Evidence for predictive role of BRCA1 and bTUBIII in gastric cancer.

Sensitivity of gastric cancer (GC) to conventional cytotoxic therapy may be at least in part attributed to molecular features of the tumor cells. We analyzed all patients with metastatic GC treated in the N.N. Petrov Institute of Oncology (St. Petersburg) within years 1999-2010 and identified 65 cases with evaluable treatment response and available biological material. Two of 65 patients (3 %) carried germ-line BRCA1 5382insC mutation and demonstrated particularly pronounced response to the treatment; both of their tumors showed loss of the remaining BRCA1 allele, thus confirming the causative role of BRCA1 heterozygosity in GC predisposition. RNA expression of TS, DPD, BRCA1, ERCC, TOP2A and bTUBIII was analyzed in the remaining 63 tumors. Low BRCA1 expression was associated with increased response rate [6/9 (67 %) vs. 17/54 (32 %), p = 0.04]. Low bTUBIII level correlated with the improved probability of tumor response [21/49 (43 %) vs. 1/13 (8 %), p = 0.02] and prolonged overall survival (10.5 vs. 7.1 months, p = 0.02); this trend was maintained both for taxane-containing and for taxane-free drug combinations. We conclude that GC should be considered as a part of BRCA1-related hereditary cancer syndrome. Tumors with BRCA1 inactivation and low bTUBIII expression demonstrate improved response to cytotoxic therapy.