Influence of KRAS mutation on recurrence patterns in patients undergoing hepatic resection of colorectal metastases.

Abstract

398 Background: There have been conflicting results about whether KRAS mutation influences outcome in patients (pts) with colorectal cancer. In pts who underwent liver resection, Karagkounis reported a worse recurrence and survival in KRAS mutated (MUT) patients (ASCO 2012, abs 3616). Methods: In 105 pts who underwent liver resection and received adjuvant (adj) hepatic arterial infusion and systemic chemotherapy and in whom KRAS data was available, we evaluated recurrence patterns and survival. Correlation between KRAS and clinical factors such as prior chemotherapy, post operative CEA, clinical risk score, and stage at diagnosis was evaluated using Fisher’s exact test and the Wilcoxon rank sum test. Kaplan-Meier methods were used to estimate median overall recurrence free survival (RFS) and overall survival (OS) at 4 years. Log-rank test was used to determine whether survival functions differed by KRAS mutation status. Cumulative incidence function was used to estimate the probability of time from adj therapy to bone, brain, lung and liver metastases separately. Results: Of 105 patients, 76 were KRAS wildtype (WT), and 29 were KRAS MUT (26-G12 and 3-G13). The median RFS was 26 months for KRAS WT pts and 15 months for KRAS MUT pts (p=0.08). OS at 4 years was 88% [95% CI: 78%-94%] for KRAS WT and 78% [95% CI: 57%-90%] for KRAS MUT pts (p= 0.15). Cumulative incidence of developing bone, brain, lung, and liver metastases by 2 years is presented in the Table. The cumulative incidence of bone and brain metastases at 2 years was 0% and 0% in KRAS WT pts versus 16.4% [95% CI: 1.1%-31.7%] and 4.7% [95% CI: 0%-14.1%] in KRAS MUT pts (Table). There was no association between clinical factors and KRAS status. Conclusions: KRAS MUT pts appeared to have worse OS and RFS, although we were unable to show a significant difference between KRAS WT and MUT for OS and RFS. In addition, cumulative incidence of bone and brain metastases at 2 years appeared to be higher for KRAS MUT pts as compared to WT pts. Results are based on small sample size and further investigation is needed. [Table: see text]

Can KRAS and BRAF mutations limit the benefit of liver resection in metastatic colorectal cancer patients? A systematic review and meta-analysis

“…This interpretation is consistent with the evidence that the percentage of KRAS mutated patients ranged from 14% (Stremitzer et al, 2012) to 37% (Teng et al, 2012) in all seven included studies, compared to 35-45% reported in metastatic and unresectable CRC, suggesting a significant association between KRAS mutations rates and tumor behavior, as described in preclinical studies (Suchy et al, 1992;Tanaka et al, 1994;Varghese et al, 2002;Webb et al, 1998). Some clinical series have also shown that KRAS mutations are associated with an increased risk of developing lung and liver metastases compared to wild-type population (Vauthey et al, 2013;Kemeny et al, 2014). Others have shown a higher incidence of lung metastases/recurrence than liver metastases/recurrence in KRAS mutated patients (Vauthey et al, 2013;Tie et al, 2011;Kim et al, 2012).…”

“…1). Three of these studies were retrospective series (Vauthey et al, 2013;Kemeny et al, 2014;Francesca Bergamo and Loupakis et al, 2014), while the others were prospective studies (Nash et al, 2010;Karagkounis et al, 2013;Stremitzer et al, 2012;Teng et al, 2012). In these 7 studies, sample sizes of the analyzed population ranged from 60 (Stremitzer et al, 2012) to 309 (Schirripa et al, 2015), while the percentage of KRAS mutated patients ranged from 14% (Stremitzer et al, 2012) to 37% (Teng et al, 2012).…”

“…Five studies reported HRs with 95% CI data for both RFS and OS (Karagkounis et al, 2013;Vauthey et al, 2013;Stremitzer et al, 2012;Kemeny et al, 2014), while two studies reported only HRs with 95% CI data for OS (Nash et al, 2010;Teng et al, 2012). Pooled analysis showed that KRAS mutations predicted a significant worse both RFS (HR: 1.53; 95% CI: 1.27-1.83) and OS (HR: 1.7; 95% CI: 1.38-2.10) in patients who underwent surgical resection of CLM (Figs.…”

“…The patients cohorts included in the seven studies of our meta-analysis are quite heterogeneous, because of different selection criteria, as well as a variable origin (primary tumor vs liver metastases) of tissue available for the mutational analysis. Indeed the mutation status was determined from liver metastasis for the majority of patients, while it was determined from the primary tumor in about 20% of patients included in both the Kemeny et al (2014) and Schirripa et al (2015) studies. Almost all seven studies included, performed the evaluation of the most common KRAS mutations in the extracted DNA (codon12/13); only two studies (Vauthey et al, 2013;Schirripa et al, 2015) evaluated both KRAS and NRAS mutations (codon12/13/61), stratifying patients according to all RAS mutation status.…”

“…The majority of such studies have shown that both KRAS and BRAF, respectively detected in about 30% and 3% of CLM, are associated with worse survival outcomes of patients undergoing liver resection (Nash et al, 2010;Karagkounis et al, 2013;Vauthey et al, 2013;Stremitzer et al, 2012), while some other studies have not found a significant association (Kemeny et al, 2014;Teng et al, 2012;Schirripa et al, 2015). The aim of this meta-analysis is to combine and analyze simultaneously all the studies reporting the survival outcomes (recurrence free survival (RFS), and/or overall survival (OS)) of patients who received resection of CLM, stratified by KRAS and/or BRAF mutation status, in order to provide a more precise estimation of the prognostic value of both KRAS and BRAF, in patients undergoing surgical therapy for CLM.…”