Cancer, the uncontrolled growth of cells, is caused by the acquisition of genetic mutations that allow cells to evade the normal biological laws governing when and where they can grow in the body. Mechanisms that maintain the accuracy of our genomes are critical for preventing cells from collecting mutations that cause cancer development and progression. Of these, DNA repair genes, which function to fix damaged or mutated DNA acquired by the cell, are central in the prevention of cancer. Inherited mutations in two of these genes, BRCA1 and BRCA2, vastly increase a woman’s risk for breast and ovarian cancer, and have led women with family histories of these diseases to seek genetic testing and sometimes extreme cancer-preventative measures if they find they are mutation carriers. Inherited mutations in these genes are also associated with increased risk for prostate, endometrial, pancreatic, and potentially other gastrointestinal cancers.
While inherited mutations in DNA repair genes, BRCA2 in particular, have been implicated in increasing the risk of developing prostate cancer, these mutations are found infrequently in the general population. Consequently, routine testing for all men diagnosed with localized prostate cancer has not been recommended. However, the frequency of DNA repair gene mutations in men with aggressive metastatic prostate cancer has not been previously established. A new study published today in the New England Journal of Medicine by Dr. Peter Nelson, of the Fred Hutchinson Cancer Research Center, and an international team of collaborating scientists, has found that ~12% of men with metastatic prostate cancer carry an inherited defect in a DNA repair gene, which likely caused their cancer. These findings have practice-changing implications.
“Our study supports genetic testing and counseling for all men with metastatic prostate cancer, regardless of age or family history” said Nelson, who led the study on behalf of the Prostate Cancer Foundation (PCF)-Stand Up to Cancer (SU2C) International Dream Team, and is a Professor of Medical Oncology at the University of Washington and the Genitourinary Oncology Clinical Research Director of the Seattle Cancer Care Alliance.
“We are now encouraging all patients with metastatic prostate cancer to obtain genetic testing and counseling for inherited mutations in DNA repair genes for two reasons,” said Nelson. “First, patients may benefit from specific therapies that are particularly active against tumors with DNA repair gene mutations, namely PARP-inhibitors (such as Olaparib) and platinum chemotherapy. Second, knowing whether you carry one of these mutations would inform family members to seek genetic counseling to determine whether they are also carriers and are at increased risk for certain types of cancer.”
The PCF–SU2C Dream Team study combined data on the frequencies of hereditary mutations in metastatic prostate cancer from seven case series across eight PCF–SU2C Dream Team institutions, for a total of 692 patients. (We’ve previously reported on preliminary case series findings from the Royal Marsden and Memorial Sloan Kettering Cancer Center.) These men were unselected for family history of cancer, race, or age at diagnosis. Inherited mutations presumed to be cancer-causing were identified across 16 different DNA repair genes in ~12% of metastatic prostate cancer patients, and ranged from 8.8% to 18.5% among the different case series.
BRCA2 was the most commonly mutated DNA repair gene in these men (5.3% of patients and 44% of all identified mutations), while BRCA1 ranked as 4th most commonly mutated in the cohort (0.9% of patients and 7% of all mutations). Other potentially cancer-promoting hereditary mutations in DNA repair genes identified in this study were in ATM (1.6% of the patients), CHEK2 (1.4%), RAD51D (0.4%), and PALB2 (0.4%). Hereditary mutations in the ATR, NBN, PMS2, GEN1, MSH2, MSH6, RAD51C, MRE11A, BRIP1, and FAM175A genes were found at a lower rate.
Nelson and colleagues also assessed the frequencies of hereditary DNA repair gene mutations in men with localized prostate cancer and in the general population using data from previously published genome sequencing studies. Hereditary DNA repair gene mutations were identified in 4.6% of men with localized prostate cancer (499 patients examined) — which included a high percentage of high-risk cancers, and in 2.7% of individuals without a known cancer diagnosis (53,105 individuals examined). The much higher frequency in patients with metastatic prostate cancer indicates that these hereditary mutations may promote the development of more aggressive prostate cancer, warranting the recommended genetic testing in this population.
When Nelson’s team analyzed the family histories of metastatic prostate cancer patients with and without inherited DNA repair gene mutations, both groups had an equivalent likelihood of having a first-degree relative (father, son, brother) with prostate cancer (~22%). However, patients with hereditary DNA repair gene mutations had a significantly higher chance of having a first degree relative with cancers other than prostate cancer, compared with non-carriers (71% versus 50%). These primarily included cancers that are known to be associated with mutations in DNA repair genes (breast, ovarian, and pancreatic cancers). Men with a family history of prostate, breast, ovarian, and/or pancreatic cancers need to be aware of an increased risk for carrying these mutations and developing prostate cancer.
Fortunately, PCF-funded investigators have found that mutations in DNA repair genes confer sensitivity to a class of drugs called PARP-inhibitors. In the recently conducted phase 2 TO–PARP clinical trial, 88% of patients whose tumors harbored DNA repair gene mutations exhibited responses to the PARP-inhibitor, Olaparib. A phase 3 trial is being planned for Olaparib, and if successful, FDA approval should follow. Olaparib is currently FDA-approved for ovarian cancer patients with BRCA1/2 mutations. Many trials with other PARP-inhibitors and with platinum chemotherapy agents such as cisplatin and carboplatin, which may also be effective against tumors with DNA repair gene mutations, are ongoing. Men with metastatic prostate cancer who carry these mutations will need to discuss their findings with their oncologist to develop a treatment plan consistent with the genetic alterations in their cancer.
For both male and female family members of patients who discover they are carriers, Nelson encourages that they seek genetic counseling and talk with their physicians to determine their own risk and recourse for prostate, breast, ovarian, and pancreatic cancers. It is important to recognize that a subset of DNA repair gene mutations have uncertain risks for the development of cancer and consequently the optimal surveillance and risk reduction strategies for carriers of these “variants of uncertain significance” have not yet been established. However, screening from a younger age (Nelson suggests before age 40 for prostate cancer and 20s-30s for breast and ovarian cancer) and seeking curative treatment if even low grade cancers are found (as opposed to active surveillance), may be warranted. “Discussing genetic testing results with an expert trained in cancer genetics is absolutely critical for guiding family testing, as well as cancer screening and treatment decisions,” said Nelson.
“The Prostate Cancer Foundation was a key supporter of this study in several ways. First, in supporting the PCF-SU2C International Dream Team that provided key preliminary data on the genomic landscape of prostate cancer patients, and support for the continued accrual and analysis of these men. The study could not have been completed without such a remarkably collaborative and interactive team. PCF also supported the efforts of many of the individual investigators that worked together on this project, including several PCF-Young Investigators,” said Nelson.
In ongoing PCF-funded studies, PCF-SU2C Dream Team scientists are examining the role of each identified DNA repair gene mutation in promoting prostate cancer and conferring sensitivity to PARP-inhibitors and platinum chemotherapy. These studies will help carriers of specific mutations to better determine their risk for prostate cancer and select treatment strategies likely to provide the greatest benefit.
“Men are often reluctant to undergo screening, including genetic testing, but knowledge is power. Get tested,” urged Nelson.
