Expression levels of ROS1/ALK/c-MET and therapeutic efficacy of cetuximab plus chemotherapy in advanced biliary tract cancer

Abstract

Aberrant expression of ROS1, ALK or c-MET (RAM) is implicated in carcinogenesis and cancer drug resistance. We retrospectively evaluated the effect of RAM expression on outcomes for advanced biliary tract cancer patients, who were treated with gemcitabine plus oxaliplatin (GEMOX), with or without cetuximab, in a randomized phase II trial. RAM expression levels on archived tissue sections were scored using immunohistochemistry (IHC). Of 110 tumors with IHC staining for all three markers, 18 were RAM(high) (IHC intensity 3+ for any markers). Ninety-two tumors were RAM(low) (IHC intensity <3+ for all markers). All RAM(high) tumors were intra-hepatic cholangiocarcinomas (IHCC). Of the patients with IHCC (n = 80), median overall survival (OS) of RAM(high) group was inferior to that of the RAM(low) group (5.7 vs. 11.7 months, p = 0.021). In multivariate analysis RAM(high) remained an independently adverse prognostic factor, with a hazard ratio of 2.01 (p = 0.039). In the RAM(low) group, GEMOX treatment with cetuximab significantly improved the disease control rate (68% vs. 41%, p = 0.044), median progression-free survival (7.3 vs. 4.9 months, p = 0.026), and marginally prolonged median OS (14.1 vs 9.6 months, p = 0.056), compared to GEMOX treatment alone. Future trials of anti-EGFR inhibitors for IHCC may consider RAM expression as a patient stratification factor.

Figure 1

(A) ROS1, ALK and c-MET expression in primary intra-hepatic cholangiocarcinoma (expression score: 0, 1+, 2+ and 3+). ROS1 and ALK are mainly localized in cytoplasm, and c-MET is localized in both cytoplasm and nucleus. (B) Break-apart Fluorescence in situ hybridization for ALK revealed wide-apart of the red and green signals (white arrows), indicating ALK translocation.

Figure 2

The comparison of PFS (A) and OS (B) in IHCC patients with RAM^low -expressed tumors (n = 62), receiving treatment of C-GEMOX or GEMOX. (C) cetuximab; GEMOX, gemcitabine and oxaliplatin; PFS, progression-free survival; OS, overall survival; IHCC, intrahepatic cholangiocarcinoma; RAM, ROS1/ALK/c-MET.