DEBU TRIPATHY, M.D.
Until fairly recently, we didn’t think of prostate cancer as an inherited disease.
Family history was one indicator that a man should undergo periodic screening, but it wasn’t until a couple of decades ago that scientists confirmed a link between inherited mutations of the BRCA gene and the development of prostate cancer.
Now, our growing understanding of that link may lead to important changes in how prostate cancer is treated. The latest development is the apparent efficacy of PARP inhibitors — originally developed as therapies for ovarian and breast cancer — in this men’s disease. Clinical trials are exploring drugs including Lynparza (olaparib), Rubraca (rucaparib) and experimental talazoparib to treat men with advanced prostate cancer and inherited mutations of the BRCA, CHEK2, ATM and PALB2 genes, all of which mediate DNA repair. The drugs are being explored both alone and, more promisingly, in combination with other types of treatments.
by inhibiting the PARP protein in cancer cells, which prevents the cells from repairing their own DNA when damaged. This, in turn, results in cell death, with BRCA-related cancers being exquisitely sensitive to these drugs because the diseased cells already have faulty DNA-repairing ability.
This strategy seems particularly useful in metastatic prostate cancer because advanced disease is the most likely to include BRCA mutations as driving factors. PARP inhibitors are also being tested in patients who do not have hereditary mutations but may have other factors that still make them sensitive to treatment.
The dynamic has become so pivotal as a part of medical treatment that experts now recommend that all men with metastatic, castration-resistant prostate cancer undergo genetic testing to look for inherited BRCA and other mutations. Knowledge of a man’s genetic mutation status can help doctors choose the most appropriate treatments. For some men, the presence of inherited gene mutations could signal the need for more aggressive and earlier treatment than would otherwise be offered. This genetic profile might also open the door to enrollment in certain clinical trials.
It’s also important to note that positive test results could mean that others in a patient’s family are affected by BRCA gene mutations, and these relatives should be tested, too. For instance, inherited BRCA mutations passed on by a father could predispose his sons and daughters to a number of cancers, including ovarian, breast and pancreatic, and early knowledge could allow them to take preventive measures.
What we now know about BRCA mutations has caused a big shift in our thinking about prostate cancer and our recommendations for the treatment of men with metastatic disease. Looked at within the larger landscape of scientific discovery, these findings offer hope, representing just one of many future opportunities to use the genetic profiles of patients and their tumors to treat and prevent disease.