Almac Diagnostics, Craigavon, United Kingdom
Emma Reilly , Andrena McCavigan , Steven M. Walker , Nuala McCabe , Eileen Parkes , D. Paul Harkin , Richard D Kennedy , Laura A Knight
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 previously reported represents activation of the cGAS STING pathway, in the TCGA prostate cancer dataset to investigate the presence of targetable immune biology. In order to assess if immune therapy could have a role in treating high risk disease, we applied a second assay (the prostate cancer metastatic signature-PCM) that predicts the risk of metastatic recurrence for early prostate cancer. 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. The subgroups were assessed for leukocyte infiltration and the expression of n = 6 immune checkpoint targets. The viability of reproducing those subgroups with RNA sequencing alone was tested in the TCGA dataset and an independent validation dataset of 321 resected primary prostate cancers. Cox proportional hazards regression analysis was performed for biochemical recurrence and metastatic events in both datasets. 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 immune signalling (p < 2e-6) and greater genomic instability with amplification of 8q and a higher incidence of TP53 mutations. The ‘Metastatic-like DDRD’ subgroup was found to have a significant association with poor survival outcome in TCGA (multivariable: p < 0.008) and the independent dataset (multivariable: p < 0.01). Conclusions: We have identified and validated a poor prognostic subgroup, representing 10-20% 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.
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