Chew, Helen K.

Abstract Background Adjuvant bisphosphonates, when given in a low-estrogen environment, can decrease breast cancer recurrence and death. Treatment guidelines include recommendations for adjuvant bisphosphonates in postmenopausal patients. SWOG/Alliance/Canadian Cancer Trials Group/ECOG-ACRIN/NRG Oncology study S0307 compared the efficacy of three bisphosphonates in early-stage breast cancer. Methods Patients with stage I–III breast cancer were randomly assigned to 3 years of intravenous zoledronic acid, oral clodronate, or oral ibandronate. The primary endpoint was disease-free survival (DFS) with overall survival as a secondary outcome. All statistical tests were two-sided. Results A total of 6097 patients enrolled. Median age was 52.7 years. Prior to being randomly assigned, 73.2% patients indicated preference for oral vs intravenous formulation. DFS did not differ across arms in a log-rank test (P = .49); 5-year DFS was 88.3% (zoledronic acid: 95% confidence interval [CI] = 86.9% to 89.6%), 87.6% (clodronate: 95% CI = 86.1% to 88.9%), and 87.4% (ibandronate: 95% CI = 85.6% to 88.9%). Additionally, 5-year overall survival did not differ between arms (log rank P = .50) and was 92.6% (zoledronic acid: 95% CI = 91.4% to 93.6%), 92.4% (clodronate: 95% CI = 91.2% to 93.5%), and 92.9% (ibandronate: 95% CI = 91.5% to 94.1%). Bone as first site of recurrence did not differ between arms (P = .93). Analyses based on age and tumor subtypes showed no treatment differences. Grade 3/4 toxicity was 8.8% (zoledronic acid), 8.3% (clodronate), and 10.5% (ibandronate). Osteonecrosis of the jaw was highest for zoledronic acid (1.26%) compared with clodronate (0.36%) and ibandronate (0.77%). Conclusions We found no evidence of differences in efficacy by type of bisphosphonate, either in overall analysis or subgroups. Despite an increased rate of osteonecrosis of the jaw with zoledronic acid, overall toxicity grade differed little across arms. Given that patients expressed preference for oral formulation, efforts to make oral agents available in the United States should be considered.

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.

Abstract Purpose: We aimed to establish the MTD of the poly (ADP-ribose) (PAR) polymerase inhibitor, veliparib, in combination with carboplatin in germline BRCA1- and BRCA2- (BRCA)-associated metastatic breast cancer (MBC), to assess the efficacy of single-agent veliparib, and of the combination treatment after progression, and to correlate PAR levels with clinical outcome. Experimental Design: Phase I patients received carboplatin (AUC of 5–6, every 21 days), with escalating doses (50-20 mg) of oral twice-daily (BID) veliparib. In a companion phase II trial, patients received single-agent veliparib (400 mg BID), and upon progression, received the combination at MTD. Peripheral blood mononuclear cell PAR and serum veliparib levels were assessed and correlated with outcome. Results: Twenty-seven phase I trial patients were evaluable. Dose-limiting toxicities were nausea, dehydration, and thrombocytopenia [MTD: veliparib 150 mg po BID and carboplatin (AUC of 5)]. Response rate (RR) was 56%; 3 patients remain in complete response (CR) beyond 3 years. Progression-free survival (PFS) and overall survival (OS) were 8.7 and 18.8 months. The PFS and OS were 5.2 and 14.5 months in the 44 patients in the phase II trial, with a 14% RR in BRCA1 (n = 22) and 36% in BRCA2 (n = 22). One of 30 patients responded to the combination therapy after progression on veliparib. Higher baseline PAR was associated with clinical benefit. Conclusions: Safety and efficacy are encouraging with veliparib alone and in combination with carboplatin in BRCA-associated MBC. Lasting CRs were observed when the combination was administered first in the phase I trial. Further investigation of PAR level association with clinical outcomes is warranted. Clin Cancer Res; 23(15); 4066–76. ©2017 AACR.

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]