DNA Damage and Repair Pathway Signature May Be Associated With Prognosis After Prostatectomy in High-Risk Prostate Cancer
In a study reported in JAMA Oncology, Evans et al identified a DNA damage and repair pathway gene signature that was significantly associated with outcomes after prostatectomy for high-risk prostate cancer independent of standard clinicopathologic factors.
Study Details
The study involved 1,090 patients (mean age at diagnosis of 65.3 years) from three U.S. academic centers divided into a training cohort (n = 545) and three pooled validation cohorts (n = 545). Profiling of 9 DNA damage and repair pathways was performed using 17 gene sets for analysis (Gene Set Enrichment Analysis) of microarray gene expression data from fresh frozen paraffin-embedded prostatectomy samples. Patients had a median follow-up of 10.3 years.
Identification of DNA Damage and Repair Pathways
Distinct clusters of DNA damage and repair pathways were identified in the training cohort, with the DNA damage and repair pathway enrichment being weakly correlated with such clinical variables as age (Spearman ρ range = –0.07 to 0.24), Gleason score (ρ range = 0.03–0.20), and prostate-specific antigen level (ρ range = –0.07 to 0.10); 13 of 17 DNA damage and repair gene sets were strongly correlated with androgen receptor pathway enrichment (ρ range = 0.33–0.82). Review of published cohorts and unpublished data from The Cancer Genome Atlas indicated that DNA damage and repair pathway genes are rarely mutated, with a mutation prevalence of < 2% for all genes except ATM (3%) and TP53 (6.8%).
Independent Prognostic Value
On multivariate analysis including standard clinicopathologic variables, a DNA damage and repair pathway profile signature developed in the training cohort was independently associated with biochemical recurrence-free (hazard ratio [HR] = 1.71, P < .001), metastasis-free (HR = 1.56, P = .02), and overall survival (HR = 1.69, P = .006) in the pooled validation cohorts. On multivariate analysis, the signature was significantly prognostic for metastasis-free survival among patients aged < 70 years (HR = 1.67, 95% confidence interval [CI] = 1.12–2.50) but not in those aged ≥ 70 years (HR = 0.77, 95% CI = 0.29–2.07).
The investigators concluded: “DNA damage and repair [DDR] 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.”
The study was supported by the Prostate Cancer Foundation and the Evans Foundation.
Felix Y. Feng, MD, of the University of Michigan Medical Center, is the corresponding author of the JAMA Oncology article.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
