Genomic Assessment of a High Grade Low PSA Prostate Cancer Cohort

Abstract

High grade prostate cancer with a paradoxically low PSA has been associated with a more aggressive phenotype compared with high grade disease with a high PSA. We sought to examine the genomic landscape of these patients using next generation DNA sequencing to identify a characteristic biology that could explain their unique clinical presentation. A database search identified 19 patients with a Gleason score (GS) of 8 or higher and a PSA less than 4 who had prostate tissue that had undergone next-generation DNA sequencing of targeted gene panels using the MSK-IMPACT assay. A comparison cohort was identified of 146 patients with a GS of 8 or higher, PSA greater than 4, and sequenced prostate tissue. Chi square tests were used to assess the significance of different characteristics between the two groups. Genomic outcomes examined included tumor mutational burden (TMB), the fraction of the genome that is copy number altered (FCNA), and specific genomic alterations, including somatic and germline mutations. Median PSA was 2.35 in the low PSA group and 9.27 in the comparison group. All patients had Gleason 8 or 9 disease. All prostate samples were radical prostatectomy specimens, except for one which was a biopsy specimen. A minority of patients received androgen deprivation therapy prior to tissue collection: 21% in the low PSA group and 13% in the high PSA group (p=0.341). The 2 groups did not differ significantly in pathologic T stage (pT2, pT3, and pT4 were 5%, 68%, and 21% in the low PSA group vs 6%, 73% and 21%, p=0.996), pathologic N stage (pN1 37% vs 51%, p=0.233), and clinical M stage at diagnosis (M1 21% vs 18%, p=0.762). While the 2 groups did not differ with respect to TMB (2.1 vs 2.0) or FCNA (0.07 vs 0.07), there were some notable genomic differences. The low PSA cohort had more germline mutations in the DNA damage response (DDR) pathway, with 26% of patients harboring a germline DDR alteration versus 8% of patients in the high PSA cohort, p=0.0097. The difference in the incidence of both germline and somatic DDR alterations approached significance: 32% of low PSA patients versus 15% of high PSA patients, p=0.059. Genes considered as part of the DDR pathway included BRCA2, BRCA1, ATM, RAD50, CHEK2, FANCA, PALB2, and MUTYH. Notably, the low PSA cohort did not harbor an increased number of alterations in genes typically associated with small cell neuroendocrine prostate cancer, including TP53 (26% vs 32%), RB1 (0% vs 2%) and PTEN (5% vs 20%). Other genes with recurring alterations in these populations included APC (16% and 6%) and TMPRSS2-ERG fusions (26% and 23%). Patients presenting with high grade prostate cancer and a PSA <4 should undergo genomic testing since about one third harbor DDR mutations and may be future candidates for PARP inhibitor therapy. Alterations commonly associated with small cell neuroendocrine prostate cancer were not seen with increased frequency.