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Clinical Significance of Androgen Receptor Splice Variant-7 mRNA Detection in Circulating Tumor Cells of Men With Metastatic Castration-Resistant Prostate Cancer Treated With First- and Second-Line Abiraterone and Enzalutamide.

ABSTRACT: Purpose We reported previously that the detection of androgen receptor splice variant-7 (AR-V7) mRNA in circulating tumor cells (CTCs) correlated with poor outcomes from the use of abiraterone and enzalutamide in patients with castration-resistant prostate cancer (CRPC). Here, we expanded our cohort size to better characterize the prognostic significance of AR-V7 in this setting. Methods We prospectively enrolled 202 patients with CRPC starting abiraterone or enzalutamide and investigated the prognostic value of CTC detection (+ v -) and AR-V7 detection (+ v -) using a CTC-based AR-V7 mRNA assay. We examined ≥ 50% prostate-specific antigen (PSA) responses, PSA progression-free survival, clinical and radiologic progression-free survival, and overall survival. We constructed multivariable models adjusting for PSA, Gleason sum, number of prior hormone therapies, prior abiraterone or enzalutamide use, prior taxane use, presence of visceral metastases, and Eastern Cooperative Oncology Group score. We also separately examined the first-line and second-line novel hormonal therapy (NHT) settings. Results Median follow-up times were 15.0, 21.7, and 14.6 months for CTC-, CTC+/AR-V7- and CTC+/AR-V7+ patients, respectively. CTC+/AR-V7+ patients were more likely to have Gleason scores ≥ 8 ( P = .05), metastatic disease at diagnosis ( P = .01), higher PSA ( P < .01), prior abiraterone or enzalutamide use ( P = .03), prior taxane use ( P = .02), and Eastern Cooperative Oncology Group ≥ 1 ( P = .01). Outcomes for the overall cohort (and separately for the first-line and second-line NHT cohorts) were best for CTC- patients, intermediate for CTC+/AR-V7- patients, and worse for CTC+/AR-V7+ patients. These correlations remained significant in multivariable models. Conclusion This expanded analysis further characterizes the importance of CTC-based AR-V7 mRNA detection in predicting outcomes in patients with CRPC receiving first- and second-line NHT and, to the best of our knowledge, is the first to suggest that this assay be interpreted using three separate prognostic categories: CTC-, CTC+/AR-V7-, and CTC+/AR-V7+.

SUBMITTER: Antonarakis ES

PROVIDER: S-EPMC5493048 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundInherited DNA-repair gene mutations are more prevalent in men with advanced prostate cancer than previously thought, but their clinical implications are not fully understood.ObjectiveTo investigate the clinical significance of germline DNA-repair gene alterations in men with metastatic castration-resistant prostate cancer (mCRPC) receiving next-generation hormonal therapy (NHT), with a particular emphasis on BRCA/ATM mutations.Design, setting, and participantsWe interrogated 50 genes for pathogenic or likely pathogenic germline mutations using leukocyte DNA from 172 mCRPC patients beginning treatment with first-line NHT with abiraterone or enzalutamide.Outcome measurements and statistical analysisWe assessed the impact of germline DNA-repair gene mutation status on ≥50% and ≥90% PSA responses, PSA progression-free survival (PSA-PFS), clinical/radiologic progression-free survival (PFS), and overall survival (OS). Survival outcomes were adjusted using propensity score-weighted multivariable Cox regression analyses.Results and limitationsAmong 172 mCRPC patients included, germline mutations (in any DNA-repair gene) were found in 12% (22/172) of men, and germline BRCA/ATM mutations specifically in 5% (9/172) of men. In unadjusted analyses, outcomes to first-line NHT were better in men with germline BRCA/ATM mutations (vs no mutations) with respect to PSA-PFS (hazard ratio [HR] 0.47; p=0.061), PFS (HR 0.50; p=0.090), and OS (HR 0.28; p=0.059). In propensity score-weighted multivariable analyses, outcomes were superior in men with germline BRCA/ATM mutations with respect to PSA-PFS (HR 0.48, 95% confidence interval [CI] 0.25-0.92; p=0.027), PFS (HR 0.52, 95% CI 0.28-0.98; p=0.044), and OS (HR 0.34, 95% CI 0.12-0.99; p=0.048), but not in men with non-BRCA/ATM germline mutations (all p>0.10). These results require prospective validation, and our conclusions are limited by the small number of patients (n=9) with BRCA/ATM mutations.ConclusionsOutcomes to first-line NHT appear better in mCRPC patients harboring germline BRCA/ATM mutations (vs no mutations), but not for patients with other non-BRCA/ATM germline mutations.Patient summaryPatients with metastatic castration-resistant prostate cancer and harboring germline mutations in BRCA1/2 and ATM benefit from treatment with abiraterone and enzalutamide.

Project description:BackgroundThe optimal sequencing of the multiple active agents now available for metastatic castration-resistant prostate cancer (mCRPC) is unclear. Prior reports have suggested diminished responses to sequential lines of androgen receptor (AR)-targeted therapies, but it is unknown whether subsequent taxane-based chemotherapy may be more effective than sequential AR-targeting treatment. We sought to evaluate the clinical activity of enzalutamide versus docetaxel in men with mCRPC who progressed on abiraterone.MethodsWe performed a single-institution retrospective analysis of consecutive mCRPC patients who had progressed on abiraterone therapy and subsequently received either enzalutamide (n=30) or docetaxel (n=31). We evaluated clinical outcomes including prostate-specific antigen decline of >30% (PSA30) or >50% (PSA50), PSA-progression-free survival (PSA-PFS), and clinical/radiographic PFS. We performed multivariable modeling to control for baseline and on-treatment differences between groups.ResultsCompared to subjects who received enzalutamide post-abiraterone, subjects who received docetaxel post-abiraterone had more bone metastases, more visceral metastases, higher baseline PSA, and had more frequent PSA tests while on-treatment. There were no significant differences in PSA30 (41% for enzalutamide vs. 53% for docetaxel) or PSA50 (34% vs. 40%) response rates between the two groups; there remained no difference after stratifying by presence/absence of prior response to abiraterone. Median PSA-PFS was 4.1 versus 4.1 months for the enzalutamide and docetaxel cohorts, respectively (HR 1.35, 95% CI, 0.53-3.66, P=0.502). Median PFS was 4.7 versus 4.4 months, respectively (HR 1.44, 95% CI, 0.77-2.71, P=0.257). PSA-PFS and PFS did not differ after stratifying by prior response to abiraterone. In multivariable analyses, there were no significant differences in PSA-PFS or PFS between the two groups.ConclusionsTreatment with either enzalutamide or docetaxel produced modest PSA responses and PFS intervals in this abiraterone-pretreated mCRPC population. In this retrospective study with small sample size, no significant differences in outcomes were observed between groups. Therefore, either enzalutamide or docetaxel may be a reasonable option in men who have progressed on abiraterone.

Project description:BackgroundWnt signaling is a cellular pathway involved in embryogenesis, development, and neoplasia. Wnt-pathway activation may accelerate prostate cancer androgen-independent growth and mediate antiandrogen resistance. Since 10-20% of advanced prostate cancers harbor Wnt-activating mutations, we aimed to characterize the clinical features and response to novel antiandrogens in such patients.ObjectiveTo determine whether men with metastatic castration-resistant prostate cancer (mCRPC) who harbor Wnt-pathway mutations have poorer responses to first-line novel hormonal therapies: abiraterone/enzalutamide.Design, setting, and participantsPatients with mCRPC who received first-line abiraterone or enzalutamide were retrospectively evaluated. Using tumor DNA analyses, we queried for activating mutations in CTNNB1 or inactivating mutations in APC or RNF43, all of which are predicted to stimulate Wnt signaling. Presence or absence of at least one Wnt-activating alteration was correlated with clinical-pathologic characteristics and treatment outcomes.Outcome measurements and statistical analysisTime to prostate-specific antigen (PSA) progression, overall survival (OS), and PSA response were measured. Cox regression models were used to test associations between Wnt status and clinical-pathologic outcomes; Kaplan-Meier and log-rank analyses were used to compare time-to-event endpoints.Results and limitationsOf 137 patients evaluated, 11% (n=15) had tumor DNA analysis showing at least one Wnt-stimulating alteration. Patients with Wnt-activating mutations had numerically fewer T3/T4 tumors than Wnt wild-type patients (31% vs 51%), but were otherwise generally balanced. Median time to PSA progression on first-line abiraterone/enzalutamide was shorter in Wnt-activated patients (6.5 vs 9.6mo, hazard ratio [HR] 2.34, p=0.003), as was OS (23.6 vs 27.7mo, HR 2.28, p=0.01). PSA responses were numerically worse in Wnt-activated patients (53% vs 75%, p=0.12). Presence of Wnt-activating alterations (adjusted HR [aHR] 2.33, p=0.007) and use of previous chemotherapy (aHR 1.83, p=0.004) were both independently associated with increased hazard of progression.ConclusionsPatients with somatic Wnt-pathway activating mutations have worse outcomes to first-line abiraterone/enzalutamide than Wnt wild-type patients. Our data suggest that additional genomically informed therapies are needed for this relevant subset of mCRPC patients.Patient summaryIn this report, we retrospectively examined outcomes of metastatic prostate cancer patients with or without Wnt-pathway mutations who received abiraterone or enzalutamide for the first time, in order to examine whether these mutations affect the prognosis. Our study suggested that patients who have Wnt-pathway activating mutations derived less benefit from abiraterone and enzalutamide when compared to patients without these mutations. We conclude that Wnt-pathway mutations might decrease the effectiveness of abiraterone and enzalutamide, and we propose that the Wnt pathway might be a good therapeutic target for these patients, in order to potentially reverse or prolong resistance to abiraterone and enzalutamide in men with Wnt mutations.

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Clinical Significance of Androgen Receptor Splice Variant-7 mRNA Detection in Circulating Tumor Cells of Men With Metastatic Castration-Resistant Prostate Cancer Treated With First- and Second-Line Abiraterone and Enzalutamide.

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