A new study in this week’s New England Journal of Medicine reports that DNA-repair germline mutations were found in nearly 12 percent of patients who had metastatic prostate cancer.
DNA-repair germline mutations are inherited mutations in genes such as the BRCA2 gene that can run in families, and that are known to predispose men to increased risk for prostate cancer because the patients’ DNA -repair mechanisms do not work as well as the DNA-repair mechanisms of people without such mutations. These type of mutations are known to be associated with elevated risk for lethal forms of prostate cancer, but we had not previously had good data on just how common these mutations are in men with metastatic prostate cancer.
In this multi-national, multi-center study, Pritchard et al. were able to recruit just under 700 men with documented metastatic prostate cancer. However, the patients were eligible for enrollment regardless of age or family history of prostate cancer. The investigators then used sophisticated DNA testing to identify the presence of mutations in 20 different DNA-repair genes known to predispose patients to high risk for cancer.
Here is what they found:
- 82/692 patients (11.8 percent) carried one or more of the germline mutations.
- 84 mutations were found among the 82 patients carrying such mutations.
- 16 of the 20 different types of DNA-repair germline mutation were identified in this cohort of men.
- The most common of the mutations were
- The BRCA2 mutation in 37/692 patients (5.3 percent) and as 37/84 (44.0 percent) of all the mutations found
- The ATM mutation in 11/692 patients (1.6 percent) and as 11/84 (13.1 percent) of all the mutations found
- The CHEK2 mutation in 10/534 patients for whom data was available (1.9 percent)
- Neither family history of prostate cancer nor age at diagnosis seemed to affect risk for identification of these particular germline mutations in this patient cohort.
Prior studies have shown that the prevalence of DNA-repair germline mutations was
- 4.6 percent among 499 men with localized prostate cancer (P < 0.001), including men with high-risk disease
- 2.7 percent among 53,105 persons without a known cancer diagnosis (P < 0.001)
The authors state that the low prevalence of these types of mutation in the population at large makes it impractical to test everyone for the presence of these mutations if they are not members of families known to be carriers of the mutations. The “New” Prostate Cancer InfoLink would note that the additional finding suggested by this study, i.e., that the presence or absence of the mutation in the germline is not highly associated with the development of prostate cancer in general (i.e., not highly associated with a family history of the disease), further complicates the question of individual risk.
While our new appreciation of the prevalence of this type of mutation in men with metastatic prostate cancer is clearly useful, and while we appear to be seeing early data on the effectiveness of drugs like the PARP inhibitors in treating men with these types of metastatic prostate cancer, we do not seem to be making much progress (yet) in understanding exactly why this type of aggressive prostate cancer may occur in particular types of patient.
Filed under: Diagnosis, Management, Risk | Tagged: DNA, gene, germline, metastatic, mutation, repair, risk |
THE "NEW" PROSTATE CANCER INFOLINK 
That’s pretty interesting, because it doesn’t seem to line up real well with what has been found concerning the BRCA gene’s relationship to breast/ovarian cancer. In breast cancer the determination of a BRCA mutation is not entirely just a yes/no answer. The degree of mutation is very important. A slight mutation results in a slightly elevated cancer risk and a weaker family history relationship, but a severe mutation is associated with almost certainly getting cancer and a strong family relationship. Angelina Jolie was supposed to have something like an 87% chance of getting cancer.
As a side note, Sergey Brin, one of the co-founders of Google, actually had his prostate proactively removed because of his BRCA gene status (and his dad had died of prostate cancer). This is all described in a book by Dr. Francis Collins entitled The Language of Life: DNA and the Revolution in Personalized Medicine. I am sure these researchers know a lot more about this than I do, and are aware of all this.
Doug:
Please note that I haven’t seen the full text of this paper, which may well address some of these issues in more detail. I only have access to the abstract.
Please see my response to today’s post regarding the availability of information to men living with advanced mCRPC. This post reiterates the importance of full and timely information.
I asked my husband’s medical oncologist yesterday if they were going to do any genetic testing because he wasn’t responding to Taxotere. His sister had breast cancer and his brother has brain cancer, so I thought there could be a genetic link. He told me it would cost $3000 and genetic mutations were very rare so it wouldn’t be worth it.
Dan is a solid Gleason 10 with PSA that doubled in 2 weeks while on Taxotere. I said that’s pretty rare too, so I wouldn’t have a problem paying for the testing. Before this experience, I assumed this was being done for every cancer patient. Guess things aren’t as advanced as I would have thought.
Mary … Apologies for the late response, but I just saw your comment.
If it were me, I would insist on genome sequencing. Foundation One has made it very clear they will do their best to accommodate all requests notwithstanding financial considerations … and men I know have had this confirmed by phone. Take a look here for more information and access to their Patient Assistance Program.
A recent biopsy sample should be used since prostate cancer morphs pretty quickly. If a tissue sample cannot be obtained, a liquid (blood) biopsy is possible but not as effective.
As both Sitemaster and I have indicated, genome sequencing is not a magic bullet. Many men do find actionable genes, not all, and then the likelihood that the treatment for an actionable gene may work is still only 10-30%.
Testing should be done sooner rather than later. To discuss further, you can reach me at rd@ancan.org or visit our website, Answer Cancer Foundation.
Onward & upwards
There are genes in the BRCA pathway that may also be actionable, for example CDK12. Reading the genome sequencing requires considerable expertise.