We have known there are families with increased risks of developing certain cancers due to genetic abnormalities. This has been particularly true in the case of women with breast cancer.
For years, we struggled with the knowledge that women in some families were highly susceptible to developing breast cancer. Counseling these women was difficult, because we had no clear roadmap to provide us evidence-based recommendations as to what was best for a particular patient.
We did the best we could, and when the family history was very strong we would occasionally recommend that the woman consulting us have prophylactic mastectomies. This was a difficult decision for many of our patients to make, in no small part because they were usually young, and responding to a case of breast cancer in a sister or mother.
As time went on, and we learned more about various genetic syndromes, we became more confident that we were honing in on better tests which would provide us the evidence and information about genetic abnormalities that we had previously lacked.
We began to understand and then map the human genome. Increasingly sophisticated and complex tests were developed which could help us answer the mysteries of familial disease.
Our ability to counsel our patients, especially those with a family history of breast and/or ovarian cancer, improved considerably about 10 years ago when testing for mutations in the genes called BRCA1 and BRCA2 became available.
Inherited abnormalities of these genes may explain 5-10% of breast cancer cases and 10-15% of ovarian cancer cases in this country every year.
Today, the usual scenario for a woman with a strong family history of breast and/or ovarian cancer is to consult her physician and possibly a genetic counselor to determine if she is a candidate for genetic testing.
If testing is appropriate, the ideal circumstance is for the woman with the cancer to be tested, since she has the greatest chance of having the genetic mutation.
If that test is positive, then the female relative who is at risk of developing the cancer needs to make a decision as to whether or not she wants to be tested.
If that test is negative, or if the relative with the cancer declines to take the test or is unable to get the test, then the relative who is at risk of developing the cancer can decide if she wants to proceed with testing after discussing the situation with her doctor and the counselor.
After a thorough explanation of the possible risks and benefits of testing, the woman can obtain a commercially available test. (The benefits are that several preventive options are available which significantly reduce the risk of cancer, including more frequent screening, prophylactic mastectomy and/or oophorectomy, and tamoxifen; the risks are the anxiety associated with the knowledge that the mutation increases one’s risk of breast and ovarian cancer substantially, and potential employment and insurance discrimination.)
Once the test results are returned, if positive, various surveillance and treatment options can be discussed. If negative, the woman may feel reassured that she is not at an increased risk from this form of inherited cancer.
But that reassurance may not be as sound as it appears at first glance. And that is the problem with the limits of our knowledge, our skills, and the application of our science in this particular situation.
I have followed the literature on this topic for several years. Scientists know that there are a number of areas on the BRCA genes where defects can occur. The problem is that current testing that is available to most women only checks for a limited number of mutations, and does not “scan” the entire gene.
The result is that women, particularly those of Ashkenazi (European) Jewish descent who have a specific “founder” mutation (that is, one that has been established for a long time and can be passed from mother OR father to daughter) have a better chance of being found with the current test than women who develop a spontaneous mutation in the gene and pass it on to their families.
But our genes are constantly undergoing mutations that are passed from generation to generation. Those “spontaneous” mutations can occur in the BRCA genes as well, and can be passed on. However, they are unique in certain families and will not show up on the test ordered by the doctor.
The other problem with genetic testing is that there are other genes besides BRCA1 and BRCA2 where mutations can occur and be passed from generation to generation. Frequently, even those that are known to be fairly common are not currently tested for in most circumstances.
Beyond that, there are probably many other places in our genetic material where mutations can occur that haven’t yet been discovered, but once again they too can become embedded in our familial genetic libraries.
An article that appears today in the Journal of the American Medical Association helps clear the clutter and clarifies the current status and limitations of our knowledge and testing for genetic abnormalities in breast and ovarian cancer (there are certainly other genetic abnormalities that can lead to increased incidence of cancers within families, but today’s blog is concentrating only on breast and ovarian cancers).
The researchers in this study went to great lengths to get a truer picture of what the real rate of mutation is in several different genes (including BRCA 1, BRCA2, CHEK2, TP53, and PTEN. Because of complexity, I don’t have the opportunity to go into each of these in detail). They wanted to know how many women with a strong family history really are at risk of breast cancer if the best available tests were offered to detect these abnormalities.
They defined women at high risk as those with breast cancer who had at least 4 cases of female breast cancer, ovarian cancer, and/or male breast cancer in their families. They then studied genetic material from 300 of these women using sophisticated testing to find out whether or not there were genetic abnormalities not picked up on previous testing. All of these women had been previously reported as having no evidence of BRCA1 or BRCA2 abnormalities.
Of the 300 families, 17% had a genetic abnormality that provided a familial basis for their breast cancer.
Among those tested for BRCA1 and BRCA2, 35 of the 300 were positive (recall that these women had previously been tested and were “negative”).
The science is too complicated for me to explain here, plus its sophistication is in fact beyond my limited knowledge.
But the practical implications are obvious: Using currently available testing in the United States, we are missing a significant number of inherited breast cancers. As a result, we cannot provide women in these families the information they need to make the best decisions for their individual health and their individual risk.
We clearly need to improve our testing paradigms to provide the best information possible to these families and these women.
The authors, from the University of Washington, pose and answer the question this way: “The clinical dilemma is what to offer to women with a high probability of carrying a mutation in BRCA1 or BRCA2 but with negative commercial test results. Technically, the answer is at hand. The mutations identified in our study that were missed by commercial testing are detectable using other approaches that are currently available…Therefore; a genetic method should be used to detect them.”
The authors go on to provide additional information, particularly regarding a test called MLPA.
They note, “All genomic alterations in our series were identified by MLPA, which allows rapid and cost-effective analysis of rearrangements across the entire BRCA1 and BRCA2 genes. We believe that for families testing negative (wild type) for BRCA1 and BRCA2 by conventional sequencing, MLPA followed by sequence confirmation of breakpoints in patients’ genomic DNA is the current best choice for evaluating the wide range of genomic rearrangements in BRCA1 and BRCA2.”
The problem, though, is that clinical testing using MLPA is not available in the United States.
I am not certain why that is the case, although I do know that several folks are looking into the question as I write this.
So here is the bottom line: If you have a strong family history of breast cancer and want to understand your own risk and what to do about it, see your physician and do your best to get a consultation with a genetic counselor if one is available in your community.
If your BRCA1 or BRCA2 test is positive, as I noted previously, there are certain options available for discussion.
But if it is negative, don’t stop there. Talk to your doctor and your counselor about possible additional testing.
The reality is that what we are doing today for most of our patients in this situation is not sufficient, and you need to be aware of that.
Hopefully, in the not too distant future, this issue will be remedied so that we can provide the best information available to women at risk.
And, remember that the search goes on to continue to look for other genetic abnormalities that will help us better understand who as at greatest risk for which cancers.
We still have much to learn.
