Prognostic implications and therapeutic response in GNAS-mutated colorectal adenocarcinoma: A retrospective cohort analysis.

Abstract

244 Background: GNAS, a key regulator of the G-protein signaling pathway, is frequently mutated in colorectal adenocarcinomas and other malignancies. Despite its role in tumorigenesis, GNAS mutations remain understudied, with no established targeted therapies. Exploring the impact of GNAS alterations on therapeutic response and outcomes in colorectal cancer (CRC) is crucial for developing effective treatment strategies. Methods: We reviewed 531 CRC cases from our institutional Molecular Tumor Board database, identifying 8 patients with GNAS mutations. The prevalence ofGNASmutations in our cohort was 1.5%, which aligns with reported rates of 2-5% in various CRC cohorts. Comprehensive clinicopathologic data, including tumor histology, staging, treatment outcomes, and response rates, were analyzed. A detailed evaluation was conducted on stage IV patients to assess their response, progression-free survival (PFS), and overall survival (OS) in comparison to historical stage IV CRC benchmarks. Results: The cohort included 8 patients with a median age of 61 years (range: 33-73 years), with balanced gender representation (50% male, 50% female). The racial distribution was 50% Black or African American, 25% White, and 12.5% Asian or Pacific Islander. The majority of patients (62.5%) were diagnosed at stage IV, with primary tumor sites predominantly in the sigmoid colon and cecum. Among the 5 stage IV patients, while no patients achieved a complete or partial response, 3 exhibited stable disease, resulting in a 60% disease control rate (including stable disease). The median progression-free survival (mPFS) was 9 months, reflecting the duration of disease control before progression, while the median overall survival (mOS) was 15 months. These outcomes are notably lower than historical benchmarks for stage IV CRC, where response rates typically range from 40-50% with mOS of 20-24 months, highlighting the potentially adverse prognostic impact of GNAS mutations. Conclusions: Patients with GNAS-mutated colorectal adenocarcinoma appear to represent a unique subset with poorer therapeutic outcomes, even when achieving stable disease. The observed disease control in the absence of objective responses underscores the complexity of treating GNAS-mutated tumors and highlights the urgent need for targeted therapies tailored to this molecular subtype. Further research into the biological mechanisms underlying GNAS mutations and their impact on CRC treatment resistance is warranted to improve patient outcomes.