Genomic evolution from hormonal therapies and suitability of prostate cancer diagnostic specimens for metastatic prostate cancer (mPC) genomic stratification.
Authors: Zurita Amado J. , Graf Ryon , Villacampa Guillermo , Raskina Kira , Sokol Ethan , Jin Dexter X. , Huang Richard S.P. , Casanova Salas Irene , Carles Joan , Ross Jeffrey S. , Schrock Alexa Betzig , Oxnard Geoffrey R. , Mateo Joaquin 
Published: February 2022

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Background: Genomic tumor testing is now recommended for all patients with mPC, but the relevance of archival vs contemporaneous tumor tissue profiling remains unclear. We studied genomic biomarkers, including homologous recombination repair (HRR) gene alterations, and genomic loss of heterozygosity (gLOH) as signature of genome-wide instability, in a cohort of mPC patients with tissue specimens collected at varying points along disease progression. Methods: Genomics and clinical data from 1302 men with mPC from the US-wide de-identified Flatiron Health Foundation Medicine clinico-genomic database. The de-identified data originated from ̃280 US cancer clinics (̃800 sites of care). Comprehensive genomic profiling of primary or metastatic tissue specimens acquired at diagnosis (“ADT naïve” n = 840), at castration resistance (“ADT exposed” n = 132) or after resistance to novel hormonal therapies (“NHT exposed” n = 330). Aim 1: compare genomic biomarkers across disease progression states in primary vs metastatic tissue specimens. Aim 2: study gLOH across clinical states. Chi-square and Wilcoxon rank sum tests for categorical and continuous variables, respectively. Multivariate analysis (MVA) used linear regression. Adjustment for multiple testing considered a false discovery rate at 0.05. Results: Most ADT-naïve samples were primary tumor specimens (80%); most post-NHT biopsies came from nodal (27%), liver (25%) or bone (16%) metastasis. There was an enrichment in more advanced disease states (ADT-naïve vs ADT-exposed vs NHT-CRPC) for aberrations in AR, MYC, TP53, PTEN and RB1 (all adjusted p-values < 0.05); prevalence of BRCA1/2 and other HRR aberrations was stable along disease progression states. Within the ADT-naïve group, there was no difference in prevalence in primary vs metastatic lesions of TP53 (36.4% vs 31.3%), PTEN (26.3% vs 33.1%), BRCA2 (8.2% vs 6.6%), RB1 (3.3% vs 6%) or MYC (5% vs 7.2%) (all adjusted p-values > 0.3). Overall, 847 cases were evaluable for gLOH scores. In MVA, prior exposure to NHT was associated with higher gLOH independent of genomic features, taxane exposure or biopsy site (primary/M1). Among the genomic features, aberrations in BRCA2, FANCA, PALB2, TP53 and RB1 were independently associated with increased gLOH. Conclusions: Progression to hormonal therapies associates with enrichment for aberrations in AR, MYC, PTEN and cell-cycle genes ( TP53, RB1) for which contemporaneous assessment would be most accurate. In turn, prevalence of mutations in BRCA1/2 and other HRR genes is stable along mPC progression, supporting potential use of primary tumor biopsies to determine mPC patient eligibility for PARPi treatment. Progression to hormonal therapies associated with higher gLOH, independently of genomic features, suggesting advanced prostate cancer is enriched for genomic instability features.