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      Circulating cell-free AR and CYP17A1 copy number variations may associate with outcome of metastatic castration-resistant prostate cancer patients treated with abiraterone

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          Abstract

          Background:

          This study aimed to investigate copy number variations (CNVs) of CYP17A1 and androgen receptor ( AR) genes in serum cell-free DNA collected before starting abiraterone in 53 consecutive patients with castration-resistant prostate cancer (CRPC).

          Methods:

          Serum DNA was isolated and CNVs were analysed for AR and CYP17A1 genes using Taqman copy number assays. The association between CNVs and progression-free/overall survival (PFS/OS) was evaluated by the Kaplan–Meier method and log-rank test.

          Results:

          Median PFS of patients with AR gene gain was 2.8 vs 9.5 months of non-gained cases ( P<0.0001). Patients with CYP17A1 gene gain had a median PFS of 2.8 months vs 9.2 months in the non-gained patients ( P=0.0014). A lower OS was reported in both cases ( AR: P<0.0001; CYP17A1: P=0.0085). Multivariate analysis revealed that PSA decline ⩾50%, AR and CYP17A1 CNVs were associated with shorter PFS ( P<0.0001, P=0.0004 and P=0.0450, respectively), while performance status, PSA decline ⩾50%, AR CNV and DNA concentration were associated with OS ( P=0.0021, P=0.0014, P=0.0026 and P=0.0129, respectively).

          Conclusions:

          CNVs of AR and CYP17A1 genes would appear to be associated with outcome of CRPC patients treated with abiraterone.

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          Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study.

          Karim Fizazi, Howard I Scher, Arturo Molina … (2012)
          Abiraterone acetate improved overall survival in metastatic castration-resistant prostate cancer at a preplanned interim analysis of the COU-AA-301 double-blind, placebo-controlled phase 3 study. Here, we present the final analysis of the study before crossover from placebo to abiraterone acetate (after 775 of the prespecified 797 death events). Between May 8, 2008, and July 28, 2009, this study enrolled 1195 patients at 147 sites in 13 countries. Patients were eligible if they had metastatic castration-resistant prostate cancer progressing after docetaxel. Patients were stratified according to baseline Eastern Cooperative Oncology Group (ECOG) performance status, worst pain over the past 24 h on the Brief Pain Inventory-Short Form, number of previous chemotherapy regimens, and type of progression. Patients were randomly assigned (ratio 2:1) to receive either abiraterone acetate (1000 mg, once daily and orally) plus prednisone (5 mg, orally twice daily) or placebo plus prednisone with a permuted block method via an interactive web response system. The primary endpoint was overall survival, analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00091442. Of the 1195 eligible patients, 797 were randomly assigned to receive abiraterone acetate plus prednisone (abiraterone group) and 398 to receive placebo plus prednisone (placebo group). At median follow-up of 20·2 months (IQR 18·4-22·1), median overall survival for the abiraterone group was longer than in the placebo group (15·8 months [95% CI 14·8-17·0] vs 11·2 months [10·4-13·1]; hazard ratio [HR] 0·74, 95% CI 0·64-0·86; p<0·0001). Median time to PSA progression (8·5 months, 95% CI 8·3-11·1, in the abiraterone group vs 6·6 months, 5·6-8·3, in the placebo group; HR 0·63, 0·52-0·78; p<0·0001), median radiologic progression-free survival (5·6 months, 5·6-6·5, vs 3·6 months, 2·9-5·5; HR 0·66, 0·58-0·76; p<0·0001), and proportion of patients who had a PSA response (235 [29·5%] of 797 patients vs 22 [5·5%] of 398; p<0·0001) were all improved in the abiraterone group compared with the placebo group. The most common grade 3-4 adverse events were fatigue (72 [9%] of 791 patients in the abiraterone group vs 41 [10%] of 394 in the placebo group), anaemia (62 [8%] vs 32 [8%]), back pain (56 [7%] vs 40 [10%]), and bone pain (51 [6%] vs 31 [8%]). This final analysis confirms that abiraterone acetate significantly prolongs overall survival in patients with metastatic castration-resistant prostate cancer who have progressed after docetaxel treatment. No new safety signals were identified with increased follow-up. Copyright © 2012 Elsevier Ltd. All rights reserved.
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            Intratumoral de novo steroid synthesis activates androgen receptor in castration-resistant prostate cancer and is upregulated by treatment with CYP17A1 inhibitors.

            Changmeng Cai, Sen Chen, Patrick Ng … (2011)
            Relapse of castration-resistant prostate cancer (CRPC) that occurs after androgen deprivation therapy of primary prostate cancer can be mediated by reactivation of the androgen receptor (AR). One important mechanism mediating this AR reactivation is intratumoral conversion of the weak adrenal androgens DHEA and androstenedione into the AR ligands testosterone and dihydrotestosterone. DHEA and androstenedione are synthesized by the adrenals through the sequential actions of the cytochrome P450 enzymes CYP11A1 and CYP17A1, so that CYP17A1 inhibitors such as abiraterone are effective therapies for CRPC. However, the significance of intratumoral CYP17A1 and de novo androgen synthesis from cholesterol in CRPC, and the mechanisms contributing to CYP17A1 inhibitor resistance/relapse, remain to be determined. We report that AR activity in castration-resistant VCaP tumor xenografts can be restored through CYP17A1-dependent de novo androgen synthesis, and that abiraterone treatment of these xenografts imposes selective pressure for increased intratumoral expression of CYP17A1, thereby generating a mechanism for development of resistance to CYP17A1 inhibitors. Supporting the clinical relevance of this mechanism, we found that intratumoral expression of CYP17A1 was markedly increased in tumor biopsies from CRPC patients after CYP17A1 inhibitor therapy. We further show that CRPC cells expressing a progesterone responsive T877A mutant AR are not CYP17A1 dependent, but that AR activity in these cells is still steroid dependent and mediated by upstream CYP11A1-dependent intraturmoral pregnenolone/progesterone synthesis. Together, our results indicate that CRPCs resistant to CYP17A1 inhibition may remain steroid dependent and therefore responsive to therapies that can further suppress de novo intratumoral steroid synthesis.
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              Antitumour activity of abiraterone acetate against metastatic castration-resistant prostate cancer progressing after docetaxel and enzalutamide (MDV3100).

              Y Loriot, D Bianchini, E Ileana … (2013)
              Androgen receptor (AR) signalling remains critically important in metastatic castration-resistant prostate cancer (mCRPC) as confirmed by recent phase III trials, showing a survival advantage for abiraterone acetate and enzalutamide (MDV3100). The antitumour activity of abiraterone and prednisolone in patients pre-treated with enzalutamide is as yet unknown. We investigated the antitumour activity of abiraterone and prednisolone in patients with mCRPC who had progressed following treatment with docetaxel (Taxotere) and enzalutamide. Clinical data were retrospectively analysed for prostate-specific antigen (PSA) and RECIST responses, clinical benefit and survival. Thirty-eight patients were included in the analysis. The median age was 71 years (range 52-84); metastatic sites included bone disease in 37 patients (97%), lymph nodes in 15 patients (39%) and visceral disease in 10 patients (26%). Abiraterone was well tolerated. Three patients (8%) attained a PSA response, defined as ≥50% decline in PSA confirmed after ≥4 weeks, while seven patients (18%) had a ≥30% PSA decline. The median progression-free survival (PFS) was 2.7 months (95% CI 2.3-4.1). Of the 12 patients assessable radiologically, only 1 (8%) attained a confirmed partial response. Abiraterone and prednisolone have modest antitumour activities in patients with mCRPC pretreated with docetaxel and enzalutamide.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Br J Cancer
                Journal ID (iso-abbrev): Br. J. Cancer
                Title: British Journal of Cancer
                Publisher: Nature Publishing Group
                ISSN (Print): 0007-0920
                ISSN (Electronic): 1532-1827
                Publication date (Print): 12 May 2015
                Publication date (Electronic): 21 April 2015
                Volume: 112
                Issue: 10
                Pages: 1717-1724
                Affiliations
                [1 ]Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS , Meldola, Italy
                [2 ]Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS , Meldola, Italy
                [3 ]Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS , Meldola, Italy
                [4 ]Pharmacy Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS , Meldola, Italy
                [5 ]The Institute of Cancer Research and the Royal Marsden , London, UK
                Author notes
                [6]

                These authors contributed equally to this work.

                Article
                Publisher Item ID: bjc2015128
                DOI: 10.1038/bjc.2015.128
                PMC ID: 4430717
                PubMed ID: 25897673
                SO-VID: f7eaf881-2610-4775-8615-a54dd8ab8a23
                Copyright © Copyright © 2015 Cancer Research UK
                License:

                From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/

                History
                Date received : 08 January 2015
                Date revision received : 24 February 2015
                Date accepted : 07 March 2015
                Categories
                Subject: Full Paper

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: abiraterone,androgen receptor,castration-resistant prostate cancer,circulating cell-free dna,cyp17a1
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: abiraterone, androgen receptor, castration-resistant prostate cancer, circulating cell-free dna, cyp17a1

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