RAS-variant allele frequency as a potential prognostic marker of overall survival in patients with metastatic colorectal cancer

Background: Presence of RAS mutations in mCRC are negatively correlated with OS. NGS enables detailed information regarding the heterogeneity of RAS mutations including specific amino acid changes as well as variant allele frequency (VAF). Recently, VAF has been postulated to have a role in identifying resistance to treatments in multiple solid tumours but its role as a prognostic marker of OS in mCRC is not established. Methods: This was a multicentre, retrospective cohort study investigating all patients with NGS confirmed RAS-mutated mCRC between 2021 and 2023. NGS results for VAF were collected and correlated with clinicopathological outcomes. A VAF of > 20 % was considered “high” whilst ≤ 20 % was considered “low.” Results: 351 patients were screened for presence of NGS-confirmed RAS-mutated mCRC. 124 patents were identified with RAS-mutated mCRC of which 95 patients had reported VAF and thus were included in the final cohort. 62 (65 %) had high VAF on NGS. The median age was 56 (36 – 89) with 61 % (n = 58) being male. All patients had histologically confirmed moderately or poorly differentiated adenocarcinoma and none had evidence of mismatch repair deficiency. The two most common RAS-mutation subtypes were G12D (n = 29, 31 %) and G13D (n = 21, 22 %). 29 patients also had concurrent TP53 mutations whilst another 19 had concurrent PIK3CA mutations. Median OS in the entire cohort was 20.8 months. High VAF was associated with poorer survival compared with low VAF (16.9 versus 23.0 months, HR 2.2 (95 % CI 1.2 – 3.9), p < 0.01). Conclusion: This is the first real world evidence of the potential prognostic significance of VAF in mCRC. Patients with low RAS VAF had better survival compared with high VAF counterparts. Presence of low RAS VAF in tumour samples may suggest that patients progress in a manner resembling RAS wild-type tumours.