PI3K/AKT signaling is commonly hijacked in prostate cancer (PC), associating with poorer prognosis and worse response to next generation hormonal treatment (NGHT) including abiraterone and enzalutamide. We studied deleterious pathway mutations in metastatic castration resistant PC (mCRPC) patients correlating these to prognosis and response to NGHT in a case-control study.
Patients with mCRPC and available treatment-naïve and/or CRPC tumor samples were evaluated. Mutation analyses involved MiSeqTM based targeted next generation sequencing (NGS); PTEN was assessed by immunohistochemistry (IHC) with the control cohort having no PTEN IHC loss. Correlations between pathway mutations and outcomes and response to NGHT utilized Cox and Kaplan-Meier analyses.
Overall 418 samples (from Feb/15 to Dec/17) were sequenced by targeted NGS; 46 (11%) had mutated pathway genes of which 26 (6%) (PIK3CA, n = 18; AKT1, n = 6; PIK3R1, n = 2) were pathogenic pathway activating mutations. Among these 25 were previously described, while an undescribed PIK3R1 mutation (R543*), located in the iSH2 domain, was also identified. We then randomly selected 56 tumour samples with normal PTEN expression by IHC as a control group without detected pathway aberrations. Overall, 43% (10/23) of patients with mutated cancers had NGHT in pre-, and 57% (13/23) in post-chemotherapy settings, while 3 were NGHT naïve. In the control group, 14 patients (25%) were pre-chemotherapy while 42 (75%) post-chemotherapy. Deleterious pathway mutations were associated with a shorter median overall survival (2.8 vs 4.3 years; HR: 2.73; p < 0.001) and median duration of NGHT (5.9 vs 10.0 mo; p < 0.001), despite a higher proportion of post-chemotherapy patients in the control group.
PI3K/AKT pathway deleterious mutations impart a poor prognosis from mCRPC and are associated with shorter responses to NGHT. We envision that these data can impact treatment selection in a targeted treatment approach for mCRPC.
Clinical trial identification
Legal entity responsible for the study
The Institute of Cancer Reserach.
CRUK, Movember, PCF, PCUK.
All authors have declared no conflicts of interest.