Primary tumor location and KRAS mutation: key prognostic factors in surgically treated colorectal liver metastases

Colorectal cancer is the second leading cause of cancer-related death globally. Approximately half of colorectal cancer patients develop liver metastasis, and the overall prognosis is significantly influenced by the extent of these liver metastases (1). Multiple studies have investigated the risk factors affecting survival in colorectal liver metastasis (CRLM), and have found that Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation, v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation, tumor morphology, carcinoembryonic antigen (CEA) levels, primary lymph node metastases, surgical margin width, primary tumor site (right or left), and the presence of extrahepatic disease influence survival following curative resection (1).

Among the various prognostic factors, tumor site is one of the most recently recognized. In 2016, Sasaki et al. were the first to propose that primary tumor location (PTL) may influence overall survival (OS) in patients undergoing resection for CRLM (2). Since then, multiple studies have supported an association between right-sided (RS) primary tumors and poorer OS in this population (3), although some have reported no significant relationship between PTL and long-term outcomes (4). A meta-analysis by Wang et al. further supported the finding that RS tumors are associated with poorer OS compared to left-sided (LS) tumors (5). However, the analysis revealed substantial heterogeneity, raising the possibility of a subgroup effect. In 2019, another group suggested that KRAS mutation status may account for this variability (1). They reported that the negative prognostic impact of RS tumors was limited to patients with wild-type KRAS, with no significant difference observed among those with KRAS mutations. Still, subsequent studies have yielded conflicting results (4,6).

This is why the study by Wu and colleagues, published in a recent issue of HepatoBiliary Surgery and Nutrition, is particularly important (7). The authors analyzed a multicenter cohort of 1,307 patients who underwent resection of both primary and metastatic colorectal cancer (mCRC) lesions. Their subgroup analysis based on KRAS mutation status revealed that the inferior survival associated with RS tumors was limited to patients with KRAS wild-type tumors [hazard ratio (HR): 1.71; 95% confidence interval (CI): 1.20–2.45; P=0.003]. In contrast, no significant survival difference was observed between RS and LS tumors among patients with KRAS mutations. The second reason this study stands out is that it is among the few on this topic to include whole-exome sequencing (WES), which was performed on tumor samples from 200 patients. This genomic analysis uncovered that LS tumors were less likely to harbor mutations in TP53, APC, and KRAS, but more likely to carry SMAD4 mutations. It would be of particular interest if the authors could further stratify WES findings by both KRAS status and tumor side. Such an analysis might help explain why tumor location is prognostic in KRAS wild-type CRLM but not in KRAS-mutated cases. For instance, if SMAD4 and TP53 mutations—which are known to confer especially poor prognosis when co-occurring with KRAS mutations—are evenly distributed across RS and LS tumors in the KRAS-mutant subgroup, this could explain the lack of survival difference. Conversely, a predominance of high-risk mutations on the RS among KRAS wild-type tumors could account for the observed prognostic impact of tumor location in that group. In addition, differences in embryological origin may contribute to the observed disparities in outcomes. The ascending colon originates from the midgut, while the descending colon originates from the hindgut. Further, the rectum and the right and left colon have different embryological origins. The exact classification of the sigmoid colon as part of the LS colon or the rectum has not been established.

Regardless of the underlying biological mechanisms driving the prognostic impact of tumor site and its interaction with KRAS mutation status, the clinical implications of these findings—along with those from similar studies—extend well beyond prognostication. PTL not only influences OS after resection but also affects pathological response to preoperative chemotherapy, recurrence patterns, and survival following recurrence (2,8). Similarly, KRAS mutational status predicts response to chemotherapy, shapes recurrence patterns, and impacts post-recurrence survival. In the context of unresectable disease, KRAS status has direct therapeutic implications. For instance, monotherapy with panitumumab, an epidermal growth factor receptor (EGFR) inhibitor, is effective only in patients with KRAS wild-type tumors (9). Notably, both RAS status and PTL inform the choice of upfront therapy for patients with mCRC: anti-EGFR agents are recommended for LS RAS wild-type tumors, while bevacizumab is preferred for RS RAS wild-type tumors (10). A more recent advance comes from the biomarker study of the PARADIGM trial, where Shitara et al. found that the effect of panitumumab plus FOLFOX6 regimen was modified by the presence of specific gene alterations related to resistance to anti-EGFR therapy, such as PTEN, HER2, MET, ALK, RET, and NTRK1 (11). By testing for these gene alterations, it may be possible to predict the sensitivity of anti-EGFR therapy more accurately than just using the PTL. Furthermore, specific KRAS variants have additional prognostic as well as clinical relevance: in patients harboring KRAS G12C mutations, combination therapy with panitumumab and sotorasib—a KRAS G12C inhibitor—has demonstrated efficacy (12).

Another clinical context in which the combination of KRAS status and tumor site may prove important is the use of evolving liver-directed therapies for CRLM, including hepatic artery infusion pumps (HAIP) which were initially introduced for unresectable CRLM but have since been adopted in the adjuvant setting following curative resection. A report from Memorial Sloan Kettering Cancer Center demonstrated that adjuvant HAIP therapy is associated with improved survival after curative resection, regardless of KRAS mutation status or primary tumor site (13). However, the study did not investigate whether outcomes differ when both KRAS status and tumor laterality are considered together. As the use of HAIP continues to expand, further research exploring its prognostic value in the context of combined molecular and anatomical factors is warranted to help refine patient selection and optimize outcomes.

Another potential area where the findings of this study may prompt further research is in liver transplantation (LT) for CRLM. Since the 2010s, LT has been explored as a treatment option for select cases of unresectable CRLM (14). Given the limited availability of donor organs, the identification of “biological contraindications” becomes particularly critical when considering LT for CRLM. Primary tumor site might play a role in patient selection for LT, as data from the University of Oslo suggest that LT does not appear to offer long-term survival benefit for patients with RS tumors (15). However, the prognostic significance of the combined effect of PTL and KRAS mutation status in the context of LT has not yet been thoroughly investigated.

In conclusion, the important contribution by Wu et al. aligns with existing literature and highlights the prognostic significance of combined stratification by primary tumor site and KRAS mutation status in the setting of CRLM. Future studies may further elucidate the biological mechanisms underlying this observed effect and pave the way for incorporating this knowledge into both surgical and medical management strategies for patients with CRLM.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, HepatoBiliary Surgery and Nutrition. The article has undergone external peer review.

Peer Review File: Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-209/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-209/coif). The authors have no conflicts of interest to declare.

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