Landscape and prognostic significance of oncogene drivers in metastatic castration sensitive prostate cancer.

Abstract

Background: Tumor suppressors are well known drivers of cancer invasion and metastasis in metastatic castration sensitive prostate cancer (mCSPC). However, oncogenes are also known to be altered in this state, however the frequency and prognosis of these alterations are unclear. Thus, we aimed to study the spectrum of oncogene mutations in mCSPC and study the significance of these alteration on outcomes.

Methods: Four hundred and seventy-seven patients with mCSPC were included who underwent next generation sequencing. Oncogene alterations were defined as mutations in ALK, AKT1-3, BRAF, CCND1-3, CTNNB1, EGFR, ERBB2, FGFR1, FGFR2, HRAS, KRAS, MDM2, MET, MITF, MYC, NOTCH1-3, NRAS, PIK3CA, PI3KCB, PIK3R1, RET. Endpoints of interests were radiographic progression-free survival (rPFS), time to development of CRPC (tdCRPC), and overall survival (OS). Kaplan Meier analysis was performed and Cox regression hazard ratios (HR) calculated.

Results: A total of 477 patients were included with baseline characteristics with 117 patients (24.5%) harbored a mutation within an oncogene. A total of 172 oncogene mutations were found within the population with the most common being MYC (n=29; 16.9%), PIK3CA (n=24; 14%), CTNNB1 (n=22, 12.8%), BRAF (n=10, 5.8%), and CCND1 (n=10, 5.8%). Oncogene mutations were associated with inferior rPFS (19.2 vs. 32.2 months, P=0.03), tdCRPC (15.7 vs. 32.4 months, P<0.001), and OS (5-year OS 75.3% vs. 55.4%, P=0.01). On multivariable analysis oncogene mutations were strongly associated with tdCRPC (HR 1.42, P=0.03).

Conclusions: Oncogenes are frequency mutated in mCSPC and associated with aggressive features and inferior outcomes. Future work will need to validate these results to better assess its significance in allowing for personalization of care.