Abstract
Simple SummaryPrimary 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.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.
Highlights
Primary tumor laterality (PTL) is the most recently identified prognostic factor associated with mortality in colon cancer, in the metastatic setting (metastatic colorectal cancer)
This variable effect of primary tumor laterality (PTL) based on KRAS status may help resolve the current debate regarding the effect of PTL on survival, which is evidenced by the fact that 21/43 published colorectal liver metastases (CRLM) studies on PTL showed a significant association between PTL and prognosis while the other 22 did not [8]
This is significant because previous studies, which demonstrated that tumor site was only significant in wild-type patients, could not prove a true variable effect of KRAS status on PTL
Summary
Primary tumor laterality (PTL) is the most recently identified prognostic factor associated with mortality in colon cancer, in the metastatic setting (metastatic colorectal cancer (mCRC)). Their meta-analysis showed high heterogeneity, implying that a subgroup effect may be present 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 KRASmutated 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. To assess if an interaction underlies the possible difference between the effects of PTL in KRAS-mutated vs wild-type CRLM, we 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]). Right-sided tumors are associated with worse OS only in patients with wild-type CRLM
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