Year: 2016
Type: article
Study design: Observational Study
Abstract: OBJECTIVES: Recent results of STAMPEDE, CHAARTED, and RTOG 0521 have suggested a clinical benefit to the early use of docetaxel in the treatment of localized high risk, locally advanced and newly metastatic prostate cancer (PCa).Docetaxel therapy is not without toxicity however (neuropathy, neutropenia and associated deaths).Improved selection of men with early castrate resistance is thus paramount to personalized use of chemotherapy in the adjuvant treatment setting.Here we investigate whether early signs of androgen insensitivity could be detected in the primary tumors of men with PCa that metastasized after local therapy and subsequently developed castrate resistant disease.METHODS: We identified 52 men with complete clinical follow up who presented with localized PCa and were treated by surgery only with eventual development of metastasis.Genome wide expression profiling was performed on the primary tumors of all men.All patients initiated androgen deprivation therapy (ADT) at the time of metastasis, and serial PSA values were obtained at least annually.Castrationresistant prostate cancer (CRPC) was defined as two consecutive rises in PSA in the castrate state (i.e.serum T < 50).An androgen response signature (ARS) was genomically derived to include canonical androgen regulated genes.Factors associated with CRPC were tested in a Cox proportional hazards model.RESULTS: Forty-one (79%) men progressed to CRPC at a median of 15 months from ADT initiation.On multivariable analysis, no pathological features or risk models available in the peri-operative period (Gleason score, lymph node involvement, CAPRA-S score, etc.) were predictive of developing CRPC.Ability to reach a nadir PSA value of <0.2ng/ml after initiation of ADT upon metastasis was a significant predictor (hazard ratio [HR] 3.02, 95% confidence interval [CI] 1.77-5.29).Importantly, higher ARS scores in the primary tumor were predictive of subsequent progression to CRPC.Specifically, greater than median ARS score was associated with a 54% reduction in the risk of CRPC (HR 0.46, 95% CI 0.24-0.87).CONCLUSIONS: Androgen signaling in primary tumors may be predictive of progression to CRPC.These novel findings may translate to better selection of men who could benefit from early initiation of androgen independent therapies such as chemotherapy or immunotherapeutics.Further prospective validation is warranted.
Source: The Journal of Urology
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funder: U.S. Department of Defense
OpenAlex ID: W2323140203