Clinical evaluation of germline polymorphisms associated with capecitabine toxicity in breast cancer: TBCRC-015

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 can...

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Veröffentlicht in:Breast cancer research and treatment 2020-06, Vol.181 (3), p.623-633
Hauptverfasser: O’Donnell, Peter H., Trubetskoy, Vassily, Nurhussein-Patterson, Ashley, Hall, Julianne P., Nath, Aritro, Huo, Dezheng, Fleming, Gini F., Ingle, James N., Abramson, Vandana G., Morrow, P. K., Storniolo, Anna Maria, Forero, Andres, Van Poznak, Catherine, Liu, Minetta C., Chang, Jenny C., Merkel, Douglas E., Peppercorn, Jeffrey M., Rugo, Hope S., Dees, E. Claire, Hahn, Olwen M., Hoffman, Philip C., Rosner, Gary L., Huang, R. Stephanie, Ratain, Mark J., Cox, Nancy, Olopade, Olufunmilayo I., Wolff, Antonio C., Dolan, M. Eileen, Nanda, Rita
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Sprache:eng
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Zusammenfassung: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 × 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.
ISSN:0167-6806
1573-7217
DOI:10.1007/s10549-020-05603-8