AUA 2017: New Studies Demonstrate Impact of BRCA, DNA Repair Gene Mutations in Prostate Cancer

Key Points

  • Cancer rates in male BRCA mutation carriers may be substantially higher than those reported for the general population in matching age groups. Additionally, prostate cancer was prevalent among BRCA1 carriers and not restricted to BRCA2, as some previous reports have shown.
  • The most commonly mutated genes in the DNA repair pathway were BRCA2 (11%), ATM (66%), MSH6 (2.5%), MSH2 (2%), ATR (1.6%), MLH1 (1.3%), and BRCA1 (1.2%).
  • DNA repair gene mutations were identified in 20.1% of prostate tumors and 18.8% of bone metastases.

Data presented at the 2017 Annual Scientific Meeting of the American Urological Association (AUA) showed new findings related to the impact of certain genetic mutations on the risk and development of prostate cancer, in particular metastatic disease.

Male BRCA Mutations

An analysis by Mano et al (Abstract PD07-10) was conducted between February 2014 and July 2016 to find the cancer rate and type in a group of 154 known male BRCA mutation carriers. Of the study cohort, 92 (60%) had mutations of the BRCA1 gene, 61 (40%) had a BRCA2 mutation, and one patient had a mutation on both genes. Patients ages 40 and older were screened for prostate, breast, colorectal, pancreatic, and skin cancers using a standard protocol and findings were reported.

  • A total of 24 patients (16%) in the cohort were diagnosed with cancer upon enrollment or during initial screening, with a median age of 55 years at diagnosis.
  • Four patients had multiple malignancies (two to four cases per patient). Prostate cancer was identified in 7 of the 93 patients (8%) with BRCA1 mutation and 3 of the 62 patients (5%) with BRCA2.

Overall, these data indicate cancer rates in male BRCA mutation carriers may be substantially higher than those reported for the general population in matching age groups. Additionally, prostate cancer was prevalent among BRCA1 carriers and not restricted to BRCA2, as some previous reports have shown.

DNA Repair Gene Mutations

Using samples from 936 localized and metastatic prostate cancers, Glass et al (Abstract PD03-02) studied the distribution of DNA repair gene mutations to characterize changes in repair pathway genes. In addition to assessing the frequency of these mutations in primary vs metastatic prostate tumors, the study also sought to find if prostate tumors with DNA repair defects were particularly sensitive to platinum-based chemotherapy and poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor therapy.

Of the samples in the study, 228 showed at least one likely functional mutation in a DNA repair gene (24.4%). Mutations were identified in 20.1% of prostate tumors and 18.8% of bone metastases. The highest rates of DNA repair mutations were found in visceral metastases (such as brain, pelvis, and liver, which were significantly higher than either prostate tissue or bone sites).

The most commonly mutated genes in the DNA repair pathway were BRCA2 (11%), ATM (66%), MSH6 (2.5%), MSH2 (2%), ATR (1.6%), MLH1 (1.3%), and BRCA1 (1.2%).

Commentary

“These studies reveal new insights into the role genetic mutations play in the development of prostate cancer, particularly metastatic disease,” said Scott Eggener, MD, Associate Professor of Surgery and Director of the Prostate Cancer Program at the University of Chicago Medicine. “For some patients, a detailed understanding of these mutations could have a meaningful impact on the timely diagnosis and treatment of their disease.”

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®.


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