Zirpoli, Gary

Abstract Background: Despite a large body of literature evaluating the association between recreational physical activity and epithelial ovarian cancer (EOC) risk, the extant evidence is inconclusive, and little is known about the independent association between recreational physical inactivity and EOC risk. We conducted a pooled analysis of nine studies from the Ovarian Cancer Association Consortium to investigate the association between chronic recreational physical inactivity and EOC risk. Methods: In accordance with the 2008 Physical Activity Guidelines for Americans, women reporting no regular, weekly recreational physical activity were classified as inactive. Multivariable logistic regression was utilized to estimate the ORs and 95% confidence intervals (CI) for the association between inactivity and EOC risk overall and by subgroups based upon histotype, menopausal status, race, and body mass index. Results: The current analysis included data from 8,309 EOC patients and 12,612 controls. We observed a significant positive association between inactivity and EOC risk (OR = 1.34; 95% CI, 1.14–1.57), and similar associations were observed for each histotype. Conclusions: In this large pooled analysis examining the association between recreational physical inactivity and EOC risk, we observed consistent evidence of an association between chronic inactivity and all EOC histotypes. Impact: These data add to the growing body of evidence suggesting that inactivity is an independent risk factor for cancer. If the apparent association between inactivity and EOC risk is substantiated, additional work via targeted interventions should be pursued to characterize the dose of activity required to mitigate the risk of this highly fatal disease. Cancer Epidemiol Biomarkers Prev; 25(7); 1114–24. ©2016 AACR.

Abstract Introduction: The use of multi-drug regimens, including taxanes (T), has increased survival for breast cancer patients. However, T-induced neuropathy, one of the most common side effects, cannot be predicted, prevented or effectively treated. Using genome wide analyses (GWA), we sought to identify common genetic variants that infer susceptibility to clinical and self-reported neuropathy. Methods: Women with high risk breast cancer were enrolled in SWOG 0221, a trial of dosing schedules for AC and T. Genotyping was performed using the Illumina 1M chip and SNPs examined in relation to CTCAE grade 3 and 4 neurotoxicity and self-reported symptoms (FACT-TAXANE) among women providing blood samples. Significant associations were tested for replication in CALGB40101. Results: Among 1269 European Americans (EA) and 139 African Americans (AA) in S0221, there were 147 and 31 grade 3+ neuropathies, respectively. In CALGB40101, grade 3 toxicity was less frequent (59/855 EA and 15/117 AA). In S0221 EA patients, loci on chromosomes 7, 10, 16 and 17 showed associations with grades 3 and 4 neuropathy at p<5×10e-06, with the most significant genetic association on chromosome 17, rs910920, p = 6.8×10e-08, odds ratio (OR) = 0.44 (95% confidence interval (CI), 0.32-0.61); this SNP is a cis eQTL, thought likely to affect transcription factor binding and linked to expression of VPS53 in lymphoblastoid cell lines. While the rs910920 association was specific to EA, the A allele in rs1858826 on chromosome 7 was associated with reduced odds of neuropathy in both EA (p = 7×10e-07) and AA (p = .02) groups. The S0221 associations at p<5×10e-06 did not replicate in CALGB40101. A subset of patients (n = 677 EA and n = 42 AA) completed the FACT-TAXANE. The most significant associations with this neuropathy phenotype (p<5×10e-07) were on chromosomes 2 (rs4267555 and rs4443044) and 3 (rs2421468). Of the 168 SNPs tested for association with neuropathy in previous studies, rs1695 in GSTP1 (p = 0.0009) and rs228591 in ATM (p = 0.0006), showed some evidence of association with FACT-TAXANE scores; the latter SNP was significant at p = .005 in ordinal regression analysis of neuropathy grades 0-4 in CALGB40101. None of these SNPs were significantly associated with grade 3 CTCAE neuropathy at p<.05, nor were the top CTCAE associations in relation to FACT-TAXANE scores. Replication of the most significant S0221 FACT-TAXANE findings in CALGB40101 is ongoing. Conclusions: Failure to replicate S0221 in CALGB40101, and the lack of coherence between self-report and clinical grade in S0221 could be attributable to differences in trial designs as well as differences in defining a complex phenotype. Larger homogeneous trials with similar dosing and criteria for defining neuropathy are needed to assess the relationship of genetics and the neuropathy symptom spectrum. Citation Format: Lara Sucheston-Campbell, Alyssa Clay, William E. Barlow, G Thomas Budd, Dan Stram, Chris Haiman, Li Yan, Gary Zirpoli, Song Yao, Dawn Hershman, Kathy S. Albain, Daniel F. Hayes, Halle Moore, Timothy J. Hobday, James A. Stewart, Claudine Isaacs, Muhammad Salim, Julie R. Gralow, Gabriel N. Hortobagyi, Robert B. Livingston, Xin Sheng, Deanna L. Kroetz, Christine B. Ambrosone. A genome-wide association study identifies novel loci associated with taxane-related sensory neuropathy in breast cancer patients enrolled in a cooperative group clinical trial (SWOG S0221). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5489. doi:10.1158/1538-7445.AM2015-5489

Abstract Because numerous chemotherapeutic agents exert their cytotoxic effects through generation of reactive oxygen species, the use of antioxidant supplements during treatment is controversial. There are published recommendations to suspend antioxidant supplement use during treatment, despite lack of empirical data from clinical studies; however, it is unclear if patients follow these recommendations. We examined use of multivitamins and vitamin supplements (MV/SP) during treatment for breast cancer, particularly in relation to physician recommendations. High-risk breast cancer patients (n=855) were queried regarding physician recommendations and use of MV/SP via self-administered questionnaires in an ancillary study embedded in a phase III trial of dose-dense compared to metronomic administration of doxorubicin/cyclophosphamide + paclitaxel (SWOG S0221). Of the 658 patients who reported discussing use of supplements during treatment with their physicians, 390 (59%) received no counseling regarding MV/SP use, 85 (13%) received recommendations not to take MV/SP, and 183 (28%) received recommendations to use MV/SP. MV/SP use during treatment was compared to use prior to diagnosis in relation to physician recommendations, with the reference group comprised of those receiving no recommendations. Of those using MV ≥ once/week before diagnosis, recommendations not to take MV/SP were associated with a tenfold reduction in MV use to < once/week during treatment. (OR=10.0, 95% CI=3.7-27.0). MV use was less likely to decrease among patients receiving recommendations to use MV/SP (OR=0.23, 95% CI=0.12-0.44). Similar findings were observed among patients who reported use of vitamin C and vitamin E supplements ≥ once/week before diagnosis, with patients who were advised to take no supplements other than a MV more than 5 times as likely to decrease use of antioxidant supplements. MV use during treatment among previous non-users increased almost sixfold among those whose physicians recommended MV/SP use during treatment (OR=5.92, 95% CI=3.29-10.6). For those reporting vitamin C or vitamin E use < once/week before diagnosis, patients whose physicians recommended MV/SP during treatment were more likely to increase their use of vitamin C (OR=2.05, 95% CI=1.00-4.19) and vitamin E (OR=5.28, 95% CI=2.24-12.4). In this study, physician recommendations were strongly associated with patient use of MV/SP during chemotherapy, regardless of the patient's frequency of use prior to diagnosis. These findings highlight the critical need to better understand the mechanisms by which antioxidants may influence chemotherapeutic outcomes, and to determine if supplement use affects toxicity and/or recurrence. Yearly follow-up in this ongoing study will allow us to assess the impact of MV/SP use treatment outcomes, providing a basis for physician recommendations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4681. doi:10.1158/1538-7445.AM2011-4681