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
Journal
BMC Cancer
ISSN
1471-2407
Date Issued
2021
Author(s)
Miguel Cordova-Delgado
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
Marcelo Garrido
Luis A. Quiñones
Gareth I. Owen
Type
Resource Types::text::journal::journal article
DOI
URL
Abstract
<jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>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 (&lt; 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.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>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 <jats:italic>GSTP1</jats:italic>, <jats:italic>ERCC2</jats:italic>, <jats:italic>ERCC1</jats:italic>, <jats:italic>TP53</jats:italic>, <jats:italic>UMPS</jats:italic>, <jats:italic>SHMT1</jats:italic>, <jats:italic>MTHFR</jats:italic>, <jats:italic>ABCC2</jats:italic> and <jats:italic>DPYD</jats:italic> were assessed. Association between patient clinical characteristics and toxicity was estimated using logistic regression models and classification algorithms.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>Reported grade ≤ 2 and 3–4 toxicities were 64.6% (61/93) and 34.4% (32/93) respectively. Selected <jats:italic>DPYD</jats:italic> SNPs were associated with higher toxicity (rs1801265; OR = 4.20; 95% CI = 1.70–10.95, <jats:italic>p</jats:italic> = 0.002), while others displayed a trend towards lower toxicity (rs1801159; OR = 0.45; 95% CI = 0.19–1.08; <jats:italic>p</jats:italic> = 0.071). Combination of paired SNPs demonstrated significant associations in <jats:italic>DPYD</jats:italic> (rs1801265), <jats:italic>UMPS</jats:italic> (rs1801019), <jats:italic>ABCC2</jats:italic> (rs717620) and <jats:italic>SHMT1</jats:italic> (rs1979277). Using multivariate logistic regression that combined age, sex, peri-operative chemotherapy, 5-FU regimen, the binary combination of the SNPs <jats:italic>DPYD</jats:italic> (rs1801265) + <jats:italic>ABCC2</jats:italic> (rs717620), and <jats:italic>DPYD</jats:italic> (rs1801159) displayed the best predictive performance. A nomogram was constructed to assess the risk of developing overall toxicity.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusion</jats:title> <jats:p>Pending further validation, this model could predict chemotherapy associated toxicity and improve GC patient quality of life.</jats:p> </jats:sec>