RAS wild-type

KRAS mutations are associated with aggressive recurrence patterns and a poor prognosis for patients with CRLM. However, survival following local therapy for recurrence appeared less pronounced regardless of KRAS status.

The efficacy of anti-EGFR therapy in mCRC appears to exhibit additional intraregional heterogeneity beyond the conventional right-left classification. These findings suggest that anatomical tumour location may reflect underlying biological differences not fully captured by this binary classification.

P=N/A, N=152, Recruiting, Gustave Roussy, Cancer Campus, Grand Paris | Active, not recruiting --> Recruiting

The substantial hereditary and potentially actionable molecular burden supports universal germline testing and comprehensive tumour genomic profiling, particularly in younger patients and in KRAS wild-type disease. PARP inhibitors should be described as improving progression-free survival or disease-control outcomes in selected BRCA-mutated metastatic PDAC rather than as having established a statistically significant overall survival benefit.

This study demonstrated that dynamic changes in plasma RAS mutation status may occur during disease progression in patients with mCRC, potentially reflecting tumor clonal evolution. The observed survival advantage in patients with RAS mutation clearance suggests potential prognostic relevance. Reassessment of RAS status using liquid biopsy at disease progression may provide clinically relevant information; however, these findings should be considered exploratory and require prospective validation in larger cohorts.

This study is the first to examine p27 localization in WT KRAS CRC. The observed association between WT KRAS expression and cytoplasmic p27 localization highlights a potential mechanism contributing to tumour progression through altered p27 function.

Furthermore, co-occurring RAS pathway mutations leading to increased wild-type RAS activation are enriched in codon 13 mutant tumors. Consistent with a role for wild-type RAS(ON) signaling, combination of RMC-8839 with a RAS(ON) multi-selective inhibitor resulted in deeper inhibition of KRAS G13C-mutant xenograft tumor growth than either inhibitor alone.

Moreover, we observed that KRASG12C/EML4-ALK tumor cells kept under constant pressure with KRASG12C inhibitors exhibit sensitivity to single-agent ALK inhibitors, suggesting a potential for rationally designed sequential treatments. Mechanistically, EML4-ALK bypasses KRASG12C inhibition by activating wild-type RAS, highlighting an additional therapeutic opportunity for multi-selective RAS inhibitors under clinical investigation.

P1/2, N=58, Completed, Associacio Per A La Recerca Oncologica | Phase classification: P=N/A --> P1/2 | --> Completed

MiR-31-3p is a promising predictive biomarker for cetuximab response in RAS wild-type mCRC, with low expression consistently associated with improved outcomes. However, tumor sidedness may modulate its predictive value. Prospective validation studies with standardized assays are needed before clinical implementation. Integration of miR-31-3p with existing markers could help identify patients unlikely to benefit from anti-EGFR therapy.

For OS, both cetuximab + chemotherapy [hazard ratio (HR)=0.853; 95% CI: 0.775-0.938; P=0.001] and panitumumab + chemotherapy (HR=0.855; 95% CI: 0.738-0.992; P=0.038) exhibited statistically significant superiority compared with bevacizumab + chemotherapy...In the present sensitivity analysis, UDP glucuronosyltransferase family 1 member A1-guided bevacizumab + 5-fluorouracil, leucovorin and irinotecan demonstrated favorable outcomes, with OS and PFS P-scores of 0.932 and 0.992, respectively; however, these findings were derived from a single trial with limited comparability...Treatment benefit from anti-EGFR therapy was markedly influenced by primary tumor location, with notable benefit observed in left-sided tumors and no benefit in right-sided tumors. These findings support tumor sidedness-guided treatment selection in clinical practice, favoring anti-EGFR-based therapy for left-sided and bevacizumab-based therapy for right-sided RAS wild-type mCRC.

Mouse embryonic fibroblasts transformed with KRASG12C also contain more saturated lipids than KRASG12D MEFs. Thus, activities of KRAS mutants depends on lipid acyl chain remodeling in an allele-specific manner.