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Family history, disease stage key in determining need for inherited prostate cancer genetic testing
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A more detailed assessment of family history of cancer — including prostate, breast, ovarian, colorectal and pancreatic cancers, as well as melanoma — and stage of disease should be used to determine need for genetic counseling and testing for inherited prostate cancer risk, according to recommendations by an international and interspecialty panel of experts published in Journal of Clinical Oncology.
“Approximately 5% to 15% of prostate cancer has an inherited predisposition from cancer risk genes, and this percentage may be as high as 20% in metastatic prostate cancer,” Veda N. Giri, MD, associate professor and director of clinical cancer genetics at Sidney Kimmel Cancer Center at Thomas Jefferson University, told HemOnc Today. “However, genetic testing for men with prostate cancer has lagged behind testing for other cancers, with current National Comprehensive Cancer Network guidelines primarily focused on BRCA testing for men with prostate cancer.”
Prostate cancer accounted for 26,730 deaths in 2017, and there is increasing evidence the disease has substantial inherited predisposition, with higher risks conferred by BRCA2, BRCA1 and HOXB13. Further, BRCA2 mutations have been associated with poor prostate cancer-specific outcomes, and emerging evidence links prostate cancer and DNA repair gene mutations.
The Philadelphia Prostate Cancer Consensus 2017 convened to address the gap in genetic testing guidelines for men with prostate cancer and to develop a framework across the spectrum of evaluation focused on the following key questions:
- Which men should be considered for genetic counseling and genetic testing?;
- Which genes should be tested based on clinical and/or familial scenarios?;
- How should genetic test results inform prostate cancer screening?; and
- Should genetic test results inform management of early-stage/localized; advanced/high-risk; or metastatic, castration-resistant prostate cancer?
More than 70 panelists showed strong consensus to test BRCA1 and BRCA2 for suspected hereditary breast and ovarian cancer, HOXB13 for suspected hereditary prostate cancer, and DNA mismatch repair genes for suspected Lynch syndrome.
Panel members recommended factoring BRCA2 mutations into prostate cancer screening discussions. BRCA2 achieved moderate consensus for factoring into early-stage management discussion, with stronger consensus in the high-risk/advanced setting.
“Urologists are often on the frontlines of diagnosis and treatment of prostate cancer,” Giri said. “These consensus recommendations point to the need to obtain family history information from men with prostate cancer, which is important in the urology setting to identify men with a potential genetic risk for prostate cancer to consider for genetic evaluation.”
The panel moderately agreed to test all men with metastatic castration-resistant prostate cancer, regardless of family history. Agreement was stronger to test BRCA1 and BRCA2 and moderate to test ATM to inform prognosis and targeted therapy among men with metastatic castration-resistant prostate cancer who chose to undergo genetic testing.
“The evidence is strong and endorsed by the consensus that alterations in DNA repair genes can direct targeted therapy,” Leonard G. Gomella, MD, FACS, chairman of urology at Thomas Jefferson University Hospital, told HemOnc Today. “In particular, mutations in genes such as BRCA1/BRCA2 and ATM suggest enhanced responsiveness to PARP inhibitors in metastatic castrate resistant prostate cancer. The PARP inhibitor olaparib (Lynparza, AstraZeneca) has been given breakthrough therapy designation by the FDA for this indication.”
Genetic test results may increasingly be used in the conversation that urologists and medical oncologists have with patients regarding management and treatment of prostate cancer, and therefore there is a need for increased collaboration between urologists, oncologists and cancer genetic specialists, according to Giri.
The prostate cancer consensus panel recommended considering genetic referral for men with any of the following:
- Family history of cancers including prostate, breast, ovarian, colon, uterine and pancreatic cancers;
- A first-degree relative who died of prostate cancer when aged younger than 60 years;
- Early age at diagnosis of prostate cancer (age 55 years or younger);
- Advanced or metastatic prostate cancer; and
- Tumor sequencing showing mutations in cancer-risk genes.
As a specialty, urology has also made major advances in addressing overtreatment of prostate cancer through the selective use of active surveillance, Gomella told HemOnc Today.
“As an example, in one recent study 49% of men with low-risk prostate cancer underwent active surveillance,” Gomella said. “Tissue-based molecular genetic testing has had an impact in the area of overtreatment. Unlike in the current status among women, we are at the earliest stages of using germline genetic testing in men to guide screening or treatment decisions.”
Other important take-home points from the consensus panel proceedings included:
- Family history is very important for men with prostate cancer, and cancer history among male and female relatives on the maternal and paternal sides of the family should be considered;
- Men with metastatic, castration-resistant prostate cancer should consider genetic counseling and genetic testing. Genes of particular importance in this setting are BRCA2, BRCA1 and ATM, where targeted therapy could be considered;
- The panel endorsed BRCA2 and HOXB13 for consideration in prostate cancer screening discussions;
- The panel endorsed BRCA2 for consideration of management discussions in early-stage and advanced prostate cancer, although more data are needed; and
- Identification of a genetic mutation in a man with prostate cancer can lead to cascade genetic testing in male and female relatives, informing their risk for cancer and screening strategies. – by Chuck Gormley
For more information:
Veda N. Giri , MD, can be reached at Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, 1025 Walnut St., Suite 1015, Philadelphia, PA 19107; email: veda.giri@jefferson.edu.
Leonard G. Gomella, MD, can be reached at Department of Urology, Thomas Jefferson University, 1025 Walnut St., Suite 1102, Philadelphia, PA 19107; email: leonard.gomella@jefferson.edu.
Disclosures: Giri reports stock or other ownership in Novopyxis. Gomella reports consultant/advisory roles with Astellas Pharma, Bayer, MDxHealth, Janssen and Pfizer. Please see the full study for all other authors’ relevant financial disclosures.
Additional reference:
Womble PR, et al. J Euro Urol. 2014; doi.org/10.1016/j.eururo.2014.08.024.
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