Guest blog by Heather H. Cheng, MD, PhD
Researchers have long been aware that prostate cancer carries a substantial familial risk. New data (Robinson, et al Cell 2015) from the Stand Up To Cancer-Prostate Cancer Foundation International Dream Team collaborative group examined the genetic sequence of 150 tumors from men with advanced, hormone-resistant, metastatic prostate cancer. This was a landmark study because although earlier research largely focused on prostate cancer when it is first diagnosed or after surgery, cancer evolves with treatment, so it was important to look at the DNA sequence of late-stage prostate cancer. Among the many findings of this study was the unexpected discovery that approximately 10% of the men with advanced prostate cancer were found to have inherited cancer risk mutations in a family of genes involved in repair of DNA damage (such as BRCA1/2). A person who inherits a mutation in one of these genes from their mother or father may be at increased risk of developing certain types of cancer. While breast and ovarian cancer risks get a lot of attention, men with these inherited mutations can be at increased risk for prostate cancer.
A more recent follow-up study that was published in the New England Journal of Medicine looked specifically at 20 inherited mutations in men with advanced prostate cancer, regardless of the men’s family history of cancer or age at diagnosis—factors commonly associated with inherited cancer risk. This study (Pritchard, et al NEJM 2016), led by Drs. Colin Pritchard, Pete Nelson and an international team of collaborators supported by a Stand Up to Cancer-Prostate Cancer Foundation research grant, studied 692 men with advanced metastatic prostate cancer from 7 different cancer centers (University of Washington, Fred Hutchinson Cancer Research Center, Memorial Sloan Kettering, Royal Marsden Cancer Institute, Dana Farber Cancer Institute, Weill Cornell Cancer Center and University of Michigan), and found that 11.8% of the men had inherited mutations in genes involved in DNA repair, including BRCA2, ATM, CHEK2, BRCA1, and others. This percentage among men with aggressive prostate cancer is notably higher than the rates of similar gene mutations in ALL men with prostate cancer (including the many men with less-aggressive prostate cancers). These findings suggest that all men with metastatic prostate cancer should be offered genetic testing for inherited cancer risk, though more work is needed to establish more precise cancer risk estimates for each gene.
These findings are very exciting, because like breast and ovarian cancer, carriers of these cancer-risk genes may have additional treatment options if they develop cancer. Some cancer treatments specifically target the weakness of the cancer that results from certain types of DNA repair defects. For example, a class of drugs called PARP inhibitors has been studied for treatment of breast and ovarian cancer with mutations of the same DNA repair genes. Recent data (Mateo, et al NEJM 2015) suggest these drugs may also be especially effective for patients with prostate cancer who have mutations in BRCA1, BRCA2, or other genes that affect the repair of DNA damage.
Another class of drugs that may also be very effective for cancers with DNA repair defects is the platinum chemotherapies, which are not typically used in prostate cancer. Data from the UW and Fred Hutchinson group (Cheng et al, European Urology 2016) also suggest platinum may be effective in men with mutations in BRCA1, BRCA2, and other genes involved in DNA repair and cancer risk. More research is needed before this becomes standard of care. Clinical trials of platinum and PARP inhibitors for men with advanced prostate cancer and DNA repair mutations have begun. For example, the Seattle Cancer Care Alliance is running a trial (Clinicaltrials.gov; NCT02598895) looking at combining docetaxel with the platinum agent carboplatin. FORCE maintains a database of clinical trials of interest to the hereditary cancer community, and will update with additional trials looking at targeted therapy for men with hereditary prostate cancer as information becomes available.
Importantly, male relatives of individuals found to have inherited mutations should be offered genetic testing and consider PSA screening and other cancer prevention/early detection methods, ideally through a clinical trial. Very soon, prostate cancer genetics will be a greater part of the clinical care of prostate cancer patients. For those in the Pacific Northwest, we have opened a new Prostate Cancer Genetics Clinic at the Seattle Cancer Care Alliance
Dr. Cheng is the Director of Prostate Cancer Genetics Clinic at the Seattle Cancer Care Alliance and Assistant Professor in the Department of Medicine at the University of Washington. She is also an Assistant Member in the Division of Clinical Research at Fred Hutchinson Cancer Research Center.
Cheng HH, et al. “Biallelic Inactivation of BRCA2 in Platinum-sensitive Metastatic Castration-resistant Prostate Cancer.” European Urology, June 2016; Vol. 69, No. 6: p. 992-995.
Mateo J, et al. “DNA-repair Defects and Olaparib in Metastatic Prostate Cancer.” New England Journal of Medicine, October 29, 2015; Vol. 373, No. 18: p.1697-1708.
Pritchard CC, et al. “Inherited DNA-repair Gene Mutations in Men with Metastatic Prostate Cancer.” New England Journal of Medicine, August 4, 2016; Vol. 375, No. 5: p. 443-53.
Robinson D, et al. “Integrative Clinical Genomics of Advanced Prostate Cancer.” Cell, May 2015; Vol. 161, No. 5: p. 1215-1228.
Tags: brca, BRCA 1, BRCA 2, brca research, BRCA1, BRCA2, gene testing, Genetic counseling, genetic testing, HBOC, hereditary cancer, hereditary cancer research, prostate cancer