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Taking Men's Genetic Health Mainstream in Prostate Cancer

Sartor, Oliver MD

doi: 10.1097/01.COT.0000512185.35615.c5
prostate cancer

prostate cancer

Thanks to the personal stories of celebrities like Angelina Jolie and the focused efforts of breast cancer patients, advocates, and physicians, the use of genetic testing for assessing breast and ovarian cancer has become well publicized and commonplace. But it's only in the past year or two that similar awareness of the utility of genetic testing for the other half of the population—men—has begun to gain traction.

Five years ago, there was little evidence for a hereditary component to diseases such as prostate cancer, melanoma, and colon cancer. Fortunately, understanding of genetic risk factors for these diseases has grown significantly, allowing men the option to pursue genetic testing to better understand their health—just as women have been doing for breast and ovarian cancer for years.

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Evaluating & Managing Risk

In August, The New England Journal of Medicine published a paper I believe is one of the most impactful studies published this year. The findings in this manuscript demonstrate that inherited DNA-repair gene defects are more common that expected (2016;375:443-53). In this study, mutations found in multiple DNA repair genes, including BRCA1, BRCA2, ATM, CHEK2, RAD51D, GEN1, and PALB2, are significantly increased in metastatic prostate cancer patients (Cell 2015;161:1215-28). The results of this study add to the growing body of evidence regarding hereditary mutations associated with prostate cancer and confirm and extend the importance of the germline mutations first described in Cell (2015;161(5):1215-28).

Importantly, the DNA-repair manuscripts in prostate cancer clearly show a family history of prostate cancer is not always relevant in determining risk. These mutations may be found in persons who do not have a known family health history of cancer. For this reason, broader testing of patients with metastatic prostate cancer without regard to family history will likely increase the yield of actionable mutations identified. Family history alone cannot be reliably used to predict an inherited DNA-repair defect that may have risk of disease associated with it and should not be the sole determinant for pursuing genetic testing in men with metastatic prostate cancer (N Engl J Med 2016;375:443-53).

The results of these clinical studies led me to broaden my own testing to all those at risk. I currently have a patient database that includes detailed family histories in more than 500 prostate cancer patients, and have gathered some intriguing insights from patients' genetic testing results. In one notable case, I saw a patient with a BRCA1 mutation, and a PSA of 300. The inevitable occurred—he died from metastatic prostate cancer. I insisted his three children be tested for possible genetic defects. His daughter had already undergone BRCA testing and found to have no mutation. Results of the more extensive genetic testing, of multiple genes, demonstrated his daughter indeed had no BRCA1 mutation, but she was CHEK2 mutation positive. His two sons had both BRCA1 and CHEK2 germline mutations, which is rare. As a result of testing, both son and daughter were able to understand their own likelihood of developing a related cancer years earlier than they might otherwise have. His son, still in his 40s, was screened for prostate cancer and subsequently found to have biopsy proven cancer. His son decided on surgery and hopefully his fate will be distinct from that of his father. So far, he has had no evidence of relapse.

This case study clearly shows the value of broader, complete genetic testing and the importance of discussing implications for a patient's whole family.

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Clinical Utility of Genetic Information

Beyond evaluating risk for disease, genetic information is increasingly important for therapeutic decision-making. This is true both with the increasing use of poly (ADP-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapy in men with metastatic prostate cancer and DNA-repair gene mutations. The detection of mutations in DNA-repair genes allows us to identify cancer subtypes that are more likely to respond to these specific therapies (N Engl J Med 2015;373(8):1697-1708, Eur Urol 2016;69(6):992-5).

In January of this year, the FDA granted Breakthrough Therapy designation for the oral PARP inhibitor olaparib for the monotherapy treatment of BRCA1/BRCA2 or ATM gene-mutated metastatic castration-resistant prostate cancer in patients who had received prior taxane-based chemotherapy and at least one newer hormonal agent. The promise offered by this therapy underscores the need to think more broadly about the use of genetic testing in men, viewing it as a guide and possible gateway to treatment rather than simply a diagnostic tool. Though data with platinum therapy is more limited, preliminary data suggest older generic platinum agents can have considerable activity in the presence of DNA repair mutations and more data are in the process of being collected.

As our understanding of hereditary disease continues to grow, research underscores the importance of using a combination of both genetic testing and family health histories to evaluate risks for prostate cancer and other diseases. Family history can convey risk even when the genetic testing is not informative. In our clinic, we have a family coordinator who takes detailed cancer histories, which we evaluate alongside genetic and clinical information. Simply ensuring you inquire about family history of cancers associated with these mutations regardless of gender can help guide diagnostic testing in patients.

I use the guidelines issued by the National Comprehensive Cancer Network to guide my genetic testing in men without metastatic prostate cancer. It's also important to choose a high-quality lab for genetic testing services that offers full panels rather than only a handful of genes. Optimally this laboratory would provide comprehensive evaluations of both pathologic variants as well as variants of unknown significance. Strong clinical support is especially helpful for practitioners who are newer to the use of genetic testing in their practice.

Use of genetic information will continue to expand for both determining risk of many inherited diseases, and making subsequent therapeutic decisions. The breast and ovarian cancer community has long been at the leading edge of this new frontier. The promise of precision medicine is powered in part by access to this type of genetic information. It will soon become common to employ genetic testing when managing metastatic prostate cancer, and I anticipate these tests will improve both the care of patients and as well as their families.

OLIVER SARTOR, MD, is the Laborde Professor for Cancer Research and Medical Director at Tulane Cancer Center, Tulane University, School of Medicine, New Orleans.

Oliver Sartor, MD

Oliver Sartor, MD

Wolters Kluwer Health, Inc. All rights reserved.
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