Is Laterality Prognostic in Resected KRAS-Mutated Colorectal Liver Metastases? A Systematic Review and Meta-Analysis

SIMPLE SUMMARY: Primary tumor laterality (PTL) is the most recently identified prognostic factor associated with mortality in patients with resected colorectal cancer liver metastases, but whether it is prognostic in all patients or only those with wild-type KRAS tumors is debated. The aim of this meta-analysis was to identify all relevant articles and synthesize their evidence to estimate the effect of PTL per KRAS mutational status. We found that PTL and KRAS mutational status have a statistically significant interaction. Specifically, PTL has a variable effect in patients with wild-type versus KRAS-mutated tumors, with right-sided tumors associated with worse survival only in the former. This meta-analysis appears to resolve a long-lasting debate. ABSTRACT: Background: It is debated whether primary tumor laterality (PTL) is prognostic in all patients with colorectal liver metastases (CRLM) or only those with KRAS wild-type or KRAS-mutated tumors; Methods: We systematically reviewed PubMed for studies reporting on resected CRLM originating from left-sided (LS) versus right-sided (RS) colon cancer stratified by KRAS status. Individual participant data (IPD) were used if available. Given that there are two definitions of PTL, we performed two meta-analyses for KRAS-mutated and two for wild-type patients. To assess if an interaction underlies the possible difference between the effects of PTL in KRAS-mutated vs. wild-type CRLM, we similarly performed two meta-analyses of interaction terms; Results: The meta-analyses included eight studies and 7475 patients. PTL had a prognostic association with OS in patients with wild-type tumors (HR for LS: 0.71 [0.60–0.84]), but not in those with KRAS-mutated tumors (HR: 0.99 [0.82–1.19]). This difference stemmed from a truly variable effect of PTL for each KRAS status (mutated vs. wild-type) as the meta-analysis of interaction terms showed a significant interaction between them (HR:1.38 [1.24–1.53]). Similar results were obtained when the second definition of PTL (LS to not include the rectum) was used; Conclusions: KRAS status modifies the association of tumor site with survival. Right-sided tumors are associated with worse OS only in patients with wild-type CRLM.