RAS/RAF/MAPK Alterations in Prostatic Adenocarcinoma: A Multi-Institutional Study.

RAS/RAF/MAPK pathway alterations are rare in prostatic adenocarcinoma (PCa) but are implicated in metastasis and progression. Previous studies suggest that these alterations are more common in rare and aggressive histologic PCa subtypes. We reviewed the clinical and morphologic features of PCa with these alterations at our 3 institutions. PCa cases with RAS/RAF/MAPK pathway alterations identified by next generation sequencing (NGS) were selected for our cohort. Clinical, morphologic, and molecular features were compiled. Additionally, PCa cases with these alterations were identified in the Cancer Genome Atlas (TCGA) for comparison. From our 3 institutions, 44 cases of PCa (4.3%) with RAS/RAF/MAPK alteration(s) were identified by NGS (20 metastatic and 24 primary samples). Primary samples included prostate biopsies, radical prostatectomies, and transurethral resections of the prostate. Alterations were found in BRAF (21 cases), HRAS (10), KRAS (5), and MAPK genes (9). Most cases were grade group 5 (23/35, 66%). Aggressive histologic features were seen in 69% of cases (24/35). De-novo or subsequent metastatic disease developed in 84% of cases (37/44). Review of the TCGA dataset showed a similar proportion of RAS/RAF/MAPK-altered cases, and a subset had aggressive histologic patterns. Our data reinforces that mutations in the RAS/RAF/MAPK pathway in PCa are uncommon, but a majority of our cases showed high Gleason grade, metastases, and castration resistance, with a subset showing aggressive histologic features. Activating BRAF fusions were identified. As a significant number of cases did not show co-occurring alterations in driver genes, RAS/RAF/MAPK alterations may be driving tumorigenesis in a subset of PCa cases.