160 Background: Predictive markers linking molecular background to treatment response and clinical outcomes are currently lacking in prostate cancer. Missense mutations in SPOP (speckle-type POZ protein) define a distinct molecular subtype, occurring in about 12% of both clinically localized and metastatic disease. SPOP mutations occur early in prostate tumorigenesis and facilitate dysregulation of the androgen-receptor (AR) signaling network, suggesting mutant SPOP can impact response to AR-directed therapies. We hypothesized that SPOP mutation will be associated with superior response to next-generation AR inhibitors in metastatic castration-resistant prostate cancer (mCRPC). Methods: This is a retrospective study to evaluate patients who progressed to mCRPC and were treated with AR-targeted therapy (i.e. enzalutamide, abiraterone acetate). Eligibility criteria inlcuded androgen deprivation therapy, metastatic disease documented by bone lesion or soft tissue identified on imaging, castrate testosterone level ( < 50g/dL), and evaluable tissue for DNA analysis. SPOP status was determined by next-generation sequencing. Time to PSA progression (PSA TTP) was defined per PCWG2 as PSA increase of 25% from nadir and a minimum of 2 ng/ml calculated from date of primary treatment initiation to the date of PSA progression. Overall survival (OS) was calculated from start of treatment to date of death. Statisitcal comparision of the SPOP mutant or wild-type was determined using Kaplan-Meier and independent t-test analysis. Results: The analysis included 69 men with mCRPC with previous or ongoing ADT and receipt of AR-directed therapy (aberaterone acetate, enzalutamide). SPOP status was determined for all patients: 7 patients SPOP mutant, 62 patients SPOP wild-type. Mutant SPOP was associated with significantly longer PSA TTP (22.5 vs. 9.7 months, p = 0.031) and improved OS (21 vs. 29 months, p = 0.12) with enzalutamide or abiraterone as compared to SPOP wild-type patients. Conclusions: Our data demonstrate that SPOP mutations predict for better outcomes with next-generation AR inhibitors in men with mCRPC. SPOP mutations are a prominent molecular sub-type with potential to impact clinical management in men with metastatic, therapy resistant prostate cancer.
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 antigenprogression-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
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