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

Breast Cancer Res Treat. 2020 Jun;181(3):623-633. doi: 10.1007/s10549-020-05603-8. Epub 2020 May 6.


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/m2/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.

Keywords: Capecitabine; Fluorouracil; Pharmacogenetics; Pharmacogenomics; Toxicity.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antimetabolites, Antineoplastic / adverse effects*
  • Biomarkers, Tumor / genetics*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology*
  • Capecitabine / adverse effects*
  • Drug-Related Side Effects and Adverse Reactions / diagnosis*
  • Drug-Related Side Effects and Adverse Reactions / etiology
  • Drug-Related Side Effects and Adverse Reactions / genetics
  • Female
  • Ferredoxin-NADP Reductase / genetics
  • Follow-Up Studies
  • Genotype
  • Germ-Line Mutation
  • Humans
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Prognosis
  • Prospective Studies
  • Quality of Life


  • Antimetabolites, Antineoplastic
  • Biomarkers, Tumor
  • Capecitabine
  • methionine synthase reductase
  • Ferredoxin-NADP Reductase
  • MTHFR protein, human
  • Methylenetetrahydrofolate Reductase (NADPH2)