SPOP mutations in prostate cancer: Clinical and genomic features.

Abstract

151 Background: Point mutations in the gene encoding speckle-type pox virus and zinc finger protein (SPOP) are the most frequently identified mutations in prostate cancer, occurring at a frequency of 6-15% across localized and disseminated cancers. Recently, SPOP gene alterations have gained attention as they appear to define a novel subclass of prostate cancers. Previous studies show that patients with mutant SPOP (mtSPOP) had superior responses to androgen deprivation therapy (ADT) and exhibit more favorable responses to abiraterone compared to wild type SPOP (wtSPOP). Methods: We retrospectively identified 59 prostate cancer patients at a single institution (Johns Hopkins) with somatic SPOP mutations from genomic testing of primary tumors (n=45), metastatic lesions (n=12), or liquid biopsies (n=2). Patient records were reviewed to determine baseline characteristics, therapies received, and clinical outcomes. The primary outcomes included best PSA response and progression-free survival (PFS) on ADT in the hormone sensitive prostate cancer (HSPC) setting and on abiraterone and/or enzalutamide in the first-line castration resistant prostate cancer (CRPC) setting. PFS was defined as either PSA, radiographic, or clinical progression. Results: The median age at diagnosis was 64 years (range 46 to 85). 17/59 (28.8%) were Black. F133 was the most frequently mutated residue, occurring in 33 (55.9%) instances (Table). There were two patients who harbored two mutations in the SPOP gene. The most frequently co-occurring mutation was in APC (15/59 [25.4%] patients), resulting in Wnt pathway activation. Concurrent ERG fusions were not observed with this cohort (0/59 [0%] patients). 41/59 (69.4%) were diagnosed with Gleason 8-10 disease. 21/59 (35.5%) were diagnosed with de novo metastatic disease. 50/59 (84.7%) patients received ADT for recurrent or metastatic disease. Median PFS on ADT was 40.7 (95% CI 23.4-71.9) months. Of the 27/59 (45.8%) patients who progressed to CRPC, 20/59 (33.9%) patients received abiraterone and 13/59 (22.0%) received enzalutamide; 9/59 (15.3%) patients received both agents. Median PFS was 7.8 (95% CI 6.7-NR) months on abiraterone and 7.3 (95% CI 3.2-NR) months on enzalutamide. Other notable therapies received in the CRPC setting include docetaxel (5/59 [8.5%] patients), cabazitaxel (5/59 [8.5%] patients), and PARP inhibitor olaparib or rucaparib (4/59 [6.8%] patients). Conclusions: SPOP mutations define a unique subset of prostate cancers enriched for black patients, high Gleason scores, absence of ERG fusions, and Wnt pathway activation. Clinical outcomes to first-line ADT appear longer than expected for genomically-unselected patients. [Table: see text]