Clinical and genomic features of SPOP‐mutant prostate cancer

Abstract

Background Inactivating missense mutations in the SPOP gene, encoding speckle‐type poxvirus and zinc‐finger protein, are one of the most common genetic alterations in prostate cancer. Methods We retrospectively identified 72 consecutive prostate cancer patients with somatic SPOP mutations, through next‐generation sequencing analysis, who were treated at the Johns Hopkins Hospital. We evaluated clinical and genomic characteristics of this SPOP‐mutant subset. Results SPOP alterations were clustered in the MATH domain, with hotspot mutations involving the F133 and F102 residues. The most frequent concurrent genetic alterations were in APC (16/72 [22%]), PTEN (13/72 [18%]), and TP53 (11/72 [15%]). SPOP‐mutant cancers appeared to be mutually exclusive with tumors harboring the TMPRSS2‐ERG fusion, and were significantly enriched for Wnt pathway (APC, CTNNB1) mutations and de‐enriched for TP53/PTEN/RB1 alterations. Patients with mtSPOP had durable responses to androgen deprivation therapy (ADT) with a median time‐to‐castration‐resistance of 42.0 (95% confidence interval [CI], 25.7–60.8) months. However, time‐to‐castration‐resistance was significantly shorter in SPOP‐mutant patients with concurrent TP53 mutations (hazard ratio [HR] 4.53; p = 0.002), HRD pathway (ATM, BRCA1/2, and CHEK2) mutations (HR 3.19; p = 0.003), and PI3K pathway (PTEN, PIK3CA, and AKT1) alterations (HR 2.69; p = 0.004). In the castration‐resistant prostate cancer setting, median progression‐free survival was 8.9 (95% CI, 6.7–NR) months on abiraterone and 7.3 (95% CI, 3.2–NR) months on enzalutamide. There were no responses to PARP inhibitor treatment. Conclusions SPOP‐mutant prostate cancers represent a unique subset with absent ERG fusions and frequent Wnt pathway alterations, with potentially greater dependency on androgen signaling and enhanced responsiveness to ADT. Outcomes are best for SPOP‐altered patients without other concurrent mutations.

The evolving landscape of prostate cancer somatic mutations

“…83,84 However, both studies could be seen as hypothesisgenerating given the small numbers 83 and mixed treatment populations. 84 Nakazawa et al recently reported on the outcome of 72 consecutive SPOPmut PCa from a single institution. 84 The SPOPmut PCa came from patients who had durable responses to first-line ADT, but their cohort included a heterogeneous group of patients with metastatic and nonmetastatic hormone-sensitive disease, as well as patients receiving concurrent chemotherapy and/or ASRi (i.e., abiraterone, enzalutamide).…”

“…Two studies examining men with advanced PCa treated with ARSi both suggested SPOPmut PCa have an increased sensitivity to ARSi 83,84 . However, both studies could be seen as hypothesis‐generating given the small numbers 83 and mixed treatment populations 84 . Nakazawa et al recently reported on the outcome of 72 consecutive SPOPmut PCa from a single institution 84 .…”

“…84 Nakazawa et al recently reported on the outcome of 72 consecutive SPOPmut PCa from a single institution. 84 The SPOPmut PCa came from patients who had durable responses to first-line ADT, but their cohort included a heterogeneous group of patients with metastatic and nonmetastatic hormone-sensitive disease, as well as patients receiving concurrent chemotherapy and/or ASRi (i.e., abiraterone, enzalutamide). Therefore, from these observations and the observations regarding the decreased frequency of SPOPmut in ARSi treated patients, one can hypothesize that increased sensitivity of SPOPmut tumors could have clinical implications, however, they will require larger prospective studies.…”

Mutator-Derived lncRNA Landscape: A Novel Insight Into the Genomic Instability of Prostate Cancer

“…The above evidence may explain why low CDK expression existed in the high GILncSig risk group in our results. Moreover, inactivating missense mutations in SPOP is one of the most common gene mutations in PCa, especially in the localized PCa ( 67 ). SPOP inactivation leads to overexpression of the androgen receptor (AR) and further promotes cell proliferation ( 68 ).…”

Developing New Treatment Options for Castration-Resistant Prostate Cancer and Recurrent Disease

“…Surprisingly, PCa patients with mutant SPOP appear to delay the onset of ADT resistance to 42.0 (95% CI: 25.7–60.8) months. Also, the better outcomes in patients with mutant SPOP treated with abiraterone and enzalutamide were observed [ 42 , 43 ]. Therefore, it implies that SPOP mutation could enhance ADT effect by maintaining AR dependency.…”