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Intermediate PSA half-life after neoadjuvant hormone therapy predicts reduced risk of castration-resistant prostate cancer development after radical prostatectomy.

ABSTRACT: The magnitude and rapidity of the tumor response to androgen deprivation is known to predict the durability of the therapy. We have investigated the predictive value of categorizing patients by the half-life of PSA under neoadjuvant androgen deprivation therapy in patients with biochemical recurrence after radical prostatectomy.Medical records of 317 patients who received neoadjuvant androgen deprivation therapy before radical prostatectomy and developed biochemical recurrence were analyzed. The patients were categorized into five groups according to PSA half-life. Risk of developing castration resistance was evaluated by Kaplan-Meier analysis and by Cox proportional risk regression analysis.The median follow-up duration was 50.1 months (IQR 31.8-68.7) and median PSA half-life was 22.1 days (IQR 12.7-38.4). Comparison of survival curves revealed that patients in the intermediate response group showed significantly lower 5-year castration-resistant prostate cancer rate (37.5%) compared to non-response and ultra-rapid response groups (63.6%, p?=?0.007; 56.1%, p?=?0.031; respectively). In the multivariate regression model, intermediate response compared to non-response was associated with significantly reduced risk of castration resistance development (hazard ratio 0.397, 95% confidence interval 0.191-0.823, p?=?0.013) and overall mortality (hazard ratio 0.138, 95% confidence interval 0.033-0.584, p?=?0.007). When subcategorized by Gleason score, Kaplan-Meier curve revealed that, in the high Gleason score stratum, 5-year castration-resistant prostate cancer rate for intermediate response group (44.0%) was exceptionally lower than that in non-response group (66.7%, p?=?0.047), while castration resistance increased in other groups.Short PSA half-life as well as no response after androgen deprivation is associated with increased risk of treatment failure compared to intermediate PSA half-life.

SUBMITTER: Kang YJ

PROVIDER: S-EPMC5701379 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Intermediate PSA half-life after neoadjuvant hormone therapy predicts reduced risk of castration-resistant prostate cancer development after radical prostatectomy.

Kang Yong Jin YJ Jang Won Sik WS Kwon Jong Kyou JK Yoon Cheol Yong CY Lee Joo Yong JY Ham Won Sik WS Choi Young Deuk YD

BMC cancer 20171123 1

<h4>Background</h4>The magnitude and rapidity of the tumor response to androgen deprivation is known to predict the durability of the therapy. We have investigated the predictive value of categorizing patients by the half-life of PSA under neoadjuvant androgen deprivation therapy in patients with biochemical recurrence after radical prostatectomy.<h4>Methods</h4>Medical records of 317 patients who received neoadjuvant androgen deprivation therapy before radical prostatectomy and developed bioche ...[more]

PMID: 29169347

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Project description:ObjectiveTreatment efficacy of androgen deprivation therapy with radical prostatectomy for intermediate- to high-risk prostate cancer is less well-studied. The NEAR trial is a single-arm, phase II investigation of neoadjuvant apalutamide monotherapy and radical prostatectomy (RP) in the treatment of D'Amico intermediate- and high-risk prostate cancer (NCT03124433).Materials and methodsPatients with histologically-proven, D'Amico intermediate- to high-risk prostate adenocarcinoma received apalutamide 240 mg once-daily for 12 weeks followed by RP + /-lymphadenectomy. Primary outcome was pathological complete response (pCR) rate. Secondary outcomes included rate of biochemical response (defined by PSA < 0.03 ng/mL at week 24 from starting apalutamide without subsequent PSA relapse), treatment-related adverse events, and RP complication rates. Correlative biomarker analyses were performed to examine for molecular predictors of treatment responses.ResultsFrom 2017 to 2019, 30 patients were recruited, of which 20 and 10 were high and intermediate risk, respectively; 25 completed treatment as per-protocol. We did not observe any pCR on trial; median reduction of cancer burden was 41.7% (IQR: 33.3%-60.0%). 18 out of 25 patients were classified as having a biochemical response (4 did not achieve PSA of <0.03 ng/mL at week 24 and 3 developed PSA relapse subsequently). Dry skin (N = 16; 53.3%), fatigue (N = 10; 33.3%) and skin rash (N = 9; 30.0%) were the most common adverse events, and there was no major peri-operative complication. We observed an association between tumours of low androgen receptor activity and PAM50 basal status with biochemical non-responders, albeit these molecular phenotypes were not associated with pathological response.ConclusionsA 12-week course of neoadjuvant apalutamide prior to RP did not meet the primary endpoint of pCR in this trial. Tumours with low androgen receptor activity or of the PAM50 basal subtype may have a reduced response to apalutamide.

Project description:BACKGROUND:Recent retrospective data suggest that neoadjuvant androgen deprivation therapy can improve the prognosis of high-risk prostate cancer (PCa) patients. Novel androgen receptor pathway inhibitors are nowadays available for treatment of metastatic PCa and these compounds are promising for early stage disease. Apalutamide is a pure androgen antagonist with a very high affinity with the androgen receptor. The combination of apalutamide with degarelix, an LHRH antagonist, could increase the efficacy compared to degarelix alone. OBJECTIVE:The primary objective is to assess the difference in proportions of minimal residual disease at prostatectomy specimen between apalutamide + degarelix vs placebo + degarelix. Various secondary endpoints are assessed: variations of different biomarkers at the tumour level (tissue microarrays to evaluate DNA-PKs, PARP, AR and splice variants, PSMA, etc.), whole transcriptome sequencing, exome sequencing and clinical (PSA and testosterone kinetics, early biochemical recurrence free survival, quality of life, safety, etc.) and radiological endpoints. METHODS:ARNEO is a single centre, phase II, randomized, double blind, placebo-controlled trial. The plan is to include at least 42 patients per each of the two study arms. Patients with intermediate/high-risk PCa and who are amenable for radical prostatectomy with pelvic lymph node dissection can be included. After signing an informed consent, every patient will undergo a pelvic 68Ga -PSMA-11 PSMA PET/MR and receive degarelix at standard dosage and start assuming apalutamide/placebo (60 mg 4 tablets/day) for 12 weeks. Within thirty days from the last study medication intake the same imaging will be repeated. Every patient will undergo PSA and testosterone testing the day of randomization, before the first drug intake, and after the last dose. Formalin fixed paraffin embedded tumour samples will be collected and used for transcriptome analysis, exome sequencing and immunohistochemistry. DISCUSSION:ARNEO will allow us to answer, first, whether the combined treatment can result in an increased proportion of patients with minimal residual disease. Secondly, It will enable the study of the molecular consequences at the level of the tumour. Thirdly, what the consequences are of new generation androgen receptor pathway inhibitors on 68Ga -PSMA-11 PET/MR. Finally, various clinical, safety and quality of life data will be collected. TRIAL REGISTRATION:EUDRaCT number: 2016-002854-19 (authorization date 3rd August 2017). clinicalTrial.gov: NCT03080116 .

Project description:Purpose: Clinicopathologic features and biochemical recurrence are sensitive, but not specific, predictors of metastatic disease and lethal prostate cancer. We hypothesize that a genomic expression signature detected in the primary tumor represents true biological potential of aggressive disease and provides improved prediction of early prostate cancer metastasis. Methods: A nested case-control design was used to select 639 patients from the Mayo Clinic tumor registry that underwent radical prostatectomy between 1987 and 2001. A genomic classifier (GC) was developed by modeling differential RNA expression using 1.4 million feature high-density expression arrays of men enriched for rising PSA after prostatectomy, including 213 that experienced early clinical metastasis after biochemical recurrence. A training set was used to develop a random forest classifier of 22 markers to predict for cases - men with early clinical metastasis after rising PSA. Performance of GC was compared to prognostic factors such as Gleason score and previous gene expression signatures in a withheld validation set. Results: Expression profiles were generated from 545 unique patient samples, with median follow-up of 16.9 years. GC achieved an area under the receiver operating characteristic curve of 0.75 (0.67 - 0.83) in validation, outperforming clinical variables and gene signatures. GC was the only significant prognostic factor in multivariable analyses. Within Gleason score groups, cases with high GC scores experienced earlier death from prostate cancer and reduced overall survival. The markers in the classifier were found to be associated with a number of key biological processes in prostate cancer metastatic disease progression. Conclusion: A genomic classifier was developed and validated in a large patient cohort enriched with prostate cancer metastasis patients and a rising PSA that went on to experience metastatic disease. This early metastasis prediction model based on genomic expression in the primary tumor may be useful for identification of aggressive prostate cancer.

Project description:ObjectiveThis systematic study aimed to assess and compare the comprehensive evidence regarding the impact of neoadjuvant hormone therapy (NHT) on surgical and oncological outcomes of patients with prostate cancer (PCa) before radical prostatectomy (RP).MethodsLiterature searches were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Using PubMed, Web of Science, Chinese National Knowledge Infrastructure, and Wanfang databases, we identified relevant studies published before July 2020. The pooled effect sizes were calculated in terms of the odds ratios (ORs)/standard mean differences (SMDs) with 95% confidence intervals (CIs) using the fixed or random-effects model.ResultsWe identified 22 clinical trials (6 randomized and 16 cohort) including 20,199 patients with PCa. Our meta-analysis showed no significant differences in body mass index (SMD = 0.10, 95% CI: -0.08-0.29, p = 0.274) and biopsy Gleason score (GS) (OR = 1.33, 95% CI: 0.76-2.35 p = 0.321) between the two groups. However, the NHT group had a higher mean age (SMD = 0.19, 95% CI: 0.07-0.31, p = 0.001), preoperative prostate-specific antigen (OR = 0.47, 95% CI: 0.19-0.75, p = 0.001), and clinic tumor stage (OR = 2.24, 95% CI: 1.53-3.29, p < 0.001). Compared to the RP group, the NHT group had lower positive surgical margins (PSMs) rate (OR = 0.44, 95% CI: 0.29-0.67, p < 0.001) and biochemical recurrence (BCR) rate (OR = 0.47, 95% CI: 0.26-0.83, p = 0.009). Between both groups, there were no significant differences in estimated blood loss (SMD = -0.06, 95% CI: -0.24-0.13, p = 0.556), operation time (SMD = 0.20, 95% CI: -0.12-0.51, p = 0.219), pathological tumor stage (OR = 0.76, 95% CI: 0.54-1.06, p = 0.104), specimen GS (OR = 0.91, 95% CI: 0.49-1.68, p = 0.756), and lymph node involvement (OR = 0.76, 95% CI: 0.40-1.45, p = 0.404).ConclusionsNHT prior to RP appeared to reduce the tumor stage, PSMs rate, and risk of BCR in patients with PCa. According to our data, NHT may be more suitable for older patients with higher tumor stage. Besides, NHT may not increase the surgical difficulty of RP.

Dataset Information

Intermediate PSA half-life after neoadjuvant hormone therapy predicts reduced risk of castration-resistant prostate cancer development after radical prostatectomy.

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Intermediate PSA half-life after neoadjuvant hormone therapy predicts reduced risk of castration-resistant prostate cancer development after radical prostatectomy.

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