Perioperative FLOT chemotherapy has improved the prognosis in patients with locally advanced resectable gastric cancer (GC). However, in 80% of cases, the tumor is resistant to the therapy, and the patients are exposed to unnecessary toxicity and delayed surgical treatment. The aim of this study was to identify molecular predictive markers of efficacy of perioperative FLOT chemotherapy in patients with locally advanced resectable GC.
The retrospective study included 185 patients. All tumor samples were assessed for HER2 and microsatellite instability (MSI) status. Among all cases there were 45 patients with locally advanced T2-4N1-2 M0 GC, who underwent a total or subtotal gastrectomy with D2 lymphadenectomy and perioperative chemotherapy with FLOT. MSI detection was performed using mononucleotide markers (NR21, NR24, NR27, BAT25, BAT26) by fragment analysis. HER2 gene amplification testing was performed using fluorescent in situ hybridization. Also 19 patients were tested for copy number changes of the FGFR1, FGFR2, KRAS, MET, EGFR, CCND1, MYC genes using multiplex-ligation probe amplification analysis. The endpoints were progression-free survival (PFS) and objective response rate (ORR).
MSI was detected in 4.8% (9/185) of GC cases. Prevalence of HER2 amplification was 7.5% (14/185). PFS in patients with HER2-positive GC, receiving perioperative chemotherapy with FLOT (4/45), was significantly lower than in patients with HER2-negative GC: the median was 156 and 317 days, respectively (p=0.0006). There was no correlation between the alteration and objective response (OR) (p=1.0). PFS in GC patients with KRAS amplification (3/19) was significantly lower comparing to patients without KRAS amplification: the median was 98 and 327 days, respectively (p<0.0001). There was no association between an increase in KRAS copy number and ORR (p=1.0). For MSI and other studied markers no statistically significant correlation with PFS and ORR was found (p>0.05).
The presence of HER2 and KRAS amplification have been shown as promising predictive markers of the treatment failure in patients treated with perioperative FLOT chemotherapy for locally advanced resectable GC.
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All authors have declared no conflicts of interest.