More evidence is emerging that men who carry germline mutations in one of three DNA repair genes are more likely to die of prostate cancer, and they do so faster and at an earlier age than men who do not carry the mutations, new research shows.
"The study results have an important translational impact because they clearly demonstrate germline mutations in these three well-established genes can be used to predict risk for lethal prostate cancer and time to death," author Jianfeng Xu, MD, DrPH, vice president of translational research at NorthShore University HealthSystem, Evanston, Illinois, said in a statement.
"This confirms major findings from previous studies and provides further direct evidence of the important role of genetic testing in prostate cancer screening and treatment," he added.
The study was published online December 15 in European Urology.
The retrospective case-case study included 313 patients who died of prostate cancer and 486 patients with low-risk localized disease.
Patients were of European American, African American, and Chinese descent.
Investigators performed whole-exome sequencing on germline DNA and compared pathogenic mutations in BRCA1, BRCA2, and ATM genes in men who had lethal prostate cancer and men with indolent disease.
They also examined the effect that germline mutations in any of these three genes had on the patients' age at the time of death from prostate cancer and the length of time patients survived after diagnosis.
The frequency of mutations was 6.07% in patients with lethal prostate cancer, which was significantly higher than that observed in patients with localized prostate cancer (1.44%; P = .0007), the investigators report.
For each individual gene, mutation rates were also consistently higher among men who died of prostate cancer than those with indolent disease. This was true for all thee racial groups.
The difference in mutation status was "particularly striking" in patients of Chinese descent. In that group, a mutation was found in more than 18% of men with lethal prostate cancer; by comparision, none were found among men with localized disease (P = .0095).
Table. Carrier Fates of Mutations in BRCA1, BRCA2, and ATM Genes in the Overall Cohort
| Lethal | Localized | P Value | |
| BRCA1 | 0.64% | 0.41% | 1.00 |
| BRCA2 | 3.51% | 0.82% | 0.013 |
| ATM | 1.92% | 0.41% | 0.06 |
Mutation Status and Advanced Disease
The median age at diagnosis was 64 years and did not differ significantly between those who carried a mutation and those who did not. However, mutation carriers were significantly more likely to have advanced prostate cancer at the time of diagnosis, the authors note.
"Mutation carriers [also] had a higher proportion of Gleason Score ≥7 (71%) than noncarriers (31%), P = .00009, and higher median PSA [prostatic-specific antigen] levels (7.90 ng/ml) than noncarriers (6.20 ng/ml), P=0.048," they add.
Men who carried one of the three germline mutations were also more likely to die earlier than noncarriers.
For example, 10% of men who died from lethal prostate cancer at age 60 years or younger carried one of the germline mutations, as did 9.08% of men aged 61 to 65 years who died of their disease.
These percentages declined as men survived into later years, to the point where no mutations were identified in men who died from prostate cancer after the age of 80 years.
Carrying one of the germline mutations also made a significant difference in how long men survived following their diagnosis.
For example, more than 12% men who died within 5 years of their diagnosis carried a mutation, compared with fewer than 1% of men who died more than 10 years after being diagnosed (P = .0006).
Higher Than Believed
Asked by Medscape Medical News if a 6% carrier rate was high enough to justify assessing the mutational status of men with prostate cancer, Dr Xu noted that the 6% carrier status identified in this study was significantly higher than previously believed.
"We used to think it was around 1% to 2%, so the carrier rate is higher than we thought, which is important," he said.
Furthermore, among men who died of their disease, some died within 5 years of their diagnosis, whereas others lived for a decade and longer.
"When you look at patients who died within 5 years of their diagnosis, the mutation carrier status was over 12%," Dr Xu observed.
"So that's an important message as well," he said.
Moreover, about half of the men who harbor one of these well-established germline mutations have no family history of prostate cancer.
"Therefore, if you only look for mutational status in men with a family history of prostate cancer, you will miss half of the men who have these mutations," Dr Xu said.
"So we think all men with newly diagnosed prostate cancer should be offered mutational testing, because knowing their carrier status will help shape treatment strategy," he added.
Indeed, if a man is found to carry one of these germline mutations, Dr Xu believes more aggressive treatment may the more appropriate strategy
We believe our evidence suggests that even if you have indolent features of prostate cancer at the time of diagnosis, if you carry these mutations, you are more likely than noncarriers to develop lethal prostate cancer," Dr Xu said.
"And we think this carrier information should be considered as part of the decision-making process in terms of who should go onto active surveillance and who should be actively treated," he concluded.
A Research Tool, Says Expert
Asked by Medscape Medical News whether he thought assessment of mutational carrier status is now ready for the clinic, Marc Garnick, MD, professor of medicine, Harvard Medical School, Boston, Massachusetts, said he still sees the test as a research tool at this time.
Dr Garnick is also editor in chief of the Harvard Medical School Annual Report on Prostate Diseases and of Harvard's Prostate Knowledge website. He said that knowing a patient's genetic profile may not be that helpful for patients who have adverse clinical features, such as a high Gleason score, high PSA values, and T3 disease, because physicians already know that these patients are going to do badly.
On the other hand, "it may be very helpful in identifying the population of people who have indolent disease, but based on their genetic profile, you know the disease is not indolent, it's an aggressive cancer," Dr Garnick said.
Some commercially available tests can help identify patients with indolent disease who may have a more aggressive genomic profile, Dr Garnick pointed out.
He also raised concerns that testing for BRCA mutations. Although for breast cancer patients, such testing is usually covered by insurance, it can result in up to $3000 in out-of-pocket costs, and insurance may not cover such testing in cases involving prostate cancer, at least not yet.
"This is important research because it is adding to the biomarker repository of how we try to determine what treatment course to take," Dr Garnick noted.
"But if insurance doesn't cover it, I'm not sure patients are going to get tested," he said.
The study was funded by the National Key Basic Research Program of China, the Key Project of the National Natural Science Foundation of China, and the Rob Brooks Fund for Personalized Cancer Care at the NorthShore University HealthSystem. Dr Xu and Dr Garnick have disclosed no relevant financial relationships.
Eur Urol. Published online December 15, 2016. Abstract
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