103 Background: Recent studies have demonstrated limited success of immune checkpoint therapies in unselected prostate cancer. We therefore assessed an immune based DNA Damage Repair Deficiency (DDRD) assay, that we have previously reported represents activation of the cGAS STING pathway, in the TCGA prostate cancer dataset to investigate the presence of targetable immune biology in prostate cancer. In addition we applied a second assay (the prostate cancer metastatic signature-PCM) that predicts the risk of metastatic recurrence for early prostate cancer, in order to assess if immune therapy could have a role in treating high risk disease. Methods: 498 samples with RNA sequencing data were scored with the PCM and DDRD assays. Integrative analysis was performed on 488 samples with RNA sequencing, promoter site methylation, somatic mutation and somatic copy number variation. Gene expression of n = 6 immune checkpoint targets was investigated with the subgroups identified using T-tests. The prevalence of immune infiltration in each subgroup was tested by applying a cut off to the leukocyte fraction. Cox proportional hazards regression analysis of 441 patients was assessed for biochemical recurrence. Results: Integrative analysis identified four patient subgroups characterised primarily by variances in copy number and genomic mutation. One of these subgroups ‘Metastatic-like DDRD’ had significantly higher PCM scores and DDRD immune scores compared to the other subgroups (p < 2E-12). This subgroup of patients showed elevated leukocyte fraction and expression of immune checkpoint genes: CD274 (PDL1), CTLA4, ICOS, IDO1, HAVCR2 (TIM3) & LAG3 (p < 2E-6). Genomic instability with amplification of 8q and a larger prevalence of somatic mutations including that of TP53 was also detected in this subgroup. These patients had an increased risk of biochemical relapse in both univariate (p < 2E-5) and multivariate (p < 0.008) analysis. Conclusions: We identified a poor prognostic subgroup, representing 17% of early prostate cancer patients that are at increased risk of developing metastatic disease and present with targetable immune biology. These patients may represent a viable target population for immune checkpoint and DNA damaging therapies in prostate cancer.
Integrative analysis reveals disease-associated genes and biomarkers for prostate cancer progression
