Incidence of KRAS G12C mutations in genitourinary malignancies; emerging target in precision medicine.
Summary
This study characterized the prevalence of KRAS G12C mutations in genitourinary malignancies, an area with limited data despite the approval of targeted therapies. Comprehensive genomic profiling was performed on over 13,000 samples of renal clear cell carcinomas, urothelial bladder carcinomas, and prostate acinar adenocarcinomas. Results indicated that KRAS G12C mutations are infrequent in these tumors, with an incidence of 0% in renal carcinomas, 0.6% in urothelial bladder carcinomas, and less than 0.01% in prostate adenocarcinomas. Despite their low frequency, these mutations represent an emerging therapeutic target, warranting further investigation, particularly in basket trials for patients harboring this actionable alteration.
Analysis
Clinique: This study, although retrospective and based on a large sample, highlights the low incidence of KRAS G12C mutations in major genitourinary malignancies. However, the discovery of KRAS G12C as a therapeutic target and the recent FDA approval of specific inhibitors provide immediate clinical actionability for this alteration. The findings justify the implementation of basket trials to evaluate the efficacy of these therapies in the small subset of bladder and prostate cancer patients harboring this mutation. Clinical impact could be within 1-3 years for integrating these tests and therapies into trials, potentially leading to practice changes within 3-5 years if results are positive. Biomol: The study utilized comprehensive genomic profiling on FFPE samples, a standard and robust technology for mutation detection. It characterized the prevalence of KRAS G12C and identified significant co-alterations, such as lower TERT co-mutations and higher KDM6A alterations in KRAS G12C-positive urothelial bladder carcinomas. These molecular discoveries, while descriptive, are crucial for understanding the genomic landscape of these tumors and could guide patient selection for targeted therapies. The detection of KRAS G12C by clinical NGS panels is already validated and could be integrated into diagnostic tests to identify patients eligible for KRAS G12C inhibitors.