Circulating androgen receptor combined with 18F-fluorocholine PET/CT metabolic activity and outcome to androgen receptor signalling-directed therapies in castration-resistant prostate cancer.

The association between choline uptake and androgen receptor (AR) expression is suggested by the upregulation of choline kinase-alpha in prostate cancer. Recently, detection of AR aberration in cell-free DNA as well as early 18F-fluorocholine positron emission tomography/computed tomography (FCH-PET/CT) were associated with outcome in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone and enzalutamide. We aimed to make a direct comparison between circulating AR copy number (CN) and choline uptake at FCH-PET/CT. We analysed 80 mCRPC patients progressing after docetaxel treated with abiraterone (n = 47) or enzalutamide (n = 33). We analysed AR CN from plasma samples using digital PCR and Taqman CN assays and total lesion activity (TLA) and metabolic tumor volume (MTV) on FCH-PET/CT at baseline. A meaningful correlation was showed among AR gain and TLA/MTV compared to AR non-gained cases (P = 0.001 and P = 0.004, respectively), independently from type of treatment. Multivariate analysis revealed that AR CN and only TLA were associated with both shorter PFS (P < 0.0009 and P = 0.026, respectively) and OS (P < 0.031 and P = 0.039, respectively). AR gain appeared significantly correlated with choline uptake represented mainly by TLA. Further prospective studies are warranted to better address this pathway of AR-signalling and to identify multiplex biomarker strategies including plasma AR and FCH-PET/CT in mCRPC patients.

Androgen receptor gene status in plasma DNA associates with worse outcome on enzalutamide or abiraterone for castration-resistant prostate cancer: a multi-institution correlative biomarker study.

BACKGROUND: There is an urgent need to identify biomarkers to guide personalized therapy in castration-resistant prostate cancer (CRPC). We aimed to clinically qualify androgen receptor (AR) gene status measurement in plasma DNA using multiplex droplet digital PCR (ddPCR) in pre- and post-chemotherapy CRPC. METHODS: We optimized ddPCR assays for AR copy number and mutations and retrospectively analyzed plasma DNA from patients recruited to one of the three biomarker protocols with prospectively collected clinical data. We evaluated associations between plasma AR and overall survival (OS) and progression-free survival (PFS) in 73 chemotherapy-naïve and 98 post-docetaxel CRPC patients treated with enzalutamide or abiraterone (Primary cohort) and 94 chemotherapy-naïve patients treated with enzalutamide (Secondary cohort; PREMIERE trial). RESULTS: In the primary cohort, AR gain was observed in 10 (14%) chemotherapy-naïve and 33 (34%) post-docetaxel patients and associated with worse OS [hazard ratio (HR), 3.98; 95% CI 1.74-9.10; P < 0.001 and HR 3.81; 95% CI 2.28-6.37; P < 0.001, respectively], PFS (HR 2.18; 95% CI 1.08-4.39; P = 0.03, and HR 1.95; 95% CI 1.23-3.11; P = 0.01, respectively) and rate of PSA decline ≥50% [odds ratio (OR), 4.7; 95% CI 1.17-19.17; P = 0.035 and OR, 5.0; 95% CI 1.70-14.91; P = 0.003, respectively]. AR mutations [2105T>A (p.L702H) and 2632A>G (p.T878A)] were observed in eight (11%) post-docetaxel but no chemotherapy-naïve abiraterone-treated patients and were also associated with worse OS (HR 3.26; 95% CI 1.47-not reached; P = 0.004). There was no interaction between AR and docetaxel status (P = 0.83 for OS, P = 0.99 for PFS). In the PREMIERE trial, 11 patients (12%) with AR gain had worse PSA-PFS (sPFS) (HR 4.33; 95% CI 1.94-9.68; P < 0.001), radiographic-PFS (rPFS) (HR 8.06; 95% CI 3.26-19.93; P < 0.001) and OS (HR 11.08; 95% CI 2.16-56.95; P = 0.004). Plasma AR was an independent predictor of outcome on multivariable analyses in both cohorts. CONCLUSION: Plasma AR status assessment using ddPCR identifies CRPC with worse outcome to enzalutamide or abiraterone. Prospective evaluation of treatment decisions based on plasma AR is now required. CLINICAL TRIAL NUMBER: NCT02288936 (PREMIERE trial).

Impact of Candidate Genetic Polymorphisms in Prostate Cancer: An Overview.

In the last few years, the presence of single nucleotide polymorphisms (SNPs) has been investigated in many tumors as predictor of disease aggressiveness and clinical outcome. We searched for relevant articles from 1998 to 2015 about the impact of SNPs in prostate cancer. Particularly, in this article, we review the pathogenetic, prognostic and predictive significance of gene polymorphisms in prostate tumor, providing a brief overview of studies in which the possible role of genetic variants was investigated in clinical settings. Because conflicting results often emerge about the impact of gene polymorphisms in prostate cancer, further larger studies are warranted in order to introduce gene polymorphism into clinical practice as biomarkers.

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

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.

Combining cytology, TRAP assay, and FISH analysis for the detection of bladder cancer in symptomatic patients.

BACKGROUND: There is a need to improve the performance of urine cytology in bladder cancer diagnosis. We assessed the diagnostic performance of (i) telomerase activity detected by telomeric repeat amplification protocol (TRAP) assay, (ii) cytology and TRAP assay in parallel, (iii) cytology in parallel with the in-series combination of TRAP assay and FISH analysis, and (iv) the in-series combination of TRAP assay and FISH analysis. PATIENTS AND METHODS: Cross-sectional study of 289 consecutive patients who presented with urinary symptoms at a north Italian hospital between 2007 and 2008. All underwent cystoscopy and cytology evaluation, and conclusive results were available for TRAP assay and FISH analysis. RESULTS: Sensitivity and specificity were 0.39 and 0.83, respectively, for cytology; 0.66 and 0.72 for TRAP; 0.78 and 0.60 for the combination of cytology and TRAP; 0.78 and 0.78 for the combination of cytology, TRAP, and FISH; and 0.65 and 0.93 for the combination of TRAP and FISH. All differences versus cytology alone were significant (P ≤ 0.011). CONCLUSION: Compared with cytology alone, the combination of cytology, TRAP, and FISH provided the best trade-off between increase in sensitivity and loss in specificity, especially among non-bleeding patients, low-grade cancers, and early-stage cancers.

Pregnancies in postmenopausal women over 50 years old in an oocyte donation program.

OBJECTIVE: To determine the potential of the aging uterus in terms of pregnancy, implantation, and abortion rates, and obstetric complications in postmenopausal women age 50 and over, receiving oocyte donation. DESIGN: Retrospective data analysis. SETTING: A tertiary infertility center. PATIENTS: Thirty-four postmenopausal women (50 to 62 years of age) undergoing a total of 61 cycles of oocyte donation. INTERVENTIONS: Hormone replacement therapy (HRT) was given using increasing doses of 17 beta-E2 (2, 4, and 6 mg) and 100 mg of P in oil. MAIN OUTCOME MEASURES: Pregnancy, abortion, and implantation rates, and pregnancy outcome. RESULTS: There were 34 patients treated through 61 cycles. Fifty-five transfer cycles were performed. A total of 18 clinical pregnancies were achieved with a pregnancy rate per transfer of 32.7% and per patient of 52.9%. There was one abortion, resulting in an abortion rate of 5.5%. Twenty-one of the 116 transferred embryos implanted, resulting in an implantation rate of 18%. No statistically different rates were found in oocytes donors. CONCLUSION: Women over the age of 50 and up to 62 can become pregnant using donated oocytes. The aging uterus after HRT allows implantation as well as in young women, and it is able to carry pregnancy to term apparently without any problems.