High-Risk Prostate Cancer and DNA Damage And Repair Gene Profiling

DNA Damage And Repair Gene Profiling Predicts High-Risk Prostate Cancer
Genetic profiling may indicate a patient’s risk of metastatic prostate cancer after surgery

Date: 08 Jan 2016
Author: By Lynda Williams, Senior medwireNews Reporter
Topic: Prostate Cancer / Translational Research / Surgery and/or Radiotherapy of Cancer

medwireNews: A gene profiling study suggests that characterising DNA damage and repair (DDR) pathway genes could help identify prostate cancer patients at high risk of developing metastases after radical prostatectomy.

“As a biomarker of disease progression, DDR pathway profiling may be used to select patients for earlier treatment intensification with approaches such as adjuvant radiation or systemic therapy and may represent an avenue toward improved personalization of therapy for prostate cancer patients”, say Felix Feng, from University of Michigan Medical Center in Ann Arbor, USA, and co-workers.

The researchers profiled 1090 men, aged an average of 65.3 years at the time of prostate cancer diagnosis and surgery, for nine DDR pathways using 17 gene sets. Gene Set Enrichment Analysis was conducted using microarray gene expression from prostatectomy samples in patients with a median of 10.3 years of follow-up.

As reported in JAMA Oncology, there were “distinct clusters” of DDR pathways. These clusters had only a weak correlation with patient age, Gleason score and prostate-specific antigen level, but 13 of the 17 DDR sets showed a strong correlation with androgen receptor pathway markers.

Initial analysis suggested that seven of the nine DDR pathways were significantly associated with metastasis-free survival and multivariate analysis showed that four of the DDR pathways, as well as Gleason score and seminal vesicle invasion, were significantly associated with metastasis-free survival.

A prognostic signature created from the DDR pathway profiles in a training cohort of 545 patients was then applied to the remaining men divided into three validation cohorts of 232, 130 and 183 patients.

A high-risk versus low-risk signature significantly correlated with the pooled likelihood of biochemical recurrence-free survival (hazard ratio [HR]=1.89), metastasis-free survival (HR=1.88) and overall survival (HR=1.90), and these relationships were independent of clinicopathological characteristics.

The DDR pathway signature’s performance was significantly stronger in men aged less than 70 years than those aged 70 years or older (HR=1.67 vs 0.77), indicating that “the DDR pathways play a different role in younger vs older patients, and that this may [be] responsible for the differential outcomes after radiotherapy”, the team comments.

By contrast, patient ethnicity did not significantly correlate with the likelihood of a low- or high-risk signature.

Noting that the genes assessed in the DDR pathways are “rarely affected by mutation”, the researchers conclude: “These findings demonstrate that DDR pathway profiling is a promising tool in the management of prostate cancer, and we have built a nomogram that would ease its use.”

Reference

Evans JR, Zhao SG, Chang L, et al. Patient-level DNA damage and repair pathway profiles and prognosis after prostatectomy for high-risk prostate cancer. JAMA Oncol 2016; Advance online publication 7 January.doi:10.1001/jamaoncol.2015.4955