Clinical evaluation of germline polymorphisms associated with capecitabine toxicity in breast cancer: TBCRC-015
- 1 June 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Breast Cancer Research and Treatment
- Vol. 181 (3), 623-633
- https://doi.org/10.1007/s10549-020-05603-8
Abstract
Purpose Capecitabine is important in breast cancer treatment but causes diarrhea and hand-foot syndrome (HFS), affecting adherence and quality of life. We sought to identify pharmacogenomic predictors of capecitabine toxicity using a novel monitoring tool. Methods Patients with metastatic breast cancer were prospectively treated with capecitabine (2000 mg/m(2)/day, 14 days on/7 off). Patients completed in-person toxicity questionnaires (day 1/cycle) and automated phone-in assessments (days 8, 15). Correlation of genotypes with early and overall toxicity was the primary endpoint. Results Two hundred and fifty-nine patients were enrolled (14 institutions). Diarrhea and HFS occurred in 52% (17% grade 3) and 69% (9% grade 3), respectively. Only 29% of patients completed four cycles without dose reduction/interruption. In 39%, the highest toxicity grade was captured via phone. Three single nucleotide polymorphisms (SNPs) associated with diarrhea-DPYD*5 (odds ratio [OR] 4.9; P = 0.0005), a MTHFR missense SNP (OR 3.3; P = 0.02), and a SNP upstream of MTRR (OR 3.0; P = 0.03). GWAS elucidated a novel HFS SNP (OR 3.0; P = 0.0007) near TNFSF4 (OX40L), a gene implicated in autoimmunity including autoimmune skin diseases never before implicated in HFS. Genotype-gene expression analyses of skin tissues identified rs11158568 (associated with HFS via GWAS) with expression of CHURC1, a transcriptional activator controlling fibroblast growth factor (beta = - 0.74; P = 1.46 x 10(-23)), representing a previously unidentified mechanism for HFS. Conclusions This is the first cancer pharmacogenomic study to use phone-in self-reporting, permitting augmented toxicity characterization. Three germline toxicity SNPs were replicated, and several novel SNPs/genes having strong functional relevance were discovered. If further validated, these markers could permit personalized capecitabine dosing.Funding Information
- Avon Foundation for Women
- The Breast Cancer Research Foundation
- Susan G. Komen for the Cure
- National Cancer Institute (K12 CA139160-01A1)
- National Institute of General Medical Sciences (U01 GM61393-12)
- University of Chicago Cancer Research Center
- Center for Clinical and Translational Science, University of Illinois at Chicago
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