(UroToday.com) A subset of men who undergo radical prostatectomy with curative intent with experience recurrence, either biochemical or local. For these men, cure can be rescued via salvage therapy with radiotherapy (RT) alone or in combination with a finite course of androgen deprivation therapy (ADT). Risk stratification modalities, including histopathological characteristics, patient-specific factors, and molecular assays, help to determine which of these men will benefit from the addition of ADT. The authors sought to determine if molecular facilitators of androgen independence, namely androgen receptor (AR) splice variants (ARV), could influence outcomes when found in primary prostate cancers as they can in advanced disease states. Accordingly, Dr. Keisuke Otani and colleagues hypothesized that ARVs found in primary prostate cancers could modulate response to salvage combined RT and ADT.
Retrospective data were collected from 46 patients with prostate cancer from a single institution. All of these men received radical prostatectomy followed by salvage therapy with RT+ADT. A majority (72%) received salvage for biochemical recurrence following an undetectable post-operative PSA whereas 11% had persistently detectable PSA following surgery. An additional 17% had gross local recurrence. All patients received concurrent ADT and median dose of RT was 64.8 Gy. Presence of ARVs was determined by ultra-deep targeted RNA sequencing of archival formalin-fixed paraffin-embedded prostatectomy samples. A custom library of greater than 3000 primers was deployed across all exons and introns of AR, allowing detection of 21 native splice junction sites and 20 splice variants with a mean sequencing coverage of 5000x. Commercial gene expression profiles with the Decipher platform were also evaluated.
Among these evaluable men, 76% (35/46) had one or more detectable AR splice variants. The most commonly detected variants were AR-45 (41%), AR-V9 (20%), and AR-V7 (13%), including patients harboring more than one. For the entire group at a median follow-up of 33.8 months, biochemical progression-free survival (BPFS) at 3 years was 60%, distant metastasis-free survival was 90%, and overall survival was 100%. Among those men with tumors harboring detectable ARVs, only the presence of AR-V7 was associated with differential outcomes. In those with ARV7-positive tumors, median BPFS was 10.9 months as compared to 73.4 months in patients with ARV7-negative tumors (HR 5.23, 95% CI 1.62-16.87, p=0.0020).
The authors provide among the first descriptions of the ARV variety and prevalence in primary prostate cancers and provide preliminary evidence that the presence of ARV7 may predict inferior outcomes to salvage RT+ADT, as compared to ARV7-negative tumors. These data represent an intriguing step in AR-mediated characterization of primary prostate cancers in a treatment-decision directed manner, however, it is yet unclear whether presence of ARV7 should result in alternative or intensified adjunctive therapies when recommending salvage therapy. Nonetheless, these are intriguing data and their future use has clear needed application. The authors suggest that investigations, including with comparison to Decipher scores, are underway.
Written by: Jones Nauseef, MD, PhD, Assistant Professor of Medicine within the Division of Hematology and Medical Oncology, Sandra and Edward Meyer Cancer Center, and Englander Institute for Precision Medicine Weill Cornell Medicine and Assistant Attending physician at NewYork-Presbyterian Hospital. @DrJonesNauseef on Twitter during the 2022 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, Thursday, Feb 17 – Saturday, Feb 19, 2022