Patient-Level DNA Damage and Repair Pathway Profiles and Prognosis After Prostatectomy for High-Risk Prostate Cancer

Abstract

IMPORTANCE A substantial number of patients diagnosed with high-risk prostate cancer are at risk for metastatic progression after primary treatment. Better biomarkers are needed to identify patients at the highest risk to guide therapy intensification. OBJECTIVE To create a DNA damage and repair (DDR) pathway profiling method for use as a prognostic signature biomarker in high-risk prostate cancer. DESIGN, SETTING, AND PARTICIPANTS A cohort of 1090 patients with high-risk prostate cancer who underwent prostatectomy and were treated at 3 different academic institutions were divided into a training cohort (n = 545) and 3 pooled validation cohorts (n = 232, 130, and 183) assembled for case-control or case-cohort studies. Profiling of 9 DDR pathways using 17 gene sets for GSEA (Gene Set Enrichment Analysis) of high-density microarray gene expression data from formalin-fixed paraffin-embedded prostatectomy samples with median 10.3 years follow-up was performed. Prognostic signature development from DDR pathway profiles was studied, and DDR pathway gene mutation in published cohorts was analyzed. MAIN OUTCOMES AND MEASURES Biochemical recurrence-free, metastasis-free, and overall survival. RESULTS Across the training cohort and pooled validation cohorts, 1090 men were studied; mean (SD) age at diagnosis was 65.3 (6.4) years. We found that there are distinct clusters of DDR pathways within the cohort, and DDR pathway enrichment is only weakly correlated with clinical variables such as age (Spearman ρ [ρ], range, −0.07 to 0.24), Gleason score (ρ, range, 0.03 to 0.20), prostate-specific antigen level (ρ, range, −0.07 to 0.10), while 13 of 17 DDR gene sets are strongly correlated with androgen receptor pathway enrichment (ρ, range, 0.33 to 0.82). In published cohorts, DDR pathway genes are rarely mutated. A DDR pathway profile prognostic signature built in the training cohort was significantly associated with biochemical recurrence-free, metastasis-free, and overall survival in the pooled validation cohorts independent of standard clinicopathological variables. The prognostic performance of the signature for metastasis-free survival appears to be stronger in the younger patients (HR, 1.67; 95%CI, 1.12–2.50) than in the older patients (HR, 0.77; 95%CI, 0.29–2.07) on multivariate Cox analysis. CONCLUSIONS AND RELEVANCE DNA damage and repair pathway profiling revealed patient-level variations and the DDR pathways are rarely affected by mutation. A DDR pathway signature showed strong prognostic performance with the long-term outcomes of metastasis-free and overall survival that may be useful for risk stratification of high-risk prostate cancer patients.

APOBEC-mediated mutagenesis in urothelial carcinoma is associated with improved survival, mutations in DNA damage response genes, and immune response

“…The TCGA does not currently include any systemic treatment-related information. However, mutations in ERCC2 49,50 and other DNA repair genes 51,52 are associated with response to platinum-based therapy, and further investigation into the role of APOBEC mutagenesis and response to both cytotoxic chemotherapy and immunotherapy is warranted. Another limitation is the lack of a specific gene expression signature observed in APOBEC-low tumors other than transcription- and translation-related genes, potentially due to the heterogeneity of this group.…”

Treatment strategies for DNA repair-deficient prostate cancer

“…The prognosis for a localized prostate cancer with HRD may be worse than for similar cancers without HRD [21,22, 23]. The optimal treatment strategy for these tumors is not known, as there are no prospective studies comparing outcomes for patients specifically with HRD for primary treatment with surgery versus radiation therapy.…”

“…Despite the promising initial data from the patients in the abiraterone/veliparib study regarding responsiveness of HRD tumors to manipulation of the AR axis, the presence of mutations in DNA repair genes was traditionally thought to confer an inferior prognosi compared to tumors without such mutations [21,22, 23]. If in fact therapies like abiraterone are found to have relatively increased efficacy in HRD tumors, the use of such therapies may abrogate this prognostic disadvantage.…”

Androgen Receptor and Poly(ADP-ribose) Glycohydrolase Inhibition Increases Efficiency of Androgen Ablation in Prostate Cancer Cells

“…Despite the initial efficacy of this treatment, resistance always develops with the emergence of CRPC 41 . Most CRPCs are characterized by further increases in AR levels and transcriptional output, including the expression of BER-associated genes 5,42 . Importantly, the high expression of DNA repair gene signatures correlates with recurrence, metastases, and poor survival 5 .…”