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Contains fulltext : 290914.pdf (Publisher’s version ) (Open Access) BACKGROUND: In node-negative breast cancer (NNBC), a high risk of recurrence is determined by clinico-pathological or tumor-biological assessment. Taxanes may improve adjuvant chemotherapy. METHODS: NNBC 3-Europe, the first randomized phase-3 trial in node-negative breast cancer (BC) with tumor-biological risk assessment, recruited 4146 node-negative breast cancer patients from 2002 to 2009 in 153 centers. Risk assessment was performed by clinico-pathological factors (43%) or biomarkers (uPA/PAI-1, urokinase-type plasminogen activator/its inhibitor PAI-1). High-risk patients received six courses 5-fluorouracil (500 mg/m(2)), epirubicin (100 mg/m(2)), cyclophosphamide (500 mg/m(2)) (FEC), or three courses FEC followed by three courses docetaxel 100 mg/m(2) (FEC-Doc). Primary endpoint was disease-free survival (DFS). RESULTS: In the intent-to-treat population, 1286 patients had received FEC-Doc, and 1255 received FEC. Median follow-up was 45 months. Tumor characteristics were equally distributed; 90.6% of tested tumors had high uPA/PAI-1-concentrations. Planned courses were given in 84.4% (FEC-Doc) and 91.5% (FEC). Five-year-DFS was 93.2% (95% C.I. 91.1-94.8) with FEC-Doc and 93.7% (91.7-95.3) with FEC. Five-year-overall survival was 97.0% (95.4-98.0) for FEC-Doc and 96.6% % (94.9-97.8) for FEC. CONCLUSIONS: With adequate adjuvant chemotherapy, even high-risk node-negative breast cancer patients have an excellent prognosis. Docetaxel did not further reduce the rate of early recurrences and led to significantly more treatment discontinuations.

PurposePIK3CA, encoding for subunit p110a of phosphatidylinositol 3 kinase, is frequently mutated in breast cancer. PIK3CAmutation was predictive for pathological complete response (pCR) in human epidermal growth factor 2 positive breast cancer. This study explores the association of PIK3CA mutation and pCR in triple-negative breast cancer (TNBC) treated with neoadjuvant chemotherapy.Materials and MethodsA total of 92 patients with TNBC derived from a prospectively randomized phase II trial GeparSixto study (NCT01426880). Exon 9 and exon 20 of PIK3CA mutations were evaluated by using classical Sanger method with formalin-fixed paraffin-embedded tumor tissues.ResultsSeven of 90 tumors (7.8%) were detectable with a PIK3CA H1047R mutation. Overall, PIK3CA H1047R mutation was significantly associated with a lower pCR rate (14.3% vs. 56.6%; odds ratio, 0.128; 95% confidence interval [CI], 0.015 to 1.108; p=0.047). In carboplatin- containing treatment patients, H1047R mutation trended to predict a lower pCR rate (20% vs. 62.5%; p=0.146). In a multivariable analysis, H1047R mutation trended to predict a lower pCR rate (hazard ratio, 0.1; 95% CI, 0.01 to 1; p=0.056).ConclusionTNBC with a PIK3CA H1047R mutation was less likely to achieve pCR after anthracyclinebased neoadjuvant chemotherapy. Development of H1047R mutant selective inhibitors might be helpful to conquer this subtype of breast cancer.

Background The phase 3 KATHERINE trial demonstrated significantly improved invasive disease–free survival with adjuvant trastuzumab emtansine (T‐DM1) versus trastuzumab in patients with HER2‐positive early breast cancer and residual invasive disease after neoadjuvant chemotherapy plus HER2‐targeted therapy. Methods Patients who received taxane‐ and trastuzumab‐containing neoadjuvant therapy (with/without anthracyclines) and had residual invasive disease (breast and/or axillary nodes) at surgery were randomly assigned to 14 cycles of adjuvant T‐DM1 (3.6 mg/kg intravenously every 3 weeks) or trastuzumab (6 mg/kg intravenously every 3 weeks). The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 (QLQ‐C30) and breast cancer module (QLQ‐BR23) were completed at screening, at day 1 of cycles 5 and 11, within 30 days after study drug completion, and at 6‐ and 12‐month follow‐up visits. Results Of patients who were randomly assigned to T‐DM1 (n = 743) and trastuzumab (n = 743), 612 (82%) and 640 (86%), respectively, had valid baseline and ≥1 postbaseline assessments. No clinically meaningful changes (≥10 points) from baseline in mean QLQ‐C30 and QLQ‐BR23 scores occurred in either arm. More patients receiving T‐DM1 reported clinically meaningful deterioration at any assessment point in role functioning (49% vs 41%), appetite loss (38% vs 28%), constipation (47% vs 38%), fatigue (66% vs 60%), nausea/vomiting (39% vs 30%), and systemic therapy side effects (49% vs 36%). These differences were no longer apparent at the 6‐month follow‐up assessment, except for role functioning (23% vs 16%). Conclusion These data suggest that health‐related quality of life was generally maintained in both study arms over the course of treatment., Patient‐reported outcomes are reported from the randomized, phase 3 KATHERINE trial, which demonstrated significantly improved invasive disease–free survival with adjuvant T‐DM1 compared with trastuzumab in patients who had residual invasive disease following neoadjuvant chemotherapy plus HER2‐targeted therapy. Patients who are treated with T‐DM1 have a greater incidence of any grade and grade ≥3 adverse events compared with trastuzumab‐treated patients; however, these adverse events appear to have a minimal impact on patient‐reported quality of life.

Background: Patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant chemotherapy (NACT) + HER2-targeted therapy have a higher risk of recurrence and death than those with pathologic complete response. In the phase III KATHERINE study, adjuvant T-DM1 reduced the risk of recurrence or death by 50% vs H in this population. Data from KATHERINE subgroups are reported here, including patients treated with non-anthracycline (AC) vs AC based NACT, patients with small tumors (cT1cN0) who typically do not receive neoadjuvant treatment, and patients with particularly higher-risk tumors defined by nodal involvement and hormone-receptor status. Methods: Eligible patients had HER2-positive early breast cancer, received taxane- and H-containing neoadjuvant therapy ± AC followed by surgery, and had residual invasive disease in the breast and/or axillary nodes. Patients received 14 cycles of adjuvant T-DM1 (3.6 mg/kg IV q3w) or H (6 mg/kg IV q3w) and endocrine and/or radiation therapy per local standards. The primary endpoint was invasive disease-free survival (IDFS), defined as time from randomization to the first occurrence of ipsilateral locoregional or contralateral invasive breast cancer recurrence, distant recurrence, or death from any cause. In this exploratory analysis, efficacy subpopulations were derived from the intent-to-treat population and safety data were reported for patients who received ≥1 dose of study treatment. Results: In the non-AC v AC based NACT analysis (N=1486), some patient characteristics were imbalanced. For non-AC/AC based NACT, respectively, these included: region (North America; 60.6% v 11.0%), race (Asian; 12.8% v 7.4%), ECOG PS 1 (28.0% v 15.7%); neoadjuvant HER2-based therapy (H + pertuzumab; 46.6% v 9.8%), and neoadjuvant carboplatin/cisplatin (78.7 v 2.3%). Benefit was observed with T-DM1 regardless of neoadjuvant AC use (Table). The all-grade incidence of selected AEs with T-DM1 including hepatotoxicity, peripheral neuropathy, hemorrhage, IRR/hypersensitivity, and cardiac dysfunction was similar between non-AC and AC NACT groups. There was a small increase in the non-AC group in all-grade thrombocytopenia (32.5% v 27.4%) and pulmonary toxicity (6.7% vs 1.7%). There was an increased incidence of grade ≥3 AEs (39.9% vs 21.7%) in the non-AC vs the AC group with T-DM1 which was likely driven by an increase in thrombocytopenia (10.4% v 4.3%) and peripheral sensory neuropathy (4.3% vs 0.5%). However, the percentage of patients with AEs leading to T-DM1 withdrawal in the non-AC vs AC groups (19.6% v 17.5%) was similar, as was the percentage with AEs leading to T-DM1 dose reduction (14.1% v 11.6%). In patients with cT1N0 tumors (n=77), baseline characteristics were well-balanced for H v T-DM1. There were only 6 IDFS events in this subgroup overall; none were observed with T-DM1 (Table). In the analysis of particularly higher-risk tumors, all subgroups showed a benefit with T-DM1; the number of patients was small in some subgroups (Table). Conclusions: T-DM1 provides clinical benefit regardless of prior non-AC vs AC based NACT, and in subgroups with small or particularly higher-risk tumors. There was an increased incidence of grade ≥3 AEs with T-DM1 in the non-AC vs the AC group but these did not result in increased treatment discontinuation and were likely driven by the imbalance in prior therapy. Table 1. Risk of IDFS event in patients treated with non-AC versus AC based NACT, patients with small tumors, and patients with particularly higher-risk tumors.Unstratified hazard ratio of IDFS (95% confidence interval [CI])Patients treated with non-AC vs AC based NACT (N=1,486)Non-AC-based NACT: H (n=179) vs T-DM1 (n=164)0.43 (0.22–0.82)AC-based NACT: H (n=564) vs T-DM1 (n=579)0.51 (0.38–0.67)Patients with small (cT1cN0) tumors (N=77)H (n=32) vs T-DM1 (n=45)6 events with H; 0 events with T-DM1(hazard ratio not applicable due to zero events in T-DM1 arm)Tumor subgroups defined by nodal and HR status (N=957)Inoperable; any HR or ypN statusH (n=190)T-DM1 (n=185)3-year IDFS event-free rate, % (95% CI)60.2 (52.7–67.8)76.0 (70.0–82.4)Unstratified hazard ratio (95% CI)0.54 (0.37–0.80)Operable; ypN positive and HR negativeH (n=52)T-DM1 (n=58)3-year IDFS event-free rate, % (95% CI)69.5 (56.1–82.9)76.0 (64.5–87.5)Unstratified hazard ratio (95% CI)0.72 (0.35–1.50)Operable; ypN positive and HR positiveH (n=167)T-DM1 (n=168)3-year IDFS event-free rate, % (95% CI)77.2 (70.2–84.1)91.4 (86.6–96.2)Unstratified hazard ratio (95% CI)0.43 (0.25–0.75)Operable; ypN0 and HR negativeH (n=68)T-DM1 (n=69)3-year IDFS event-free rate, % (95% CI)77.2 (66.5–87.9)91.1 (84.3–97.9)Unstratified hazard ratio (95% CI)0.43 (0.17–1.06) Citation Format: Max S Mano, Sibylle Loibl, Eleftherios P. Mamounas, Gunter von Minckwitz, Chiun-Sheng Huang, Michael Untch, Norman Wolmark, Irene L. Wapnir, Youngsen Yang, Alison K. Conlin, Sherko Kümmel, Mahasti Saghatchian, Michael P. DiGiovanna, Claudia Strunk, Martina Zimovjanova, Chunyan Song, Haying Liu, David Tesarowski, Steven Blotner, Lisa H. Lam, Melanie Smitt, Charles E. Geyer Jr. Adjuvant trastuzumab emtansine (T-DM1) vs trastuzumab (H) in patients with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer: KATHERINE subgroup analysis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-14-01.

Purpose:Next-generation sequencing (NGS) can be used for comprehensive investigation of molecular events in breast cancer. We evaluated the relevance of genomic alterations for response to neoadjuvant chemotherapy (NACT) in the GeparSepto trial.Experimental Design:Eight hundred fifty-one pretherapeutic formalin-fixed paraffin-embedded (FFPE) core biopsies from GeparSepto study were sequenced. The panel included 16 genes for mutational (AKT1, BRAF, CDH1, EGFR, ERBB2, ESR1, FBXW7, FGFR2, HRAS, KRAS, NRAS, SF3B1, TP53, HNF1A, PIK3CA, and PTEN) and 8 genes for copy-number alteration analysis (CCND1, ERBB2, FGFR1, PAK1, PIK3CA, TOP2A, TP53, and ZNF703).Results:The most common genomic alterations were mutations of TP53 (38.4%) and PIK3CA (21.5%), and 8 different amplifications (TOP2A 34.9%; ERBB2 30.6%; ZNF703 30.1%; TP53 21.9%; PIK3CA 24.1%; CCND1 17.7%; PAK1 14.9%; FGFR 12.6%). All other alterations had a prevalence of less than 5%. The genetic heterogeneity in different breast cancer subtypes [lum/HER2neg vs. HER2pos vs. triple-negative breast cancer (TNBC)] was significantly linked to differences in NACT response. A significantly reduced pathologic complete response rate was observed in PIK3CA-mutated breast cancer [PIK3CAmut: 23.0% vs. wild-type (wt) 38.8%, P < 0.0001] in particular in the HER2pos subcohort [multivariate OR = 0.43 (95% CI, 0.24–0.79), P = 0.006]. An increased response to nab-paclitaxel was observed only in PIK3CAwt breast cancer, with univariate significance for the complete cohort (P = 0.009) and the TNBC (P = 0.013) and multivariate significance in the HER2pos subcohort (test for interaction P = 0.0074).Conclusions:High genetic heterogeneity was observed in different breast cancer subtypes. Our study shows that FFPE-based NGS can be used to identify markers of therapy resistance in clinical study cohorts. PIK3CA mutations could be a major mediator of therapy resistance in breast cancer.

PURPOSE The aim of the current work was to clarify whether a preoperative lymphoscintigraphy (LSG) enhances staging accuracy of sentinel lymph node biopsy (SLNB). PATIENTS AND METHODS In a prospective, multicenter, randomized phase III trial, patients with cN0 early breast cancer or extensive/high-grade ductal carcinoma in situ planned for standard radioactive-labeled colloid LSG with subsequent SLNB were randomly assigned 1:1 to receive SLNB either with knowledge of the LSG findings or without. As the false-negative rate of SLNB correlates with the number of resected sentinel lymph nodes (SLNs), our primary end point was the mean number of histologically detected SLNs per patient. One thousand one hundred two evaluable patients were necessary to demonstrate noninferiority of SLNB without LSG. Stratified one-sided 95% CI for the difference (without LSG − with LSG) in the mean number of histologically detected SLNs had to be greater than −0.27 (10% noninferiority margin). Stratification was performed according to tumor focality and trial site. Additional predefined secondary end points (rates of node-positive patients and of completion axillary lymph node dissection) were analyzed to rule out differences in the reliable detection of nodal metastases. RESULTS Between May 2014 and October 2015, 1,198 patients were randomly assigned in 23 German and Swiss breast centers. Modified intention-to-treat analysis (n = 1,163) showed a mean number of histologically detected SLNs of 2.21 with LSG and 2.26 without LSG (difference 0.05; stratified 95% CI, −0.18 to infinity), thus establishing noninferiority of omitting preoperative LSG. Secondary end points displayed no statistically significant differences. CONCLUSION We show that SLNB is equally effective irrespective of the surgeon’s knowledge of preoperative LSG results. SLNB without LSG will speed up the preoperative workflow and reduce cost.

Ki-67 has been clinically validated for risk assessment in breast cancer, but the analytical validation and cutpoint-definition remain a challenge. Intraclass correlation coefficients (ICCs) are a statistical parameter for Ki-67 interobserver performance. However, the maximum degree of variance among pathologists allowed for meaningful biomarker results has not been defined. Different amounts of variance were added to central pathology Ki-67 data (n = 9069) from three cohorts (IBCSGVIII + IX, BIG1-98, GeparTrio) by simulation of 4500 evaluations for each cohort, which were grouped by ICCs, ranging from excellent (ICC = 0.9) to poor concordance (ICC = 0.1). Endpoints were disease-free survival (DFS) and pathological complete response (pCR, GeparTrio). Ki-67 was a significant continuous prognostic marker for DFS over a wide range of cutpoints between 8% and 30% in all three cohorts. In our modelling approach, Ki-67 was a stable prognostic marker despite increased interpathologist variance. Even for a poor ICC of 0.5, one or more significant Ki-67 cutoffs were detected in 86.8% (GeparTrio), 92.4% (IBCSGVIII + IX) and 100% of analyses (BIG1-98). Similarly, in GeparTrio, even with an extremely low ICC of 0.2, 99.6% of analyses were significant for pCR. Our study shows that Ki-67 is a continuous marker which is extremely robust to pathologist variation. Even if only 50% of variance is attributable to true Ki-67-based proliferation (ICC = 0.5), this information is sufficient to obtain statistically significant differences in clinical cohorts. This stable performance explains the observation that many Ki-67 studies achieve significant results despite relevant interobserver variance and points to a high clinical validity of this biomarker. For clinical decisions based on analysis of individual patient data, ongoing efforts to further reduce interobserver variability, including ring trials and standardized guidelines as well as image analysis approaches, should be continued.

We analyzed the predictive potential of pretreatment soluble carbonic anhydrase IX levels (sCAIX) for the efficacy of bevacizumab in the phase III neoadjuvant GeparQuinto trial. sCAIX was determined by enzyme-linked immunosorbent assay (ELISA). Correlations between sCAIX and pathological complete response (pCR), disease-free and overall survival (DFS, OS) were assessed with logistic and Cox proportional hazard regression models using bootstrapping for robust estimates and internal validation. 1,160 HER2-negative patient sera were analyzed, of whom 577 received bevacizumab. Patients with low pretreatment sCAIX had decreased pCR rates (12.1 vs. 20.1%, p = 0.012) and poorer DFS (adjusted 5-year DFS 71.4 vs. 80.5 months, p = 0.010) compared to patients with high sCAIX when treated with neoadjuvant chemotherapy (NCT). For patients with low sCAIX, pCR rates significantly improved upon addition of bevacizumab to NCT (12.1 vs. 20.4%; p = 0.017), which was not the case in patients with high sCAIX (20.1% for NCT vs. 17.0% for NCT-B, p = 0.913). When analyzing DFS we found that bevacizumab improved 5-year DFS for patients with low sCAIX numerically but not significantly (71.4 vs. 78.5 months; log rank 0.234). In contrast, addition of bevacizumab worsened 5-year DFS for patients with high sCAIX (81 vs. 73.6 months, log-rank 0.025). By assessing sCAIX levels we identified a patient cohort in breast cancer that is potentially undertreated with NCT alone. Bevacizumab improved pCR rates in this group, suggesting sCAIX is a predictive biomarker for bevacizumab with regards to treatment response. Our data also show that bevacizumab is not beneficial in patients with high sCAIX.

Background GeparOcto compared efficacy and safety of two chemotherapy regimens in high-risk early breast cancer (BC): sequential treatment with intense dose-dense epirubicin, paclitaxel, and cyclophosphamide (iddEPC) and weekly treatment with paclitaxel plus non-pegylated liposomal doxorubicin (M, Myocet®) with additional carboplatin (PM(Cb)) in triple-negative BC (TNBC). Patients and methods Patients with cT1c-cT4a-d and centrally assessed human epidermal growth factor receptor (HER)2-positive BC or TNBC were eligible, irrespective of nodal status, luminal B-like tumours only if pN+. Patients were randomised (stratified by BC subtype, Ki67, lymphocyte-predominant BC) to receive 18 weeks of E (150 mg/m2) followed by P (225 mg/m2) followed by C (2000 mg/m2), each q2w for 3 cycles or weekly P (80 mg/m2) plus M (20 mg/m2) plus, in TNBC, Cb (area under curve (AUC) 1.5). HER2-positive BC patients additionally received trastuzumab (6 [loading dose 8]mg/kg q3w) and pertuzumab (420 [840]mg q3w) with all P and C cycles. Primary end-point was pathological complete response (pCR, ypT0/is ypN0), secondary end-points included other pCR definitions, pCR in stratified subpopulations, tolerability and compliance. This trial is registered with ClinicalTrials.gov number NCT02125344 . Results 945/961 randomised patients started treatment. The median age was 48 years; 7.6% had cT3-4, 46% cN+, 66% G3, 40% HER2-positive, 43% TNBC. pCR rate with iddEPC was 48.3%, with PM(Cb) 48.0%, respectively (PM(Cb) versus iddEPC odds ratio 0.99; 95% confidence interval 0.77–1.28, P = 0.979) with no significant differences observed in TNBC, HER2-positive, luminal B-like subtypes. 16.4% with iddEPC and 34.1% with PM(Cb) discontinued treatment (P Conclusions In high-risk early BC there is no difference in pCR rates following neoadjuvant treatment with iddEPC or weekly PM(Cb), respectively. iddEPC is one of the effective dose-dense regimens feasible in daily practice.

IMPORTANCE: Adding carboplatin to standard neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) likely benefits a subset of patients; however, determinants of benefit are poorly understood. OBJECTIVE: To define the association of molecular subtype, tumor proliferation, and immunophenotype with benefit of carboplatin added to NAC for patients with stages II to III TNBC. DESIGN, SETTING, AND PARTICIPANTS: This was a prespecified secondary analysis of a phase 3, double-blind, randomized clinical trial (BrighTNess) that enrolled 634 women across 145 centers in 15 countries. Women with clinical stages II to III TNBC who had undergone pretreatment biopsy were eligible to participate. Whole transcriptome RNA sequencing was performed on the biopsy specimens. The prespecified end point was association of pathologic complete response (pCR) with gene expression–based molecular subtype, with secondary end points investigating established signatures (proliferation, immune) and exploratory analyses of immunophenotype. Data were collected from April 2014 to March 2016. The study analyses were performed from January 2018 to March 2019. INTERVENTIONS: Neoadjuvant chemotherapy with paclitaxel followed by doxorubicin and cyclophosphamide, or this same regimen with carboplatin or carboplatin plus veliparib. MAIN OUTCOMES AND MEASURES: Association of gene expression–based molecular subtype (PAM50 and TNBC subtypes) with pCR. RESULTS: Of the 634 women (median age, 51 [range, 22-78] years) enrolled in BrighTNess, 482 (76%) patients had evaluable RNA sequencing data, with similar baseline characteristics relative to the overall intention-to-treat population. Pathologic complete response was significantly more frequent in PAM50 basal-like vs nonbasal-like cancers overall (202 of 386 [52.3%] vs 34 of 96 [35.4%]; P = .003). Carboplatin benefit was not significantly different in basal-like vs nonbasal-like subgroups (P = .80 for interaction). In multivariable analysis, proliferation (hazard ratio, 0.36; 95% CI, 0.21-0.61; P

Optimization of axillary staging among patients converting from clinically node-positive disease to clinically node-negative disease through primary systemic therapy is needed. We aimed at developing a nomogram predicting the probability of positive axillary status after chemotherapy based on clinical/pathological parameters. Patients from study arm C of the SENTINA trial were included. Univariable/multivariable analyses were performed for 13 clinical/pathological parameters to predict a positive pathological axillary status after chemotherapy using logistic regression models. Odds ratios and 95%-confidence-intervals were reported. Model performance was assessed by leave-one-out cross-validation. Calculations were performed using the SAS Software (Version 9.4, SAS Institute Inc., Cary, NC, USA). 369 of 553 patients in Arm C were included in multivariable analysis. Stepwise backward variable selection based on a multivariable analysis resulted in a model including estrogen receptor (ER) status (odds ratio (OR) 3.916, 95% confidence interval (CI) 2.318–6.615, p

Importance Patients with breast cancer remain at risk of relapse after adjuvant therapy. Celecoxib has shown antitumor effects in preclinical models of human breast cancer, but clinical evidence is lacking. Objective To evaluate the role of celecoxib as an addition to conventional therapy for women with ERBB2 (formerly HER2)–negative primary breast cancer. Design, Setting, and Participants The Randomized European Celecoxib Trial (REACT) was a phase 3, randomized, double-blind study conducted in 160 centers across the UK and Germany testing 2 years of adjuvant celecoxib vs placebo among 2639 patients recruited between January 19, 2007, and November 1, 2012, with follow-up 10 years after treatment completion. Eligible patients had completely resected breast cancer with local and systemic therapy according to local practice. Patients with ERBB2-positive or node-negative and T1, grade 1 tumors were not eligible. Randomization was in a 2:1 ratio between celecoxib or placebo. Statistical analysis was performed from May 5, 2019, to March 5, 2020. Interventions Patients received celecoxib, 400 mg, or placebo once daily for 2 years. Main Outcomes and Measures The primary end point was disease-free survival (DFS), analyzed in the intention-to-treat population using Cox proportional hazards regression and log-rank analysis. Follow-up is complete. Results A total of 2639 patients (median age, 55.2 years [range, 26.8-86.0 years]) were recruited; 1763 received celecoxib, and 876 received placebo. Most patients’ tumors (1930 [73%]) were estrogen receptor positive or progesterone receptor positive and ERBB2 negative. A total of 1265 patients (48%) had node-positive disease, and 1111 (42%) had grade 3 tumors. At a median follow-up of 74.3 months (interquartile range, 61.4-93.6 years), DFS events had been reported for 487 patients (19%): 18% for those who received celecoxib (n = 323; 5-year DFS rate = 84%) vs 19% for those who received placebo (n = 164; 5-year DFS rate = 83%); the unadjusted hazard ratio was 0.97 (95% CI, 0.80-1.17; log-rankP = .75). Rates of toxic effects were low across both treatment groups, with no evidence of a difference. Conclusions and Relevance In this randomized clinical trial, patients showed no evidence of a DFS benefit for 2 years’ treatment with celecoxib compared with placebo as adjuvant treatment of ERBB2-negative breast cancer. Longer-term treatment or use of a higher dose of celecoxib may lead to a DFS benefit, but further studies would be required to test this possibility. Trial Registration ClinicalTrials.gov Identifier:NCT02429427and isrctn.org Identifier:ISRCTN48254013

Background: About one third of patients with hormone-receptor-positive (HR+), HER2- primary breast cancer with residual invasive disease after neoadjuvant chemotherapy will relapse despite adjuvant endocrine therapy. The risk of relapse can be assessed more accurately using the CPS-EG scoring system (Mittendorf et al. JCO 2011). Therapeutic inhibition of cyclin-dependent kinase 4 and 6 (CDK 4/6) by palbociclib combined with endocrine therapy demonstrated highly relevant efficacy in metastatic breast cancer. Thus, we hypothesize that palbociclib may also be active in these high-risk patients with primary breast cancer. Methods: PENELOPE-B (NCT01864746) is a double-blind, placebo-controlled, phase III study in women with centrally confirmed HR+, HER2- primary breast cancer without a pathological complete response after taxane-containing neoadjuvant chemotherapy and at high-risk of relapse (CPS-EG score ≥3 or 2 and ypN+). After completion of neoadjuvant chemotherapy and locoregional therapy, patients were randomized (1:1) to receive 13 cycles of palbociclib 125mg daily or placebo on days 1-21 in a 28d cycle in addition to standard endocrine therapy. Randomization was stratified by lymph node status (at surgery), age, Ki-67, global region, and CPS-EG score. Primary endpoint is invasive disease-free survival (iDFS). Final analysis was planned after 290 iDFS events with efficacy boundary p15% in 27.7 %; 54.7% of patients had risk status CPS-EG score ≥3. 1118 patients (89%) completed at least 7 cycles of therapy. 50.1% of patients received aromatase inhibitor (AI), 49.8% tamoxifen, 6.6% AI + gonadotropin-releasing hormone (GnRH) and 9.7% tamoxifen + GnRH. Most common related serious adverse events (SAEs) were infections and vascular disorders. 8 fatal SAEs were reported. Conclusions: PENELOPE-B evaluates the effect of palbociclib for 1 year compared to placebo in addition to endocrine therapy in high-risk primary breast cancer patients. The database was locked with 308 events on September 25th 2020. After breaking the blind for analysis, top line results will be available as of mid October 2020. Results of the final iDFS analysis will be presented at the meeting. Citation Format: Sibylle Loibl, Frederik Marmé, Miguel Martin, Michael Untch, Hervé Bonnefoi, Sung-Bae Kim, Harry Bear, Nicole Mc Carthy, Mireia Melé Olivé, Karen Gelmon, José García Sáenz, Catherine M Kelly, Toralf Reimer, Masakazu Toi, Hope S Rugo, Sabine Seiler, Valentina Nekljudova, Carsten Denkert, Michael Gnant, Andreas Makris, Nicole Burchardi, Gunter von Minckwitz. Phase III study of palbociclib combined with endocrine therapy (ET) in patients with hormone-receptor-positive (HR+), HER2-negative primary breast cancerand with high relapse risk after neoadjuvant chemotherapy (NACT): First results from PENELOPE-B [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS1-02.

Purpose: This study aimed to evaluate the prognostic impact of circulating tumor cells (CTC) detected in patients with operable or locally advanced breast cancer before and after neoadjuvant therapy (NT) within the clinical trial GeparQuattro. Experimental Design: Data on CTCs enumerated with the CellSearch system were available for 213 and 207 patients before and after NT, respectively. Associations of CTCs with disease-free survival (DFS) and overall survival (OS) were analyzed by nonparametric Kaplan–Meier estimates and parametric Cox regression. Results: After a median follow-up of 67.1 months, the detection of ≥1 CTC/7.5 mL and ≥2 CTCs/7.5 mL before NT was associated with reduced DFS (P = 0.031 and P < 0.0001, respectively) and OS (P = 0.0057 and P < 0.0001, respectively), whereas CTCs detected after NT did not correlate with DFS or OS. In parametric univariate and multivariate Cox models, ≥1 CTC/7.5 mL, ≥2 CTCs/7.5 mL, and absolute CTC numbers before NT revealed to be independent prognostic parameters of DFS and OS. CTC-negative patients with pathologic complete response (pCR) exhibited the best prognosis, whereas those with CTCs and less tumor response were at high risk of tumor relapse. In HER2 (ERBB2)-positive and triple-negative patients, ≥2 CTCs/7.5 mL detected before NT also were significantly associated with worse DFS and OS. Conclusions: Detection of CTCs before NT is an independent prognostic factor of impaired clinical outcome, and combined with pCR, it could be helpful to stratify breast cancer patients for therapeutic interventions. Clin Cancer Res; 23(18); 5384–93. ©2017 AACR.

The GeparSepto study demonstrated that the use of nab-paclitaxel instead of paclitaxel prior to anthracycline-based chemotherapy could lead to a significantly increased pCR rate, especially in the triple negative subpopulation. We report efficacy and safety for patients treated with two different doses of nab-paclitaxel in comparison to weekly solvent-formulated paclitaxel. Patients were treated for 12 weeks with either intravenous nab-paclitaxel 150 mg/m2 (nP150) weekly, after study amendment 125 mg/m2 (nP125) weekly or solvent-based paclitaxel 80 mg/m2 (P80) weekly followed by epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2 on day 1 for four 3-week cycles. 229 patients received nP150, 377 nP125. Baseline characteristics were fairly balanced between these two sequential cohorts as well as compared to 601 patients receiving P80 except for hormone receptor status, HER2 status, and Ki67. Taxane treatment was discontinued in 26.8% (nP150), 16.6% (nP125), and 13.3% of (P80) patients, respectively. Median relative total dose intensity (mRTDI) based on 125 mg/m2 for nP was 103% with nP150, 95% with nP125, 99% with P80 before and 98% with P80 after the amendment. PSN grade 3–4 was observed in 14.5% of patients with nP150, 8.1% of patients with nP125 (p = 0.018), and 2.7% of patients with P80. Overall pCR before the amendment was 33.6% after nP150 and 23.5% after P80 (OR 1.65 [95% CI 1.10–2.50]; p = 0.022); pCR after the amendment was 41.4% after nP125, and 32.4% after P80 (1.48 [95% CI 1.10–1.99]; p = 0.013). Nab-paclitaxel 125 mg/m2 was associated with a better safety profile and compliance without compromising the efficacy compared to nab-paclitaxel 150 mg/m2.

Background: The achievement of pCR (breast and axilla) is strongly prognostic for event-free (EFS) and overall survival (OS) in EBC (Cortazar 2014), and modulation of therapy improves long-term outcomes for patients with HER2-positive disease not achieving pCR (Von Minckwitz 2019). We sought to investigate prognostic factors for EFS and OS among patients with and without pCR following neoadjuvant systemic treatment consisting of chemotherapy plus anti-HER2 therapy. Methods: We used individual data from 3,710 patients randomized in 11 neoadjuvant trials for HER2-positive EBC with N≥100 patients enrolled, available data for pCR, EFS, and OS, and follow-up ≥3 years. We assessed baseline clinical tumor size (cT) and clinical nodal status (cN) as prognostic factors using stratified (by trial and treatment) Cox models separately for hormone-receptor (HR)-positive vs. HR-negative disease, and for patients who achieved pCR (pCR+; ypT0/is, ypN0) vs. patients who did not achieve pCR (pCR-). Results: The median follow-up overall was 61.2 months. The table shows hazard ratios and 5-year Kaplan-Meier estimates of OS (5yr OS) according to HR and pCR. Comparable results were observed for EFS. Both cT (1-2 vs. 3-4) and cN (cN- vs. cN+) were independent prognostic factors for OS in most subsets, including in pCR+ patients. Conclusions: These results confirm that patients achieving pCR have far better long-term outcomes than patients who do not, and that traditional poor prognostic features namely tumour size and nodal status remain important even after a pCR, with no clear evidence that the relative impact of unfavourable (cT3-4 or cN+) features is different in patients who achieve a pCR than in those who did not. Key words: neo-adjuvant therapy, HER2-targeted therapy, pathological complete response, prognostic factors, overall survival Funding: German Breast Group HR pCRBaseline cT/cN DeathsPatients5yr OS (%)Hazard ratio* [95% CI]HR+ pCR+cT1-2/cN-521298.6%1.0 (reference)(N= 637)cT3-4/cN-46592.9%0.49 [0.21-1.14]cT1-2/cN+720095.1%0.82 [0.34-1.99]cT3-4/cN+1016094.0%0.40 [0.13-1.25]HR+ pCR-cT1-2/cN-1737796.3%1.0 (reference)(N=1399)cT3-4/cN-2514381.8%0.51 [0.36-0.73]cT1-2/cN+4844888.9%0.71 [0.49-1.03]cT3-4/cN+6443184.9%0.36 [0.23-0.58]HR- pCR+cT1-2/cN-319698.1%1.0 (reference)(N=860)cT3-4/cN-89090.4%0.56 [0.32-0.98]cT1-2/cN+1928092.4%0.49 [0.24-0.98]cT3-4/cN+3029489.5%0.27 [0.12-0.64]HR- pCR-cT1-2/cN-2114083.2%1.0 (reference)(N=814)cT3-4/cN-207871.4%0.46 [0.34-0.64]cT1-2/cN+4225181.6%0.76 [0.53-1.09]cT3-4/cN+11634561.9%0.35 [0.22-0.56]*Hazard ratio cT1-2/cN- vs. higher risk cohorts Citation Format: Sibylle Loibl, Michael Untch, Marc Buyse, André Robidoux, Luca Gianni, Andreas Schneeweiss, Pierfranco Conte, Martine Piccart, Hervé Bonnefoi, Christian Jackisch, Valentina Nekljudova, Joseph Costantino, Pinuccia Valagussa, Colin Neate, Richard Gelber, Coralie Poncet, Pierre Squifflet, Everardo Saad, Dominik Heinzmann, Carsten Denkert, Charles E Geyer, Javier Cortes, Valentina Guarneri, Evandro de Azambuja, David Cameron, Gustavo Ismael, Gunter von Minckwitz, Norman Wolmark, Patricia Cortazar. Pathologic complete response (pCR) and prognosis following neoadjuvant chemotherapy plus anti-HER2 therapy of HER2-positive early breast cancer (EBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-06-02.

Purpose: To characterize the pharmacokinetics (PK) of, and perform an exploratory exposure–response (E–R) analysis for, pertuzumab in patients with HER2-positive early breast cancer (EBC) within the APHINITY study (NCT01358877, BIG 4–11/BO25126/TOC4939G). Methods: A previously developed pertuzumab two-compartment linear population pharmacokinetic (popPK) model was subjected to external validation to examine appropriateness for describing pertuzumab concentrations from the APHINITY study. Pharmacokinetic drug–drug interactions (DDIs) between pertuzumab, trastuzumab, and chemotherapy were assessed by comparing observed serum or plasma C max ,C min ,and AUC last geometric mean ratios with 90% CIs. Predictions of pertuzumab C max,ss ,C min,ss ,and AUC ss were derived from individual parameter estimates and used in an exploratory E–R analysis. Results: Using data from 72 patients, based on goodness-of-fit, the popPK model was deemed appropriate for predictions of individual exposures for subsequent comparisons to historical data, assessment of DDIs, and E–R analyses. No evidence of DDIs for pertuzumab on trastuzumab, trastuzumab on pertuzumab, or pertuzumab on chemotherapy PK was observed. Analyses of differences in exposure between patients with and without invasive disease-free survival events did not indicate improved efficacy with increased exposure. Overall Grade ≥ 3 diarrhea prevalence was higher with pertuzumab versus placebo, but was not greater with increasing pertuzumab exposure. No apparent E–R relationship was suggested with respect to other grade ≥ 3 AEs. Conclusion: Overall, the limited available data from this exploratory study suggest that no dose adjustments are needed for pertuzumab when administered in combination with trastuzumab and an EBC chemotherapy regimen., SCOPUS: ar.j, info:eu-repo/semantics/published

PURPOSE The GeparSepto trial demonstrated that weekly nanoparticle albumin-bound (NAB)–paclitaxel significantly improves the pathologic complete remission rate compared with weekly solvent-based (sb) paclitaxel followed by epirubicin plus cyclophosphamide as neoadjuvant treatment in patients with primary breast cancer (BC). Here, we report data on long-term outcomes. METHODS Patients with histologically confirmed primary BC were randomly assigned in a 1:1 ratio to 12 times weekly NAB-paclitaxel 150 mg/m2 (after study amendment, 125 mg/m2) or weekly sb-paclitaxel 80 mg/m2 followed in both arms by four times epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 every 3 weeks. Patients with human epidermal growth factor receptor 2 (HER2)-positive BC received dual antibody treatment with trastuzumab (8 mg/kg loading dose followed by 6 mg/kg every 3 weeks) and pertuzumab (840 mg loading dose followed by 420 mg every 3 weeks) concurrently to chemotherapy and continued for 1 year. RESULTS A total of 1,206 patients started treatment, 606 with NAB-paclitaxel and 600 with sb-paclitaxel. After a median follow-up of 49.6 months (range, 0.5 to 64.0 months), 243 invasive disease–free survival (iDFS) events were reported (143 in the sb-paclitaxel and 100 in the NAB-paclitaxel arm). At 4 years, overall patients treated with NAB-paclitaxel had a significantly better iDFS compared with sb-paclitaxel (84.0% v 76.3%; hazard ratio, 0.66; 95% CI, 0.51 to 0.86; P = .002), whereas overall survival did not significantly differ between the two treatment arms (89.7% v 87.2%, respectively; hazard ratio, 0.82; 95% CI, 0.59 to 1.16; P = .260). Long-term follow-up of the treatment-related peripheral sensory neuropathy (PSN) showed a significant decrease of the median time to resolve PSN after NAB-paclitaxel 125 mg/m2 compared with NAB-paclitaxel 150 mg/m2. CONCLUSION The significantly higher pathologic complete response rate with NAB-paclitaxel translated into a significantly improved iDFS in patients with early BC as compared with sb-paclitaxel. PSN improved much faster under NAB-paclitaxel 125 mg/m2 compared with NAB-paclitaxel 150 mg/m2.

The E-VITA study evaluated the efficacy and tolerability of two schedules of eribulin and lapatinib in patients with trastuzumab-pretreated HER-2-positive metastatic breast cancer. This multicenter, open-label phase II trial, randomly assigned patients with trastuzumab-pretreated HER-2-positive metastatic breast cancer to lapatinib 1000 mg daily with eribulin 1.23 mg/m (equivalent to 1.4 mg/m eribulin mesylate) days 1+8 every 21 days (split-dose arm) or eribulin 1.76 mg/m (equivalent to 2.0 mg/m eribulin mesylate) day 1 every 21 days (3-weekly arm). Time to progression and tolerability were defined as primary end points; no sample size calculation for formal comparison of efficacy data has been performed. Secondary end points included objective response rate, clinical benefit rate, and overall survival. Overall, 43 patients of a planned number of 80 patients were recruited. At a median follow-up of 28.7 months, the median time to progression was 8.1 months [95% confidence interval (CI): 4.8-9.4] in the split-dose arm and 6.5 months (95% CI: 4.6-13.4) in the 3-weekly arm. Objective response rate was 52.4% (95% CI: 31.0-73.7) in the split-dose arm and 45.0% (95% CI: 23.2-66.8) in the 3-weekly arm, and clinical benefit rate was 71.4% (95% CI: 52.1-90.8) and 75.0% (95% CI: 56.0-94.0), respectively. Overall survival was also similar in both arms. The most frequent grade 3-4 adverse events were neutropenia (58.5%) and leukopenia (39.0%). The combination of eribulin and lapatinib showed an acceptable safety profile with less toxicity observed in the eribulin 1.23 mg/m day 1+8 group. This might be an alternative regimen when other treatment options are exhausted. Therefore, further clinical studies are warranted.

Purpose BRCA1/2 mutations are frequent in patients with triple-negative breast cancer (TNBC). These patients are often treated with primary systemic chemotherapy. The aim of this study was to analyze the effects of BRCA1/2 mutations on pathologic complete response (pCR) and disease-free survival (DFS) in a cohort of patients with TNBC treated with anthracycline and taxane–containing chemotherapy, with or without bevacizumab. Patients and Methods Germline DNA was sequenced to identify mutations in BRCA1 and BRCA2 in 493 patients with TNBC from the GeparQuinto study. The pCR rates were compared in patients with and without mutation, as well as in patients treated with and without bevacizumab. In addition, the influence of BRCA1/2 mutation status and pCR status on DFS was evaluated relative to treatment. Results BRCA1/2 mutations were detected in 18.3% of patients with TNBC. Overall, patients with mutations had a pCR rate of 50%, compared with 31.5% in patients without a mutation (odds ratio [OR], 2.17; 95% CI, 1.37 to 3.46; P = .001). The pCR rate among patients treated with bevacizumab was 61.5% for BRCA1/2 mutation carriers and 35.6% for those without mutations (OR, 2.90; 95% CI, 1.43 to 5.89; P = .004). pCR was a strong predictor of DFS for patients without BRCA1/2 mutations (hazard ratio, 0.18; 95% CI, 0.11 to 0.31) but not for patients with BRCA1/2 mutations (hazard ratio, 0.74; 95% CI, 0.32 to 1.69). Conclusion The addition of bevacizumab may increase the pCR after standard neoadjuvant chemotherapy for patients with TNBC with BRCA1/2 mutations. In patients treated with anthracycline and taxane–based chemotherapy (with or without bevacizumab), pCR was a weaker predictor of DFS for BRCA1/2 mutation carriers than for patients without mutations.

PurposeThe GeparQuinto phase III trial demonstrated a lower pathologic complete response (pCR; pT0 ypN0) rate when lapatinib was added to standard anthracycline–taxane chemotherapy compared with trastuzumab in patients with human epidermal growth factor receptor 2 (HER2) –positive breast cancer. Here, we report the long-term outcomes.MethodsPatients with HER2-positive tumors (n = 615) received neoadjuvant treatment with epirubicin (E) plus cyclophosphamide (C), followed by docetaxel (T) in combination with either lapatinib (L) or trastuzumab (H; ECH-TH arm: n = 307; ECL-TL arm: n = 308). All patients received adjuvant trastuzumab for a total of 12 months and 18 months in the ECH-TH and ECL-TL arms, respectively. Median follow-up was 55 months.ResultsThree-year disease-free survival (DFS), distant DFS (DDFS), and overall survival (OS) were not significantly different between the two treatment arms. Long-term outcomes correlated with pCR (DFS: hazard ratio [HR], 0.63; P = .042; DDFS: HR, 0.55; P = .021; and OS: HR, 0.31; P = .004). A benefit only for OS was observed in patients who were treated with trastuzumab and achieved pCR versus no pCR (HR, 0.15; P = .010), whereas no difference was found in patients with pCR versus without pCR in the lapatinib arm. DFS and DDFS remained unchanged in both treatment arms according to hormone receptor status, whereas OS was significantly better in hormone receptor–positive patients who were treated with neoadjuvant lapatinib (HR, 0.32; P = .019), followed by adjuvant trastuzumab. No difference was observed in hormone receptor–negative patients; however, the small number of events limits this interpretation. Within the hormone receptor–negative cohort, pCR was significantly associated with DFS, DDFS, and OS ( P = .002, .005, and .002, respectively).ConclusionpCR correlated with long-term outcome. In patients with hormone receptor–positive tumors, prolonged anti-HER2 treatment—neoadjuvant lapatinib for 6 months, followed by adjuvant trastuzumab for 12 months—significantly improved survival compared with anti-HER2 treatment with trastuzumab alone.

Purpose: Scoring proliferation through Ki67 immunohistochemistry is an important component in predicting therapy response to chemotherapy in patients with breast cancer. However, recent studies have cast doubt on the reliability of “visual” Ki67 scoring in the multicenter setting, particularly in the lower, yet clinically important, proliferation range. Therefore, an accurate and standardized Ki67 scoring is pivotal both in routine diagnostics and larger multicenter studies. Experimental Design: We validated a novel fully automated Ki67 scoring approach that relies on only minimal a priori knowledge on cell properties and requires no training data for calibration. We applied our approach to 1,082 breast cancer samples from the neoadjuvant GeparTrio trial and compared the performance of automated and manual Ki67 scoring. Results: The three groups of autoKi67 as defined by low (≤15%), medium (15.1%–35%), and high (>35%) automated scores showed pCR rates of 5.8%, 16.9%, and 29.5%, respectively. AutoKi67 was significantly linked to prognosis with overall and progression-free survival P values POS < 0.0001 and PPFS < 0.0002, compared with POS < 0.0005 and PPFS < 0.0001 for manual Ki67 scoring. Moreover, automated Ki67 scoring was an independent prognosticator in the multivariate analysis with POS = 0.002, PPFS = 0.009 (autoKi67) versus POS = 0.007, PPFS = 0.004 (manual Ki67). Conclusions: The computer-assisted Ki67 scoring approach presented here offers a standardized means of tumor cell proliferation assessment in breast cancer that correlated with clinical endpoints and is deployable in routine diagnostics. It may thus help to solve recently reported reliability concerns in Ki67 diagnostics. Clin Cancer Res; 21(16); 3651–7. ©2014 AACR.

Studies assessing the effect of bevacizumab (BEV) on breast cancer (BC) outcome have shown different effects on progression-free and overall survival, suggesting that a subgroup of patients may benefit from this treatment. Unfortunately, no biomarkers exist to identify these patients. Here, we investigate whether single nucleotide polymorphisms (SNPs) in VEGF pathway genes correlate with pathological complete response (pCR) in the neoadjuvant GeparQuinto trial. HER2-negative patients were randomized into treatment arms receiving either BEV combined with standard chemotherapy or chemotherapy alone. In a pre-planned biomarker study, DNA was collected from 729 and 724 patients, respectively from both treatment arms, and genotyped for 125 SNPs. Logistic regression assessed interaction between individual SNPs and both treatment arms to predict pCR. Five SNPs may be associated with a better response to BEV, but none of them remained significant after correction for multiple testing. The two SNPs most strongly associated, rs833058 and rs699947, were located upstream of the VEGF-A promoter. Odds ratios for the homozygous common, heterozygous and homozygous rare rs833058 genotypes were 2.36 (95% CI, 1.49-3.75), 1.20 (95% CI, 0.88-1.64) and 0.61 (95% CI, 0.34-1.12). Notably, some SNPs in VEGF-A exhibited a more pronounced effect in the triple-negative subgroup. Several SNPs in VEGF-A may be associated with improved pCR when receiving BEV in the neoadjuvant setting. Although none of the observed effects survived correction for multiple testing, our observations are consistent with previous studies on BEV efficacy in BC. Further research is warranted to clarify the predictive value of these markers.

BACKGROUND Although greater than 40% of breast cancers occur in patients aged ≥65 years, these individuals are frequently undertreated. Taxane-based adjuvant chemotherapy is considered the treatment of choice but to the authors' knowledge has only limited evidence in elderly patients. METHODS Patients aged ≥65 years with a Charlson comorbidity index ≤2 and pT1/2 pN0/1 disease and either human epidermal growth factor receptor 2 (HER2)-positive, hormone receptor-negative, grade 3 (according to Common Terminology Criteria for Adverse Events [version 3.0]), high uPA/PAI-1 or any stage pT3/4 pN2/3 breast cancer were randomized to receive 4 cycles of adjuvant epirubicin and cyclophosphamide (EC) (epirubicin at a dose of 90 mg/m2 and cyclophosphamide at a dose of 600 mg/m2 intravenously [iv] on day 1 every 3 22 days) or 6 cycles of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) (cyclophosphamide at a dose of 500 mg/m2, methotrexate at a dose of 40 mg/m2, and 5-fluorouracil at a dose of 600 mg/m2 iv on days 1 plus 8 every 29 days) versus 6 cycles of nab-paclitaxel and capecitabine (nPX) (nab-paclitaxel at a dose of 100 mg/m2 iv on days 1, 8, and 15 every 21 days with 1 week of rest every 6 weeks plus capecitabine at a dose of 2000 mg/m2 orally on days 1-14 every 21 days). Primary endpoints were treatment discontinuations and overall frequency of adverse events. RESULTS Thirteen of 198 patients (6.6%) discontinued EC/CMF and 69 of 193 patients (35.8%) discontinued nPX (P

Background: Anthracycline/taxane based regimen are standard of care for neoadjuvant therapy in breast cancer. A reverse sequence of taxanes followed by anthracyclines was suggested to achieve higher pCR rates (H.Earl, Lancet Oncol 2014). Dual HER2 blockade was shown to be superior to trastuzumab alone increasing the pCR rate by 20%. Nab-paclitaxel (nP) is a solvent-free formulation of paclitaxel (P) encapsulated in albumin which might further improve the pCR rate in breast cancer patients receiving neoadjuvant treatment and cause lower toxicity. Methods: In the GeparSepto study (NCT01583426) patients were randomized to either nP (125 mg/m2) q1w or P (80mg/m2) q1w for 12 weeks followed by 4 cycles of conventionally dosed EC (E, epirubicin 90mg/m2; C, cyclophosphamide 600 mg/m2) q3w. The primary objective is to compare the pathological complete response rate (pCR, ypT0 ypN0). Further objectives are to compare the pCR rate in predefined subgroups, pCR by other definitions, clinical response rate, rate of breast conserving surgery and toxicity and compliance. Patients with untreated, histologically confirmed uni- or bilateral, cT2- cT4d carcinoma, and no clinically relevant cardiovascular and other co-morbidities were included. HER2+ patients received trastuzumab (loading dose 8mg/kg; 6 mg/kg) plus pertuzumab (loading dose 840 mg; 420 mg) q3w concomitantly. HER2, estrogen receptor, progesterone receptor, Ki67 and SPARC status were centrally assessed prior to randomization for stratification. To increase the pCR rate from 33% with P to 41% with nP, corresponding to an odds ratio of 1.41 with an alpha of 0.05 and a power of 80%, 1200 patients would be needed. A window-of opportunity study was integrated to investigate response to anti-HER2 treatment without chemotherapy, HER2+ patients were randomized to receive 6 weeks of either trastuzumab, pertuzumab or the combination with biomaterial collection at the start and the end of the window. Results: A total of 1204/1229 (window study n=71) recruited patients (7/2012 - 12/2013) from 69 German centers were evaluable, 606 receiving nP. Baseline characteristics are well balanced; median age was 49/50 years (P/nP), 33/33% of the patients presented with HER2+ tumors, 23/23% triple negative breast cancer TNBC (ER and PR 20% 69/69%; SPARC positive 15.7/16%. 265 patients reported SAEs (119 P/146 nP) and 4 died on study (1 P: cardiac decompensation; 3 nP: accident at home, multiorgan failure, sepsis during EC). The pCR rate (ypT0 ypN0) is 29% with P and 38% with nP, OR 1.5; p Conclusions: GeparSepto showed that the pCR rate is significantly higher with nab-paclitaxel compared to solvent-based paclitaxel given weekly before anthracycline based chemotherapy. Subgroupanalyses and 2ndary endpoints will be presented at the meeting. The trial was financially supported by Roche and Celgene. The window-substudy was funded within the EU-FP7 project RESPONSIFY No 278659. Citation Format: Michael Untch, Christian Jackisch, Andreas Schneeweiß, Bettina Conrad, Bahriye Aktas, Carsten Denkert, Holger Eidtmann, Hermann Wiebringhaus, Sherko Kümmel, Jörn Hilfrich, Mathias Warm, Stefan Paepke, Marianne Just, Claus Hanusch, John Hackmann, Jens-Uwe Blohmer, Michael Clemens, Serban Dan Costa, Bernd Gerber, Valentina Nekljudova, Sibylle Loibl, Gunter von Minckwitz. A randomized phase III trial comparing neoadjuvant chemotherapy with weekly nanoparticle-based paclitaxel with solvent-based paclitaxel followed by anthracyline/cyclophosphamide for patients with early breast cancer (GeparSepto); GBG 69 [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S2-07.

(1) PURPOSE The aim of the prospective trial was to determine if cell survival in a breast cancer spheroid model following cytostatic treatment in vitro predicts treatment response in breast cancer patients receiving equivalent neoadjuvant therapy. (2) PATIENTS AND METHODS Three-dimensional spheroids were directly generated from fresh tumor biopsy samples of 78 patients eligible for neoadjuvant therapy. Cell survival in vitro, as well baseline clinical and pathological characteristics were correlated with the outcome following treatment of each patient to determine the factor(s) most highly associated with pathological complete response (pCR i.e.ypT0/ypN0) at surgery. (3) RESULTS Cell survival after treatment in the breast cancer spheroid model proved to be a sensitive and specific predictor for pCR in individual breast cancer patients. A mean cell survival of 21.8% was found in the breast cancer spheroid model for 22 patients with pCR versus 63.8% in 56 patients without pCR (P = .001). A receiver operator characteristic analysis determined an area under the ROC curve of 0.86 (95% CI: 0.77 to 0.96) for cell survival compared to classic factors i.e. negative hormone receptor and positive Her2/neu status, and age ≤ 50 years at primary diagnosis (AUC = 0.80, 95% CI: 0.70 to 0.90). A cutoff of 35% cell survival was proposed, which grouped patients according to likelihood for pCR. Out of the 32 patients with values below this threshold, 21 patients (65.6%) and one patient (2.2%) with a cell survival greater than 35% achieved pCR respectively; (sensitivity 95.5% (95% CI: 0.86 to 1.00); specificity 80.4% (95% CI: 0.70 to 0.91)).The specificity was improved to 81% (95% CI: 58 to 95%) if the patient was treated per-protocol. A positive correlation was also found between cell survival in vitro and residual tumor size (P = .021), indicating the possibility of the model to predict degree of response. (4) CONCLUSION The breast cancer spheroid model is a valuable predictor for treatment outcome in patients undergoing neoadjuvant chemotherapy for primary breast cancer. Preclinical selection of the most efficient drugs is a prerequisite to improve pCR. Citation Format: Kathrin ML Halfter, Nina Ditsch, Hans-Christian Kolberg, Holger Fischer, Tanja Hauzenberger, Franz Edler von Koch, Ingo Bauerfeind, Gunter von Minckwitz, Ilona Funke, Alexander Crispin, Barbara Mayer. Prospective cohort study using the breast cancer spheroid model as a predictor for response to neoadjuvant therapy – The SpheroNEO study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-13.

ABSTRACT Kyoto Breast Cancer Consensus Conference, Kyoto, Japan, 18–20 February 2014 The loco-regional management of breast cancer is increasingly complex with application of primary systemic therapies, oncoplastic techniques and genetic testing for breast cancer susceptibility. Personalization of loco-regional treatment is integral to optimization of breast cancer care. Clinical and pathological tumor stage, biological features and host factors influence loco-regional treatment strategies and extent of surgical procedures. Key issues including axillary staging, axillary treatment, radiation therapy, primary systemic therapy (PST), preoperative hormonal therapy and genetic predisposition were identified and discussed at the Kyoto Breast Cancer Consensus Conference (KBCCC2014). In the first of a two part conference scene, consensus recommendations for axillary management are presented and focus on the following topics: indications for completion axillary lymph node dissection in primary surgical patients with ≤2 macrometastases or any sentinel nodal deposits after PST; the timing of sentinel lymph node biopsy in the context of PST; use of axillary irradiation as a component of primary treatment plans and the role of intraoperative node assessment in the post-Z0011 era.

BACKGROUND: A potential predictive and prognostic effect of pretreatment pVEGF-A concentrations was suggested in exploratory analyses of phase III trials in HER2-negative mBC (AVADO), gastric cancer (AVAGAST), and pancreatic cancer (AViTA). This led to initiation of the MERiDiAN trial evaluating pVEGF-A prospectively in patients (pts) receiving 1st-line paclitaxel ± BEV in HER2-negative mBC. Potential predictive value was also noted for pVEGFR-2 in AVADO, AViTA, and in early BC in BEATRICE. We report prespecified pVEGF-A and pVEGFR-2 analyses in TANIA. METHODS: TANIA is an open-label randomized phase III trial evaluating the addition of BEV (15 mg/kg q3w or 10 mg/kg q2w) to the investigator’s choice of chemotherapy (CT) in pts with HER2-negative mBC who experience disease progression (PD) on/after 1st-line BEV-containing therapy. Allocation to BEV or no BEV is continued with 3rd-line therapy after 2nd PD (ie no crossover permitted). The primary endpoint is PFS from randomization to 2nd-line PD/death. Pts consenting to the optional biomarker substudy provided 6 mL plasma samples in EDTA before drug administration at randomization, at wks 7 and 13, every 12 wks thereafter, and at 2nd PD. pVEGF-A and shedded pVEGFR-2 were measured using the IMPACT assay (v2.03). The median concentration for each marker before 2nd-line treatment was prespecified as the cut-off between low (≤ median) and high (> median) biomarker subgroups. 2nd-line PFS was analyzed in each subgroup. RESULTS: The PFS benefit from BEV seen in the ITT population (N=494; stratified hazard ratio [HR] 0.75, 95% CI 0.61–0.93) was observed consistently within subgroups of the biomarker population (N=312). However, there was no differential BEV effect according to pVEGF-A or shedded pVEGFR-2 concentrations. The stratified HR for PFS was 0.69 (95% CI 0.46–1.04) in pts with low pVEGF-A (≤1010.6 pg/mL [median]) and 0.80 (95% CI 0.54–1.18) in pts with high pVEGF-A (interaction p=0.47). As all pts had received prior BEV, unlike earlier trials showing a potential predictive effect of pVEGF-A, we explored pVEGF-A concentrations according to BEV-free interval. The BEV-free interval was ≤12 wks in 117/150 pts (78%) in the CT arm and 136/162 pts (84%) in the BEV+CT arm. Median pVEGF-A was much lower in the subgroup of 59 pts with a BEV-free interval >12 wks (45.1 pg/mL) than in pts with a BEV-free interval ≤12 wks (1135.3 pg/mL). Analyses of 2nd-line PFS according to shedded pVEGFR-2 concentration showed stratified PFS HRs of 0.68 (95% CI 0.45–1.02) for low pVEGFR-2 (≤9.6 ng/mL [median]) and 0.90 (95% CI 0.60–1.34) for high pVEGFR-2 (interaction p=0.49). CONCLUSIONS: The potential predictive effect of pVEGF-A in AVADO was not observed in TANIA, although high pVEGF-A concentrations in pts recently treated with BEV complicate interpretation. pVEGF-A is being evaluated prospectively in BEV-naïve pts in the ongoing MERiDiAN trial. Shedded pVEGFR-2 showed no predictive effect in TANIA and the suggested trend was in the opposite direction to the effect seen in AVADO and BEATRICE. Further analyses are planned to evaluate the impact of gene expression, cell-free DNA, protein expression, and DNA mutations on treatment effect in TANIA. Citation Format: Javier Cortes, Eduard Vrdoljak, Fabio Puglisi, Norbert Marschner, Joseph Gligorov, Christoph Zielinski, Cristian Villanueva, Gilles Romieu, István Lang, Eva Ciruelos, Corinne Veyret, Andrea Fontana, Mikkel Oestergaard, Sabine de Ducla, Ulrich Freudensprung, Gunter von Minckwitz. Plasma (p) biomarker results from the TANIA trial evaluating continued or reintroduced bevacizumab (BEV) after 1st-line BEV for HER2-negative metastatic breast cancer (mBC) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-08.

BACKGROUND: The GeparQuinto study showed that adding bevacizumab to 24 weeks of anthracycline-taxane-based neoadjuvant chemotherapy increases pathological complete response (pCR) rates from 14.9% to 18.4% (P=0.04) overall; specifically in patients with TNBC (27.9% to 39.3% (P=0.003) (von Minckwitz et al, NEJM 2012). No difference in pCR rate was observed for adding everolimus to paclitaxel patients who had no early response to neoadjuvant chemotherapy (Huober et al, Eur J Cancer 2013). Here, we present disease-free (DFS) and overall survival (OS) analyses. PATIENTS AND METHODS: Patients (n = 1948) with HER2-negative tumors of a median tumor size of 4 cm were randomly assigned to neoadjuvant treatment with 4xEC à 4x docetaxel with or without bevacizumab, 15 mg/Kg q3w before surgery. 408 patients not clinically responding to EC ± Bev were randomized to 12x weekly paclitaxel with or without everolimus 5mg/day. Patients with HR-positive tumors received endocrine treatment after surgery. 379 events are required to show a HR of 0.75 (α=0.05, ß=0.8) between the bevacizumab arms. 397 relapses and 234 deaths were observed after a median follow up of 3.8 years overall, of those 115 relapses and 75 deaths occurred in the non-responding cohort. RESULTS: Overall, 3-year DFS was 80.8% and 3-year OS was 89.7%. Outcome was not different for patients receiving bevacizumab (HR 1.03; P = 0.780 for DFS and HR 0.974; P = 0.842 for OS) compared to patients receiving chemotherapy alone. Patients with TNBC showed no improvement in DFS (HR 0.991; P = 0.948) and OS (HR 1.02; P = 0.891) when treated with bevacizumab. No other predefined subgroup (HR+/HER2-; locally advanced (cT4 or cN3) or not; cT1-3, cT4a-c, cT4d; pCR or not, CR, PR, NC after first 4 cycles chemotherapy) showed a benefit from bevacizumab. No difference in DFS (HR 0.997; P=0.987) and OS (HR 1.11; P=0.658) was observed for patients who had no early response to neoadjuvant chemotherapy receiving paclitaxel with or without everolimus overall as well as in subgroups. CONCLUSIONS: Long-term results finally do not support the neoadjuvant use of bevacizumab in addition to an anthracycline-taxane-based chemotherapy or everolimus in addition to paclitaxel for patients who had no early response to neoadjuvant chemotherapy. Citation Format: Bernd Gerber, Sibylle Loibl, Michael Untch, Holger Eidtmann, Mahdi Rezai, Peter A Fasching, Hans Tesch, Holm Eggemann, Iris Schrader, Kornelia Kittel, Claus Hanusch, Jens Huober, Christine Solbach, Christian Jackisch, Georg Kunz, Jens-Uwe Blohmer, Maik Hauschild, Tanja Fehm, Valentina Nekljudova, Gunter von Minckwitz. Neoadjuvant chemotherapy with or without bevacizumab or everolimus: Survival analysis of The HER2-negative cohort of the GEPARQUINTO study (GBG 44) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-11-01.

ABSTRACT Kyoto Breast Cancer Consensus Conference, Kyoto, Japan, 18–20 February 2014 The loco-regional management of breast cancer is increasingly complex with application of primary systemic therapies, oncoplastic techniques and genetic testing for breast cancer susceptibility. Personalization of loco-regional treatment is integral to optimization of breast cancer care. Clinical and pathological tumor stage, biological features and host factors influence loco-regional treatment strategies and extent of surgical procedures. Key issues including axillary staging, axillary treatment, radiation therapy, primary systemic therapy (PST), preoperative hormonal therapy and genetic predisposition were identified and discussed at the Kyoto Breast Cancer Consensus Conference (KBCCC2014). In the second of a two part conference scene, consensus recommendations for radiation treatment, primary systemic therapies and management of genetic predisposition are reported and focus on the following topics: influence of both clinical response to PST and stage at presentation on recommendations for postmastectomy radiotherapy; use of regional nodal irradiation in selected node-positive patients and those with adverse pathological factors; extent of surgical resection following downstaging of tumors with PST; use of preoperative hormonal therapy in premenopausal women with larger, node-negative luminal A-like tumors and managing increasing demands for contralateral prophylactic mastectomy in patients with a unilateral sporadic breast cancer.

Introduction: Triple negative breast cancer (TNBC) represents 10-20% of all breast cancer entities [1][2] and has a known aggressive behavior and poor outcome. Patients treated in the setting of randomized clinical trials often do not represent actual treatment characteristics in real-life scenarios. To determine the stage-related survival and effect of surgical performance in TNBC with current multimodal treatment, we set out to analyze data of a large population-based registry of primary breast cancers which covering >50% of all breast cancer cases in Germany. Patients and methods: We analyzed data from a prospectively collected cancer registry of >200 certified breast units of the West-German Breast Center (WBC) in Germany from 2009-2011. From a cohort of 39570 primary breast cancer patients treated in this period, 12759 underwent adjuvant systemic therapy, out of which 2037 were TNBC cases with adjuvant chemotherapy. Inclusion criteria were triple negative breast cancers (Her2-new1+/2+ (Fish negative) and estrogen receptor (ER) and progesterone receptor (PR) The use of first, second and third generation chemotherapy was analyzed as well as the effect of clear/unclear resection margins and its impact on survival data. Results: 2037 patients were eligible for this study. Overall survival rates were as follows: T1 a and T1b 100 %, T1c 90,7 %, T2 90,9 %, T3 68,1 % and T4 64,3 %. No statistical differences were detected in between stages T1 and T2, and also not in between T3 and T4. Combining T1/T2 and T3/T4 and performing group-wise comparisons, differences for combined stages were highly statistically significant (3,9 x E-09). Inflammatory TNBC was prognostically worst with a survival-rate of 33,3 % at 24-months. (p Unclear resection-margins versus clear margins in TNBC exerted a negative impact on DFS (87 vs. 73 %; p=0,00002) and DDFS (p=0,0004). Age was an independent risk factor for survival with a cut-off at 35 years.(p=0,044) Third-generation chemotherapies (anthracycline+taxanes) were associated with a significant improved overall-survival at 24-months compared to first generation chemotherapies (non-anthracycline, non-taxane) (95 % vs. 87 %; p=0,0029) Conclusion: Standard 3rd generation (anthracycline- and taxane-containing) chemotherapy and optimal surgical performance with clear margins is vital for patients with early, triple-negative breast cancer (TNBC). Within T1 and T2 stages, no stage-related deterioration of prognosis was detected, however these stages were markedly different from stages T3/T4, declining from 90-100% to 64-68 %. This analysis of a large database of a population-based study demonstrates that tumor size, margins and guideline-adapted chemotherapy matter in triple-negative, early breast cancer. [1] Schwentner et al. 2013 [2] Elsawaf et al. 2013. Citation Format: Peter Kern, Gunter von Minckwitz, Carolin Pütter, Annika Flach, Sofia Pavlidou, Rainer Kimmig, Mahdi Rezai. Stage-related risk categorization and influence of free margins on survival in triple negative early breast cancer - a population-based study of 2037 TNBC patients with adjuvant chemotherapy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-13-01.

Aims: There is evidence that the benefit of anti-HER2 treatment in combination with chemotherapy may not be limited to patients with HER2 amplification. This study tested if phosphorylated HER2 (pHER2) and co-activation of HER2 downstream targets are predictive of response to anti-HER2 treatment in HER2 non-amplified patients. Methods: Patients initially classified as HER2 positive (IHC, FISH) by local testing from the GeparQuattro and GeparQuinto trials received neoadjuvant anti-HER2 treatment (trastuzumab or lapatinib) in combination with anthracycline-taxane-based chemotherapy. However, on a central pathology review 98 out of 1060 patients were considered HER2 non-amplified. In order to assess the potential benefit from anti-HER2 treatment in these patients the levels of pHER2 and downstream targets including pHER3, EGFR, AKT, PI3K, ERK, PTEN, S6RP and their phosphorylated forms were quantitatively assessed using reverse-phase protein arrays. Histopathological complete response (pCR; ypT0/is) and disease free and overall survival served as reference standard. Optimal cutpoints for each protein were calculated to achieve maximum separation between pCR and non-pCR using ROC analysis. Results: 25 (26%) patients achieved pCR. The level of pHER2 was not significantly different between groups of histopathologic responders and non-responders. S6RP and pS6RP were the only proteins significantly associated with pCR (p=0.01 and 0.03, respectively) with a higher pretherapeutic expression in patients who subsequently achieved pCR. In contrast, low expression of S6RP and pS6RP were associated with longer disease free (p Conclusions: Expression of S6 ribosomal protein (S6RP), a downstream target of S6 kinase, and its phosphorylated form pS6RP are significantly associated with short and long-term outcome following anti-HER2 treatment in HER2 non-amplified breast cancer patients. In contrast, activation status of the HER2 pathway reflected by pHER2 and other downstream targets was not predictive of response, and showed no significant correlation with S6RP expression. These results suggest that S6RP and pS6RP may be novel predictive biomarkers for response to anti-HER2 treatment in non-amplified patients, possibly through a mechanism independent of global HER2 pathway activation. Citation Format: Stefanie Avril, Gunter von Minckwitz, Sibylle Gündisch, Stephan Gade, Katharina Malinowsky, Peter A Fasching, Thomas Karn, Arndt Hartmann, Michael Untch, Carsten Denkert, Karl-Friedrich Becker, Sibylle Loibl. Assessment of phosphorylated HER2 protein as predictive biomarker to stratify anti-HER2 treatment in HER2 non-amplified patients – A translational study in the GeparQuattro and GeparQuinto trials [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-36.

Background: Patients (pts) with breast cancer who do not achieve a pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) have a poor prognosis and might be candidates for post-neoadjuvant clinical trials investigating novel agents. The CPS-EG score (Mittendorf et al. JCO 2011) – a combination of clinical/pathological parameters - is currently used as criterion for selecting patients with highest risk of recurrence after NACT. Here, we examined whether the gene expression test EndoPredict (EP) performed on surgical specimen after NACT provides independent prognostic information for predicting the likelihood of recurrence in breast cancer patients with ER-positive, HER2-negative (ER+/HER2-) disease. Methods:The molecular EP score was determined by qRT-PCR in 76 available surgical specimen classified as ER+/HER2- from breast cancer pts with residual disease after NACT participating in the neoadjuvant GeparTrio trial. The pre-specified clinical/molecular hybrid score EPclin was determined using ypT and ypN after NACT as clinical variables. Patients were classified as having low or high risk according to pre-defined cut-off values. CPS-EG score was calculated based on stage before and after NACT and pretreatment grade and ER status. Primary endpoint was disease-free survival (DFS). Associations were assessed with uni- and multivariate Cox proportional hazard models. The unbiased c-index was estimated for common clinical/pathological parameters and EP/EPclin scores. Results: Among the 76 ER+/HER2- breast cancer pts evaluated, EP classified 50% of all pts (n=38) as low risk. EP high-risk patients had a significantly increased risk for relapse compared to the low-risk group (continuous EP HR 1.14 [95% CI 1.05-1.27] p-value 0.02; log-rank p=0.015). Multivariable Cox regression and unbiased c-index estimates (using EP and CPS-EG score as continuous variable) showed that the EP-score (HR 1.15 [95% CI 1.03-1.29 p=0.014] and CPS-EG (HR 1.51 [95% CI 1.07-2.13] p=0.019) provide independent prognostic information. Using the composite EPclin score 13 pts (17%) were classified as being EPclin low. The risk of relapse was significantly higher for EPclin high compared to low (continuous EPclin HR 1.78 [95% CI 1.29-2.46] p Conclusions: Our study shows that EPclin performed on surgical specimen of ER+/HER2- pts after NACT is an independent predictor of recurrence in pts not achieving a pCR after NACT. EP/EPclin low risk patients are probably sufficiently treated with (neo-)adjuvant chemo-endocrine treatment alone, whereas EP(clin) high risk patients have an increased risk of recurrence, despite receiving standard (neo-)adjuvant chemo-endocrine therapy. The identification of molecular luminal high-risk patients could help to identify high risk patients as candidates for novel drug-based approaches in addition to endocrine therapy to overcome resistance in post-neoadjuvant trials. Citation Format: Sibylle Loibl, Jan C Brase, Stephan Gade, Jens Huober, Kristin Krappmann, Knut Engels, Falko Fend, Berit Maria Pfitzner, Joern Hilfrich, Christoph Thomssen, Hans Juergen Holzhausen, Silvia Darb-Esfahani, Christian Schem, Keyur Mehta, Ralf Kronenwett, Gunter von Minckwitz, Carsten Denkert. Predicting residual risk of recurrence after neoadjuvant chemotherapy- a retrospective analysis of EndoPredict® in the GeparTrio trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-12.

Purpose Modulation of immunologic interactions in cancer tissue is a promising therapeutic strategy. To investigate the immunogenicity of human epidermal growth factor receptor 2 (HER2) –positive and triple-negative (TN) breast cancers (BCs), we evaluated tumor-infiltrating lymphocytes (TILs) and immunologically relevant genes in the neoadjuvant GeparSixto trial. Patients and Methods GeparSixto investigated the effect of adding carboplatin (Cb) to an anthracycline-plus-taxane combination (PM) on pathologic complete response (pCR). A total of 580 tumors were evaluated before random assignment for stromal TILs and lymphocyte-predominant BC (LPBC). mRNA expression of immune-activating (CXCL9, CCL5, CD8A, CD80, CXCL13, IGKC, CD21) as well as immunosuppressive factors (IDO1, PD-1, PD-L1, CTLA4, FOXP3) was measured in 481 tumors. Results Increased levels of stromal TILs predicted pCR in univariable (P < .001) and multivariable analyses (P < .001). pCR rate was 59.9% in LPBC and 33.8% for non-LPBC (P < .001). pCR rates ≥ 75% were observed in patients with LPBC tumors treated with PMCb, with a significant test for interaction with therapy in the complete (P = .002) and HER2-positive (P = .006), but not the TNBC, cohorts. Hierarchic clustering of mRNA markers revealed three immune subtypes with different pCR rates (P < .001). All 12 immune mRNA markers were predictive for increased pCR. The highest odds ratios (ORs) were observed for PD-L1 (OR, 1.57; 95% CI, 1.34 to 1.86; P < .001) and CCL5 (OR, 1.41; 95% CI, 1.23 to 1.62; P < .001). Conclusion Immunologic factors were highly significant predictors of therapy response in the GeparSixto trial, particularly in patients treated with Cb. After further standardization, they could be included in histopathologic assessment of BC.

Obesity is associated with an increased risk of breast cancer (BC) and poorer outcome. We assessed the impact of body mass index (BMI) on pathological complete response (pCR), disease-free (DFS), and overall survival (OS), according to BC subtypes in patients with primary BC treated with neoadjuvant chemotherapy. 8,872 patients with primary BC from eight neoadjuvant trials were categorized according to BMI: underweight (

Aims: Identify sensitive end points and populations for similarity studies of trastuzumab and biosimilar monoclonal antibodies. Methods: We performed meta-analyses of trastuzumab clinical trials data: overall response rate (ORR) and progression-free survival in metastatic breast cancer (MBC), and total pathologic complete response (tpCR) and event-free survival in the neoadjuvant setting. Fitted models predicted the maximum loss in long-term efficacy for different similarity trial designs. Immunogenicity rates were investigated in different early breast cancer (EBC) study phases. Results: Using the same equivalence margins for ORR (MBC) and tpCR (EBC), the predicted maximum loss in long-term efficacy with a biosimilar candidate versus the reference product is smaller for tpCR than for ORR. In EBC this predicted loss could be controlled with feasible patient numbers for a typical clinical trial. Analyses suggested that a treatment-free follow-up phase is preferable for immunogenicity characterization. Conclusion: Treatment of patients with neoadjuvant breast cancer represents a sensitive setting for establishing biosimilarity of efficacy and immunogenicity. tpCR is a sensitive end point in this setting to establish biosimilarity between a biosimilar candidate and its reference product.

Purpose: This study aimed to evaluate a modified EPclin test (mEPclin), a combination of EndoPredict (EP) score, post-neoadjuvant pathologic tumor size and nodal status, for predicting the risk of distance recurrence after neoadjuvant chemotherapy (NACT) in patients with residual estrogen receptor (ER)–positive/HER2-negative breast cancer. We also compared the prognostic power of the mEPclin with that of the CPS-EG score. Experimental Design: A total of 428 formalin-fixed, paraffin-embedded tumor samples from GeparTrio and GeparQuattro studies were evaluated for mRNA expression of eight cancer-related and three reference genes. The mEPclin score was computed using a modified algorithm and predefined cut-off values were used to classify each patient at low or high risk. Primary endpoint was disease-free survival (DFS). Results: A higher continuous mEPclin score was significantly associated with increased risk of relapse [HR, 2.16; 95% confidence interval (CI), 1.86–2.51; P < 0.001] and death (HR, 2.28; 95% CI, 1.90–2.75; P < 0.001). Similarly, patients classified at high risk by dichotomous mEPclin showed significantly poorer DFS and overall survival compared with those at low risk. In contrast with CPS-EG, the mEPclin remained significantly prognostic for DFS in multivariate analysis (HR, 2.13; 95% CI, 1.73–2.63; P < 0.001). Combining CPS-EG and other clinicopathological variables with mEPclin yielded a significant improvement of the prognostic power for DFS versus without mEPclin (c-indices: 0.748 vs. 0.660; P < 0.001). Conclusions: The mEPclin score independently predicted the risk of distance recurrence and provided additional prognostic information to the CPS-EG score to assess more accurately the prognosis after NACT in the luminal non-pCR patient population. Therefore, this approach can be used to select patients for additional post-neoadjuvant therapies. Clin Cancer Res; 24(14); 3358–65. ©2018 AACR.

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 randomized clinical trial used archived DNA samples 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 prospective investigation. DNA samples 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 nonstandard 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 clinicaltrials.gov Identifier:NCT01426880

The estrogen receptor (ER) is involved in control of progesterone receptor (PgR) expression and lack of PgR may be also a surrogate of altered growth factor signaling. The aim of this study was therefore to investigate PgR expression as predictive factor for response to neoadjuvant therapy and long-term outcome.Five thousand and six hundred and thirteen patients with primary breast cancer and positive ER expression from ten German neoadjuvant trials of anthracycline and taxane-based chemotherapy were included. Pathologic complete response (pCR), disease-free survival (DFS), distant disease-free survival (DDFS), overall survival (OS), and local recurrence-free survival (LRFS) were compared according to PgR expression.The lack of PgR expression (1172 patients) was associated with grade 3 (38.4 vs. 26.3%; p 0.001), nodal involvement (cN2) (6.8% vs. 4.7%; p = 0.004), and HER2 positivity (36.2 vs. 22.3%; p 0.001). pCR rates of PgR-negative tumors were higher in the entire cohort (13.8 vs. 7.5%; p 0.001) and in the HER2-negative subgroup (11.2 vs. 5.8%; p 0.001). In multivariable logistic regression, PgR negativity was an independent predictive factor for pCR overall (OR 1.76; p 0.001) and in the HER2-negative patients (OR 1.99; p 0.001). Patients with PgR-negative disease had significantly worse outcome (p 0.001, respectively). Multivariable Cox regression analysis revealed that PgR was an independent prognostic factor for DFS, OS, DDFS, and LRFS.ER-positive/PgR-negative breast carcinomas are associated with higher response but also worse long-term outcome after neoadjuvant therapy. PgR negativity is an independent predictive factor for pCR after neoadjuvant chemotherapy in ER-positive HER2-negative breast cancer.

The GENEVIEVE study compared the pathological complete response (pCR) rate (ypT0/is ypN0/+) in patients with operable human epidermal growth factor receptor 2 (HER2)-negative breast cancer (BC) treated with either cabazitaxel or paclitaxel.GENEVIEVE was a prospective, multicentre, randomised, open-label, phase II study comparing the efficacy and the safety of four 3-weekly cycles cabazitaxel versus 12 weeks of paclitaxel given as neoadjuvant treatment. Primary end-point was the pCR rate defined as the complete absence of invasive carcinoma on histological examination of the breast irrespective of lymph node involvement (ypT0/is, ypN0/+) after the taxane treatment. Patients could receive an anthracycline-based therapy thereafter.Overall, 333 patients were randomised and started treatment with 74.7% and 83.2% of patients completing treatment in the cabazitaxel and paclitaxel arms, respectively. Patients in cabazitaxel arm had a significantly lower pCR rate compared to the paclitaxel arm (1.2% versus 10.8%; p = 0.001). A total of 42 (25.3%) patients in the cabazitaxel arm and 17 (10.2%) in the paclitaxel arm had at least one serious adverse event (p 0.001). Dose reductions were observed in 9.6% patients in the cabazitaxel arm compared to 11.4% in the paclitaxel arm (p = 0.721). Main reason for dose reductions was non-haematological toxicities in 3.0% versus 7.8% (p = 0.087), respectively.The GENEVIEVE study showed no short-term effect of cabazitaxel in triple-negative or luminal B/HER2-negative primary BC, while there seemed to be no differences in drug exposure and patient compliance between the two arms.ClinicalTrials.gov NCT01779479.

Aim The Neoadjuvant PI3K inhibition in HER2 OverExpressing Breast cancEr (NeoPHOEBE) trial evaluated the efficacy and safety of buparlisib, a pan-phosphatidylinositol 3-kinase (PI3K) inhibitor, plus trastuzumab and paclitaxel as neoadjuvant treatment for human epidermal growth factor receptor-2 positive (HER2+) breast cancer. Methods NeoPHOEBE was a neoadjuvant, phase II, randomised, double-blind study. Women with HER2+ breast cancer were randomised within two independent cohorts by PIK3CA mutation status and, in each cohort stratified by oestrogen receptor (ER) status to receive buparlisib or placebo plus trastuzumab (first 6 weeks) followed by buparlisib or placebo with trastuzumab and paclitaxel. Primary end-point was pathological complete response (pCR) rate; key secondary end-point was objective response rate (ORR) at 6 weeks. Exploratory end-points were evaluation of Ki67 levels and change in tumour infiltrating lymphocytes (TILs) in intermediate biopsies at day 15. Results Recruitment was suspended mainly due to liver toxicity after enrolment of 50 of the planned 256 patients. In each arm (buparlisib n = 25; placebo n = 25) 21 patients (84%) had wild type PIK3CA and 4 patients (16%) had mutant PIK3CA . Overall, pCR rate was similar between buparlisib and placebo arms (32.0% versus 40%; one-sided P = 0.811). A trend towards higher ORR (68.8% versus 33.3%; P = 0.053) and a significant decrease in Ki67 (75% versus 26.7%; P = 0.021) was observed in buparlisib versus placebo arm in the ER+ subgroup ( P interaction = 0.03). Conclusions Addition of the pan-PI3K inhibitor buparlisib to taxane-trastuzumab-based therapy in HER2+ early breast cancer was not feasible. However, the higher ORR and Ki67 reduction in the ER+, HER2+ subgroup indicates a potential role for PI3K-targeted therapy in this setting and may warrant further investigation with better-tolerated second-generation PI3K inhibitors. Trial registration identifier NCT01816594 .

Early assessment of response to neoadjuvant chemotherapy (NAC) for breast cancer allows therapy to be tailored; however, optimal response assessment methods have not been established. We estimated the accuracy of ultrasound (US) to predict pathologic complete response (pCR) using common response criteria and pCR definitions, and estimated incremental accuracy over known prognostic variables. Participants undergoing US after two cycles in the GeparTrio trial randomised to no change in NAC were eligible. US response by World Health Organisation (WHO) criteria (1D or 2D) and Response Evaluation Criteria In Solid Tumours (RECIST) was assessed. Four pCR definitions were applied. Sensitivity (correct prediction of pCR), specificity (correct prediction of no-pCR) and diagnostic odds ratios (DORs) were calculated. Areas under the curve (AUCs) were derived from logistic regression including patient variables with and without US. In 832 patients, DORs decreased as pCR definitions became less stringent (p = 0.01). For WHO-2D, DORs were as follows: 4.07 (ypT0,ypN0), 3.75 (ypT0/is,ypN0), 3.14 (ypT0/is,ypN+/-) and 2.65 (ypT0/is/1a,ypN+/-). DORs did not differ between US criteria (p = 0.60). High sensitivity and lower specificity were found for WHO-2D and RECIST; WHO-1D was highly specific with low sensitivity. Sensitivity was highest for WHO-2D predicting ypT0,ypN0 (sensitivity = 81.7%, specificity = 47.6% vs. 42.3% and 80.4% for WHO-1D). Adding US to models including patient variables (age, T-stage, histology and subtype) improved AUCs for predicting pCR by 2-3%. In conclusion, US accuracy is highest for predicting ypT0,ypN0, shown to be most prognostic of long-term survival. WHO-2D and RECIST maximise sensitivity; WHO-1D maximises specificity. US modestly improves the prediction of pCR by patient characteristics.

2014 ASCO Annual Meeting, Chicago, IL, USA, 28 May–3 June 2014Advances in translational and clinical research have improved our understanding of breast and colorectal cancers, and have enabled remarkable progress in their treatment. These advances continue to be of paramount importance for breast and colorectal cancers. This report will describe and comment on the key messages from selected abstracts presented at the 50th American Society of Medical Oncology annual meeting that will impact clinical practice in the near future.

SummaryWithin 2 decades, neoadjuvant therapy (NAT) has become a standard treatment option in breast cancer. The advantage of NAT is the ability to monitor the treatment effect. Pathological complete response (pCR) after NAT is a very good predictor for long-term outcome. Clinical factors, such as age and body mass index, as well as recently identified biomarkers can predict the chance of achieving a pCR. Hormone-receptor status, proliferation markers, immune infiltrates and genetic alterations, such as germline BRCA and PIK3CA, can now be measured almost on a routine basis due to the decreased analysis costs.

Purpose Phosphatidylinositol 3-kinase (PI3K)/AKT pathway aberrations are common in breast cancer, with mutations in PIK3CA being the most common. This study investigated the association between PIK3CA genotype and pathologic complete response (pCR) rates in human epidermal growth factor receptor 2 (HER2) –positive breast cancer treated with either dual or single anti-HER2 treatment in addition to neoadjuvant chemotherapy. Patients and Methods PIK3CA mutations in 504 tumor samples from participants in the neoadjuvant GeparQuattro, GeparQuinto, and GeparSixto studies were evaluated. All HER2-positive patients received either trastuzumab or lapatinib or the combination plus anthracycline-taxane chemotherapy. PIK3CA mutations were evaluated in formalin-fixed, paraffin-embedded tissues from core biopsies with a tumor cell content of ≥ 20% by using classical Sanger sequencing of exon 9 and exon 20. Results Overall, 21.4% of the patients harbored a PIK3CA mutation. Detection of a PIK3CA mutation was significantly associated with a lower pCR rate (19.4% with PIK3CA mutation v 32.8% with PIK3CA wild-type; odds ratio [OR], 0.49; 95% CI, 0.29 to 0.83; P = .008). In the 291 hormone receptor (HR) –positive tumors, pCR rate was 11.3% with a PIK3CA mutation compared with 27.5% with PIK3CA wild-type (OR, 0.34; 95% CI, 0.15 to 0.78; P = .011). In 213 patients with HR-negative tumors, pCR rate was 30.4% with PIK3CA mutation and 40.1% without (OR, 0.65; 95% CI, 0.32 to 1.32; P = .233; interaction test P = .292). In multivariable analysis, HR status and PIK3CA status provided independent predictive information. In patients with PIK3CA mutation, the pCR rates were 16%, 24.3%, and 17.4% with lapatinib, trastuzumab, and the combination, respectively (P = .654) and in the wild-type group, they were 18.2%, 33.%, and 37.1%, respectively (P = .017). Disease-free survival and overall survival were not statistically significantly different between patients with mutant and wild-type PIK3CA. Conclusion HER2-positive breast carcinomas with a PIK3CA mutation are less likely to achieve a pCR after neoadjuvant anthracycline-taxane–based chemotherapy plus anti-HER2 treatment, even if a dual anti-HER2 treatment is given.

510 Background: In TNBC, the interplay between immunophenotype, tumor proliferation (prolif) and achievement of pathologic complete response (pCR) with neoadjuvant chemotherapy (NAC) remains unknown. Methods: RNA seq was performed on pre-tx research biopsies of stage II/III TNBC enrolled in BrighTNess. NAC regimens included paclitaxel alone or with carboplatin (Cb) or Cb plus veliparib, followed by AC. Computational analysis included subtyping (i.e. PAM50, Pietenpol), prolif (PAM50) and GeparSixto immune signature (GSIS). Cb-containing arms were combined due to similar pCR. Results: High quality RNA seq data was obtained from 482 of 634 pts. PAM50 classified 80.1% of tumors as basal-like. TNBC subtypes were mostly BL1 or BL2 (23.3%), IM (22.4%) or M/MSL (31.7%); 6% were LAR. pCR was higher for basal vs non-basal tumors (52.3% vs 35.4%, p = 0.003). IM had the highest pCR rate (64.2%, 95% CI 59.9%,68.5%). Basal-like was not a significant predictor for Cb benefit (p-interaction = 0.8). Prolif (OR = 0.30 p < 0.001) and GSIS (OR 0.68 p < 0.001) were significantly correlated with pCR but did not correlate with each other (Pearson’s r2 = 0.027). In multivariate analysis, prolif (HR = 0.36 95% CI, 0.21-0.61 p = 0.0002) and GSIS (HR = 0.62 95% CI, 0.49-0.79 p < 0.0001) increased the ability to predict pCR beyond standard clinico-pathologic variables (likelihood ratio = 14.9, p = 0.0001115). Among all pts, those above the median for both prolif. and GSIS had the highest pCR (67%; 84/125) while those below the median for both had the lowest pCR rate (34%; 42/125). Tumors with higher inferred CD8+ T-cell infiltration demonstrated greater benefit from Cb using either TIMER (HR = 0.83 [0.73-0.95]) or CIBERSORT (HR = 0.83 [0.76-0.91]). Tumors with higher inferred total macrophages, particularly immune suppressive M2 macrophages had a higher pCR rate on the non-Cb arm (AC-T) using CIBERSORT (HR = 1.27 [1.07,1.50]). Conclusions: Immunophenotype and proliferation are independent predictors of pCR to standard NAC regimens in TNBC. PAM50 is not a significant predictor of Cb benefit. Exploratory findings suggest that tumor infiltrating immunophenotype (i.e. CD8 T cells and macrophages) may predict response to specific NAC regimens in TNBC. Clinical trial information: NCT02032277.

513 Background: The phase 3 KATHERINE (NCT01772472) study, met its primary endpoint by demonstrating significantly improved invasive disease-free survival with adjuvant T-DM1 compared to H in pts with residual invasive disease after neoadjuvant chemotherapy plus HER2-targeted therapy. PROs are reported here. Methods: Eligible pts had HER2-positive early breast cancer, received taxane- and H-containing neoadjuvant therapy (with/without anthracyclines) followed by surgery, and had residual invasive disease in the breast and/or axillary nodes. Pts were randomized to 14 cycles of adjuvant T-DM1 (3.6 mg/kg IV q3w) or H (6 mg/kg IV q3w) and adjuvant endocrine and radiation therapy per standard of care. The EORTC Quality of Life Questionnaire–Core 30 (QLQ-C30) and QLQ–Breast Cancer (QLQ-BR23) were completed at screening, at day 1 of cycles 5 and 11, within 30 days after study drug completion, and at 6 and 12 months’ follow-up. Results: Of 1,486 pts randomized (T-DM1, n = 743; H, n = 743), 612 (82%) and 640 (86%), respectively, had valid baseline and ≥1 post-baseline PRO assessments. During the study, pts in both arms had similar mean scores on the QLQ-C30 and QLQ-BR23 function and symptom scales. There was no clinically meaningful change (≥10 points) from baseline in the mean scores in either arm, including on symptoms similar to AEs seen with T-DM1 (eg, fatigue). While more pts in the T-DM1 arm reported clinically meaningful deterioration in role functioning (49% vs 41%), appetite loss (38% vs 28%), constipation (47% vs 38%), fatigue (66% vs 61%), nausea/vomiting (39% vs. 30%), and systemic therapy side effects (49% vs 36%) at ≥1 assessment, the proportion reporting clinically meaningful change in functioning was similar between arms at any given assessment. Conclusions: Mean scores showed only small deterioration from baseline in patient-reported treatment-related symptoms in both study arms. While more pts in the T-DM1 arm reported deterioration at some point in several symptoms, baseline global health status and functioning were generally maintained in both arms over the treatment course. Clinical trial information: NCT01772472.

BACKGROUND: The open-label randomized phase III TANIA trial demonstrated statistically significantly improved progression-free survival (PFS; primary endpoint) with the addition of BEV to 2nd-line chemotherapy (CT) in patients (pts) with HER2-negative LR/mBC progressing after 1st-line BEV-containing therapy. We describe efficacy in clinically relevant subgroups to assess consistency of the BEV treatment effect. METHODS: Pts whose HER2-negative LR/mBC had progressed during/after 1st-line BEV–CT were randomized 1:1 to investigator’s chosen 2nd-line single-agent CT given either alone or with BEV (15 mg/kg q3w or 10 mg/kg q2w). 2nd-line therapy was continued until disease progression (PD), unacceptable toxicity or consent withdrawal. At PD, BEV was continued with 3rd-line CT (investigator’s choice) in pts initially randomized to BEV–CT but was not permitted in pts randomized to CT alone. The primary endpoint was PFS from randomization to 2nd-line PD/death. Sample size was calculated based on a log-rank test assuming median PFS of 7→9.3 mo with a corresponding hazard ratio (HR) of 0.75. PFS events were required in 384 of 488 pts for 80% power at 2-sided α=0.05. Subgroup analyses of the primary endpoint were prespecified and included subgroups defined by stratification factors. RESULTS: From Jan 2011 to Apr 2013, 494 pts were enrolled. The data cut-off for the primary analysis was Dec 20, 2013 (median follow-up: CT 15.9 mo; BEV–CT 16.1 mo). The PFS benefit seen in the overall population was observed consistently in most subgroups. SubgroupPts with PFS events/Total No. of pts (%)Median 2nd-line PFS, moUnstratified HR (95% CI)CTBEV–CTCTBEV–CTAll203/247 (82)204/247 (83)4.26.30.75 (0.61-0.93)aHormone receptor statusbTriple negative56/60 (93)45/56 (80)2.14.90.59 (0.40-0.88)Positive, HER2 negative147/187 (79)159/191 (83)4.76.70.84 (0.67-1.05)1st-line PFS, mob1.5×ULN36/40 (90)36/37 (97)2.15.80.73 (0.46-1.16)CT choicebTaxane25/32 (78)26/32 (81)3.26.90.55 (0.31-0.98)Non-taxane non-vinorelbine156/191 (82)151/188 (80)4.46.00.84 (0.68-1.06)Vinorelbine22/24 (92)27/27 (100)2.46.50.41 (0.22-0.75)CT choice (not stratified)Capecitabine117/146 (80)125/151 (83)4.96.20.92 (0.72-1.19)Non-capecitabine86/101 (85)79/96 (82)3.26.50.55 (0.40-0.75)BEV-free interval, wk≤6138/165 (84)130/149 (87)4.25.80.82 (0.64-1.04)>665/81 (80)74/98 (76)4.47.60.72 (0.51-1.00)aStratified.bStratification factor. CONCLUSIONS: PFS was statistically significantly improved with the addition of BEV to 2nd-line CT in BEV-pretreated pts, meeting the primary objective of TANIA. This effect was seen consistently within subgroups based on stratification factors. Within the limitations of exploratory subgroup analyses with small sample sizes, further subgroup analyses may suggest some potential inconsistencies in treatment effect. These hypothesis-generating observations require further exploration of potential differences in disease and pt characteristics in TANIA, which may have influenced physicians’ CT choice. Citation Format: Fabio Puglisi, Javier Cortes, Eduard Vrdoljak, Joseph Gligorov, Norbert Marschner, Christoph Zielinski, Michele de Laurentiis, Etienne Brain, Christelle Lévy, Anja Welt, Zsuzsanna Kahan, Moshe Inbar, Sabine de Ducla, Ulrich Freudensprung, Gunter von Minckwitz. Subgroup efficacy analyses of the randomized phase III TANIA trial evaluating continued or reintroduced bevacizumab (BEV) after 1st-line BEV for HER2-negative locally recurrent/metastatic breast cancer (LR/mBC) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr PD2-4.

An intermediate endpoint is a surrogate marker of treatment efficacy assessed earlier than the true outcome of interest. A suitable intermediate endpoint in neoadjuvant trials of specific breast cancer subtypes is pathological complete response (pCR) rate, defined as no invasive (+/-noninvasive) residual cancer in breast and nodes at surgery. On the basis of available evidence, Food and Drug Administration the US allowed to use of pCR as a surrogate endpoint for accelerated approval process. However, surrogacy to long-term outcome remains an unresolved issue. Literature data provide indications that triple-negative, HER2-positive, and high-grade hormone receptor-positive breast cancer subtypes achieved the highest pCR rate; the prognostic impact of pCR on survival is established only for these aggressive subtypes. In the German experience, early response after two to four cycles of neoadjuvant treatment strongly correlated with both pCR rate and long-term outcome. Therefore, early response may be considered a predictive marker for pCR and used for driving clinical trial design.

Background: Phosphatidylinositol 3-kinase (PI3K)/AKT pathway and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) aberrations are common in breast cancer (BC). PIK3CA mutation is associated with lower pCR rates especially in patients treated with double anti-HER2 therapy (Loibl et al. JCO accepted). Another mechanism of resistance for trastuzumab-based treatment could be loss of PTEN, resulting also in downstream activation of the pathway. We investigated the correlation between PIK3CA, PTEN, p4EBP1 (phosphorylated E4 binding protein 1) and pCR in pts receiving neoadjuvant therapy. Methods: In addition to PIK3CA we retrospectively evaluated PTEN and p4EBP1 by immunohistochemistry in HER2+ patients who received EC followed by docetaxel within the G4 study (Untch et al. 2011). The G4 study demonstrated a higher pCR rate by adding trastuzumab to chemotherapy. HER2 and hormone receptors (HR) were centrally assessed. PTEN was assessed using the automated quantitative immunofluorescence analysis (Aqua) using an antibody (Cell Signalling Technology). p4EBP1 assessed by immunohistochemistry with an immunreactive score ranging from 0-12. PTEN was categorized by an optimized cut-off determined by the cut-off finder software (http://molpath.charite.de/cutoff/) and p4EBP1 was measured as a continuous variable and correlated with PIK3CA genotype and pCR (ypT0, ypN0). Central HER2+ve cases with a tumor cell content of ≥20% were selected (n=181). Results: Median age was 48years (22-77); HR+ve 51%; Grade 3, 47.4%; pCR rate 32%. p4EBP1 analysis was available from 137 and PTEN from 108 patients. PIK3CA genotype was available in 83 of these patients. 58 pts had PIK3CA and PTEN assessable, 14/58 had a PIK3CA mutation (mut) (25%). Overall, pCR rate in PTEN low tumors was 27.6% vs 57.1% in PTEN high (p=0.010). Within the PIK3CA mut cohort 13/14 (92.9%) tumors were PTEN low. Within the PIK3CA wild-type (wt) cohort 30/44 (68.2%) were PTEN low (p=0.066). The tumours were grouped into 4 subsets using PIK3CA (mut vs wt) and PTEN (low vs. high). pCR rate was 57.1% (8/14) in PTEN high/PIK3CA wt cohort and decreased to 15.4% in the PTEN low/PIK3CA mut cohort. The group with either PTEN low and PIK3CA wt or PTEN high and PIK3CA mut had a pCR rate of 32.2% (p=0.015). In multivariable analysis after adjustment for baseline parameters PTEN was an independent predictor for pCR in the complete cohort (OR 12.3 [95% 1.82-82.9] p=0.010) and in PIK3CA wt cohort (OR 10.3 [95% CI 1.31-81.62] p=0.027). Within the HR+ve group PTEN low tumors had a pCR rate of 22.2% vs 61.5% in the PTEN high group (p=0.007). In multivariable analysis PTEN was independently predictive for pCR in the HR+ve group (OR 49.5 [95% 3.4-707] p=0.004). p4EBP1 correlated weakly with PIK3CA (p=0.049) but not with PTEN. There was no association of p4EBP1 with pCR. Conclusion: Low PTEN was significantly associated with lower pCR and added independent predictive information not only in the overall HER2+ve cohort but also in the PIK3CA wt and HR+ve cohort. It will be confirmed in a larger sample size if PTEN assessment adds information to PIK3CA genotype to select patients with low pCR rates after trastuzumab therapy. Citation Format: Sibylle Loibl, Silvia Darb-Esfahani, Alexander Klimowicz, Gunter von Minckwitz, Bianca Lederer, Jens Huober, Arndt Hartmann, Holger Eidtmann, Berit Maria Pfitzner, Peter A Fasching, Katharina Tiemann, Christian Jackisch, Keyur Mehta, Michael Untch, Carsten Denkert. PTEN and PIK3CA but not p4EBP1 are associated with low rates of pathological complete response (pCR) to trastuzumab based chemotherapy in primary HER2-overexpressing breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr PD5-7.