Mayer, Ingrid A.

PurposeBevacizumab improves progression-free survival but not overall survival in patients with metastatic breast cancer. E5103 tested the effect of bevacizumab in the adjuvant setting in patients with human epidermal growth factor receptor 2–negative disease.Patients and MethodsPatients were assigned 1:2:2 to receive placebo with doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel (arm A), bevacizumab only during AC and paclitaxel (arm B), or bevacizumab during AC and paclitaxel followed by bevacizumab monotherapy for 10 cycles (arm C). Random assignment was stratified and bevacizumab dose adjusted for choice of AC schedule. Radiation and hormonal therapy were administered concurrently with bevacizumab in arm C. The primary end point was invasive disease–free survival (IDFS).ResultsFour thousand nine hundred ninety-four patients were enrolled. Median age was 52 years; 64% of patients were estrogen receptor positive, 27% were lymph node negative, and 78% received dose-dense AC. Chemotherapy-associated adverse events including myelosuppression and neuropathy were similar across all arms. Grade ≥ 3 hypertension was more common in bevacizumab-treated patients, but thrombosis, proteinuria, and hemorrhage were not. The cumulative incidence of clinical congestive heart failure at 15 months was 1.0%, 1.9%, and 3.0% in arms A, B, and C, respectively. Bevacizumab exposure was less than anticipated, with approximately 24% of patients in arm B and approximately 55% of patients in arm C discontinuing bevacizumab before completing planned therapy. Five-year IDFS was 77% (95% CI, 71% to 81%) in arm A, 76% (95% CI, 72% to 80%) in arm B, and 80% (95% CI, 77% to 83%) in arm C.ConclusionIncorporation of bevacizumab into sequential anthracycline- and taxane-containing adjuvant therapy does not improve IDFS or overall survival in patients with high-risk human epidermal growth factor receptor 2–negative breast cancer. Longer duration bevacizumab therapy is unlikely to be feasible given the high rate of early discontinuation.

LBA1 Background: In hormone receptor (HR)-positive, HER2-negative, axillary node (AN)-negative breast cancer, the 21-gene expression assay (Oncotype DX Recurrence Score [RS]) is prognostic for distant recurrence, prognostic for low recurrence with endocrine therapy alone if low (0-10), and predictive of chemotherapy benefit if high (26 or higher). We performed a prospective, randomized trial of endocrine therapy (ET) versus chemoendocrine therapy (CET) in women with a mid-range RS of 11-25. Methods: Eligibility criteria included women 18-75 years of age with HR-positive, HER2-negative, axillary node (AN)-negative breast cancer and tumors 1.1-5.0 cm in size (or 0.6-1.0 cm and int/high grade) and agreed to have chemotherapy assigned or randomized based on the RS. Women with a mid-range RS (11-25) were randomized to receive ET or CET. The primary endpoint was invasive disease-free survival (iDFS), and the trial was designed to show non-inferiority for ET alone by not rejecting equality (hazard ratio [HR] margin up to 1.322 for omission of chemotherapy, 1-sided type I error rate 10%, type II error rate 5%). The target sample size was adjusted to compensate for non-adherence to randomized treatment, and the protocol-specified final analysis was triggered after 835 iDFS events. Results: Of the 10,253 eligible women enrolled between 4/7/06-10/6/10, 6711 (65.5%) had a RS of 11-25 and adequate information. There were 836 iDFS events at final analysis with a median followup of 90 months. ET was non-inferior to CET for iDFS (HR 1.08, 95% confidence intervals [CI] 0.94, 1.24, p=0.26) in the intention-to-treat (ITT) population. ET was also non-inferior for distant recurrence-free interval (DRFI; HR 1.03, p=0.80), recurrence-free interval (RFI; HR 1.12, p=0.28), and overall survival (OS; HR 0.97, p=0.80). Nine year rates were similar for iDFS (83.3% vs. 84.3%), DRFI (94.5% vs. 95.0%), RFI (92.2% vs. 92.9%), and OS (93.9% vs. 93.8%). Recurrence accounted for 338 (41.6%) the first iDFS event, of which 199 (23.8%) were distant recurrences. Treatment interaction tests were significant for age (iDFS p=0.03; RFI p= 0.02), but not menopause, tumor size, grade, or RS (continuous or RS 11-15, 16-20, 21-25). Conclusions: In women with HR-positive, HER2-negative, AN-negative breast cancer and a RS of 11-25, adjuvant ET was not inferior to CET in the ITT analysis. (Funded by NCI, BCRF, and Komen Foundation.) Clinical trial information: NCT00310180.

36 Background: Black race is associated with worse outcomes in localized breast cancer. We evaluated the characteristics of patients enrolled in the Trial Assigning Individualized Options for Treatment (TAILORx) by race and ethnicity. Methods: The analysis included 10,071 evaluable patients with Recurrence Score (RS) data. Eligibility criteria included: (1) T1-2, N0 disease, (2) estrogen receptor (ER) and/or progesterone receptor (PR) positive disease that was also HER2/neu negative, (3) age 75 years or younger and medically appropriate for adjuvant systemic chemotherapy. Results: The study population included 8,501 whites (84%), 722 blacks (7%), 423 Asians (4%), and the remainder other/unknown race. With regard to ethnicity, 7,916 were nonHispanic (79%), 919 were Hispanic (9%), and 1,236 were of unreported ethnicity (12%). There was no significant difference in RS distribution (p = 0.14), median RS (17 vs. 17), and mean RS (19.6 vs. 18.4) in blacks compared with nonblacks. There was likewise no difference in Hispanic vs. nonHispanic ethnicity for RS distribution (p = 0.53), median RS (17 vs. 17), and mean RS (18.6 vs. 18.4). Blacks were significantly more likely to be younger (39% vs. 30% < 50 years), have larger tumors (37% vs. 31% > 2 cm), poor histologic grade (25% vs. 17%), and PR-negative disease (14% vs. 10%) (Chi square test p < 0.05). Hispanic women were also significantly younger (39% vs. 30% < 50 years), and demonstrated marginal but statistically significant differences in tumor size (65% vs. 69% > 2 cm), histologic grade (20% vs. 18% poor), and PR expression (12% vs. 10% negative) (Chi square test < 0.05). In 974 patients with information on body mass index (BMI), there was no correlation between BMI and RS (r = -0.04). BMI was higher for blacks than whites (medians 31.6 vs. 28.9, p = 0.02, Wilcoxon test), but not in Hispanics. Conclusions: In patients selected for participation in TAILORx there were no significant differences in RS by race, ethnicity, and BMI. Black and Hispanic patients were significantly younger, and blacks had tumors that were larger and more likely to be associated with poor grade. Clinical trial information: NCT00310180.

Purpose To provide recommendations on the appropriate use of breast tumor biomarker assay results to guide decisions on systemic therapy for metastatic breast cancer. Methods A literature search and prospectively defined study selection identified systematic reviews, meta-analyses, randomized controlled trials (RCTs), prospective–retrospective studies, and prospective comparative observational studies published from 2006 through September 2014. Results The literature search revealed 17 articles that met criteria for further review: 11 studies reporting discordances between primary tumors and metastases in expression of hormone receptors or human epidermal growth factor receptor 2 (HER2), one RCT that addressed the use of a biomarker to decide whether to change or continue a treatment regimen, and five prospective–retrospective studies that evaluated the clinical utility of biomarkers. Recommendations In patients with accessible metastases, biopsy for confirmation of disease process and retesting of estrogen receptor, progesterone receptor, and HER2 status should be offered, but evidence is lacking to determine whether changing anticancer treatment on the basis of change in receptor status affects clinical outcomes. With discordance of results between primary and metastatic tissues, the Panel consensus is to use preferentially the estrogen receptor, progesterone receptor, and HER2 status of the metastasis to direct therapy if supported by the clinical scenario and patient's goals for care. Carcinoembryonic antigen, cancer antigen 15-3, and cancer antigen 27-29 may be used as adjunctive assessments, but not alone, to contribute to decisions regarding therapy. Recommendations for tumor rebiopsy and use of circulating tumor markers are based on clinical experience and Panel informal consensus in the absence of studies designed to evaluate the clinical utility of the markers. As such, it is also reasonable for clinicians to not use these markers as adjunctive assessments.

Abstract Background: Preclinical and clinical data indicate a key role for the PI3-kinase (PI3K) pathway in the pathogenesis of resistance to endocrine therapies in hormone receptor-positive (HR) breast cancer (BC) and suggest that combining PI3K inhibitors with endocrine therapy may partially overcome this resistance. FERGI is the first randomized Phase II study testing pictilisib (GDC-0941), a PI3K inhibitor, in combination with fulvestrant to evaluate this hypothesis in MBC patients with and without PIK3CA-mutant tumors. Methods: 168 post-menopausal pts with ER-positive, HER2-negative MBC were randomized (1:1) to receive fulvestrant with either pictilisib 340 mg QD (n=89, "combination" arm) or matching placebo (n=79, "control" arm). To be eligible, pts had to have relapsed during or within 6 mos of completing adjuvant AI treatment or have progressed on an AI for MBC. Pts were stratified based on tumor PIK3CA mutation status, resistance to prior AI therapy and presence of measurable disease. The primary endpoint was PFS by investigator assessment in the intent-to-treat (ITT) group and in pts with centrally confirmed PIK3CA-mutant tumors. The primary analysis was based on a 6 mo median duration follow up. Results: Baseline disease and prior treatment characteristics were similar between study arms. Observed treatment-emergent AEs were consistent with those previously described for single agent pictilisib and fulvestrant (primary toxicities were rash and GI disorders). In the ITT population (84 events) the median PFS (mPFS) was 6.2 mo in the combination arm vs 3.8 months for the control arm (HR, 0.77; 95% CI, 0.50-1.19). For pts with PIK3CA-mutant tumors (37 events), mPFS was 6.2 mo in the combination arm vs 5.1 mo in the control arm (HR, 0.92; 95% CI, 0.48-1.76). For pts without a detectable PIK3CA mutant tumor (43 events), mPFS was 5.8 months in the combination arm vs 3.6 months in the control arm (HR, 0.64; 95% CI, 0.35-1.17). Exploratory post-hoc subgroup analysis suggested improvement in PFS in pts with ER+ and PR+ tumors (centrally confirmed) treated with pictilisib plus fulvestrant. In the ER+/PR+ subgroup (57 events) mPFS was 7.2 mo in the combination arm vs 3.7 mo in the control arm (HR, 0.46; 95% CI, 0.27 to 0.78). This improvement was independent of tumor PIK3CA mutation status. Multivariate analysis suggests that this treatment effect in pts with ER+/PR+ tumors is maintained after adjusting for possible baseline imbalances. A similar analysis on pts with luminal A tumors (per PAM50 analysis) was also consistent with the findings in pts ER+/PR+ disease. Conclusions: This is the first report of a blinded, randomized clinical study evaluating a PI3K inhibitor in pts with MBC. In the ITT population, the addition of pictilisib to fulvestrant was associated with a mPFS improvement of 3.8 mo to 6.2 mo. Exploratory subgroup analyses suggested in pts with ER+/PR+ tumors are more likely to derive benefit from the addition of pictilisib to fulvestrant irrespective of PIK3CA mutation status, though the subgroup analyses are limited by the sample size. Additional biomarker analyses will be reported. Citation Format: Ian Krop, Stephen Johnston, Ingrid A Mayer, Maura Dickler, Vinod Ganju, Andres Forero-Torres, Bohuslav Melichar, Serafin Morales, Richard de Boer, Steven Gendreau, Mika Derynck, Mark Lackner, Jill Spoerke, Ru-Fang Yeh, Gallia Levy, Vivian Ng, Carol O'Brien, Heidi Savage, Yuanyuan Xiao, Timothy Wilson, Soo Chin Lee, Katarina Petrakova, Susanne Vallentin, Denise Yardley, Matthew Ellis, Martine Piccart, Edith A Perez, Eric Winer, Peter Schmid. The FERGI phase II study of the PI3K inhibitor pictilisib (GDC-0941) plus fulvestrant vs fulvestrant plus placebo in patients with ER+, aromatase inhibitor (AI)-resistant advanced or metastatic breast cancer – Part I results [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 S2-02.