Salim, Muhammad

Abstract Background S0221 investigated weekly vs every 2 weeks dosing of doxorubicin (A) and cyclophosphamide (C) followed by paclitaxel in patients with high-risk early breast cancer. After an interim analysis, random assignment to the 2 AC arms was stopped for futility, and the trial was modified to study only the paclitaxel schedules. Methods Between December 2003 and November 2010, a total of 2716 patients were randomly assigned in a 2 × 2 factorial design to 15 weeks of weekly A and daily C vs 6 cycles of every 2 weeks AC; and weekly paclitaxel for 12 weeks vs 6 cycles of every 2 weeks paclitaxel. Between January 2011 and January 2012, an additional 578 patients were assigned to 4 cycles of every 2 weeks AC and randomly assigned to weekly vs every 2 weeks paclitaxel. Updated survival was assessed using log-rank tests and Cox regression models. We compared outcomes by breast cancer subtype as well. Results At a median follow-up of 12.1 years, there were no statistically significant differences among the 4 treatment arms in disease-free survival (DFS) (P = .91) or overall survival (P = .34) in the original protocol. Among the 578 patients assigned AC for 4 cycles and randomly assigned to paclitaxel weekly vs every 2 weeks paclitaxel, there were no overall differences in DFS (P = .32) or overall survival (P = .42). Conclusion As there were no statistically significant outcome differences in DFS or overall survival between the studied schedules of AC and paclitaxel with extended follow-up in the original or revised protocol, either paclitaxel schedule may be recommended, with selection based on toxicity, cost, or patient preference.

Importance The Breast Cancer Index (BCI) previously identified premenopausal patients with tumors in which the ratio of expression of HOXB13 relative to IL17BR (hereafter, BCI [H/I]–low tumors) as likely to derive greatest benefit from ovarian function suppression (OFS)–containing adjuvant therapy in the Suppression of Ovarian Function Trial (SOFT) trial. Objectives To assess BCI as a predictive biomarker of benefit from exemestane plus OFS vs tamoxifen plus OFS and to validate BCI as a prognostic biomarker for premenopausal patients. Design, Setting, and Participants This prognostic study used a prospective-retrospective translational design within the Tamoxifen and Exemestane (TEXT) and SOFT trials (enrolled November 2003 to April 2011). Blinded BCI testing in all available tumor samples was completed in March 2024. Premenopausal women with hormone receptor–positive breast cancer randomized to tamoxifen plus OFS or exemestane plus OFS who had BCI assessed were included. Analysis occurred from March to August 2024. Exposure 5 years of adjuvant tamoxifen plus OFS or exemestane plus OFS. Main Outcomes and Measures The primary outcomes were breast cancer-free interval (BCFI) for predictive analyses and distant recurrence-free interval (DRFI) for prognostic analyses after a median follow-up of 13 years in the TEXT cohort. Secondary objectives examined the predictive performance of BCI (H/I) in the combined TEXT and SOFT cohort overall and in prespecified clinical subgroups. Results Of 1782 patients in the TEXT study, 1034 (58.0%) had BCI (H/I)–low tumors; 915 (51.3%) of patients had N0 disease and 1077 (60.4%) were younger than 45 years. Patients with BCI (H/I)–low tumors had a 6.6% absolute benefit in 12-year BCFI (HR, 0.61; 95% CI, 0.44-0.85) for exemestane plus OFS vs tamoxifen plus OFS, while those with BCI (H/I)–high tumors had a 6.3% absolute benefit (HR, 0.78; 95% CI, 0.57-1.07; P for interaction = .29). Results were consistent in the combined TEXT plus SOFT cohort (2896 patients) and adjusting for clinicopathological variables. Clinical subgroup analyses consistently showed benefit of exemestane plus OFS vs tamoxifen plus OFS for BCI (H/I)–low tumors, and more variable relative treatment effects among BCI (H/I)–high tumors, including by age. Post hoc exploratory time-varying estimates suggested the treatment × BCI associations may differ in years 0 to 5 vs greater than 5 years. BCI and BCI N+ as continuous indices were prognostic for distant recurrence in N0 (HR, 1.27; 95% CI, 1.11-1.44; P < .001) and N1 (HR, 1.58; 95% CI, 1.21-2.05; P < .001) cancers. The 12-year DRFI was 96.3%, 90.3%, and 84.9% for BCI low-, intermediate-, and high-risk N0 cancers, respectively. Conclusions and Relevance In this study of premenopausal women with hormone receptor–positive breast cancer, BCI (H/I) status did not clearly predict greater benefit of adjuvant exemestane plus OFS vs tamoxifen plus OFS for women with BCI (H/I)–low tumors than for those with BCI (H/I)–high tumors; BCI continuous indices were reconfirmed as prognostic for premenopausal women. These findings support prior results of SOFT, which compared tamoxifen-alone vs OFS with either exemestane or tamoxifen, indicating premenopausal patients with BCI (H/I)–low tumors may benefit from more intensive endocrine therapy.

Abstract Background Although physical activity has been consistently associated with reduced breast cancer mortality, evidence is largely based on data collected at one occasion. We examined how pre- and postdiagnosis physical activity was associated with survival outcomes in high-risk breast cancer patients. Methods Included were 1340 patients enrolled in the Diet, Exercise, Lifestyle and Cancer Prognosis (DELCaP) Study, a prospective study of lifestyle and prognosis ancillary to a SWOG clinical trial (S0221). Activity before diagnosis, during treatment, and at 1- and 2-year intervals after enrollment was collected. Patients were categorized according to the Physical Activity Guidelines for Americans as meeting the minimum guidelines (yes/no) and incrementally as inactive, low active, moderately active (meeting the guidelines), or high active. Results In joint-exposure analyses, patients meeting the guidelines before and 1 year after diagnosis experienced statistically significant reductions in hazards of recurrence (hazard ratio [HR] = 0.59, 95% confidence interval [CI] = 0.42 to 0.82) and mortality (HR = 0.51, 95% CI = 0.34–0.77); associations were stronger at 2-year follow-up for recurrence (HR = 0.45, 95% CI = 0.31 to 0.65) and mortality (HR = 0.32, 95% CI = 0.19 to 0.52). In time-dependent analyses, factoring in activity from all time points, we observed striking associations with mortality for low- (HR = 0.41, 95% CI = 0.24 to 0.68), moderate- (HR = 0.42, 95% CI = 0.23 to 0.76), and high-active patients (HR = 0.31, 95% CI = 0.18 to 0.53). Conclusions Meeting the minimum guidelines for physical activity both before diagnosis and after treatment appears to be associated with statistically significantly reduced hazards of recurrence and mortality among breast cancer patients. When considering activity from all time points, including during treatment, lower volumes of regular activity were associated with similar overall survival advantages as meeting and exceeding the guidelines.

CRA1008 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Monday, June, 3, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.

7574 Background: Patients (pts) with relapsed aggressive NHL are usually treated with intensive platinum-based chemotherapy regimens prior to stem cell transplant (SCT). This study was designed to learn the toxicity and efficacy of adding 4 doses of rituximab to the standard DHAP salvage chemotherapy regimen. Methods: Eligible pts had biopsy-proven relapsed CD20+ NHL and were eligible for platinum-based chemotherapy. Pts were treated with rituximab 375 mg/m2 d1,8,15, and 22 as well as cis-platinum 100 mg/m2 d3, cytosine arabinoside 2 g/m2 IV q 12 hours x two doses d4, dexamethasone 40 mg PO/IV d3–6, and G-CSF d5–14. Pts were restaged after 1 and 2 cycles; responding pts could proceed to SCT or further cycles of DHAP at MD discretion. There was no provision for rituximab maintenance. The goal was to achieve an overall response rate (ORR) of ≥ 75%. Results: Fifty-eight pts were enrolled between 10/29/00 and 6/20/03. The median age was 63 years (range, 43–83). One pt was ineligible because the tumor was CD20-. All 57 eligible pts completed one cycle; 48 pts completed 2 cycles. The ORR was 70% (40/57) with 16 (28%) CR/CRu and 24 (42%) PR. For all 57 pts, the median TTP was 13.1 months (mos) (95% CI: 7.3–18.2) and the median OS 30.5 mos (95% CI: 17.8–52.5). Seventeen pts (30%) proceeded to SCT. The median duration of response (DR), time to progression (TTP) and overall survival (OS) for the SCT pts were 41.6, 42.3, and 43.6 mos, respectively. The median DR, TTP, and OS for the 25 pts who responded to RDHAP but did not proceed to SCT were 12.4, 13.1, and 38.8 mos, respectively. The incidence of grade 3 and 4 thrombocytopenia was 53% and 39%, respectively. The incidence of grade 3 and 4 neutropenia was 11% and 68%, respectively. Six pts (11%) had nephrotoxicity–five grade 3 and two grade 4 (one pt had both) and one pt required dialysis. Conclusions: The addition of rituximab to standard DHAP is safe with similar toxicity profile to DHAP alone. Despite a high ORR, the CR rate and the % pts proceeding to SCT in this cooperative group setting remain low. New agents are needed that can be added to these regimens to increase the effectiveness and reduce toxicity to allow more pts to proceed to SCT. No significant financial relationships to disclose.

PURPOSE Despite reported widespread use of dietary supplements during cancer treatment, few empirical data with regard to their safety or efficacy exist. Because of concerns that some supplements, particularly antioxidants, could reduce the cytotoxicity of chemotherapy, we conducted a prospective study ancillary to a therapeutic trial to evaluate associations between supplement use and breast cancer outcomes. METHODS Patients with breast cancer randomly assigned to an intergroup metronomic trial of cyclophosphamide, doxorubicin, and paclitaxel were queried on their use of supplements at registration and during treatment (n =1,134). Cox proportional hazards regression adjusting for clinical and lifestyle variables was used. Recurrence and survival were indexed at 6 months after enrollment using a landmark approach. RESULTS There were indications that use of any antioxidant supplement (vitamins A, C, and E; carotenoids; coenzyme Q10) both before and during treatment was associated with an increased hazard of recurrence (adjusted hazard ratio [adjHR], 1.41; 95% CI, 0.98 to 2.04; P = .06) and, to a lesser extent, death (adjHR, 1.40; 95% CI, 0.90 to 2.18; P = .14). Relationships with individual antioxidants were weaker perhaps because of small numbers. For nonantioxidants, vitamin B12 use both before and during chemotherapy was significantly associated with poorer disease-free survival (adjHR, 1.83; 95% CI, 1.15 to 2.92; P < .01) and overall survival (adjHR, 2.04; 95% CI, 1.22 to 3.40; P < .01). Use of iron during chemotherapy was significantly associated with recurrence (adjHR, 1.79; 95% CI, 1.20 to 2.67; P < .01) as was use both before and during treatment (adjHR, 1.91; 95% CI, 0.98 to 3.70; P = .06). Results were similar for overall survival. Multivitamin use was not associated with survival outcomes. CONCLUSION Associations between survival outcomes and use of antioxidant and other dietary supplements both before and during chemotherapy are consistent with recommendations for caution among patients when considering the use of supplements, other than a multivitamin, during chemotherapy.

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.

238 Background: Dual inhibition of the EGFR pathway using erlotinib and the monoclonal antibody panitumumab results in greater antitumor activity in preclinical pancreatic cancer models. A trial evaluating this approach was conducted. Methods: A safety analysis was initially performed with 6 patients at P 4 mg/kg every two weeks, E 100 mg daily, G 1000 mg/m2 weekly of a 28-day cycle. PGE was well tolerated with a grade 3 fatigue as only dose-limiting toxicity. Patients (pts) were then randomized to either PGE or GE alone. Eligibility included: no prior chemo, ECOG PS 0-1, bilirubin <2x UL, AST <2.5x UL. CT scans every 2 cycles. Results: 93 pts (46-GE; 47-PGE) were randomized from January to August, 2010. Median age 61 years and 65% male. ECOG PS 0 (51%) and PS 1 (49%). No significant differences in baseline characteristics observed between treatment arms. 81 pts evaluable for AEs; 37 (46%) had a maximum grade 3 (at least possibly related to treatment), and 12 (15%) maximum grade 4 or 5. Treatment arms similar with respect to the overall AEs with exception grade 1-3 acneiform rash, GE (65%) vs. PGE (85%). Commonly occurring grade 4 AEs (at least possibly related) consisted of thrombosis (3 pts) and thrombocytopenia (2 pts). Two grade 5 events occurred in PGE arm—duodenal hemorrhage (possibly related) and pancolitis with multisystem failure (unlikely). An additional PGE pt died 30 days off study (grade 5 CHF, possibly). 54 patients (67%; 31-GE, 23-PGE) ended treatment; 38 (70%) for disease progression (24-GE; 14-PGE). Other reasons for treatment discontinuation: AEs (9; 17%), pt refusal (4; 7%), death on study (2; 4%), other (1). In 81 pts with at least 1 cycle of chemotherapy, the median PFS for GE 2.0 months and 3.3 months for PGE. Accrual for the study was recently completed and overall and 6-month survival data will be presented. Conclusions: This study involved an initial run-in design to define tolerable doses of dual EGFR inhibitors, PGE, in pancreatic cancer patients. Although preliminary, the randomized phase II portion has been completed and differences between GE and PGE in terms of relevant clinical outcomes, PFS, are observed. No significant financial relationships to disclose.