Genome wide association study to identify predictors for severe skin toxicity in colorectal cancer patients treated with cetuximab

PLoS One. 2018 Dec 17;13(12):e0208080. doi: 10.1371/journal.pone.0208080. eCollection 2018.

Abstract

EGFR-antibodies are associated with significant skin toxicity, including acneiform rash and folliculitis. It remains impossible to predict the occurrence of severe skin toxicity due to the lack of predictive markers. Here, we present the first genome-wide association study (GWAS) to find single nucleotide polymorphisms (SNPs) associated with EGFR inhibitor-induced skin toxicity using data of the multicentre randomized phase III CAIRO2 trial (clinicaltrials.gov NCT00208546). In this study, advanced or metastatic colorectal cancer patients were treated with capecitabine, oxaliplatin and bevacizumab with or without cetuximab. Germline DNA was available in 282 of the 368 patients in the cetuximab arm. Mild skin toxicity occurred in 195 patients (i.e. CTC grade 1 or 2, respectively 91 and 104 patients) and severe skin toxicity (i.e. grade 3) in 36 patients. Grade 4 skin toxicity did not occur. None of the SNPs reached the formal genome wide threshold for significance of 5x10(-8), though SNPs of at least 8 loci did show moderate association (p-value between 5x10(-7) and 5x10(-5)) with the occurrence of grade 3 (severe) skin toxicity. These SNPs did not overlap with SNPs associated with cetuximab efficacy as found in a previous GWAS in the same CAIRO2 cohort. If formally proven by replication, the SNPs associated with severe EGFR induced skin toxicity may be helpful to predict the occurrence and severity of skin toxicity in patients that will receive cetuximab and allow for adequate information on the risk of skin toxicity and prophylactic measurements.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents, Immunological / adverse effects*
  • Biomarkers / analysis
  • Cetuximab / adverse effects*
  • Clinical Trials, Phase III as Topic
  • Colorectal Neoplasms / drug therapy*
  • Drug Eruptions / diagnosis*
  • Drug Eruptions / etiology
  • Drug Eruptions / genetics
  • Drug Eruptions / prevention & control
  • Female
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Prognosis
  • Randomized Controlled Trials as Topic
  • Severity of Illness Index
  • Treatment Outcome

Substances

  • Antineoplastic Agents, Immunological
  • Biomarkers
  • Cetuximab

Associated data

  • ClinicalTrials.gov/NCT00208546

Grant support

The authors received no specific funding for this work. The CAIRO2 study was supported by the Dutch Cancer Foundation KWF (grant 2005-02) and by unrestricted scientific grants from Roche, Merck-Serono, Sanofi-Avantis en DxS. The funders had no role in study design, data collection and analysis, and preparation of the manuscript.