Mismatch repair-deficient or other molecular subtypes and efficacy of chemotherapy for advanced gastric cancer

Abstract

Abstract Background Molecular subtypes including mismatch repair-deficient (MMR-D) affect the efficacy of immune checkpoint inhibitors in patients (pts) with advanced gastric cancer (AGC). However, the association between the subtypes and efficacy of standard chemotherapy remains unclear. Methods AGC pts received chemotherapy from October 2015 to July 2018 with available molecular features were analyzed in this study. We investigated the efficacy of first- (fluoropyrimidine + platinum ± trastuzumab) or second-line (taxanes ± ramucirumab or irinotecan) chemotherapy according to four subtypes: MMR-D, EBV+, HER2+ and others (all-negative). Results Total 410 pts were analyzed: MMR-D, n = 24 (5.9%); EBV+, n = 16 (3.9%); HER2+, n = 56 (13.7%); all-negative, n = 314 (76.6%) with no overlapping between molecular subgroups. Among 285 pts receiving standard first-line chemotherapy, the median PFS were 4.2, 6.0, 7.5, 7.6 months and the ORR were 31, 62, 62, 51% in MMR-D, EBV+, HER2+, and all-negative groups, respectively. Multivariate analysis showed shorter PFS in MMR-D group vs. all-negative (HR 1.98, 95% confidence interval, 1.13-3.47; p = 0.016), while other comparison between subgroups did not show significant difference. In 262 pts receiving second-line chemotherapy, there was no significant difference in efficacy among the four subtypes: the median PFS were 3.9, 6.6, 3.7, 3.9 months and the ORR were 37, 43, 14, 32% in MMR-D, EBV+, HER2+ and all-negative groups, respectively. Twelve MMR-D pts received subsequent immune checkpoint inhibitors, which showed higher ORR (64%) and longer PFS (median PFS: 13.0 months) compared with earlier line chemotherapy. Conclusion MMR-D might result in shorter PFS with first-line chemotherapy for AGC compared with other subgroups. Meanwhile immune checkpoint inhibitors achieved a longer PFS than standard chemotherapy in most MMR-D pts, supporting earlier use of immune checkpoint inhibitors.