A case-control study of a combination of single nucleotide polymorphisms and clinical parameters to predict clinically relevant toxicity associated with fluoropyrimidine and platinum-based chemotherapy in gastric cancer

Miguel Cordova-Delgado, María Loreto Bravo, Elisa Cumsille, Charlotte N. Hill, Matías Muñoz-Medel, Mauricio P. Pinto, Ignacio N. Retamal, María A. Lavanderos, Juan Francisco Miquel, Maria Rodriguez-Fernandez, Yuwei Liao, Zhiguang Li, Alejandro H. Corvalán, Ricardo Armisén, Marcelo Garrido, Luis A. Quiñones, Gareth I. Owen*

*Corresponding author for this work

Abstract

Background: Fluoropyrimidine plus platinum chemotherapy remains the standard first line treatment for gastric cancer (GC). Guidelines exist for the clinical interpretation of four DPYD genotypes related to severe fluoropyrimidine toxicity within European populations. However, the frequency of these single nucleotide polymorphisms (SNPs) in the Latin American population is low (< 0.7%). No guidelines have been development for platinum. Herein, we present association between clinical factors and common SNPs in the development of grade 3–4 toxicity. Methods: Retrospectively, 224 clinical records of GC patient were screened, of which 93 patients were incorporated into the study. Eleven SNPs with minor allelic frequency above 5% in GSTP1, ERCC2, ERCC1, TP53, UMPS, SHMT1, MTHFR, ABCC2 and DPYD were assessed. Association between patient clinical characteristics and toxicity was estimated using logistic regression models and classification algorithms. Results: Reported grade ≤ 2 and 3–4 toxicities were 64.6% (61/93) and 34.4% (32/93) respectively. Selected DPYD SNPs were associated with higher toxicity (rs1801265; OR = 4.20; 95% CI = 1.70–10.95, p = 0.002), while others displayed a trend towards lower toxicity (rs1801159; OR = 0.45; 95% CI = 0.19–1.08; p = 0.071). Combination of paired SNPs demonstrated significant associations in DPYD (rs1801265), UMPS (rs1801019), ABCC2 (rs717620) and SHMT1 (rs1979277). Using multivariate logistic regression that combined age, sex, peri-operative chemotherapy, 5-FU regimen, the binary combination of the SNPs DPYD (rs1801265) + ABCC2 (rs717620), and DPYD (rs1801159) displayed the best predictive performance. A nomogram was constructed to assess the risk of developing overall toxicity. Conclusion: Pending further validation, this model could predict chemotherapy associated toxicity and improve GC patient quality of life.

Bibliographical note

Funding Information:
MG is an advisor for Merck Sharp & Dohme and Novartis, participates at the speakers’ bureau for Bristol-Myers & Squibb and Bayer. Also receives research funding from Bristol-Myers & Squibb (Inst) and Novartis (Inst). Also, has received travel accommodations and expenses from Roche. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. The other authors have no conflicts of interest to declare.

Funding Information:
This study was funded by the grants issued by the Government of Chile: CONICYT FONDAP-15130011 (GIO), BMRC CTU06 (GIO), Millennium Institute on Immunology & Immunotherapy IMII P09/016-F (GIO), FONDECYT 1180241 (GIO), FONDECYT 1180173 (MG) and FONDECYT 1191928 (AHC). The first author (MCD) is a CONICYT doctoral scholarship recipient (#21150695).

Funding Information:
We would like to thank the patients and their families for participating in this study, to the RED UC Christus and the department of pathology at the ?Hospital Cl?nico UC? for the access to patient data and paraffin embedded samples and to the Biomedical Research Consortium of Chile for the initial support in this project.

Publisher Copyright:
© 2021, The Author(s).

Keywords

  • Chemotherapy toxicity
  • Fluoropyrimidines
  • Platinums
  • Predictive models
  • Single nucleotide polymorphism

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