Germline mutations and risk for advanced prostate cancer

Many people are increasingly interested in whether genetic testing can help them to understand their risk for cancer. The basic answer is that “Yes, it can.” However, what is also clear is that it is only going to be helpful for a small percentage of the population.

A recent paper by Slavin et al., pubished in the Journal of Clinical Oncology, looked at the germline mutations carried by 10,888 unselected patients with advanced (Stage III or IV) cancer who underwent Guardant360 testing for germline mutations between November 2015 and December 2016. And we should remember here that a germline mutation is an hereditary or familial mutation passed down to you through your parents from your ancestors.

In this study, 6 percent (i.e., about 650 patients) were men with advanced forms of prostate cancer.

Of those roughly 650 men, “putative germline findings” — which means the identification of a germline mutation believed to place a man at increased risk for clinically significant prostate cancer over time — were found in 3.46 percent or about 22 men. And it is important to understand that being a carrier of such a mutation (e.g., a BRCA1/2 gene or similar) is not a guarantee that you will get clinically significant prostate cancer at all. It is only an indicator of potential risk.

So … in 1,000 men who had advanced prostate cancer, and were therefore at risk of dying from their disease, all we are able to tell is that about 35 might have got this form of cancer because they had a germline mutation that had increased their risk level. By comparison, about 965 of those men with advanced prostate cancer had no known, relevant, genetic risk for clinically significant prostate cancer at birth.

The bottom line to this is that genetic testing for risk of advanced prostate cancer is not going to be a very efficient process because it is not going to tell us much about who is really going to go on to get any form of prostate cancer (let alone clinically significant, advanced prostate cancer). One of the reasons for this is that risk for clinically significant prostate cancer is determined by many, many things over the first 40 to 60 years of a man’s life, of which your germline DNA is just one.

Genetic testing is a useful tool in terms of people who come from families with high and known levels of genetic risk (e.g. Ashkenazi Jews; families who are carriers of the BRCA1/2 genes, etc.). However, as yet, the value of genetic testing for risk of prostate cancer is not of any great potential in testing for risk of prostate cancer for the vast majority of us. Could it become so in the future? Maybe … but only if the cost comes down considerably and the accuracy of the information available goes up exponentially.

On the other side of the same coin … germline and somatic testing for the presence of genes that modify risk may be valuable in the work-up of men initially diagnosed with high-risk prostate cancer because we are getting closer to having insight into how the presence of such genes may affect the selection of treatments that might work well for such patients. And in that context, see the full text of this recent publication by Zafeiriou et al. in European Urology.

One Response

  1. +/- 3% is consistent with estimates of BRCA prevalence in prostate cancer that I have seen before. That still amounts to +/- 5,000 men annually; that is a significant number that impacts many more family members so we should not get too caught up in percentages.

    I am not that familiar with the Guardant test vs the Color, Ambry (both germline) and Foundation Medicine liquid and solid tissue tests. I do know the Foundation Medicine tests are unable to distinguish as to whether the BRCA mutation is germline or somatic. This can be a very important distinction for family members.

    As Sitemaster astutely points out, genomic sequencing may be appropriate where high risk is indicated. Color can now be had for less than $100, so if a man has high-risk characteristics then it is a relatively reasonable investment. By way of example, a man I recently counseled is Ashkenazi Jewish and lost his father and sister to cancer — although neither cancer is widely associated with BRCA. He was diagnosed with metastatic prostate cancer, we encouraged him to test, and he is BRCA2+.

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