New Insights Regarding Genetic Contribution to Inherited Prostate Cancer

17
Dec

Newly published research from Sidney Kimmel Cancer Center – Jefferson Health (SKCC) investigators provides a snapshot of the spectrum of genetic changes that are responsible for inherited prostate cancer, supporting current guidelines for genetic testing of patients with prostate cancer, as well as suggesting expanded testing to encompass additional patients.

Previous studies on this topic have largely focused on prostate cancer patients with a family history of other inherited cancers, such as breast or ovarian cancers, or patients who meet strict eligibility criteria, such as early age of disease onset or presence of metastatic disease. In the new study, published in The Prostate, Veda Giri, MD, Director of the Jefferson Clinical Cancer Genetics Service and the Men’s Genetic Risk Clinic at SKCC, and colleagues assessed pathogenic germline mutations in 1,328 men with prostate cancer (see Figure 1).

Germline mutations are inherited and hence may be transmitted from generation to generation, substantially raising the lifetime risk for specific cancers. In contrast, sporadic mutations arise in somatic tissues in the body and are not inherited. The 1,328 patients analyzed in the new study represent a cross-section of men with prostate cancer, including individuals with and without a family history of cancer, with different stages of disease and without regard to whether the prostate cancer had metastasized.

The investigators discovered that the overall rate of pathogenic germline mutations was 15.6 percent and that the rate for mutations in DNA repair genes was 10.9 percent. Current National Comprehensive Cancer Network guidelines suggest that germline testing should be considered for prostate cancer patients with a family history of other inherited cancers, multiple family members with a diagnosis of prostate cancer at an early age, metastatic disease or high risk of progression to metastasis, or Ashkenazi Jewish ancestry. The new SKCC study generally supports these guidelines but also raises the possibility that broader testing might be useful for prostate cancer patients who do not necessarily fall into any of these categories.

“The results from this large study have identified a spectrum of gene mutations in men with prostate cancer, supporting the role of multigene testing in this context. We also found that men with prostate cancer with a family history of breast cancer were twice as likely to carry specific genetic mutations linked with prostate cancer, which helps identify men for genetic testing. The scope of men potentially eligible for genetically informed prostate cancer management and treatment is quite substantial based on these results,” Giri said.

In addition to supporting an expanded scope for testing for germline mutations in prostate cancer, the new study also holds promise for improved diagnosis and treatment of prostate cancer based on the particular mutations detected in individual patients. For example, the study found that pathogenic germline mutations in DNA repair genes were about twofold more prevalent in patients with advanced disease, indicating that this type of multigene testing can help identify those patients at high risk for aggressive disease progression and inform their treatment as new options and data emerge. Most promisingly, information about germline mutations present in an individual patient, coupled with knowledge of the specific cellular pathway affected by each mutation, can lead to the application of “precision therapy,” in which targeted agents or chemotherapy drugs are selected to most effectively target the specific cellular abnormalities driving cancer progression in that patient.

“Our study results provide further leads regarding the spectrum of genetic mutations predisposing to prostate cancer or potentially driving prostate cancer aggressiveness,” Giri said. “Looking to the future, basic science work will be important to define which genes are important drivers of aggressive prostate cancer — information that may be incorporated into management discussions with patients. It is important to uncover genetic mutations across populations as well to inform tailored management, treatment, and drug development.”