Albain, Kathy S.

521 Background: S0221 investigated weekly vs q 2 week dosing of doxorubicin/cyclophosphamide (AC) and paclitaxel (P) in patients (pts) with high risk early breast cancer as previously reported (JCO 33:58-64, 2015). After enrollment of 2716 pts randomization to the two AC arms was stopped for futility and an additional 578 pts received 4 cycles of q 2 week AC and were randomized to P weekly (Pw) or P q 2 weeks (P2). We report updated results of the original trial design and the first report of the 578 pts treated with AC x 4 and Pw x 12 or P2 x 6. Methods: Between December 2003 and November 2010, 2716 pts were randomized in a 2x2 factorial design to 1) 15 weeks of weekly AC (A 24 mg/m2/week and C 60 mg/m2/day po) vs 6 cycles of q 2 week AC (A 60 mg/m2 and C 600 mg/m2) and 2) Pw (paclitaxel 80 mg/m2/week x 12) vs P2 (paclitaxel 175 mg/m2 q 2 weeks x 6), with growth factor support as previously described. After study amendment 578 patients received 4 cycles of q 2 week AC followed by Pw or P2. Updated survival was assessed using log-rank tests and Cox regression models. Results: At a median follow-up of 8.5 years, among the pts treated in the original protocol, there were no significant differences among the four treatments for DFS (p=0.21) or OS (p=0.08). The triple-negative subset had worse DFS (P<0.001) than the HER2-positive or ER/PR+/HER2- subsets, with 5 year DFS of 75% vs 83% and 84%, respectively. While we previously found in the triple negative subset that the arm using q 2 weeks for both AC and paclitaxel was marginally superior, the differences among the arms are no longer significant for DFS (p=0.12) or OS (p=0.11). Among the 578 pts assigned ACx4 and randomized to Pw v P2 there were no overall differences in DFS (p=0.70) or OS (p=0.63) after 4.4 years median follow-up. Conclusions: There were no significant differences in DFS or OS between any of the schedules with extended follow-up in the original cohort and no difference in outcome by paclitaxel schedule for the 578 additional patients in the revised protocol. Either paclitaxel schedule may be recommended, with selection based on toxicity, cost, or patient preference rather than efficacy. Support: NCI grants CA32102, CA38926, CA21115, CA21076, CA77597, CA25224, CA77202, CCSRI15469, and Amgen, Inc. Clinical trial information: NCT00070564.

506 Background: Pembro is an anti-PD-1 antibody with single agent activity in HER2– metastatic BC. I-SPY 2 is a multicenter, phase 2 platform trial which evaluates novel neoadjuvant therapies; the primary endpoint is pathological complete response (pCR, ypT0/Tis ypN0). We report current efficacy results, with final results at ASCO. Methods: Patients (pts) with invasive BC ≥2.5 cm by exam or ≥2 cm by imaging are assigned weekly paclitaxel x 12 (control) +/- an experimental agent, followed by doxorubicin/cyclophosphamide x 4. Combinations of hormone-receptor (HR), HER2, & MammaPrint (MP) status define the 8 signatures studied. MP low HR+ BC is excluded. Adaptive randomization is based on each arm’s Bayesian probability of superiority over control. Graduation by signature is based on an arm’s Bayesian predictive probability of a successful 1:1 randomized phase 3 trial with a pCR endpoint. We provide raw & Bayesian estimated pCR rates adjusted for covariates, time effects over the course of the trial, & serial MRI modeling for pts not yet assessed for pCR surgically. Results: 69 pts were randomized to pembro (HER2- subsets only) from Dec 2015 until it graduated in Nov 2016. 46 pts have undergone surgery (table); the other 23 have on-therapy MRI assessments. In 29 HR–/HER2– (TNBC) pts, pembro increased raw & estimated pCR rates by >50% & 40%, respectively; in 40 HR+/HER– pts, it did so by 13% and 21%. 5 pts had immune-related grade 3 adverse events (AEs); 1 hypophysitis & 4 adrenal insufficiency. 4 pts presented after completion of AC (149-179 d after starting pembro); 1 presented prior to AC (37 d after starting pembro). 7 pts had grade 1-2 thyroid abnormalities. Conclusion: Pembro added to standard therapy improved pCR rates in all HER2- BCs that meet I-SPY 2 eligibility, especially in TNBC. Immune-mediated AEs were observed; pt follow up is ongoing. Clinical trial information: NCT01042379. [Table: see text]

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.

CRA1008 Background: S0221 is a SWOG-coordinated phase III adjuvant chemotherapy intergroup trial in node-positive and high-risk node-negative operable breast cancer which hypothesized that 1) the weekly AC+G regimen is superior to ddAC x 6 and 2) 12 weeks of weekly paclitaxel (wP) is superior to q 2 week paclitaxel x 6 (ddP). Methods: Between December 2003 and November 2010, 2,716 patients were randomized in a 2 x 2 factorial design to 1) AC+G vs ddAC and 2) P 80 mg/m2/week x 12 vs P 175 mg/m2 q 2 weeks x 6. If there was no significant interaction between the factors, the trial was powered to find a disease-free survival hazard ratio (HR) ≤ 0.82 for weekly vs q 2 week for each factor. At the first interim analysis, the AC randomization was halted for futility, and S0221 was closed to accrual 10 November 2010. S0221 reopened 15 December 2010, after which time all patients received 4 cycles of ddAC and randomization to P weekly x 12 and ddP x 6 continued. Accrual halted at a total of 3,294 in January 2012. Results: By September 7, 2012, 487 events and 340 deaths had occurred, prompting the third planned interim analysis. The Data Safety and Monitoring Committee recommended reporting the results since the futility boundary was crossed. A Cox model adjusting for the AC arms had a HR = 1.08 (95% CI 0.90-1.28; p=0.42), with the 99.5% CI excluding the original alternative hypothesis that the HR=0.82. There was no significant interaction of the two factors. Estimated 5-year progression-free survivals were 82% for weekly P and 81% for ddP. Toxicity data were available for 1,385 patients treated with ddP and 1,367 treated with weekly P. Grade 5 toxicity occurred in 4 patients on ddP and 2 on weekly P. Percent grade 3-4 toxicity per arm are shown in the Table. Conclusions: Either ddPx6 or weekly P x 12 are acceptable schedules of P administration. The differences in leukopenia likely reflect ascertainment bias against weekly P. If this is accepted, weekly P x 12 produces less overall toxicity than 6 cycles of ddP. Support: NCI grants CA32102, CA38926, CA21115, CA21076, CA77597, CA25224, CA77202, CCSRI15469, and Amgen, Inc. Clinical trial information: NCT00070564. [Table: see text]

LBA500 Background: The primary endpoint of NSABP B-35, a phase III trial comparing 1 mg/day anastrozole to 20 mg/day tamoxifen, each given for 5 years, was breast cancer-free interval (BCFI), defined as the time from randomization to any breast cancer (BC) event including local, regional, or distant recurrence or contralateral disease, invasive or DCIS. Methods: Postmenopausal women with ER-receptor or PgR-receptor positive (by IHC analysis) DCIS and no invasive BC who had undergone a lumpectomy with clear resection margins were randomly assigned to receive either 20 mg/day tam or 1 mg/day A (blinded) for 5 years. Stratification was by age (<60 v ≥60). Results: From 1/6/2003 to 6/15/2006, 3,104 pts were entered and randomized (1552 in groups tam and A each). As of 2/28/15, follow-up information was available on 3,083 pts for OS and on 3,077 pts for all other disease-free endpoints, with mean time of follow-up of 8.6 years. There were 198 BCFI events, 114 in the tam group and 84 in the A group (HR, 0.73; p=0.03). 10-year point estimates for BCFI were 89.2% for tam and 93.5% for A. A significant time-by-treatment interaction (p=0.02) indicated that the effect was not evident until later in the study. There was a significant interaction between treatment and age group (p=0.04); benefit of A is only in women <60 years old. As to secondary endpoints, there were 495 DFS events, 260 in the tam group and 235 in the A group (HR, 0.89; p=0.21). 10-year point estimates for DFS were 77.9% for tam and 82.7% for A. There were 186 deaths, 88 in the tam group and 98 in the A group (HR, 1.11; p=0.48). 10-year point estimates for OS were 92.1% for tam, 92.5% for A. There were 8 deaths due to breast cancer in the tam group and 5 in the A group. There were 63 cases of invasive breast cancer in the tam group and 39 in the A group (HR, 0.61; p=0.02). There was a non-significant trend for a reduction in breast second primary cancers with A (HR, 0.68; p=0.07). Conclusions: Anastrozole provided a significant improvement compared to tamoxifen for BCFI, which was seen later in the study, primarily in women <60 years. Support: CA12027, 37377, 69651, 69974; 180868, 180822, 189867 196067, 114732; AstraZeneca Pharmaceuticals LP. Clinical trial information: NCT00053898.