Abstract
Taxanes have resulted in improved survival for breast cancer patients, but often cause neurological toxicities. Identification of biomarkers related to toxicities could be important for dictating treatment regimen. We evaluated single nucleotide polymorphisms (SNPs) in the Fanconi Anemia (FA)/BRCA pathway in relation to grade 3/4 neurotoxicities in patients (n = 888) from SWOG0221, a phase III adjuvant trial for breast cancer of 4 dose/schedules of cyclophosphamide (C), doxorubicin (A), and paclitaxel (T). In a separate cohort, we measured the correlation of significant FANCD2 SNPs with corresponding gene expression. For FANCD2, permutation testing revealed that 4 (out of 20) SNPs were significantly associated with an almost two-fold increased risk of toxicity. Two FANCD2 haplotypes were also associated with neurological toxicity, with odds ratios (OR) in the overall population of 1.8 (95% confidence interval (CI) 1.3, 2.5) and 1.7 (95% CI, 1.2, 2.4). Although numbers were small, an African-American-specific haplotype was associated with an almost 3-fold increase in risk of neurologic toxicity (OR = 2.84, 95% CI = 1.2, 6.9). Expression analyses revealed that significant FANCD2 SNPs were associated with FANCD2 expression levels (P = 0.03). There were no associations between SNPs in BRCA1 and neurotoxicities. In this trial of CA+T for breast cancer, SNPs in FANCD2, but not in BRCA1, were associated with a 70–80% increase in the odds of grade 3/4 neurological toxicities and increased expression of the gene. If replicated, women with these genotypes should be closely monitored for toxicities and could be targeted for preventive measures or alternative therapeutic approaches.
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Acknowledgments
This study was supported by National Institute of Health (NIH) R01 CA116395, and the following PHS Cooperative Agreement grant numbers awarded by the National Cancer Institute, DHHS: CA32102, CA38926, CA63844, CA63845, CA 20319, CA46282, CA46441, CA35261, CA63848, CA67575, CA14028, CA35281, CA128567, CA45560, CA58882, CA13612; CA46368, CA45808, CA58658, CA76447, CA37981, CA04919; CA95860; CA27057, CA42777, CA22433, CA74647, CA86780, CA68183, CA58861, CA45807, CA35192, CA35178, CA58416, CA35176, CA67663, CA35431, CA12644, CA16385, CA11083, CA45377, CA35128, CA35262, CA52654, CA76429, CA58723, CA46113, CA76132, CA45450, CA35119, CA45461, CA21115, CA21076, CA77597, CA25224, CA77202, CCSRI 15469, and in part by Amgen, Inc. The Roswell Park Cancer Institute (RPCI) Genomics Core Facility is a CCSG Shared Resource (NIH P30 CA016056-27). Support was also provided by the Fashion Footwear Charitable Foundation of New York/QVC Presents Shoes on Sale ™ (DFH) and Drs. Ambrosone, Gralow, Hayes, Hershman, and Hortobagyi are recipients of funding from the Breast Cancer Research Foundation. Funding agencies had no involvement in the study design, data collection, analysis and interpretation, or in the writing of the report and submission. We acknowledge and thank Dr. Frank L. Meyskens, Jr., M.D., Associate Chair for the Cancer Control & Prevention Committees of the Southwest Oncology Group, for his administrative support.
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Sucheston, L.E., Zhao, H., Yao, S. et al. Genetic predictors of taxane-induced neurotoxicity in a SWOG phase III intergroup adjuvant breast cancer treatment trial (S0221). Breast Cancer Res Treat 130, 993–1002 (2011). https://doi.org/10.1007/s10549-011-1671-3
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DOI: https://doi.org/10.1007/s10549-011-1671-3