Emanuela Bianchi

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.

PSA flare with abiraterone in patients with metastatic castration-resistant prostate cancer.

BACKGROUNDnThe aim of this study was to assess early serum prostate-specific antigen (PSA) changes in patients treated with abiraterone and to correlate those changes with clinical outcome.nnnPATIENTS AND METHODSnWe retrospectively evaluated 103 patients with castrate-resistant prostate cancer (CRPC) treated with compassionate use of abiraterone in Romagna, Italy. In these patients, serum PSA levels were monitored every 4 weeks, and a time course of serum PSA levels was obtained. The PSA flare phenomenon was evaluated. The log-rank test was applied to compare survival between groups of patients according to early PSA level changes.nnnRESULTSnOf 103 patients, 43 (41.7%) had an immediate PSA response, whereas 9 (8.7%) had an initial PSA flare. Of the 9 patients with PSA flare, 5 attained a subsequent PSA response. The temporary PSA flare exceeded baseline values by a median of 19.7% (range, 5%-62.9%). The median PFS of the 9 patients in the PSA-flare group was higher compared with patients without the PSA flare (10.5 vs. 6.4 months; P = .0999) but was similar to the subgroup of patients with immediate PSA response (10.5 vs. 10.7 months; P = .7019). In the multivariate analysis, only the PSA response remained as a predictor of progression-free survival (PFS) (P < .0001) and overall survival (OS) (P = .0003), respectively.nnnCONCLUSIONnPSA flare occurs not infrequently in patients with CRPC who respond to abiraterone. Patients should be informed of this possible PSA flare phenomenon.

Chromogranin A predicts outcome in prostate cancer patients treated with abiraterone.

In this retrospective study, we evaluated the chromogranin A (CgA) baseline value as a predictor of clinical outcome in patients with metastatic castration-resistant prostate cancer (CRPC) treated with abiraterone 1000 mg per day, whose disease progressed after docetaxel chemotherapy. In the 48 evaluable patients, serum CgA level was normal when <120 u200ang/ml (group A, n=16), within three times the upper normal value (UNV) when between 120 and 360 (group B, n=16), more than three times the UNV when ≥360u200a ng/ml (group C, n=16). Decline in PSA level ≥50% or more (PSA RR) was observed in 26 of 48 (54%) patients. PSA response rate did not correlate with the CgA groups. CgA levels more than three times the UNV predicted an early radiological progressive disease in eight of 11 cases (73%). The median progression-free survival (PFS) among the CgA groups A, B, and C was 9.2, 9.2, and 4.8 months respectively, P=0.0459. The median overall survival (OS) among the CgA groups was 19.0, 18.8, and 10.8 months respectively, P=0.2092. In the multivariate analysis, PSA RR (nonresponsive vs responsive) and CgA levels (group 3 vs groups 1+2) were predictors of PFS (P=0.0002 and P=0.0047 respectively), whereas PSA RR only was significantly associated with OS (P=0.0024), while CgA levels remained of borderline significance (P=0.0919). A serum CGA level more than three times the UNV predicted PFS and showed a trend vs OS prediction, independently from PSA response, in CRPC patients treated with abiraterone.

Chromogranin A is a potential prognostic marker in prostate cancer patients treated with enzalutamide

In this retrospective study, we assessed chromogranin A (CgA) baseline value as a possible factor associated with poor prognosis in metastatic castration‐resistant prostate cancer (CRPC).

Systemic immune-inflammation index predicts the clinical outcome in patients with mCRPC treated with abiraterone

Background: A systemic immune-inflammation index (SII) based on neutrophil (N), lymphocyte (L), and platelet (P) counts has shown a prognostic impact in several solid tumors. The aim of this study is to evaluate the prognostic role of SII in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone post docetaxel. Patients and Methods: We retrospectively reviewed consecutive mCRPC patients treated with abiraterone after docetaxel in our Institutions. X-tile 3.6.1 software, cut-off values of SII, neutrophil-to-lymphocyte ratio (NLR) defined as N/L and platelets-to-lymphocyte ratio (PLR) as P/L. Overall survival (OS) and their 95% Confidence Intervals (95% CI) was estimated by the Kaplan-Meier method and compared with the log-rank test. The impact of SII, PLR, and NLR on overall survival (OS) was evaluated by Cox regression analyses and on prostate-specific antigen (PSA) response rates were evaluated by binary logistic regression. Results: A total of 230 mCRPC patients treated abiraterone were included. SII ≥ 535, NLR ≥ 3 and PLR ≥ 210 were considered as elevated levels (high risk groups. The median OS was 17.3 months, 21.8 months in SII < 535 group and 14.7 months in SII ≥ 535 (p < 0.0001). At univariate analysis Eastern Cooperative Oncology Group (ECOG) performance status, previous enzalutamide, visceral metastases, SII, NLR, and PLR predicted OS. In multivariate analysis, ECOG performance status, previous enzalutamide, visceral metastases, SII, and NLR remained significant predictors of OS [hazard ratio (HR) = 5.08, p < 0.0001; HR = 2.12, p = 0.009, HR = 1.77, 95% p = 0.012; HR = 1.80, p = 0.002; and HR = 1.90, p = 0.001, respectively], whereas, PLR showed a borderline ability only (HR = 1.41, p = 0.068). Conclusion: SII and NLR might represent an early and easy prognostic marker in mCRPC patients treated with abiraterone. Further studies are needed to better define their impact and role in these patients.

The emerging role of anti-angiogenic therapy in ovarian cancer (Review)

The introduction of new therapeutic agents into clinical practice of ovarian cancer, in addition to the role of surgery and chemotherapy, has been the subject of numerous studies because this tumor remains worldwide the most lethal gynecological cancer. It is now known that angiogenesis plays a vital role for ovarian physiology, but also in ovarian carcinogenesis and so it has become the main target of ovarian cancer treatment. In this review, the most common molecular pathways of angiogenesis have been investigated leading to the identification of novel targets, including monoclonal antibodies and tyrosine kinase inhibitors. The fundamental targets of anti-angiogenic drugs are vascular endothelial growth factor receptor and its ligand, but also platelet-derived growth factor, fibroblast growth factor and angiopoietin. Moreover, improved knowledge of angiogenic process allowed the discovery of other molecules, such as semaphorins, neuropilins, clusterin, some transcriptional factors, and the identification of features, including stemness, epithelial-mesenchymal transition, downregulation of certain microRNAs, the alteration of immune system, that contribute to angiogenesis and possibly to resistance mechanisms. The following patent and literature review aim to highlight recent findings of approved and novel anti-angiogenic drugs that make the treatment of patients with ovarian cancer a rapidly growing field of oncology.

Prognostic value of 18F–choline PET/CT metabolic parameters in patients with metastatic castration-resistant prostate cancer treated with abiraterone or enzalutamide

PurposeThe role of 18F–choline positron emission tomography/computed tomography (FCH-PET/CT) in patients with metastatic castration-resistant prostate cancer (mCRPC) has been firmly established in recent years. We analyzed the prognostic value of functional parameters such as mean standardized uptake volume (SUVmean), maximum standardized uptake volume (SUVmax), metabolic total volume (MTV; the volume of interest consisting of all spatially connected voxels within a fixed threshold of 40% of the SUVmax), and total lesion activity (TLA: the product of MTV and mean standardized uptake value) estimated with FCH-PET/CT in mCRPC patients in progression after docetaxel and treated with new antiandrogen receptor therapies, abiraterone or enzalutamide.MethodsWe retrospectively studied 94 mCRPC patients, mean age 74xa0years (range 42–90), previously treated with docetaxel who were treated with either abiraterone (n = 52) or enzalutamide (nxa0=xa042). An FCH-PET/CT was performed at baseline, and patients were evaluated on a monthly basis for serological PSA response and every 3xa0months for radiological response. We measured MTV, SUVmean, SUVmax and TLA for each lesion and analyzed the sum of MTV (SMTV), SUVmean (SSUVmean), SUVmax (SSUVmax) and TLA (STLA) values for a maximum of 20 lesions. Univariate analysis was used to correlate these data with PFS and OS.ResultsWe observed a median SMTV of 130xa0cm3, median SSUVmax of 106.5 and a median STLA of 495,070. All of these parameters were significant for PFS and OS in univariate analysis, while only STLA was significant for PFS and OS in multivariate analysis after adjusting for lesion and age (pxa0<xa00.0001 and pxa0=xa00.001, respectively). Baseline PSA values maintained a certain reliability for OS (pxa0=xa00.034).ConclusionsSemiquantitative parameters of FCH-PET/CT play a prognostic role in mCRCP patients treated with abiraterone or enzalutamide.

Long-term clinical impact of PSA surge in castration-resistant prostate cancer patients treated with abiraterone

Background: Early changes in PSA have been evaluated in association to treatment outcome. The aim of this study was to assess PSA surge phenomenon in castration‐resistant prostate cancer (CRPC) patients treated with abiraterone and to correlate those variations with long‐term treatment outcome.

759PDAR AND CYP17A1 COPY NUMBER VARIATIONS MAY PREDICT CLINICAL OUTCOME OF PATIENTS WITH METASTATIC CASTRATION-RESISTANT PROSTATE CANCER TREATED WITH ABIRATERONE

ABSTRACT Aim: Abiraterone acetate is a potent inhibitor of cytochrome P450 17 alpha-hydrolase (CYP17A1) causing decrease of synthesis of testosterone in the adrenal glands, testicles and tumor microenvironment with survival advantage in patients with metastatic castration-resistant prostate cancer (CRPC). We analyzed the predictive role of copy number variations (CNVs) of CYP17A1 and androgen receptor (AR) genes, in serum cell free DNA of CRPC patients treated with abiraterone. Patients and methods: The study was conducted on a consecutive series of 53 CRPC patients treated with abiraterone after at least one chemotherapeutic regimen with docetaxel. DNA was isolated from serum collected before starting abiraterone treatment and CNVs were analyzed for AR and CYP17A1 genes using Taqman copy number assays. Results: AR gene resulted amplified in 16 cases, CYP17A1 in 15. 10 cases were amplified for both genes. The median progression-free survival (PFS) of patients with AR gene amplification was 2.8 vs. 9.5 months of normal individuals. Patients with CYP17A1 gene amplification had a median PFS of 2.8 months vs. 9.2 months in the diploid patients. A lower overall survival (OS) was reported in patients with AR and CYP17A1 gene amplification (AR: P Conclusions: The CNVs of AR and CYP17A1 genes are promising markers predicting outcome in patients with CRPC treated with abiraterone. Further studies are warranted to validate these biomarkers to be used through a “liquid biopsy”, for outcome prediction to abiraterone in these patients. Disclosure: All authors have declared no conflicts of interest.

Treatment of Metastatic, Castration-Resistant, Docetaxel-Resistant Prostate Cancer: A Systematic Review of Literature With a Network Meta-Analysis of Randomized Clinical Trials

INTRODUCTIONnTo compare the efficacy of abiraterone acetate, enzalutamide, cabazitaxel and Radium-223 in the treatment of castration-resistant, docetaxel-resistant metastatic prostate cancer.nnnMETHODSnAn indirect comparison of Overall Survival (OS) and time to PSA progression among abiraterone acetate, enzalutamide, cabazitaxel and Radium-223 was performed with a network metaanalysis. OS in the entire population of patients was the primary endpoint. OS in ECOG 0-1/2, BPISF≤ 4/>4, pretreated with 1 or 2 courses of chemotherapy, age≤65/>65 patients, patients with only bone metastases or bone and visceral metastases, and time to PSA progression were the secondary endpoints. An indirect comparison of the Hazard Ratio and the 95% Confidence Interval was performed, assuming an alpha error of 5% as an index of statistical significance. The among-the-trial heterogeneity was assessed using a qualitative methodological and clinical analysis.nnnRESULTSnFour trials were selected. In three trials, the comparator was placebo, in one trial it was mitoxantrone, the effect of which in improving survival was considered negligible. No significant difference in OS among abiraterone acetate, enzalutamide, cabazitaxel and radium 223 was observed in neither the entire population nor all the subgroups of patients. Enzalutamide resulted significantly better than abiraterone acetate, cabazitaxel or radium-223 in time to PSA progression.nnnCONCLUSIONnSince no significant difference in efficacy seems to exist between the four therapeutic options in the treatment of castration-resistant, docetaxel-resistant, metastatic prostate cancer, the safety of the treatment, patients compliance and costs should represent the criteria to guide clinicians choice in clinical practice.