Impact of driver genetic alterations on survival in colorectal cancer patients from genetically homogeneous Sardinian population: a real-world study

Background. Colorectal cancer (CRC) is the third most diagnosed malignancy and the second leading cause of cancer-related mortality worldwide. Recent therapeutic ad-vancements have significantly improved clinical management, underscoring the im-portance of routine molecular profiling to guide personalized treatment strategies. This study aims to evaluate the prognostic impact of main molecular alterations - including allele frequency (AF) of RAS mutations - on survival outcomes in a real-world hospi-tal-based cohort of patients with metastatic CRC. Methods. A total of 208 consecutive patients with a histologically confirmed diagnosis CRC and complete clinical, molecular, and survival data were retrospectively analysed. Somatic mutations in KRAS, NRAS, BRAF and occurrence of microsatellite instability (MSI) were assessed using pyrose-quencing and real-time PCR assays, respectively, on formalin-fixed, paraffin-embedded tumour samples. Associations between mutational status, clinicopathological parameters, and overall survival (OS) were evaluated. Results. Overall, 138 patients (66.3%) har-boured at least one somatic mutation: 115 (55.3%) in KRAS, 8 (3.8%) in NRAS, and 15 (7.2%) in BRAF. MSI was detected in 17/208 (8.2%) patients. A statistically significant improvement in OS was observed in patients lacking mutations in any of the three genes - referred to as wild-type (WT) patients - with BRAF mutated cases showing the worst survival (p = 0.041). Increasing age at the time of first-line therapy for advanced disease stage was associated with a statistically significant increase in the hazard of death (p = 0.031). Conclusions. In advanced disease stage, RAS/BRAF wild-type colorectal cancers were significantly associated with a survival advantage.