RESUMEN

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.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Compuestos de Platino/administración & dosificación , Polimorfismo de Nucleótido Simple , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Anciano , Capecitabina/efectos adversos , Estudios de Casos y Controles , Intervalos de Confianza , Proteínas de Unión al ADN/genética , Dihidrouracilo Deshidrogenasa (NADP)/genética , Endonucleasas/genética , Femenino , Fluorouracilo/efectos adversos , Frecuencia de los Genes , Genes p53 , Genotipo , Gutatión-S-Transferasa pi/genética , Glicina Hidroximetiltransferasa/genética , Humanos , Leucovorina/efectos adversos , Modelos Logísticos , Masculino , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Persona de Mediana Edad , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Complejos Multienzimáticos/genética , Nomogramas , Oportunidad Relativa , Compuestos Organoplatinos/efectos adversos , Orotato Fosforribosiltransferasa/genética , Orotidina-5'-Fosfato Descarboxilasa/genética , Pirimidinas , Calidad de Vida , Estudios Retrospectivos , Neoplasias Gástricas/patología , Proteína de la Xerodermia Pigmentosa del Grupo D/genética

RESUMEN

Gastric cancer (GC) is a heterogeneous disease. This heterogeneity applies not only to morphological and phenotypic features but also to geographical variations in incidence and mortality rates. As Chile has one of the highest mortality rates within South America, we sought to define a molecular profile of Chilean GCs (ClinicalTrials.gov identifier: NCT03158571/(FORCE1)). Solid tumor samples and clinical data were obtained from 224 patients, with subsets analyzed by tissue microarray (TMA; n = 90) and next generation sequencing (NGS; n = 101). Most demographic and clinical data were in line with previous reports. TMA data indicated that 60% of patients displayed potentially actionable alterations. Furthermore, 20.5% were categorized as having a high tumor mutational burden, and 13% possessed micro-satellite instability (MSI). Results also confirmed previous studies reporting high Epstein-Barr virus (EBV) positivity (13%) in Chilean-derived GC samples suggesting a high proportion of patients could benefit from immunotherapy. As expected, TP53 and PIK3CA were the most frequently altered genes. However, NGS demonstrated the presence of TP53, NRAS, and BRAF variants previously unreported in current GC databases. Finally, using the Kendall method, we report a significant correlation between EBV+ status and programmed death ligand-1 (PDL1)+ and an inverse correlation between p53 mutational status and MSI. Our results suggest that in this Chilean cohort, a high proportion of patients are potential candidates for immunotherapy treatment. To the best of our knowledge, this study is the first in South America to assess the prevalence of actionable targets and to examine a molecular profile of GC patients.