KRAS mutation as a prognostic factor in patients undergoing hepatic resection for metastatic colorectal cancer.

Abstract

444 Background: It is well known that KRAS mutations limit the efficacy of anti-EGFR therapy in patients with metastatic colorectal cancer (mCRC). However the role of KRAS mutations in patients who undergo a curative liver resection for mCRC is less clear. The purpose of our study was to evaluate the relationship between KRAS mutation status and survival in this patient population. Methods: We examined an IRB approved tissue repository and retrospective database of 129 patients from 1998-2010 who underwent curative liver resection for mCRC. Tumors were sequenced for KRAS codons 12, 13, and 61 mutations using pyrosequencing. Overall survival (OS) and disease-free survival (DFS) were analyzed using the Kaplan-Meier method and compared using the log-rank test. Multivariate analysis was performed using the Cox proportional hazards regression method. Results: The median follow-up for our cohort was 20.4mo (0.4-112). Mean age was 61.4±12.3. Prior to surgical resection 55 (43%) patients received chemotherapy. 35 (27%) tumors were KRAS mutant (mt), 83 (64%) were wild-type (wt), and 11 (9%) were not characterized. Median OS for KRAS wt patients was 40.3mo vs. 27.1mo for KRAS mt patients (p=0.046). Median DFS for KRAS wt was 13.6mo vs. 7.7mo for KRAS mt patients (p=0.037). 8 patients received cetuximab post–operatively. Cetuximab status was unknown in 50 patients. When we excluded those treated with cetuximab, the median OS was 40mo for KRAS wt vs. 25mo for KRAS mt patients (p=0.007). There were no differences in OS or DFS in patients who received cetuximab (p=0.7). In a multivariable model with pre-operative chemotherapy (p=0.2), extent of resection (p=0.053), and cetuximab therapy (p=0.7), the presence of KRAS mutation was independently associated with poor prognosis (HR=2.7 [1.3-5.5]). Conclusions: In patients undergoing curative liver resection for mCRC, KRAS mutation status is independently predictive of a worse outcome regardless of cetuximab therapy. KRAS status may be associated with more aggressive tumor biology. Our data supports the critical need to define KRAS mutation status and to develop therapies against KRAS and its downstream effectors.