BackgroundLoss of the tumor suppressor phosphatase and tensin homolog (PTEN) occurs frequently in prostate cancers. Preclinical evidence suggests that activation of PI3K/AKT signaling through loss of PTEN can result in resistance to hormonal treatment in prostate cancer.ObjectiveTo explore the antitumor activity of abiraterone acetate (abiraterone) in castration-resistant prostate cancer (CRPC) patients with and without loss of PTEN protein expression.Design, setting, and participantsWe retrospectively identified patients who had received abiraterone and had hormone-sensitive prostate cancer (HSPC) and/or CRPC tissue available for PTEN immunohistochemical analysis.Outcome measurements and statistical analysisThe primary end point was overall survival from initiation of abiraterone treatment. Relationship with outcome was analyzed using multivariate Cox regression and log-rank analyses.Results and limitationsA total of 144 patients were identified who had received abiraterone post-docetaxel and had available tumor tissue. Overall, loss of PTEN expression was observed in 40% of patients. Matched HSPC and CRPC tumor biopsies were available for 41 patients. PTEN status in CRPC correlated with HSPC in 86% of cases. Loss of PTEN expression was associated with shorter median overall survival (14 vs 21 mo; hazard ratio [HR]: 1.75; 95% confidence interval [CI], 1.19–2.55; p = 0.004) and shorter median duration of abiraterone treatment (24 vs 28 wk; HR: 1.6; 95% CI, 1.12–2.28; p = 0.009). PTEN protein loss, high lactate dehydrogenase, and the presence of visceral metastases were identified as independent prognostic factors in multivariate analysis.ConclusionsOur results indicate that loss of PTEN expression was associated with worse survival and shorter time on abiraterone treatment. Further studies in larger and prospective cohorts are warranted.Patient summaryPTEN is a protein often lost in prostate cancer cells. In this study we evaluated if prostate cancers that lack this protein respond differently to treatment with abiraterone acetate. We demonstrated that the survival of patients with loss of PTEN is shorter than patients with normal PTEN expression.

Metastatic involvement of the viscera in men with advanced castration-resistant prostate cancer (CRPC) has been poorly characterized to date.In 359 CRPC patients treated between June 2003 and December 2011, the frequency of radiologically detected visceral metastases before death was 32%. Of the 92 patients with computed tomography performed within 3 months of death, 49% had visceral metastases. Visceral metastases most commonly involved the liver (20%) and lung (13%). Median survival from diagnosis of visceral disease was 7.1 months (95% CI 5.9 -8.3). Survival was impacted by the degree of bone involvement at detection of visceral disease, varying from 6.1 months in men with >6 bone metastases to 18.2 months in men with no bone metastases (p = 0.001). Heterogeneity was noted in clinical phenotypes and PSA trends at development of visceral metastases. Visceral metastases are now more commonly detected in men with CRPC, likely due to the introduction of novel survival-prolonging treatments.Visceral disease was previously considered uncommon in men with advanced prostate cancer and has been associated with neuroendocrine phenotypes and poor outcome [1]. In recent Phase III post-docetaxel trials, 23-29% of participants had visceral metastases [2][3][4]. Autopsy studies on men who died from prostate cancer suggested a higher prevalence of visceral metastases, up to 66% of selected cases [5], but these metastases did not appear clinically relevant. Subset analyses of patients with visceral disease in the post-docetaxel abiraterone and enzalutamide Phase III trials showed hazard ratios of 0.79 (0.60-1.05) and 0.78 (0.56-1.09) respectively, suggesting these patients may derive benefit from targeting of the androgen receptor (AR) [3,4]. The Phase III clinical trials of sipuleucel-T, radium 223 and abiraterone in chemotherapy-naïve CRPC specifically excluded men with visceral disease. With the introduction of several new survival-prolonging treatments (reviewed in[6]) we hypothesized that more patients will develop visceral involvement, requiring improved recognition and molecular characterization in order to improve individual patient management. To explore the prevalence of visceral disease in CRPC, we examined our database of clinical trial participants. This population has been described previously [7] and all patients provided consent for data collection in IRB-approved protocols. Patients had regular 12 weekly (or 6 weekly if specified in trial protocols) computed tomography (CT) scans of the thorax, abdomen and pelvis performed for restaging or for investigation of new symptoms. Brain CT scans were performed in response to neurological symptoms. Bone metastases were assessed using standard bone scans. These prospectively collected scans were reviewed for evidence of visceral involvement, defined as disease involving liver, lungs, adrenal glands, peritoneum or pleura, brain and dura. Descriptive statistics, Kaplan Meier survival analyses and Cox regressions were performed using SPSS Statistics v20 (IBM). Q...

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