Molecular features and race-associated outcomes of SPOP-mutant metastatic castration-resistant prostate cancer
Stangl A, Wilner C, Li P, Maahs L, Hwang C, and Pilling A. Molecular features and race-associated outcomes of SPOP-mutant metastatic castration-resistant prostate cancer. Prostate 2023.
BACKGROUND: Inactivating alterations in SPOP frequently occur in prostate cancer and promote increased dependency on androgen receptor (AR)-mediated oncogenic signaling. The presence of SPOP mutation (SPOP-mutant [SPOP-mut]) may therefore impact therapeutic outcomes with AR-directed therapies and docetaxel in metastatic castration-resistant (mCRPC).
METHODS: This was a retrospective study of mCRPC patients treated at an urban academic hospital (n = 103). Patients underwent tumor DNA sequencing to determine SPOP mutational status (SPOP-mut). Outcomes measured were overall survival (OS) from diagnosis and treatment with second-generation AR signaling inhibitor (ARSI) or docetaxel and time to PSA progression (prostate-specific antigen-progression-free survival [PSA-PFS]) compared by SPOP status using Kaplan-Meier curves and log-rank test. The univariable and multivariable Cox proportional hazard model evaluated the association of SPOP mutation and outcomes adjusted for clinicopathologic features.
RESULTS: SPOP-mut was associated with longer PSA-PFS in mCRPC (median 1.79 vs. 0.84 years; p = 0.06) and multivariate analysis (hazard ratio [HR] = 0.37; 95% confidence interval [CI]: 0.17-0.84; p = 0.02). SPOP-mut demonstrated a higher median PSA decline compared to SPOP wild-type (median decline 100% vs. 92%, p = 0.02). SPOP-mut was not associated with OS from the start of ARSI or docetaxel (median OS not reached vs. 2.0 years) or PSA-PFS on docetaxel (median PSA-PFS 0.4 vs. 0.5 years) in mCRPC. The majority of SPOP mutations were identified in African American (AA) patients (69.2%) compared to Caucasian patients (30.8%). Race-associated multivariate analysis revealed no significant differences in OS from the start of ARSI or the start of docetaxel and no differences in ARSI or docetaxel PSA-PFS between AA and Caucasian patients. Molecular profiling demonstrated that AA patients had a higher frequency of SPOP mutations and greater heterogeneity of SPOP variants within the coding sequence. Analysis of concurrent genomic alterations revealed that SPOP mutations co-occur with APC mutations (p = 0.001) and alterations in the Wnt pathway (p = 0.017).
CONCLUSIONS: Inactivating mutations in SPOP are associated with better response to ARSI treatment in mCRPC overall. Additional analysis with a larger cohort is needed to evaluate the association of SPOP status and outcomes with docetaxel. Race-associated clinical outcomes and molecular features were observed, suggesting the benefit of biomarker-directed therapy selection for individualized patient subsets in guiding treatment decisions for mCRPC patients.
ePub ahead of print