4.96 , P = 0.0036 ; OR = 6.52 , P = 0.0058 ) . HR deficiency remained a significant predictor of RCB 0/I when adjusted for clinical variables ( OR = 5.86 , P = 0.012 ) . In two other trials of neoadjuvant cisplatin therapy , HR deficiency predicted RCB 0/I and pCR ( OR = 10.18 , P = 0.0011 ; OR = 17.00 , P = 0.0066 ) . In a multivariable model of RCB 0/I , HR deficiency retained significance when clinical variables were included ( OR = 12.08 , P = 0.0017 ) . When restricted to BRCA1/2 nonmutated tumors , response was higher in patients with high HRD scores : RCB 0/I P = 0.062 , pCR P = 0.063 in the neoadjuvant platinum , gemcitabine , and iniparib trial ; RCB 0/I P = 0.0039 , pCR P = 0.018 in the neoadjuvant cisplatin trials . Conclusions : HR deficiency identifies TNBC tumors , including BRCA1/2 nonmutated tumors more likely to respond to platinum-containing therapy . Clin Cancer Res ; 22(15 ) ; 3764–73 . © 2016 AACR PURPOSE One third of patients with triple-negative breast cancer ( TNBC ) achieve pathologic complete response ( pCR ) with st and ard neoadjuvant chemotherapy ( NACT ) . CALGB 40603 ( Alliance ) , a 2 × 2 factorial , open-label , r and omized phase II trial , evaluated the impact of adding carboplatin and /or bevacizumab . PATIENTS AND METHODS Patients ( N = 443 ) with stage II to III TNBC received paclitaxel 80 mg/m(2 ) once per week ( wP ) for 12 weeks , followed by doxorubicin plus cyclophosphamide once every 2 weeks ( ddAC ) for four cycles , and were r and omly assigned to concurrent carboplatin ( area under curve 6 ) once every 3 weeks for four cycles and /or bevacizumab 10 mg/kg once every 2 weeks for nine cycles . Effects of adding these agents on pCR breast ( ypT0/is ) , pCR breast/axilla ( ypT0/isN0 ) , treatment delivery , and toxicities were analyzed . RESULTS Patients assigned to either carboplatin or bevacizumab were less likely to complete wP and ddAC without skipped doses , dose modification , or early discontinuation result ing from toxicity . Grade ≥ 3 neutropenia and thrombocytopenia were more common with carboplatin , as were hypertension , infection , thromboembolic events , bleeding , and postoperative complications with bevacizumab . Employing one-sided P values , addition of either carboplatin ( 60 % v 44 % ; P = .0018 ) or bevacizumab ( 59 % v 48 % ; P = .0089 ) significantly increased pCR breast , whereas only carboplatin ( 54 % v 41 % ; P = .0029 ) significantly raised pCR breast/axilla . More-than-additive interactions between the two agents could not be demonstrated . CONCLUSION In stage II to III TNBC , addition of either carboplatin or bevacizumab to NACT increased pCR rates , but whether this will improve relapse-free or overall survival is unknown . Given results from recently reported adjuvant trials , further investigation of bevacizumab in this setting is unlikely , but the role of carboplatin could be evaluated in definitive studies , ideally limited to biologically defined patient subsets most likely to benefit from this agent BACKGROUND Carboplatin plus paclitaxel administered every 3 weeks is st and ard first-line chemotherapy for patients with advanced ovarian cancer . A weekly paclitaxel schedule combined with carboplatin every 3 weeks prolonged progression-free survival and overall survival in a Japanese phase 3 trial . The aim of our study was to assess whether a weekly schedule of carboplatin plus paclitaxel is more effective than the same drugs given every 3 weeks . METHODS We did a multicentre , r and omised , phase 3 study at 67 institutions in Italy and France . Women with FIGO stage IC-IV ovarian cancer , an ECOG performance status of 2 or lower , and who had never received chemotherapy were r and omly allocated in a 1:1 ratio to receive either carboplatin ( AUC 6 mg/mL per min ) plus paclitaxel ( 175 mg/m(2 ) ) every 3 weeks for six cycles or carboplatin ( AUC 2 mg/mL per min ) plus paclitaxel ( 60 mg/m(2 ) ) every week for 18 weeks . R and omisation was done by computer-based minimisation , stratified by centre , residual disease after surgery , and ECOG performance status . The study was not blinded . Co primary endpoints were progression-free survival and quality of life ( assessed by the Functional Assessment of Cancer Therapy Ovarian Trial Outcome Index [ FACT-O/TOI ] score ) , and analysis was by modified intention to treat . This report presents the final analysis . The study is registered with Clinical Trials.gov , number NCT00660842 . FINDINGS 822 patients were enrolled into the study between Nov 20 , 2008 , and March 1 , 2012 ; 12 withdrew their consent immediately after r and omisation and were excluded , and 810 were eligible for analysis . 404 women were allocated treatment every 3 weeks and 406 were assigned to the weekly schedule . After median follow-up of 22·3 months ( IQR 16·2 - 30·9 ) , 449 progression-free survival events were recorded . Median progression-free survival was 17·3 months ( 95 % CI 15·2 - 20·2 ) in patients assigned to treatment every 3 weeks , versus 18·3 months ( 16·8 - 20·9 ) in women allocated to the weekly schedule ( hazard ratio 0·96 , 95 % CI 0·80 - 1·16 ; p=0·66 ) . FACT-O/TOI scores differed significantly between the two schedules ( treatment-by-time interaction p<0·0001 ) ; with treatment every 3 weeks , FACT-O/TOI scores worsened at every cycle ( weeks 1 , 4 , and 7 ) , whereas for the weekly schedule , after transient worsening at week 1 , FACT-O/TOI scores remained stable . Fewer patients assigned to the weekly group than those allocated treatment every 3 weeks had grade 3 - 4 neutropenia ( 167 [ 42 % ] of 399 patients vs 200 [ 50 % ] of 400 patients ) , febrile neutropenia ( two [ 0·5 % ] vs 11 [ 3 % ] ) , grade 3 - 4 thrombocytopenia ( four [ 1 % ] vs 27 [ 7 % ] ) , and grade 2 or worse neuropathy ( 24 [ 6 % ] vs 68 [ 17 % ] ) . Three deaths during the study were attributed to chemotherapy ; two women died who were allocated treatment every 3 weeks and one death was recorded in the group assigned the weekly regimen . INTERPRETATION A weekly regimen of carboplatin and paclitaxel might be a reasonable option for first-line treatment of women with advanced ovarian cancer . FUNDING None 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 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 BACKGROUND Pre clinical data suggest that triple-negative breast cancers are sensitive to interstr and crosslinking agents , and that synergy may exist for the combination of a taxane , trastuzumab , and a platinum salt for HER2-positive breast cancer . We therefore aim ed to assess the efficacy of the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive breast cancer . METHODS Patients with previously untreated , non-metastatic , stage II-III , triple-negative breast cancer and HER2-positive breast cancer were enrolled . Patients were treated for 18 weeks with paclitaxel ( 80 mg/m(2 ) once a week ) and non-pegylated liposomal doxorubicin ( 20 mg/m(2 ) once a week ) . Patients with triple-negative breast cancer received simultaneous bevacizumab ( 15 mg/kg intravenously every 3 weeks ) . Patients with HER2-positive disease received simultaneous trastuzumab ( 8 mg/kg initial dose with subsequent doses of 6 mg/kg intravenously every 3 weeks ) and lapatinib ( 750 mg daily ) . Patients were r and omly assigned in a 1:1 ratio with dynamic allocation and minimisation , stratified by biological subtype and Ki-67 level to receive , at the same time as the backbone regimens , either carboplatin ( AUC 1·5 [ 2·0 for the first 329 patients ] once a week ) or no carboplatin . The primary endpoint the proportion of patients who achieved a pathological complete response ( defined as ypT0 ypN0 ) , analysed for all patients who started treatment ; a p value of less than 0·2 was deemed significant for the primary endpoint . This trial is registered with Clinical Trials.gov , number NCT01426880 . FINDINGS 296 patients were r and omly assigned to receive carboplatin and 299 to no additional carboplatin , of whom 295 and 293 started treatment , respectively . In this final analysis , 129 patients ( 43·7 % , 95 % CI 38·1 - 49·4 ) in the carboplatin group achieved a pathological complete response , compared with 108 patients ( 36·9 % , 31·3 - 42·4 ) without carboplatin ( odds ratio 1·33 , 95 % CI 0·96 - 1·85 ; p=0·107 ) . Of the patients with triple-negative breast cancer , 84 ( 53·2 % , 54·4 - 60·9 ) of 158 patients achieved a pathological complete response  with carboplatin , compared with 58 ( 36·9 % , 29·4 - 44·5 ) of 157 without ( p=0·005 ) . Of the patients with HER2-positive tumours , 45 ( 32·8 % , 25·0 - 40·7 ) of 137 patients achieved a pathological complete response with carboplatin compared with 50 ( 36·8 % , 28·7 - 44·9 ) of 136 without ( p=0·581 ; test for interaction p=0·015 ) . Haematological and non-haematological toxic effects that were significantly more common in the carboplatin group than in the no-carboplatin group included grade 3 or 4 neutropenia ( 192 [ 65 % ] vs 79 [ 27 % ] ) , grade 3 or 4 anaemia ( 45 [ 15 % ] vs one [ < 1 % ] ) , grade 3 or 4 thrombocytopenia ( 42 [ 14 % ] vs one [ < 1 % ] ) , and grade 3 or 4 diarrhoea ( 51 [ 17 % ] vs 32 [ 11 % ] ) ; carboplatin was more often associated with dose discontinuations ( 141 [ 48 % ] with carboplatin and 114 [ 39 % ] without carboplatin ; p=0·031 ) . The frequency of grade 3 or 4 haematological events decreased from 82 % ( n=135 ) to 70 % ( n=92 ) and grade 3 or 4 non-haematological events from 78 % ( n=128 ) to 59 % ( n=77 ) in the carboplatin arm when the dose of carboplatin was reduced from AUC 2·0 to 1·5 . INTERPRETATION The addition of neoadjuvant carboplatin to a regimen of a taxane , an anthracycline , and targeted therapy significantly increases the proportion of patients achieving a pathological complete response . This regimen seems to increase responses in patients with triple-negative breast cancer , but not in those with HER2-positive breast cancer . FUNDING GlaxoSmithKline , Roche , and Teva BACKGROUND Although several r and omised trials in patients with triple-negative breast cancer have shown that the addition of carboplatin , with or without poly(ADP-ribose ) polymerase ( PARP ) inhibitors , to neoadjuvant chemotherapy increases the likelihood of achieving a pathological complete response , the use of these therapies in this setting has remained controversial . The BrighTNess trial was design ed to assess the addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to st and ard neoadjuvant chemotherapy in triple-negative breast cancer . METHODS We did a phase 3 , r and omised , double-blind , placebo-controlled trial ( BrighTNess ) across 145 sites in 15 countries . Patients aged 18 years and older with previously untreated histologically or cytologically confirmed clinical stage II-III triple-negative breast cancer , who were c and i date s for potentially curative surgery and had an Eastern Cooperative Oncology Group performance status of 0 or 1 , were r and omly assigned ( 2:1:1 ) by an interactive response technology system via permuted blocks ( block size of four ) within strata to receive one of three segment 1 regimens : paclitaxel ( 80 mg/m2 intravenously weekly for 12 doses ) plus carboplatin ( area under the curve 6 mg/mL per min , intravenously every 3 weeks , for four cycles ) plus veliparib ( 50 mg orally , twice a day ) ; paclitaxel plus carboplatin plus veliparib placebo ( twice a day ) ; or paclitaxel plus carboplatin placebo ( every 3 weeks for four cycles ) plus veliparib placebo . Following segment 1 , all patients were assigned to segment 2 in which they received doxorubicin and cyclophosphamide every 2 - 3 weeks for four cycles . R and omisation for segment 1 was stratified by germline BRCA mutation status , nodal stage , and planned schedule of doxorubicin and cyclophosphamide administration . The primary endpoint was pathological complete response in breast and lymph nodes as determined by site pathologists following completion of neoadjuvant therapy . Efficacy analyses were done by intention to treat and safety analyses included all patients who received at least one dose of study treatment . These are the first results of an ongoing clinical trial ; the data cutoff for the analyses presented was Dec 8 , 2016 . This study is registered with Clinical Trials.gov , number NCT02032277 . FINDINGS Between April 4 , 2014 , and March 18 , 2016 , 634 patients were r and omly assigned : 316 to paclitaxel plus carboplatin plus veliparib , 160 to paclitaxel plus carboplatin , and 158 to paclitaxel alone . The proportion of patients who achieved a pathological complete response was higher in the paclitaxel , carboplatin , and veliparib group than in patients receiving paclitaxel alone ( 168 [ 53 % ] of 316 patients vs 49 [ 31 % ] of 158 , p<0·0001 ) , but not compared with patients receiving paclitaxel plus carboplatin ( 92 [ 58 % ] of 160 patients , p=0·36 ) . Grade 3 or 4 toxicities , and serious adverse events were more common in patients receiving carboplatin , whereas veliparib did not substantially increase toxicity . The most common grade 3 or 4 events overall were neutropenia ( 352 [ 56 % ] of 628 patients ) , anaemia ( 180 [ 29 % ] ) , and thrombocytopenia ( 75 [ 12 % ] ) through complete treatment , and febrile neutropenia ( 88 [ 15 % ] of 601 patients ) during segment 2 . The most common serious adverse events were febrile neutropenia ( 80 [ 13 % ] of 628 patients ) and anaemia ( 20 [ 3 % ] ) . INTERPRETATION Although the addition of veliparib and carboplatin to paclitaxel followed by doxorubicin and cyclophosphamide improved the proportion of patients with triple-negative breast cancer who achieved a pathological complete response , the addition of veliparib to carboplatin and paclitaxel did not . Increased toxicities with the addition of carboplatin ( with or without veliparib ) to paclitaxel were manageable and did not substantially affect treatment delivery of paclitaxel followed by doxorubicin and cyclophosphamide . Given the consistent results with previous studies , the addition of carboplatin appears to have a favourable risk to benefit profile and might be considered as a potential component of neoadjuvant chemotherapy for patients with high-risk , triple-negative breast cancer . FUNDING AbbVie
Background The role of platinum-based neoadjuvant chemotherapy in triple-negative breast cancer ( TNBC ) patients is highly controversial and it is not endorsed by current guidelines .
Our meta- analysis aim ed to better eluci date its activity , efficacy and safety .