Hershman, Dawn L.

Abstract Introduction. Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of paclitaxel treatment. There is conflicting data on the benefits and harms of supplement use for the treatment and prevention of CIPN. We examined dietary supplement use before diagnosis and during treatment in relation to CIPN among breast cancer patients registered to a clinical trial (SWOG 0221; ClinicalTrials.gov Identifier: NCT00070564) before diagnosis and during treatment in relation to CIPN. Methods. At trial registration (baseline), breast cancer patients (n = 1,225) completed questionnaires to capture use before and at diagnosis of multivitamins and other dietary supplements. Of these patients, 1,068 completed a 6-month follow-up questionnaire to capture use during treatment. We examined the use of multivitamins, vitamins C, D, E, B6, and B12, folic acid, iron, calcium, glucosamine, and combined fish oil, eicosapentaenoic acid (EPA), omega-3, flaxseed and cod liver oil at these timepoints in relation to CIPN. CIPN was assessed via the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE) and the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity (FACT/GOG-Ntx) subscale. Odds ratios and 95% confidence intervals were computed using unconditional logistic regression. Results. Multivitamin use before diagnosis was associated with reduced symptoms of CIPN (CTCAE adjusted OR = 0.60, 95% CI = 0.42-0.87; FACT/GOG-Ntx adjusted OR = 0.78, 95% CI = 0.61-1.00). Although in a similar direction as use prior to diagnosis, multivitamin use during treatment was less strongly associated with CIPN (CTCAE adjusted OR = 0.73, 95% CI = 0.49-1.08; FACT/GOG-Ntx 0.77, 95% CI = 0.60-0.99). Other supplement use, either before diagnosis or during treatment, was not associated with CIPN. Conclusions. Our results indicate that supplement use during treatment may not appreciably affect experience of CIPN symptoms. Future analyses of the relationships between supplement use and survival outcomes will better inform patient decision making. Acknowledgments: supported by R01 CA116395 (CBA); S0221 supported, in part, by National Cancer Institute/Division of Cancer Prevention SWOG NCORP Research Base grant 5UG1CA189974-02; National Cancer Institute (NCI), National Clinical Trials Network (NCTN): CA180888, CA180819; and in part by Amgen, Inc. Citation Format: Gary R. Zirpoli, Susan E. McCann, Lara E. Sucheston-Campbell, Dawn L. Hershman, Gregory Ciupak, Warren Davis, Joseph M. Unger, Halle C.F. Moore, James A. Stewart, Claudine Isaacs, Timothy J. Hobday, Muhammad Salim, Robert B. Livingston, Gabriel N. Hortobagyi, Julie R. Gralow, Daniel F. Hayes, G. Thomas Budd, Kathy S. Albain, Christine B. Ambrosone. Supplement use and chemotherapy-induced peripheral neuropathy in breast cancer patients treated on SWOG study S0221. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3413.

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

Abstract Background: Taxane-induced peripheral neuropathy is a dose-limiting side effect that leads to suboptimal cancer treatment and diminished quality of life. The mode of taxane neurotoxicity is unclear, but may be through stabilization of microtubules and induction of spindle checkpoint, leading to cell cycle arrest at G2/M. Fanconi Anemia (FA) genes, including FANCD2, and FANCA, appear to be involved in G2/M phase checkpoint maintenance as well as spindle checkpoint in response to internal and external signals, such as taxane treatment. Thus, we hypothesized that variants in FA genes could impact severity of taxane-induced neuropathies.Methods: Using DNA extracted from blood collected from 893 breast cancer patients participating in a trial evaluating metronomic dosing of cyclophosphamide, doxorubicin and paclitaxel (S0221), we genotyped for single nucleotide polymorphisms (SNPs) that represent all of the variability across FANCA (44 SNPs) and FANCD2 (24 SNPs) in all race/ethnicity groups, as well as a panel of ancestry informative markers to control for potential population stratification, using Illumina GoldenGate platform. SNPs with minor allele frequency (MAF) less than 0.10 and those out of Hardy Weinberg Equilibrium (HWE) proportions (p<0.001) were removed from analyses. Ordinal regression was used to test for allelic and haplotypic association with grade 3 or 4 toxicities relative to 0, 1, and 2 toxicities, adjusting for age, genetic admixture index and treatment arm. To adjust for multiple testing, permutation analyses were performed on both single SNP and haplotype models.Results: Eighteen SNPs in FANCD2 and 38 SNPs in FANCA passed MAF and HWE proportion requirements. For FANCD2, 4 SNPs spanning 67.5 Kb (rs7648104, rs2272125 [coding SNP], rs6786638 and rs644215), were significantly associated with taxane-induced neuropathy (p<0.001) after controlling for multiple testing, with each SNP resulting in approximately a twofold increase in odds of severe taxane-induced neuropathy. Haplotype estimation showed that all 18 SNPs comprise a single haplotype. Two major (>1% frequency) haplotypes were found. The frequencies of the risk haplotype in cases (patients with grade 3 or 4 neuropathy) and controls (patients with ≤ grade 2 neuropathy) were 0.25 and 0.15, respectively. Ordinal regression analyses were highly significant (p<0.0005); patients with at least one copy of the risk haplotype had more than a twofold increased risk of grade 3 or 4 taxane-induced neuropathy (OR=2.2, 95% CI 1.44, 3.44). For FANCA, no SNPs or haplotypes were significantly associated with grade 3 or 4 neurotoxicity, either prior to or after correction for multiple testing.Conclusions: These results indicate that the Fanconi-Anemia pathway may be important for neurological sensitivity to taxanes, and that genotypic markers might be able to be used to identify patients at increased risk for severe taxane-induced neuropathy. Further studies will elucidate potential associations with survival outcomes. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2001.

AbstractPurpose: Passive immunotherapy with antitumor antibodies has the potential to induce active tumor immunity via the opsonic enhancement of immunogenicity of tumor antigen. We have assessed whether immune sensitization to the HER-2/neu tumor antigen occurs during treatment with the anti-HER-2/neu monoclonal antibody trastuzumab.Experimental Design: Twenty-seven patients treated with trastuzumab and chemotherapy were assessed for the induction of HER-2/neu–specific immunity. Sera and peripheral blood mononuclear cells obtained before and after trastuzumab therapy were compared for the presence of anti-HER-2/neu endogenous Igλ antibodies and HER-2/neu–specific CD4 responses by ELISA and enzyme-linked immunospot, respectively.Results: Anti-HER-2/neu antibodies were detectable in 8 of 27 (29%) patients before trastuzumab treatment and in 15 of 27 (56%) patients during trastuzumab treatment. In the overall study population, anti-HER-2/neu humoral responses significantly increased during therapy (P < 0.001) and were not associated with development of an anti-idiotypic response. In 10 evaluable individuals, 6 showed augmented HER-2/neu–specific CD4 T-cell responses during therapy. Of the 22 individuals treated for metastatic disease, those patients showing objective clinical responses exhibited more frequent (P = 0.004) and larger (P = 0.006) treatment-associated anti-HER-2/neu humoral responses.Conclusion: Humoral immune sensitization occurs during treatment with chemotherapy and trastuzumab. Further studies are warranted to investigate whether augmented anti-HER-2/neu humoral and cellular immunity contributes mechanistically to clinical outcome.