Shapiro, Charles L.

1007 Background: Determining optimal adjuvant chemotherapy for early stage breast cancer depends on efficacy and toxicity. We sought to determine if T is equivalent to AC but with reduced toxicity. Methods: Pts with operable breast cancer with 0-3 positive nodes were enrolled on a 2x2 factorial design study which addressed (1) superiority of 6 vs. 4 cycles of therapy (previously reported, Shulman, JCO 2012) and (2) equivalence of single-agent T to standard AC, defined as upper bound of 95% confidence interval (CI) of hazard ratio (HR) of T vs. AC < 1.30 for the primary endpoint of relapse-free survival (RFS). A planned target of 567 RFS events required 4,646 pts with 4 yrs FU. At activation in 2002, T (80mg/m2) was q1wk for 12 or 18 wks and AC (60/600 mg/m2) was q3wk for 4 or 6 cycles. In 2003 (570 pts enrolled) schedules were revised to 4 or 6 cycles q2wk for both T (175 mg/m2) and AC. The 6-cycle arms were dropped in 2008 (3,171 pts enrolled) due to slow accrual. Relative effectiveness of T to AC is shown by hazard ratio (HR). Logrank p-values are measures of discordance but are not relevant for the equivalence question and are not adjusted for multiple comparisons. Results: After enrolling 3,871 pts, the study closed in 2010 due to slowing accrual. With a median follow-up of 6.1 yrs there are 437 RFS events. The HR of 1.26 (95% CI: 1.05-1.53; p = 0.02) does not allow a conclusion of equivalence of T with AC. With 266 deaths the HR for overall survival (OS) is 1.27 (95% CI=1.00-1.62; p = 0.05), favoring AC. The estimated absolute advantage of AC at 5 yrs is 3% (91 vs. 88%) for RFS and 1% (95 vs. 94%) for OS. All 9 treatment-related deaths were in pts receiving AC and are included in the survival analysis. The incidence of Grade 3+ toxicity for AC vs T was 33% vs. 4% for hematologic toxicity and 36% vs 22% for non-hematologic toxicity. Conclusions: This trial did not show equivalence of T to AC, a conclusion that is very unlikely to change with additional follow-up. T was less toxic than AC. Clinical trial information: CDR0000069444/NCT00041119.

Purpose Skeletal-related events (SREs) such as pathologic fracture, spinal cord compression, or the necessity for radiation or surgery to bone metastasis cause considerable morbidity, decrements in quality of life, and costs to the health care system. The results of a recent large randomized trial (Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology [CALGB/Alliance 70604]) showed that zoledronic acid (ZA) every 3 months was noninferior to monthly ZA in reducing the risks of SREs. We sought to determine the cost-effectiveness (CE) of monthly ZA, ZA every 3 months, and monthly denosumab in women with breast cancer and skeletal metastases. Methods Using a Markov model, costs per SRE avoided were calculated for the three treatments. Sensitivity analyses were performed where denosumab SRE probabilities were assumed to be 50%, 75%, and 90% lower than the ZA SRE probabilities. Quality-adjusted life-years were also calculated. The analysis was from the US payer perspective. Results The mean costs of the denosumab treatment strategy are nine-fold higher than generic ZA every 3 months. Quality-adjusted life-years were virtually identical in all the three treatment arms; hence, the optimal treatment would be ZA every 3 months because it was the least costly treatment. The sensitivity analyses showed that relative to ZA every 3 months, the incremental costs per mean SRE avoided for denosumab ranged from $162,918 to $347,655. Conclusion ZA every 3 months was more CE in reducing the risks of SRE than monthly denosumab. This analysis was one of the first to incorporate the costs of generic ZA and one of the first independent CE analyses not sponsored by either Novartis or Amgen, the makers of ZA and denosumab, respectively. ZA every 3 months is the more CE option and more reasonable alternative to monthly denosumab.

Abstract Introduction: AI-induced joint symptoms negatively impact drug adherence and quality of life. Based on observations that n-3 polyunsaturated fatty acids (PUFAs) have anti-inflammatory effects and that the mechanism of AI-induced joint symptoms may be partly due to inflammation, we hypothesized that women taking more n-3 PUFAs are less likely to develop AI-induced joint symptoms. Methods: We conducted a randomized, double-blind, placebo-controlled study comparing n-3 PUFA vs placebo in postmenopausal breast cancer patients starting adjuvant AIs. Participants were randomized to n-3 supplements [2.58 g eicosapentaenoic acid + 1.74 g docosahexaenoic acid/day; Marine Nutriceuticals, Mt. Bethel, PA] vs matched placebo for 24 weeks (wks). Primary endpoints was feasibility; secondary outcomes were self-reported symptoms as assessed by the Brief Pain Inventory short form (BPI-SF), Functional Assessment of Cancer Treatment, Breast & Endocrine Symptoms (FACTB-ES), and Stanford's Health Assessment and Disability Index (HAQ) at baseline prior to AI receipt, 12 and 24 wks. Compliance and toxicity were evaluated monthly. Serial peripheral blood n-3 PUFA levels and inflammatory cytokines (IL-6, TNFR2, IL-17) were drawn. MRI of hands/wrists was performed in selected patients using a 3 Tesla dedicated wrist coil at baseline and treatment end. Results: Forty-four women were enrolled and randomized to study drug; 42 received ≥1 cycle (4 wks) of treatment; 36 had ≥1 post treatment evaluation at wk 12 or 24. Median age was 59.5 (range 43-76); history of prior taxane (n=15, 34%). The two groups’ baseline characteristics were similar. Overall, 93% and 88% of patients took &gt;80% of the placebo and n-3 PUFA doses, respectively. Baseline erythrocyte n-3 PUFA was similar for both groups (6.6% ± 1.6%, 7.2% ±1.9%, p=0.20), but higher in the n-3 PUFA arm by wk 24 (6.5%±1.0% vs 15.0%±3.3%, p&lt;0.001). Most toxicities were grade 1; the n-3 PUFA arm had only 1 (2.5%) grade 3 toxicity (diarrhea). The n-3 PUFA arm reported lower mean BPI-SF scores after treatment [(-.0.28/ -0.25 at week 12/24); but not statistically significant compared to placebo (p=0.494 and 0.601)]. Based on BPI-SF, the n-3 PUFA arm reported less interference of pain symptoms compared to placebo at 12 weeks (-.72, p=0.08). This arm also had a decreased walking, activity and working (WAW) score on BPI-SF at 12 weeks (-.81 p=0.05), and reported significantly greater pain relief from medications at 12 (p=0.043) and 24 weeks (p=0.011). Both arms had similar baseline and wk 24 serum IL-6 levels; levels decreased from baseline to wk 24 in the n-3 PUFA arm (-0.54±0.25, p=0.048). There was a non-significant trend (p= 0.2) toward decreased wrist inflammation by MRI imaging at 24 wks in the n-3 PUFA arm. Conclusions: This is the first randomized pilot study to show that n-3 PUFA supplementation to prevent AI-induced joint symptoms is feasible and well tolerated. There is preliminary evidence that this intervention may help reduce the burden of AI-induced arthralgias. OSU Study #11022; ClinicalTrials.gov Identifier: NCT01478477. Grants from the National Cancer Institute (CA037447-26) to the Alliance for Clinical Trials in Oncology supported this pilot study. Citation Format: Maryam B Lustberg, Tonya Orchard, Xueliang Pan, Raquel Reinbolt, Amanda Logan, Joanne Lester, Rachel M Layman, Erin Macrae, Ewa Mrozek, Bhuvaneswari Ramaswamy, Robert Wesolowski, Michael Berger, Michael Knopp, Charles Loprinzi, Charles L Shapiro, Lisa Yee. Prevention of aromatase Inhibitor (AI)-induced joint symptoms with omega-3 fatty acid supplementation: A randomized placebo-controlled pilot study [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 P1-09-03.

Purpose Recent advances in DNA sequencing have led to the development of breast cancer susceptibility gene panels for germline genetic testing of patients. We assessed the frequency of mutations in 17 predisposition genes, including BRCA1 and BRCA2, in a large cohort of patients with triple-negative breast cancer (TNBC) unselected for family history of breast or ovarian cancer to determine the utility of germline genetic testing for those with TNBC. Patients and Methods Patients with TNBC (N = 1,824) unselected for family history of breast or ovarian cancer were recruited through 12 studies, and germline DNA was sequenced to identify mutations. Results Deleterious mutations were identified in 14.6% of all patients. Of these, 11.2% had mutations in the BRCA1 (8.5%) and BRCA2 (2.7%) genes. Deleterious mutations in 15 other predisposition genes were detected in 3.7% of patients, with the majority observed in genes involved in homologous recombination, including PALB2 (1.2%) and BARD1, RAD51D, RAD51C, and BRIP1 (0.3% to 0.5%). Patients with TNBC with mutations were diagnosed at an earlier age (P < .001) and had higher-grade tumors (P = .01) than those without mutations. Conclusion Deleterious mutations in predisposition genes are present at high frequency in patients with TNBC unselected for family history of cancer. Mutation prevalence estimates suggest that patients with TNBC, regardless of age at diagnosis or family history of cancer, should be considered for germline genetic testing of BRCA1 and BRCA2. Although mutations in other predisposition genes are observed among patients with TNBC, better cancer risk estimates are needed before these mutations are used for clinical risk assessment in relatives.