Abstract
BackgroundFluoropyrimidine 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.MethodsRetrospectively, 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.ResultsReported 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.ConclusionPending further validation, this model could predict chemotherapy associated toxicity and improve GC patient quality of life.
Highlights
Gastric cancer (GC) is the sixth most common malignancy and the third leading cause of cancer death [1,2,3,4]
Selected DPYD single nucleotide polymorphisms (SNPs) were associated with higher toxicity, while others displayed a trend towards lower toxicity
SNPs selection SNPs were selected based on: (1) scientific evidence regarding the SNPs/toxicity relationship, using the PharmGKB database [48]; (2) allelic and genotypic frequency of the SNPs in the American population [32]; (3) relationship of the SNPs with the toxicity collected in our patients literature-based criteria; (4) functional impact of SNPs at the protein level according to PolyPhen [49] and SIFT [50]
Summary
Gastric cancer (GC) is the sixth most common malignancy and the third leading cause of cancer death [1,2,3,4]. Current standard first-line treatment for GC patients consists of chemotherapy regimens that combine fluoropyrimidines and platinum compounds. Previous studies have demonstrated that single nucleotide polymorphisms (SNPs) are associated with chemotherapy-associated toxicity [10,11,12]. This can be explained by gene variations that alter the enzymatic activity of key proteins affecting pharmacokinetic and pharmacodynamic processes [13, 14]. In this regard, platinum-based compounds can trigger cell arrest or apoptosis by forming Pt-DNA adducts [15]. We present association between clinical factors and common SNPs in the development of grade 3–4 toxicity
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