Pharmacogenetic study in gastric cancer patients treated with adjuvant fluorouracil/leucovorin or epirubicin/cisplatin/fluorouracil before and after chemoradiation on CALGB 80101 (Alliance)
Jai N Patel, Chen Jiang, Kouros Owzar, Flora Mulkey, Jasmine A Luzum, Harvey J Mamon, Daniel G Haller, Tomislav Dragovich, Steven R Alberts, Georg Bjarnason, Christopher G Willet, Donna Niedzwiecki, Peter Enzinger, Mark J Ratain, Charles Fuchs, Howard L McLeod, Jai N Patel, Chen Jiang, Kouros Owzar, Flora Mulkey, Jasmine A Luzum, Harvey J Mamon, Daniel G Haller, Tomislav Dragovich, Steven R Alberts, Georg Bjarnason, Christopher G Willet, Donna Niedzwiecki, Peter Enzinger, Mark J Ratain, Charles Fuchs, Howard L McLeod
Abstract
There is a lack of pharmacogenetic predictors of outcome in gastric cancer patients. The aim of this study was to assess previously identified candidate genes associated with 5-fluorouracil (5-FU), cisplatin, or epirubicin toxicity or response in a cohort of resected gastric cancer patients treated on CALGB (Alliance) 80101. Gastric or gastroesophageal cancer patients randomized to adjuvant 5-FU/leucovorin or epirubicin/cisplatin/5-FU before and after 5-FU chemoradiation were genotyped for single nucleotide polymorphisms (SNPs) in GSTP1 (rs1695), ERCC1 (rs11615 and rs3212986), XRCC1 (rs25487), UGT2B7 (rs7439366) and the 28 base-pair tandem repeats in TYMS (rs34743033). Logistic regression and log rank tests were used to assess the association between each SNP and incidence of grade 3/4 neutropenia and leukopenia, overall (OS) and progression-free survival (PFS), respectively. Toxicity endpoint analyses were adjusted for the treatment arm, while OS and PFS were also adjusted for performance status, sex, age, lymph node involvement, and primary tumor site and size. Of 281 subjects with successful genotyping results and available clinical (toxicity and efficacy) data, 166 self-reported non-Hispanic White patients were included in the final analysis. There was a lack of evidence of an association among any SNPs tested with grade 3/4 neutropenia and leukopenia or OS and PFS. Age, lymph node involvement, and primary tumor size were significantly associated with OS and PFS. This study failed to confirm results of previous gastric cancer pharmacogenetic studies.
Trial registration: ClinicalTrials.gov NCT00052910.
Conflict of interest statement
Conflicts of Interest:
The authors declare the following relevant conflicts of interest. Howard McLeod serves on the Board of Directors of Cancer Genetics Inc and is a cofounder of Interpares Biomedicine and Clariifi. Jai Patel serves on the Clinical Advisory Council for VieCure Inc. Mark Ratain is co-inventor on a pending patent application for a genomic prescribing system. Harvey Mamon is a co-author on chapters, including gastric cancer, in Up-To-Date and served as an advisor for Merck Sharp & Dohme. Peter Enzinger serves as a paid consultant for Astellas, AstraZeneca, Celgene, Daiichi-Sankyo, Five-Prime, Lilly, Loxo, Merck, Taiho, Takeda, and Zymeworks. All remaining authors have declared no conflicts of interest.
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Source: PubMed