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

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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/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.

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Acknowledgements

We are grateful first to all of the patients who generously volunteered to participate in this study. We thank the TBCRC investigators, research nurses, and study coordinators for their efforts on behalf of the patients. We are appreciative of the funding support provided to the TBCRC by its three foundation partners: The AVON Foundation, The Breast Cancer Research Foundation, and the Susan G. Komen for the Cure. Additional support for this research was provided by NIH/NCI K12 CA139160-01A1 (PHO), NIH/NIGMS U01 GM61393-12 (MJR, NC, MED), a University of Chicago Cancer Research Center Protocol-Specific Award (PHO, MED), and a University of Chicago Clinical and Translational Science Award Pilot and Collaborative Translational and Clinical Studies Award (PHO).

Author information

Author notes

  1. Minetta C. Liu

    Present address: Mayo Clinic, Rochester, USA

  2. Nancy Cox

    Present address: Vanderbilt University, Nashville, USA

  3. Vassily Trubetskoy

    Present address: Universitatsmedizin Berlin Campus Charite Mitte, Berlin, Germany

  4. P. K. Morrow

    Present address: Amgen Inc, Thousand Oaks, USA

  5. Jeffrey M. Peppercorn

    Present address: Massachusetts General Hospital, Boston, USA

  6. R. Stephanie Huang

    Present address: University of Minnesota, Minneapolis, USA

Authors and Affiliations

  1. The University of Chicago, 5841 S. Maryland Avenue, MC 2115, Chicago, IL, 60637, USA

    Peter H. O’Donnell, Vassily Trubetskoy, Ashley Nurhussein-Patterson, Julianne P. Hall, Aritro Nath, Dezheng Huo, Gini F. Fleming, Olwen M. Hahn, Philip C. Hoffman, R. Stephanie Huang, Mark J. Ratain, Nancy Cox, Olufunmilayo I. Olopade, M. Eileen Dolan & Rita Nanda

  2. Mayo Clinic, Rochester, USA

    James N. Ingle

  3. Vanderbilt University, Nashville, USA

    Vandana G. Abramson

  4. MD Anderson Cancer Center, Houston, USA

    P. K. Morrow

  5. Indiana University, Bloomington, USA

    Anna Maria Storniolo

  6. University of Alabama-Birmingham, Birmingham, USA

    Andres Forero

  7. University of Michigan, Ann Arbor, USA

    Catherine Van Poznak

  8. Georgetown University, Washington, USA

    Minetta C. Liu

  9. Baylor College of Medicine, Houston, USA

    Jenny C. Chang

  10. NorthShore University Health System, Evanston, USA

    Douglas E. Merkel

  11. Duke University, Durham, USA

    Jeffrey M. Peppercorn

  12. University of California, San Francisco, USA

    Hope S. Rugo

  13. University of North Carolina, Chapel Hill, USA

    E. Claire Dees

  14. Johns Hopkins University, Baltimore, USA

    Gary L. Rosner & Antonio C. Wolff

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  1. Peter H. O’Donnell
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the Translational Breast Cancer Research Consortium (TBCRC)

Contributions

Conceptualization: PHO, DH, GFF, JNI, GLR, MJR, NC, OIO, ACW, MED. Funding acquisition: PHO, JNI, MJR, NC, OIO, ACW, MED, RN. Enrollment of patients/collection of data: ANP, AN, GFF, JNI, VGA, PKM, AMS, AF, CVP, MCL, JCC, DEM, JMP, HSR, ECD, OMH, PCH, RSH, OIO, ACW, RN. Analysis: PHO, VT, ANP, JPH, AN, RSH, MJR, NC. Original draft: PHO. Review, editing, and approval of final version: all authors.

Corresponding author

Correspondence to Peter H. O’Donnell.

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The authors declare no potential conflicts of interest.

Ethical approval

Each participating site received approval for the conduct of this study by their respective Institutional Review Board prior to activation (clinicaltrials.gov #NCT00977119).

Informed consent

All patients were enrolled using a process of written informed consent.

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O’Donnell, P.H., Trubetskoy, V., Nurhussein-Patterson, A. et al. Clinical evaluation of germline polymorphisms associated with capecitabine toxicity in breast cancer: TBCRC-015. Breast Cancer Res Treat 181, 623–633 (2020). https://doi.org/10.1007/s10549-020-05603-8

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