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LBA1 Background: PARP inhibitors (PARPi) target cancers with homologous recombination repair defects by synthetic lethality. The PARPi olaparib (OL) is licensed for metastatic HER2-negative breast cancer with BRCA1/2 germline mutation (gBRCAm). Despite (neo)adjuvant chemotherapy ([N]ACT), recurrence rates in patients (pts) with gBRCAm early breast cancer (EBC) can be high. Novel adjuvant treatments are needed. Methods: OlympiA (NCT02032823), a randomized, double-blind, phase III study, enrolled pts with gBRCAm and HER2-negative (TNBC or hormone-receptor+ [HR+]) high-risk EBC after primary local treatment and ACT/NACT. Eligible pts with TNBC had ≥pT2 or ≥pN1 disease prior to ACT or non-pCR after NACT; those with HR+ BC had ≥4 positive nodes prior to ACT or non-pCR and CPS&EG score ≥3 after NACT. Pts were randomized 1:1 to 1 year of continuous oral OL (300 mg BID) or placebo (PL). Endocrine therapy and bisphosphonates were allowed. The primary endpoint was invasive disease-free survival (IDFS) in the ITT population. Secondary endpoints included distant DFS (DDFS), overall survival (OS) and safety. Safety analysis included adverse events of special interest (AESI) (myelodysplastic syndrome/ acute myeloid leukemia, new primary malignancy, pneumonitis). Per protocol IDMC interim analysis (IA) review was triggered at 165 IDFS events in the first 900 pts, with superiority boundaries based on a hierarchical multiple testing procedure: P < 0.005 for IDFS, followed by P < 0.005 for DDFS and p1% of OL pts were; anemia (8.7%), neutropenia (4.8%), leukopenia (3.0%), fatigue (1.8%), and lymphocytopenia (1.2%). SAEs and AESI were not increased by OL, SAE 8.7% vs 8.4% and AESI 3.3% vs 5.1%, OL vs PL respectively. Conclusions: Adjuvant OL following ACT or NACT significantly improved IDFS and DDFS with acceptable toxicity in pts with gBRCAm and high-risk HER2-negative EBC. Clinical trial information: NCT02032823.

1097 Background: In BROCADE3 (NCT02163694), addition of the PARP inhibitor (PARPi) V to CP improved PFS in patients (pts) with g BRCA-associated advanced breast cancer (hazard ratio 0.71 [95% CI 0.57–0.88], p = 0.002). Reversion mutations may account for resistance to platinum-based CT and PARPi. Efficacy, safety, and exploratory biomarker analyses for pts randomized to PL + CP who received crossover (Cx) V monotherapy after progression are reported. Methods: 513 total pts were randomized 2:1 to V + CP or PL + CP. V/PL, C, and P could be discontinued independently prior to progression, leading to varying platinum-free intervals at the time of progression. After progression, pts in the PL + CP arm could receive open-label Cx V monotherapy (300–400 mg BID continuous), beginning within 60 d of progression and continuing to second progression. Adverse events (AEs) and activity during Cx V were assessed. Exploratory analysis of BRCA reversion mutations restoring BRCA1/2 protein function that emerged during PL + CP treatment was performed on plasma circulating tumor DNA using targeted-amplicon next generation sequencing. Results: At data cutoff, 75 pts initially randomized to PL + CP had ≥1 dose of Cx V. Mean (range) duration of Cx V was 154 d (2–966). Activity during Cx V is in the Table. Mean (range) platinum-free interval at time of first dose of Cx V was 3.1 mos (0.4–10.9) vs 8.1 mos (1.0–34.9) in pts who had progressed vs had not progressed by 24 wks after first dose of Cx V. BRCA reversion analysis was completed for 18 Cx pts. Reversion mutations were identified in 1/18 pts (5.6%). This patient had Cx V duration of 19 d and had progressed by 24 wks. BRCA reversion analysis on additional Cx pts will be presented. Most common AEs during Cx V were nausea (61%), vomiting (29%), fatigue (24%), and diarrhea (21%). Any grade anemia, neutropenia, and thrombocytopenia occurred in 7%, 15%, and 7% of pts. Three pts (4%) experienced a convulsion event. Conclusions: Platinum-free interval may influence efficacy of subsequent PARPi. Impact of BRCA reversion mutations warrants further evaluation. Cross-resistance may limit PARPi efficacy after platinum failure. Clinical trial information: NCT02163694 . [Table: see text]

1091 Background: In BROCADE3 (NCT02163694), addition of PARP inhibitor V to CP resulted in improved progression-free survival (PFS) (HR 0.71 [95% CI 0.57−0.88], p=0.002) in patients (pts) with advanced HER2-negative breast cancer and g BRCA1/2 mutation. A subset of pts transitioned to V/placebo (PL) monoTx at an intensified dose/schedule after CP discontinuation prior to progression (investigator discretion). Here, we evaluate the impact of this transition on efficacy and safety. Methods: Pts were randomized 2:1 to CP with V (n=337) or PL (n=172). V (120 mg po BID) or PL was given on Days (D) −2 to 5, C (AUC 6) on D1, and P (80 mg/m2) on D1, 8, and 15 (21-day cycles). Pts who transitioned to monoTx received V/PL 300-400mg BID daily until progression. A Cox model with a time varying covariate indicating transition from V/PL with CP to V/PL monoTx was fit to estimate treatment effect during combination and monoTx phases. PFS by cycles of CP prior to monoTx and AEs during monoTx are summarized. Results: A subgroup of 136 (40%) and 58 (34%) pts on the V and PL arms, respectively, received monoTx. When a Cox model with a time-varying covariate was fit for PFS (per investigator), the nominal P-value for treatment by covariate interaction was 0.038. The HRs (95% CI) for V vs PL during combination therapy and monoTx were 0.81 (0.62–1.06) and 0.49 (0.33–0.73). The Table summarizes PFS by cycles of C and/or P prior to monoTx. Common AEs (>20% of pts) during V or PL monoTx were nausea (52%/10%), fatigue (23%/12%), headache (21%/17%), and diarrhea (21%/9%). Seizures (2.2%/0%) were reported during monoTx. Rates of cytopenias for V or PL monoTx were: anemia 12%/14%; neutropenia 13%/12%; and thrombocytopenia 10%/5%. Conclusions: These analyses suggest that pts treated with V + CP derive benefit from both combination therapy as well as V monoTx after CP discontinuation. Pts receiving V monoTx after ≤ 6 cycles of VCP experienced a similar benefit to those who transitioned to monoTx after 7–12 cycles of VCP, suggesting that V maintenance therapy may be suitable following a limited duration of combination therapy. Clinical trial information: NCT02163694 . [Table: see text]

e12587 Background: In the phase 3 TAILORx study, the first invasive disease-free survival event (in all arms) was often opposite BC or other second primary cancer. Our goal was to investigate differences in the 21-gene RS results between the primary BC and a second primary BC, as well as the association with clinicopathological characteristics. Methods: This analysis of the prospectively-designed CHS registry included all CHS pts with estrogen receptor (ER)+ HER2-negative BC who underwent RS testing between 1/2006 and 6/2019 and for whom ≥2 RS results were identified which were > 1 year apart. Results: Of the 10,244 RS assays ordered in this time frame, 371 involved pts for whom the assay was performed at least twice. Our analysis focused on the 42 pts for whom the assays were performed > 1 year apart. All pts were females; 76% were initially diagnosed with node-negative BC; median (interquartile range [IQR]) age at first diagnosis was 56 (43-64) yrs. Tumor characteristics for the first and subsequent primary BC are presented (Table). The median time (IQR) between the first and latest RS assay was 4.5 (2.9-6.4) yrs. In 28 pts (67%), the latest primary BC was ipsilateral and in 14 (33%) it was contralateral. The median (IQR) difference between the first and latest RS value was 7 (1-12). The second/third primary BC had higher RS than the first BC in the majority (76%) of pts. Higher RS in the latest primary BC (compared to the first primary BC) was more common when the latest primary BC was ipsilateral than when it was contralateral (86% vs 57%, P= 0.04). Conclusions: In ER+ HER2-negative BC pts, second/third primary BC is generally associated with higher RS result (compared to the first primary BC), particularly if the later primary BC is ipsilateral. [Table: see text]

Purpose The efficacy of lapatinib versus trastuzumab combined with taxanes in the first-line setting of human epidermal growth factor receptor 2 (HER2) –positive metastatic breast cancer (BC) is unknown. Patients and Methods The MA.31 trial compared a combination of first-line anti-HER2 therapy (lapatinib or trastuzumab) and taxane therapy for 24 weeks, followed by the same anti-HER2 monotherapy until progression. Stratification was by prior (neo)adjuvant anti-HER2 therapy, prior (neo)adjuvant taxane, planned taxane, and liver metastases. The primary end point was intention-to-treat (ITT) progression-free survival (PFS), defined as time from random assignment to progression by RECIST (version 1.0) criteria, or death for patients with locally assessed HER2-positive tumors. The primary test statistic was a stratified log-rank test for noninferiority. PFS was also assessed for patients with centrally confirmed HER2-positive tumors. Results From July 17, 2008, to December 1, 2011, 652 patients were accrued from 21 countries, resulting in 537 patients with centrally confirmed HER2-positive tumors. Median follow-up was 21.5 months. Median ITT PFS was 9.0 months with lapatinib and 11.3 months with trastuzumab. By ITT analysis, PFS was inferior for lapatinib compared with trastuzumab, with a stratified hazard ratio (HR) of 1.37 (95% CI, 1.13 to 1.65; P = .001). In patients with centrally confirmed HER2-positive tumors, median PFS was 9.1 months with lapatinib and 13.6 months with trastuzumab (HR, 1.48; 95% CI, 1.20 to 1.83; P < .001). More grade 3 or 4 diarrhea and rash were observed with lapatinib (P < .001). PFS results were supported by the secondary end point of overall survival, with an ITT HR of 1.28 (95% CI, 0.95 to 1.72; P = .11); in patients with centrally confirmed HER2-positive tumors, the HR was 1.47 (95% CI, 1.03 to 2.09; P = .03). Conclusion As first-line therapy for HER2-positive metastatic BC, lapatinib combined with taxane was associated with shorter PFS and more toxicity compared with trastuzumab combined with taxane.

Purpose Olaparib is an oral poly (ADP-ribose) polymerase inhibitor with activity in germline BRCA1 and BRCA2 (BRCA1/2) –associated breast and ovarian cancers. We evaluated the efficacy and safety of olaparib in a spectrum of BRCA1/2-associated cancers. Patients and Methods This multicenter phase II study enrolled individuals with a germline BRCA1/2 mutation and recurrent cancer. Eligibility included ovarian cancer resistant to prior platinum; breast cancer with ≥ three chemotherapy regimens for metastatic disease; pancreatic cancer with prior gemcitabine treatment; or prostate cancer with progression on hormonal and one systemic therapy. Olaparib was administered at 400 mg twice per day. The primary efficacy end point was tumor response rate. Results A total of 298 patients received treatment and were evaluable. The tumor response rate was 26.2% (78 of 298; 95% CI, 21.3 to 31.6) overall and 31.1% (60 of 193; 95% CI, 24.6 to 38.1), 12.9% (eight of 62; 95% CI, 5.7 to 23.9), 21.7% (five of 23; 95% CI, 7.5 to 43.7), and 50.0% (four of eight; 95% CI, 15.7 to 84.3) in ovarian, breast, pancreatic, and prostate cancers, respectively. Stable disease ≥ 8 weeks was observed in 42% of patients (95% CI, 36.0 to 47.4), including 40% (95% CI, 33.4 to 47.7), 47% (95% CI, 34.0 to 59.9), 35% (95% CI, 16.4 to 57.3), and 25% (95% CI, 3.2 to 65.1) of those with ovarian, breast, pancreatic, or prostate cancer, respectively. The most common adverse events (AEs) were fatigue, nausea, and vomiting. Grade ≥ 3 AEs were reported for 54% of patients; anemia was the most common (17%). Conclusion Responses to olaparib were observed across different tumor types associated with germline BRCA1/2 mutations. Olaparib warrants further investigation in confirmatory studies.

140 Background: Olaparib is a PARP inhibitor that has shown activity in relapsed gastric cancer (GC) when combined with chemotherapy. MEDIOLA assesses the efficacy and safety of a chemo-free combination of olaparib and durvalumab, an anti-programmed cell death ligand-1 (PD-L1) agent in patients (pts) with solid tumors, including relapsed GC (NCT02734004). Methods: Eligible pts had GC that relapsed following platinum-containing therapy. Pts received olaparib 300 mg PO BID for a 4-wk run-in to allow for serial biopsies, followed by combination olaparib and durvalumab (1.5 g IV q 4 wks) until progressive disease (PD) as measured by RECIST 1.1. Tumor measurements were taken at baseline, 4 wks and q 8 wks thereafter. Primary endpoints were disease control rate (DCR) at 12 wks, safety, and tolerability. The secondary endpoints included DCR at 28 wks, objective response rate (ORR), duration of response (DoR), progression-free survival, and OS. Biomarker endpoints included PD-L1 expression and evaluation of tumor infiltrating lymphocytes. Bayesian predictive probability design was used for statistical analysis. Results: Forty pts were included in the safety and 39 in the efficacy analysis. Among 39 pts, median age was 57 yrs (range 28–77). Nineteen pts (48%) had a grade 3 AE; three pts (8%) a grade 4 AE. Most common AEs were anemia, lipase increase, fatigue, dysphagia, hyponatremia, and alkaline phosphatase increase. Ten pts (25%) had immune-mediated AEs, most commonly rash. The ORR was 10%; two pts had complete response; two had partial response. Median DoR was 11.1 months. DCR at 12 wks was 26%. Further efficacy and biomarker data will be presented. Conclusions: The combination of olaparib and durvalumab was tolerable, with no unexpected AEs. All responses occurred after the addition of durvalumab and were durable, suggesting synergistic treatment effect of the combination in some pts. Furthermore, several pts with early PD showed unexpectedly long survival. DCR at 12 wks was below the target (70%) due to a high rate of early PDs following the olaparib run-in. To address the early treatment failures, an upfront addition of more aggressive therapies to the combination should be explored. Clinical trial information: NCT02734004.

514Background: Women who carry germ line mutations in BRCA1/2 face a very high risk of breast and ovarian cancer. Recommendations for BRCA mutation carriers advocate intensified screening and BSO. ...

PurposeTAnDEM is the first randomized phase III study to combine a hormonal agent and trastuzumab without chemotherapy as treatment for human epidermal growth factor receptor 2 (HER2)/hormone receptor–copositive metastatic breast cancer (MBC).Patients and MethodsPostmenopausal women with HER2/hormone receptor–copositive MBC were randomly assigned to anastrozole (1 mg/d orally) with or without trastuzumab (4 mg/kg intravenous infusion on day 1, then 2 mg/kg every week) until progression. The primary end point was progression-free survival (PFS) in the intent-to-treat population.ResultsOverall, 103 patients received trastuzumab plus anastrozole; 104 received anastrozole alone. Patients in the trastuzumab plus anastrozole arm experienced significant improvements in PFS compared with patients receiving anastrozole alone (hazard ratio = 0.63; 95% CI, 0.47 to 0.84; median PFS, 4.8 v 2.4 months; log-rank P = .0016). In patients with centrally confirmed hormone receptor positivity (n = 150), median PFS was 5.6 and 3.8 months in the trastuzumab plus anastrozole and anastrozole alone arms, respectively (log-rank P = .006). Overall survival in the overall and centrally confirmed hormone receptor–positive populations showed no statistically significant treatment difference; however, 70% of patients in the anastrozole alone arm crossed over to receive trastuzumab after progression on anastrozole alone. Incidence of grade 3 and 4 adverse events was 23% and 5%, respectively, in the trastuzumab plus anastrozole arm, and 15% and 1%, respectively, in the anastrozole alone arm; one patient in the combination arm experienced New York Heart Association class II congestive heart failure.ConclusionTrastuzumab plus anastrozole improves outcomes for patients with HER2/hormone receptor–copositive MBC compared with anastrozole alone, although adverse events and serious adverse events were more frequent with the combination.

543 Background: Elderly BC pts are generally undertreated, despite evidence suggesting that they may benefit from adjuvant chemotherapy (CT). We compared treatments/clinical outcomes in elderly vs younger Clalit Health Services (CHS) pts undergoing RS testing. Methods: This exploratory analysis of the CHS registry included BC pts with N0/N1mi/N1 disease who were RS-tested from 1/2006 (CHS approval of the test) through 12/2010 (N0) or 12/2011 (N1mi/N1). Medical records were reviewed to verify treatments/recurrences/survival. Results: The analysis included 458 elderly and 2052 younger pts, with a median (range) follow-up of 5.7 (0.9-9.6) and 6.1 (0.1-10.3) yrs, respectively. In the elderly/younger pts, median age was 73/58 yrs, 48%/52% had grade 2 tumors, median tumor size was 1.6/1.5 cm, 70%/72% were N0 and 30%/28% were N1mi/N1. RS distribution (

TPS1111 Background: Patients (pts) with HR+ breast cancer (BC) often havedysregulatedphosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway, which further leads to resistance to endocrine therapy (ET). In a phase 1 study, alpelisib (BYL719), a PI3Kα-specific inhibitor in combination with fulvestrant (FUL) has demonstrated antitumor activity in pts with estrogen receptor-positive, HER2– advanced BC (ABC) with PIK3CA-altered tumors. SOLAR-1 (NCT02437318) aims to assess the efficacy of ALP + FUL in PIK3CA-mutant and non-mutant tumors in HR+, HER2– ABC setting. Methods: SOLAR-1 is a phase 3, randomized, double-blind study conducted in men and postmenopausal women with HR+, HER2– ABC. Pts are randomly (1:1) allocated to oral alpelisib/placebo (300 mg qd) and intramuscular FUL (500 mg) until disease progression or treatment (tx) discontinuation. Stratification factors are presence of liver and/or lung metastases and prior use of CDK4/6 inhibitors. The eligibility criteria for the targeted BC patient population are shown in the Table. The primary endpoint is progression-free survival (PFS; RECIST v1.1; local assessment), while overall survival (OS) is a key secondary endpoint in the PIK3CA-mutant cohort. Other secondary endpoints are PFS and OS in the PIK3CA non-mutant cohort, the association between PFS and baseline PIK3CAstatus in ctDNA, overall response rate, clinical benefit rate, and safety. Recruitment of the planned 560 pts is currently ongoing. Clinical trial information: NCT02437318. [Table: see text]

with the inherent limitations of all phase II trials. The impact of olaparib on overall survival as well as on patient-reported outcomes such as symptom benefit is best addressed in randomized phase III trials. The primary aim of this trial was to look for an efficacy signal in heavily pretreated patients with germline BRCA mutations and a wide range of cancers that included ovarian, breast, pancreatic, and prostate, as well as others. These patients typically have limited treatment options and the results of phase II trials can drive progress. Indeed, the results of this study were included in the consideration by the US Food and Drug Administration for the approval of olaparib for women with BRCA-associated recurrent ovarian cancer after more than three lines of therapy (an unmet clinical need). McNamara et al 2 also question the dose modifications for toxicity and whether patients received adequate dose intensity. Future studies are needed to determine minimally effective dose. This is particularly relevant in patients who have been heavily pretreated who may be at risk of increased toxicities and require dose reductions. We agree that knowledge of poststudy treatment after olaparib

155 Background: BRCA-mutated tumors are more susceptible to platinum therapy and PARP inhibitors due to underlying defects in homologous recombination repair of DNA damage. In preclinical models the potent oral PARP1/2 inhibitor veliparib was shown to enhance sensitivity to C and to have single-agent activity in BRCA+ cell lines. Phase 1 trials suggest promising antitumor activity and acceptable toxicity of veliparib plus C/P in triple-negative BC (Puhalla et al. Cancer Res 2012;72:PD09-06) and single-agent activity of veliparib in BRCA+ BC (Somlo et al. J Clin Oncol 2014;32:abstr. 1021). This phase III trial assesses efficacy and toxicity of veliparib plus C/P vs C/P alone in patients with HER2− BRCA-associated locally advanced or metastatic BC (NCT02163694). Methods: Phase III randomized, double-blind, placebo-controlled, multicenter trial. Eligible patients (female or male; ≥ 18 years) have HER2−metastatic/locally advanced unresectable BC with (suspected) deleterious BRCA1/2 germline mutations and received 2 or fewer prior lines of DNA-damaging chemotherapy for metastatic BC. In addition, patients must have received ≤ 1 prior line of platinum therapy (any setting) without progression within 12 months of completing treatment. Patients are randomized 2:1 to C/P with veliparib or C/P with placebo, stratified by estrogen and/or progesterone receptor expression, prior platinum therapy, and central nervous system metastases. Veliparib (120 mg p.o. BID) or placebo will be given on Days −2 to 5, C (AUC 6 mg/mL/min i.v.) on Day 1, and P (80 mg/m2i.v.) on Days 1, 8, and 15 (21-day cycles). Treatment continues until unacceptable toxicity or progressive disease (PD). Patients in the placebo arm who discontinue due to PD are eligible for crossover to veliparib monotherapy. The primary objective is to assess if the addition of veliparib to C/P increases progression-free survival; additional objectives include evaluation of overall survival, clinical benefit rate, objective response rate, quality of life, and safety. Enrollment began in July 2014 with a planned sample size of 270 patients. Clinical trial information: NCT02163694.

Background: The PARPi olaparib (Ola) was recently granted FDA accelerated approval in advanced BMOC. Despite impressive clinical activity in BMOC, the impact of baseline pt factors remains unclear. We hypothesized that the platinum chemotherapy (Plt chemo) to PARPi interval (PTPI) can be used to refine the conventional prediction of response to PARPi based on the clinical categorization of pts into Plt sensitive (Plt-S) and Plt resistant (Plt-R). Methods: Retrospective study of pt with advanced BMOC treated in relapsed setting with ≥ 200 mg bid Ola between 4/2006 – 8/2013 in multiple centers. Pearson Chi2, odds ratios (OR) and Fisher’s exact probability tests were used for statistical analyses. Results: 108 advanced BMOC pts were assessed; median age 55y (range 38-79); 83 (77%) pts had high grade serous carcinoma. BRCA1:BRCA2 mutations ratio 71:29. Median prior lines of chemo: 3 (range 1-10). 41 (38%) pts had prior breast cancer (BC). 64% had Plt-S disease and 36% had Plt-R disease prior to Ola. Median PTPI was 53 weeks (w) (range 4-244). Median PTPI was 68.7w for Plt-S pts versus (vs) 25.9w for Plt-R pts (p < 0.0001). RECIST complete or partial responses (CR/PR) were observed in 23/65 (35%) Plt-S pts vs 5/38 (13%) Plt-R pts (p < 0.02). Pts with > 52w PTPI had higher CR/PR rates than those with < 52w PTPI independent of their Plt status (37% vs 18%, respectively, p = 0.053). Pts who had only 1 prior line of chemo had higher CR/PR rates vs pts who had > 1 prior line (p < 0.005). No differences in CR/PR rates were noted between pts with BRCA1 vs pts with BRCA2 mutations, pts with prior BC vs pts without, or use of chemo for BC vs none. Median progression-free survival was 70w for pts with PR/CR vs 28w for pts without (log-rank, p = 0.0004). Median survival was 161w for pts with CR/PR and 64w for pts without (log-rank, p = 0.0005). Conclusions: These data suggest that prediction of response to PARPi in advanced BMOC based on conventional Plt-S/Plt-R categorization may be refined by PTPI. Treatment of Plt-R BMOC pts with a non-Plt agent prior to Ola in order to prolong PTPI may be an appropriate clinical strategy. These findings should be validated prospectively in a larger data set.

TPS1109 Background: In a Phase II proof-of-concept study (NCT00494234), treatment with the PARP inhibitor olaparib (Lynparza; 400 mg twice daily [bid]; capsules) resulted in antitumor activity in p...

601 Background: Lapatinib (L) was associated with shorter progression-free survival (PFS) than trastuzumab (T) when combined with a taxane (Tax) as first line therapy for HER2+ MBC. We report the e...

1023 Background: Pathological complete response (pCR) has been demonstrated to serve as a surrogate for outcome in patients receiving neo-adjuvant systemic therapy (NAT) for triple negative (TN) br...

610 Background: The gold standard endpoint in randomized clinical trials (RCTs) in MBC is OS, which has the disadvantage of requiring extended follow-up and being confounded by subsequent anti-cancer therapies. Although therapeutics have been approved based on PFS, its use as a primary endpoint is controversial. This study, the first IPD meta-analysis of targeted agents in MBC, aimed to collect data from RCTs of HER2-targeted agents in HER2+ MBC, assessing to what extent PFS correlates with, and may be used as, a surrogate for OS. Methods: A search was conducted in April 2011. Eligible RCTs accrued HER2+ MBC patients (pts) in 1992-2008. Collaboration was obtained from industrial partners (Roche, GSK) for industry-led studies. Investigator-assessed PFS was defined as the time from randomization to clinical or radiological progression, or death. A correlation approach was used: at the individual level, to estimate the association between PFS and OS using a bivariate survival model and at the trial level, to estimate the association between treatment effects on PFS and OS. Squared correlation values close to 1.0 would indicate strong surrogacy. Results: The search strategy resulted in 2137 eligible pts in 13 RCTs testing trastuzumab or lapatinib. We collected IPD data from 1963 pts in 9 RCTs. One phase II RCT did not have sufficient follow-up data so that 1839 pts in 8 RCTs were retained (5 evaluating trastuzumab, 3 lapatinib); 6 out of 8 RCTs were first-line. At the individual level, the Spearman rank correlation using Hougaard copula was equal to r=0.66 (95% CI 0.65 to 0.66) corresponding to an r2 of 0.42. At the trial level, the squared correlation between treatment effects on PFS and OS was provided by R2=0.33 (95% CI -0.22 to 0.86) using Hougaard copula and R2=0.53 (95% CI 0.22 to 0.83) using log hazard ratios from Cox models. Conclusions: In RCTs of HER2-targeted agents in HER2+ MBC, PFS is moderately correlated with OS and treatment effects on PFS are modestly correlated with treatment effects on OS, similarly to first-line chemotherapy in MBC (Burzykowski et al JCO 2008). PFS does not completely substitute for OS.

1040 Background: The randomized phase III TURANDOT trial compared first-line BEV plus paclitaxel (PAC) vs BEV plus capecitabine (CAP) in HER2-negative metastatic BC (mBC). BEV-based regimens are often favored in TNBC [Dawood 2012] because of efficacy in subgroup analyses and a lack of effective treatments. We performed an exploratory subgroup analysis of TURANDOT to provide more data on BEV-based therapy in TNBC. Methods: Patients (pts) with HER2-negative mBC who had received no prior chemotherapy for mBC were randomized to either BEV–PAC (BEV 10 mg/kg d1 and 15 + PAC 90 mg/m2 d1, 8, and 15 q4w) or BEV–CAP (BEV 15 mg/kg d1 + CAP 1000 mg/m2bid d1–14 q3w). The primary endpoint was overall survival (OS); secondary endpoints included objective response rate (ORR), progression-free survival (PFS), and safety. Results: Of 561 pts treated, 130 had TNBC. Baseline characteristics were typical of a poor-prognosis population and generally balanced between treatment arms, although fewer pts receiving BEV–PAC than BEV–CAP had ECOG PS 1/2 (25% vs 40%, respectively), positive lymph nodes (56% vs 72%), metastatic disease at first diagnosis (19% vs 30%), and liver metastases (27% vs 43%). Median age was 54 vs 56 years, respectively. At data cut-off, median follow-up was 21.4 vs 19.2 mo for BEV–PAC and BEV–CAP, respectively. The safety profiles in the TNBC subgroup were similar to the overall population. The predominant grade ≥3 AEs were hematologic AEs and neuropathy with BEV–PAC and hand-foot syndrome and diarrhea with BEV–CAP. Conclusions: One-year OS rates up to 78% in TURANDOT are among the highest seen in TNBC. BEV-based therapy is a valid option in a setting with limited active treatments. BEV–PAC may be favored based on 1-year OS, PFS, and ORR. Clinical trial information: NCT00600340. [Table: see text]

11024 Background: The oral PARP inhibitor olaparib has shown antitumor activity as monotherapy in patients (pts) with breast and ovarian cancer with gBRCA1/2 mutations. This multicenter non-comparative study evaluated whether tumors in gBRCA1/2 mutation carriers are responsive to olaparib regardless of tumor type (NCT01078662). Methods: Heavily pretreated pts with advanced cancer refractory to standard therapy (98% of breast cancer pts had ≥3 lines of prior chemotherapy for metastatic disease) and with a gBRCA1/2 mutation, received olaparib 400 mg bid (capsule) until disease progression. Primary objective: tumor response by RECIST 1.1. Secondary objectives: PFS, OS and safety. Results: 298 pts received treatment and were evaluable. Enrollment is complete, 33 pts remain on study. Median duration of treatment in this heavily pretreated population was 5.5 months (range

278 Background: Somatic inactivation of genes involved in homologous recombination (HR) may confer increased sensitivity to poly (ADP-ribose)- polymerase (PARP) inhibition and DNA cross-linking agents (eg. mitomycin C, platinum-based chemotherapy). Studies in BRCA associated ovarian cancer have demonstrated favorable outcomes with platinum based treatments. The role of BRCA mutations in pancreatic cancer outcome is understudied. In this study, the clinical features and therapeutic responses of BRCA 1/2 mutation carriers with pancreatic malignancies are reported. Methods: Patients with BRCA1/2 -associated pancreatic ductal adenocarcinoma (PDAC) diagnosed between January 1994-June 2012 were identified from clinical databases at three participating institutions. Demographic, clinical, and therapeutic response data were collected and analyzed using non-parametric models. Progression-free (PFS) and overall survival (OS) were analyzed. Results: Overall, 63 patients with PDAC and a BRCA1 (n=17), BRCA2 (n=43) or both (n=1) mutations were included. Mean age at diagnosis was 60.2 (range 33-83), 37 (58.7%) were male, 48 (76.2%) were Jewish, 26 (41.3%) were smokers, 55 (87.3%) had a family history of malignancy of which 18 (32.7%) had a history of PDAC. Twenty-five (39.7%) patients underwent a primary resection, and 30 (47.6%) had stage IV disease at presentation. PFS on platinum-based first-line chemotherapy in 12 metastatic BRCA positive cases (median: 90 days) was not statistically different than that of non-platinum chemotherapy treated carriers (n=18, median: 92 days) (p= 0.6412). Two patients with advanced disease were down-staged from unresectable to resectable using combination gemcitabine/cisplatin therapy. One of these is disease free at 50 months after surgery. Median OS for all 51 patients (excluding patients receiving experimental treatments) was 14.02 months (9.48-18.2). Conclusions: The natural history of BRCA associated PDAC appears similar to non-carriers. The role of platinum agents in these individuals remains unclear as data are not mature, however, to date, no difference in median PFS was observed. Surgical downstaging may be possible in a subset of these patients.

5022 Background: Emerging clinical data point to the clinical utility of PARPi in BDOC. However, the impact of PARPi exposure on the prospects of response to further CT remains unclear. In our previous single centre study, we provided the first clinical data relating to the use of post-PARPi CT (JCO 2010: 28(15S), A5041). Our aim here was to re-examine this issue in a larger multi-institutional population. Methods: We included pts with advanced BDOC who received CT, having progressed on ≥200 mg bd olaparib. Pt, tumor and treatment characteristics and clinical outcomes were documented. Relationships between post-PARPi CT overall survival (OS) and other variables were explored using Cox regression. Results: We collected data on 75 pts (median age 51 y [range 31-77], BRCA1:BRCA2 54:21, mean 3 previous lines of CT [95% CI 2.5-3.4], pre-PARPi platinum (Plt) resistance rate 49% and olaparib RECIST-response rate [RR] 39% [95% CI 28-50]). Following olaparib, most pts received Plt alone or in combination with taxane (Tx) or liposomal doxorubicin (PLD). Weekly Plt was used in 36% of all Plt-treated pts, mainly in combination with weekly Tx. Overall RECIST and CA125 (GCIG) RRs were 38% and 48%, respectively; these responses occurred independently of PARPi response or pre-PARPi Plt sensitivity (all p>.1). The median progression free survival and OS of RECIST responders were 7.9 m (95% CI 5.8-10.9) and 10.5 m (95% CI 1.4-19.6), respectively. In all pts, the median OS from the start of post-PARPi CT was 7.9 m (95% CI 5.7-10.1) while that from diagnosis was 64.9 m (95% CI 52.9-76.9). Factors associated with improved OS on post-PARPi CT in the MVA included best olaparib response of non-disease progression (p=.003, HR 0.28), optimal initial debulking (p=.01, HR 0.36) and pre-PARPi Plt sensitivity (p=.05, HR 0.46). Conclusions: These data indicate potential for meaningful responses to CT in BDOC pts with PARPi resistance. Analysis to identify molecular predictors of response is ongoing. [Table: see text]

1513 Background:Inherited BRCA1/BRCA2 mutations are associated with increased breast /ovarian cancer risks, and acceptable prevention measures (e.g. risk reducing salpingo-oophorectomy) reduce morb...

TPS108 Background: The EGFR pathways are important therapeutic targets in HER2/neu+ BC. Lapatinib (L) a dual, inhibitor of EGFR and HER2/neu tyrosine kinase activity improves overall survival (OS) ...

10572 Background: L is a reversible, oral small molecule inhibitor of EGFR and HER2. L demonstrated a clinical overall response rate of 39%, median progression free survival (PFS) of 14.6 weeks and...

e21035 Background: GLP-1 is a hormone secreted from endocrine L cells in the gut in response to food intake and promotes insulin secretion and satiety. These activities indicated GLP-1 as a potenti...

636 Background: IBC is an uncommon (∼2–6%) form of breast cancer with a significantly worse prognosis than non-IBC. Lapatinib is a reversible, oral small molecule inhibitor of EGFR and HER-2/neu tyrosine kinases (also known as ERBB1 and ERBB2, respectively). EGF103009 was initially designed as a two stage, Green-Dahlberg study of lapatinib monotherapy in 30 subjects in each of two cohorts, HER2+ and EGFR+/HER2-. Following a 50% response rate in the first 30 HER2+ patients, this cohort was expanded to 120 patients in order to improve the precision of estimated ORR; this represents the only prospective clinical study ever conducted in HER2+ IBC. Methods: Patients with HER2+ (IHC 3+ / FISH Ampified) IBC that was refractory to anthracyclines, taxanes, and trastuzumab (where available) were enrolled. Pretreatment and day 28 fresh biopsies were collected for each subject to assay for relevant biomarkers. Patients received lapatinib daily (1,500 mg/d). Skin lesions were assessed at 4 week intervals and RECIST-me...

11002 Background: The 21-gene recurrence score (RS) aims to quantify chemotherapy benefit in lymph node-negative, estrogen receptor (ER)-positive breast cancer (BC) patients. We aimed to elucidate the association between the RS and clinical-pathological features in a population-based Israeli cohort. Methods: Study population included all Israeli BC female patients referred to the RS assay from October 2004 until October 2006. Clinical and pathology data were collected upon referral, RS risk was categorized as previously defined (low < 18, intermediate 18–30, high = 31) and chemotherapy benefit was also assessed for each patient using NCCN guidelines, St. Gallen recommendations and Adjuvant! Online. Results: 300 patients were referred to the assay by 70 physicians from 16 institutions. Low, intermediate and high RS were noted in 109 (36 %), 134 (45 %) and 57 (19%) of the patients respectively, compared to 54%, 21% and 25% respectively, in the validation study (JCO;24:3726). Median age was 54 and median tumor size was 1.6 cm. Similar age distribution, tumor size and ER staining intensity were noted in all risk categories. Interestingly, no association has been identified between the RS and the presence of lymph nodes micrometastases. High tumor grade was noted in 15%, 20% and 56%; progesterone expression in 88% 72% 43%; non-infiltrative ductal carcinoma (IDC) 24%, 12% and 6%; and Her2 expression in 2%, 3% and 19% of the low, intermediate and high risk categories respectively (p No significant financial relationships to disclose.

807 Background: Neo-adjuvant chemotherapy has been proven to increase the rate of breast-conservation and represents the standard of care in patients with locally advanced breast cancer. Dose-dense...

650 Background: HER2/neu over-expression (HER2+) occurs in approximately 25% of breast cancers and is often associated with a more aggressive disease. In this study we examined the effects of hormo...

8113 Background: The hormone ghrelin and the adipocytokines leptin and adiponectin participate in body weight regulation. In response to severe weight loss, ghrelin and adiponectin levels increase ...