Abstract 4865: Prognostic value of BRCA2 and AR gene alterations in advanced prostate cancer patients treated with PSMA-targeted radionuclide therapies
Authors: Vlachostergios Panagiotis J. , Conteduca Vincenza , Hackett Amy L. , Manohar Jyothi , Lee Aileen , Case Aidan , Sun Michael , Niaz Muhammad J. , Elemento Olivier , Molina Ana M. , Nanus David M. , Beltran Himisha , Bander Neil H. , Tagawa Scott T. 
Published: August 2019

Abstract
Background: PSMA-targeted radionuclide therapy (TRT) is being developed for treatment of pts with prostate cancer (PC). Several targeting agents were shown to be active and tolerable in early phase studies & randomized trials are underway. Because of the DNA damaging effects of ionizing radiation and the relationship between AR pathway & PSMA expression, we hypothesized that pts with germline or somatic gene alterations in DNA damage repair (DDR) & crosstalk pathways (AR, MYC) treated with PSMA-TRT may demonstrate differential treatment responses & outcomes.
Methods: We examined a single-institution cohort of advanced PC pts with available germline (targeted) or/and somatic (targeted or whole exome) DNA testing, clinical data (Halabi CALGB prognostic factors) & outcome. The Kaplan-Meier method & Cox regression analysis were used to evaluate the associations of mutations/copy number alterations (CNA) with PSA response (≥50%,≥30%,any), radiographic response, PFS and OS. Stepwise forward-selection was used in the multivariable regression model & p for entry was set at 0.1. For final analyses, p≤0.05 was used for significance.
Results: We analyzed 53 pts treated with PSMA-TRT. 16 (30.2%) received 177Lu-J591, 28 (56.6%) 177Lu-PSMA-617, 4 (7.5%) had both concurrently, 2 (3.8%) 225Ac-J591 (3 additional received &gt;1 agent sequentially & are analyzed based upon 1st drug). 6 (11.3%) had pathogenic germline DDR mutations while 31 (58.5%) had ≥1 mutation/CNA in DDR genes. The most frequently affected genes were: TP53 (n=21, 39.6%), BRCA2 (n=14, 26.4%), CHEK2 (n=10, 18.9%), FANCA (n=10, 18.9%), RB1 (n=9, 16.9%), ATM (n=5, 9.4%), ERCC5 (n=5, 9.4%), ERCC3 (n=3, 5.7%), ERCC2 (n=2, 3.8%), BRCA1(n=2, 3.8%), MSH6 (n=2, 3.8%), FANCD2 (n=2, 3.8%), FANCF (n=2, 3.8%). AR amplifications (ampl) or resistance-mutations were found in 22 pts (41.5%), and MYC ampl in 9 pts (16.9%). 19 (35.8%) pts had ≥50% PSA decline, 24 (45.3%) experienced ≥30% decline & 39 (73.6%) had any PSA decline. 4 pts experienced a PR while 18 had SD. BRCA2 inactivating mutations, deletions or losses were associated with any PSA decline (p=0.011). PFS was significantly longer in patients with RB1 deletion or loss (5 vs 3 mos, p=0.003). BRCA2 alterations were predictive of longer OS vs wild-type (49 vs 17 mos, p=0.09). AR ampl or mutations and MYC ampl predicted shorter OS (AR: 13 vs 63 mos, p=0.02; MYC: 8 vs 24 mos, p=0.06). On multivariate analysis after adjusting for Halabi prognostic groups (low vs high risk), BRCA2 & AR alterations retained their significance as independent prognosticators of OS (BRCA2 HR 0.1 [0.02-0.42], p=0.002; AR HR 7.2 [2.09-25.14], p=0.002).
Conclusions: Knowledge of molecular alterations in BRCA2, AR and RB1 genes may have potential utility for prediction of clinical outcomes in pts being considered for PSMA-TRT. These findings merit further testing and validation in larger prospective trials.
Citation Format: Panagiotis J. Vlachostergios, Vincenza Conteduca, Amy L. Hackett, Jyothi Manohar, Aileen Lee, Aidan Case, Michael Sun, Muhammad J. Niaz, Olivier Elemento, Ana M. Molina, David M. Nanus, Himisha Beltran, Neil H. Bander, Scott T. Tagawa. Prognostic value of BRCA2 and AR gene alterations in advanced prostate cancer patients treated with PSMA-targeted radionuclide therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4865.