Study Finds Key Predictors of Positive Genetic Test Results in Men with Prostate Cancer

Genetic testing can identify men with prostate cancer who have pathogenic variants in genes associated with hereditary cancer. Results of genetic testing may be useful to inform treatment and management, identify men who are at greater risk for aggressive prostate cancer, and provide information about increased risks for other cancers for both the patient and their family members. In addition to potentially informing additional therapeutic options, genetic testing may enable individuals at increased risk to undergo personalized screening or prevention measures to help lower their risk of being diagnosed with advanced stage cancer. One challenge, however, is determining which men should undergo genetic testing.

Surprisingly, there is little evidence that men who meet the classic definition of hereditary prostate cancer have pathogenic variants in the DNA repair genes.  This classic definition includes men with one of the following:

          ·   3 or more generations of prostate cancer
          ·   3 or more first degree relatives (son(s), brother(s), father) with prostate cancer
          ·   2 or more men with prostate cancer diagnosed at age 55 or younger

Recent data suggests that aggressive prostate cancer and a family history of other cancers may be better predictors for pathogenic variants in men with prostate cancer1,2 . As a result, in 2017, expert consensus guidelines recommended genetic testing for men with any of the following:

          ·   Meets the definition for hereditary prostate cancer (see above)
          ·   2 or more close relatives with a cancer associated with hereditary breast and ovarian cancer or Lynch syndrome
          ·   Metastatic castration-resistant prostate cancer
          ·   Somatic pathogenic variants identified via tumor testing

However, these testing guidelines are based on limited evidence. Thus, there was an urgent need to determine a more robust way to identify pathogenic variants in men with prostate cancer.

A recently published Ambry Genetics’ study in Genetics in Medicine, described an analysis of 1,812 men with prostate cancer who underwent clinical genetic testing. This study analyzed the clinical variables reported on the test requisition forms to determine the most reliable predictors of positive results.

Key Findings:

1.    Pathogenic variants were found in 12% of men who underwent multigene panel testing who had no prior testing.

2.    Predictors of positive results included:

          ·   Increasing Gleason score
          ·   Personal history of breast or pancreatic cancer
          ·   Family history of breast, ovarian, or pancreatic cancer
          ·   Family history of Lynch-syndrome associated cancers

3.    Among all men with no prior genetic testing, the pooled frequency of pathogenic variants in therapeutically actionable genes (BRCA1/2 and mismatch repair genes) was 7.4%.

4.    Among men with prior genetic testing, 15% were found to have pathogenic variants via multi-gene panel testing that may have been missed based on previous test results (IHC, somatic and limited germline testing).

          ·   2 men with abnormal IHC results were found to have a pathogenic variant in a non-mismatch repair gene
          ·   One man was found to have a germline pathogenic variant in the setting of normal IHC results
          ·   3 men with previous limited germline testing were found to have germline pathogenic variants upon expanded testing

Together, these results highlight the utility of multi-gene panel testing for men with prostate cancer; particularly men with aggressive disease, or with a personal or family history of other cancers.

Read the complete study from Genetics in Medicine

Check out more information about ProstateNext (Ambry Genetics' 14-gene panel for hereditary prostate cancer), or contact us if you are interested in learning more about genetic testing. 

 

References

1. Pritchard CC, Mateo J, Walsh MF et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic PC. N Eng J Med 2016;375:443-453.

2. Leongamornlert D, Saunders E, Dadev T et al. Frequent germline deleterious mutations in DNA repair
    genes in familial PC cases are associated with advanced disease. BR J Cancer. 2014 Mar 18;110(6):1663-72

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