Use of MTHFR A1298C polymorphism to predict response in a phase II international clinical trial of patients with advanced gastric (GC) or gastroesophageal junction (GEJ) adenocarcinoma treated with first-line lapatinib plus capecitabine.

Abstract

4076 Background: The international, phase II clinical trial, LPT109747, demonstrated that lapatinib (1250mg/d, continuous) plus capecitabine (100mg/m2 BID, 14 of 21 days) had efficacy and was well tolerated as first-line treatment for advanced GC or GEJ adenocarcinoma. HER2 overexpression was not required at study entry. The response rate (RR) was 22.4% (17.9% confirmed). The present study aimed to identify germline single nucleotide polymorphisms (SNPs) in genes involved in 5-FU metabolism (TYMS and MTHFR) and HER signaling (EGF, EGFR, HER2, VEGF, IL8, COX-2, CCND1) to identify pts that may benefit from this regimen. Methods: 67 pts were included, with a median age 61 y (range: 22-89 y); 75% GC, 25% GEJ. The median progression-free survival (PFS) and overall survival (OS) were 14.3 wks (95% CI:12.3, 18.9) and 27.6 wks (95% CI:22.1, 40.6), respectively. For the current study, whole blood was available for DNA extraction from 56 pts. There were no differences in baseline pts characteristics, RR and PFS between the pts included in the analysis and the entire study population. Intratumoral HER2 mRNA levels was assessed using laser capture microdissection and quantitative real-time PCR. SNPs were evaluated using PCR-based protocols, and the associations with RR and PFS were analyzed using Fisher’s exact test, Kaplan-Meier curves, and log-rank tests as appropriate. Results: There was a statistically significant association between the MTHFR A1298C SNP rs1801131 and RR (p=0.0399). Pts carrying the AA genotype were more likely to respond to treatment (47.6%) compared with pts with either the AC or CC genotype (13.3%). No significant associations between other SNPs and RR or PFS were observed. Although not significant, high HER2 mRNA expression (>0.07, n=10) before treatment was associated with shorter PFS compared to low HER2 mRNA expression (<0.07, n=9; p=0.098). Conclusions: Although exploratory, this study suggests that MTHFR A1298C may be useful in predicting clinical outcome in metastatic GC pts treated with lapatinib plus capecitabine.