IDH1 Mutations Are Associated with Favorable Outcomes in Prostate Cancer

Prostate cancer with isocitrate dehydrogenase 1 (IDH1) or isocitrate dehydrogenase 2 (IDH2) mutation appears to be a unique molecular subclass, but its associated clinical features have not been previously described. Here, we performed a retrospective analysis of clinical and molecular features of prostate cancer with IDH1 p.R132 or IDH2 p.R172 mutations. A series of 99 IDH1-mutated and 12 IDH2-mutated cases was identified using genomics databases at multiple institutions. An IDH1/2 wild-type control cohort was generated with matched clinical features at diagnosis. IDH-mutated cases frequently presented with localized disease (91%), but exhibited high tumor stage (42% T3) and grade (54% grade group 5). Compared with matched controls, patients with IDH1 mutations exhibited longer overall survival (hazard ratio [HR], 0.16; 95% confidence interval [CI], 0.04-0.68; p = 0.01), metastasis-free survival (HR, 0.22; 95% CI, 0.09-0.58; p = 0.002), and progression-free survival on hormonal therapy (HR, 0.35; 95% CI, 0.16-0.76; p = 0.036). IDH1-mutant cases were enriched for concurrent activating mutations of FOXA1 and CTNNB1 and tended to lack TMPRSS2-ERG fusions, SPOP mutations, and RB1 alterations. IDH1 mutations were associated with global transcriptional repression and evidence of metabolic and epigenetic reprogramming. These results depict IDH-mutant prostate cancer as a subtype that can present with high tumor stage and grade, but is associated with favorable outcomes.