Oncogenic Genomic Alterations, Clinical Phenotypes, and Outcomes in Metastatic Castration-Sensitive Prostate Cancer

Abstract

Background: The genomic underpinning of clinical phenotypes and outcomes in metastatic castration-sensitive prostate cancer is unclear.Methods: In patients with metastatic castration-sensitive prostate cancer at a tertiary referral center, clinical-grade targeted tumor sequencing was performed to quantify tumor DNA copy number alterations and alterations in predefined oncogenic signaling pathways. Disease volume was classified as high-volume (4 bone metastases or visceral metastases) vs. low-volume.Results: Among 424 patients (88% white), 213 (50%) had high-volume disease and 211 (50%) had low-volume disease; 275 (65%) had de-novo metastatic disease and 149 (35%) had metastatic recurrence of non-metastatic disease. Rates of castration resistance (adjusted hazard ratio, 1.84; 95% CI, 1.40-2.41) and death (adjusted hazard ratio, 3.71; 95% CI, 2.28-6.02) were higher in high-volume disease. Tumors from high-volume disease had more copy number alterations. The NOTCH, cell cycle, and epigenetic modifiers pathways were the highest-ranking pathways enriched in high-volume disease. De-novo metastatic disease differed from metastatic recurrences in the prevalence of CDK12 alterations but had similar prognosis. Rates of castration resistance differed 1.5-fold to 5-fold according to alterations in AR, SPOP (inverse), and TP53, and the cell cycle, WNT (inverse), and MYC pathways, adjusting for disease volume and other genomic pathways. Overall survival rates differed 2-fold to 4-fold according to AR, SPOP (inverse), WNT (inverse), and cell cycle alterations. PI3K pathway alterations were not associated with prognosis once adjusted for other factors. Conclusion:This study identified genomic features associated with prognosis in metastatic castration-sensitive disease that may aid in molecular classification and treatment selection. Translational RelevanceThe genomic landscape of metastatic castration-sensitive prostate cancer is not well defined, and disease stratification for the purpose of initial treatment selection has primarily relied on clinical phenotypes, including volume of disease at the time of metastasis. Here, we describe tumor genomics in a large cohort of patients with metastatic castrationsensitive prostate cancer and show genomic features that are associated with clinical phenotypes, including with disease volume. We identify genomic alterations that are associated with prognosis in metastatic castration-sensitive disease (overall survival and time to castration resistance), demonstrating that alterations in AR, TP53 and the cell cycle and MYC pathways occur in tumors with worse prognosis, while alterations in SPOP and the WNT pathway occur in tumors with better prognosis. Our findings may aid in molecular classification of metastatic castrationsensitive prostate cancer, and pathways that are prognostically relevant could be targeted in studies of intensified upfront therapy.

TP53 alterations of hormone-naïve prostate cancer in the Chinese population

“…Moreover, unlike the primary HNPCs in the West, which harbor infrequent alterations in the Wnt pathway, our data identified a subset of localized HNPCs (16%) in Chinese patients that harbored aberrations in the Wnt signaling pathway. The Wnt alteration prevalence in our cohort appears similar to that of metastatic prostate cancer in Western populations [10,39]. Activated Wnt signaling is more common in high-risk PCa and promotes cell proliferation in an androgen-independent manner [40].…”

Prostate Cancer Foundation Hormone-Sensitive Prostate Cancer Biomarker Working Group Meeting Summary

“…BRCA2 mutations are found in 3-7% and CDK12 in approximately 5%, higher in de novo metastatic disease. 18,[28][29][30] There also seems to be a relation between genetic alterations and volume of disease. In a study performed by Gilson and colleagues, a feasibility and prevalence study was performed using archival primary tumor samples from 54 men in the STAMPEDE trial with de novo mHSPC.…”

“…No difference was found in PI3K pathway alterations. 29 It is also important to consider when genetic alterations occur. TMPRSS2-ERG and SPOP have been shown to occur early in prostate cancer pathogenesis whereas DDR alterations may occur early (detectable in primary tumors) or potentially late as acquired events.…”

Early-onset metastatic and clinically advanced prostate cancer is a distinct clinical and molecular entity characterized by increased TMPRSS2–ERG fusions

“…Tumor mutational burden (TMB), microsatellite instability (MSI), and patient ancestry were determined as previously described [12][13][14]. TMB cutoffs were defined as: low TMB (<6.0 Mutations/Mb), intermediate TMB (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) Mutations/ Mb), and high TMB (≥20 Mutations/Mb).…”