Multigene Testing Can Inform Predisposition to Inherited Prostate Cancer

Comprehensive genetic testing using multigene testing panels for prostate cancer can arm genetic counselors with the information they need to guide precision therapy, even in men with early stage disease but a strong family history of the disease.

Between 5% and 10% of prostate cancer is a result of inherited mutations that can lead to hereditary cancer syndromes. Variants in the BRCA1/2 genes, for example, have been shown to increase a person’s risk of prostate cancer by 3.8- to 8.4-fold and reduce survival. A recurrent mutation in the HOXB₁₃ gene is responsible for a 2- to 8-fold increased risk for prostate cancer and a 2- to 10-fold increase in early onset of the disease. Research studies have also pointed to a greater incidence of germline mutations in DNA repair genes in men with metastatic prostate cancer.

For the current study, published in JCO Precision Oncology, researchers developed the Genetic Evaluation of Men study with 3 primary objectives:

• Implement prospective multigene panel testing for inherited prostate cancer in the context of genetic counseling
• Characterize the genetic variant spectrum in clinically available cancer risk genes to inform men and their families about cancer risks, screening, and precision treatment
• Develop a registry of men with and without prostate cancer that encompasses detailed personal/family history (FH) of cancer, diet, exercise, and exposures that are not usually available from commercial genetic testing laboratory databases

Eligibility criteria for participation in the study included considerations for age, race, FH, and disease stage/grade. The multigene panel testing included 28 cancer risk genes.

Of the 200 predominantly white men (69%) included in the study, 125 (62.5%) had prostate cancer. FH showed mainly prostate cancer (69.0%) followed by breast (48.5%) and colorectal (27.5%); 42.0% had a personal/FH of cancer that met criteria for a hereditary cancer syndrome: hereditary breast and ovarian cancer (HBOC, 21.5%), hereditary prostate cancer (9.5%), and Lynch syndrome (4%).

While only 11 men (5.5%; 95% CI, 3.0% to 9.9%) had mutations, 63.6% of these were in the DNA repair genes—an FH of breast cancer had a significant association with mutation status (P = .004), and FH that met criteria of HBOC syndrome had a significant association with prostate cancer (odds ratio, 2.33; 95% CI, 1.05 to 5.18). A significant number of men (70, 35%) carried mutations of uncertain significance.

Forty-four percent of mutation carriers were diagnosed before 60—over 66% had a Gleason score ≥7 and over 44% had a Gleason score ≥8. Two men with metastatic prostate cancer had germline mutations in ATM or BRCA2. More than 45% of the 11 mutation carriers had mutations concordant with their personal/FH.

The authors conclude that their findings can help fill in a practice gap for genetic counseling “to inform men about potential multigene test results before proceeding with genetic testing.” The knowledge around defects in the DNA repair genes, identified in this study, could qualify men with advanced or metastatic prostate cancer for treatment with PARP inhibitors. For men at high risk for prostate cancer, the study can help devise future screening strategies.

Reference

Giri VN, Obeid E, Gross L, et al. Inherited mutations in men undergoing multigene panel testing for prostate cancer: emerging implications for personalized prostate cancer genetic evaluation [published online May 4, 2017]. JCO Prec Oncol. doi: 10.1200/PO.16.00039.