Genetic Tests and Breast Cancer Risk: Not Perfect

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.

14 thoughts on “Genetic Tests and Breast Cancer Risk: Not Perfect

  1. There is an national nonprofit organization that is devoted to hereditary breast and ovarian cancer and that provides support for individuals and families who have a BRCA mutation or strong family history of breast or ovarian cancer. I encourage people looking for support or further information to visit FORCE at:

  2. If you are of Ashkenazi / Sephardic Jewish descent and have survived pancreatic cancer with whipple surgery for a total resectable tumor on the pancreas, is it recommended now because of your risk of getting breast or ovarian cancer, that your family receive genetic counseling and testing for BRCA1 and BRCA2?

    If you are a possible carrier fo the BRCA2 and are of Ashkenazi Jewish descent and have had breast, ovarian or pancreatic cancer and since they have identified the found alleles such as those in the Ashkenazi Jewish popluation, it only makes sense to our family that oncologists and family physicians inform you that possible genetic testing can be done for you and your family.

    “Germline BRCA2 6174delT Mutations in Ashkenazi Jewish Pancreaatic Patients” have identified that pancreatic cancer is inherited in the descendant line.

    Some families are not informed by their physicians of the possibility that they are now at an increased risk of being possible carriers of the BRCA1 and BRCA2 mutation for breast, ovarian and pancreatic cancers even though knowing that their patients have been identified as Ashkenazi Jewish.

    Our only information received about genetic testing and findings regarding this issued of genetic testing of Ashkenazi Jewish descent and cancer was from that of John Hopkins and from your valuable blog.

    If patients are required to fill out family disease information on forms at the physician’s office and then the physician never discusses with the patient that clinical / abstract studies have shown that certain cancers have been proven to be of genetic nature in certain groups, then how can the patient or their families ever be informed?

    Family physicians are our first stop for preventive health information and sometimes also our last stop before dying.

    I applaud all physicians working on any cure or preventitive measure for cancer.

  3. Dr. Len,

    My insurance won’t cover genetic testing for BRCA1 and 2. They said I have to show signs of cancer first. I am also supposed to start getting MRI’s next year at the age of 29 because it is 10 years before my mother was diagnosed. My insurance won’t cover that either.

    My mother died of breast cancer 18 years ago at the age of 41. She was pre-menopausel. My husband and I know have two daughters. My husband’s mother is a 7 year survivor and was diagnosed at the age of 53. She was also pre-menopausel. I am only 27. I want to take all preventive measures possible including protecting my daughters. I know that there is a greater risk of ovarian cancer depending on which genetic mutation a person has… Do you think I should have the genetic testing? What is the ratio for false-positives? I want to face any risk factors head on…

  4. I have received the genetic testing and have tested positive for the BRCA2. I have an appointment this week with a cancer doctor to explain my test and what I should do about them. My mother is currently going through chemo for ovarian cancer. There are 4 generations of ovarian cancer in my family and my sister and several cousins have had breast cancer. I have 2 children and 3 grandaughters. They can not afford the genetic testing and I’m still trying to pay of the $3200 for my test. Is there any help out there for people who need help with the cost of testing?

  5. Given your family history, it was clearly appropriate for you to have BRCA testing. My question would be if you have health insurance, and if so why it wasn’t covered since it is clearly medically indicated?

    Also we recommend that you have counseling with a genetics counselor before and after undergoing the test so you can understand the implications for your immediate and related family members who may also be affected.

    I would suggest you contact our call center at 800 ACS 2345, since they may be able to refer you to resources that can help with the cost of the test.

    This is obviously important to you and your family, and you must have a clear understanding from the counselors and your physicians as to your options, both for you and your children.

  6. Dear Dr., Hi, I am a 54 yr old with an incredibally strong family of breast ca… here is my delimma, first my hx., my grandmother on moms sided, bilateral breast ca with bil. mastectomies 1952, her twin breast ca with mast., grandmother on dads side, bil breast with mets to brain(passed away from disease), my mom and her two sisters all positive for breast, one sister, deceased, her two daughters, one with ca bil. currently in tx., other with pre ca masses, her other sister(moms sister) mult. nodes , positive for ca,she has no daughters, My mom, breast ca with mastectomy, lampathetic ca, my younger sister 45 yrs old breast ca bil. with positive genetic test, newly diagnoised. I have been positive for several pre cancerous lumps, and fiberous cyctic breast disease, just yesterday, 2 new masses in left breast, one in right, and one they have been watching for 6 months. My twin sister has had a mass in the past that she had been on tomoxifen for. do i need the genetic test to have propheletic masectomies, or will I bee positive because my siister is, and I have 3 daughters in late 20’s and one in 30’s, who need the test and can we all have the surgery to remove our breasts, my girls don’t want to live with this fear like I have had to, they want control of their bodies and their health. Please give me some direction, I have already set up my surgery for removal, what about my girls? Thanks, Lynn

  7. Lynn, I normally don’t provide specific medical advice on this blog. You can contact our cancer information center at 800 ACS 2345 to discuss this further. I suspect they will have you talk to one of the nurses at the center, given the complexity of your situation.

    What has me concerned is that it appears from your note that you may be planning surgery but haven’t had an in depth discussion with someone who is well experienced in breast cancer and its hereditary/risk aspects. I don’t know where you live, but your situation suggests that you need a consultation with a center that deals with these issues, such as you would find at a comprehensive cancer center.

    Given the fact that your sister is BRCA positive, you need genetic counseling and then should consider the BRCA test before you or your daughters undergo any surgery.

    Hopefully your doctor has discussed this approach with you and your daughters. I would not recommend surgery unless and until you are fully informed about the appropriate tests and options by someone who is well versed in these issues.

    Please call us at the phone number above to get further information. You can refer them to this email comment.


  8. Despite the dramatic advances in cancer researches, scientists are yet to locate the exact cause of breast cancer. But, they have identified several risk factors that are believed to increase a person’s chances of getting the disease. Genetic factor is one the most important among them.

    Many types of cancers are genetic, that is they run in the family. It has been found out that about 10% of breast cancer cases are the result of genetic inheritance. In case of genetic breast cancer, the person inherits a mutated or altered gene from one of her parents. This mutated gene eventually affects the breast health and the person gets breast cancer.

  9. My daughter had a brest cancer, but neither me or any of my relatives have or had brest cancer. However, my husband died of lung cancer, his brother had also lung cancer and his aunts died of varied types of cancer. Should my daughter have a BRAC test?

  10. After testing positive for BRAC 2 at age 29 it was strongly suggested that I have a hysterectomy and my breasts remove. I have chosen the surgeries. I am recoving now from the hysterectomy and awaiting my next surgery. The recover is painful and long however it out ways the cancer risk in the future. I have a strong history on both side of my family.

  11. My father, age 54 test positive for brac2. I’ve test negative. My sister test positive for brac2. Due to my father passing this brac2 and not my mother, how will his brac2 effect my sister or will it skip a generation??

    1. Please call our cancer information center at 800 227 2345. Although we cannot provide specific advice, BRCA can be passed by men as well as women. The impact of BRCA on those affected is the same whether the passage comes from a father or mother.

  12. I’m sure this subject has already been addressed, however, it is new to me, I have a strong history of cancer in my family, one of my sisters is battling colon cancer after surviving both ovarian and cervical cancer, I lost a sister six years ago to cervical cancer and a brother who survived prostate cancer, my sister who has colon cancer just tested positive for the braca 1 gene, and her oncologist suggested that her remaining sisters be tested, easy enough right? Not so, I am disabled due to an automobile accident wich happened while working, my insurance coverage is through medicare, and everyone knows that they don’t pay for much, so getting them to pay for the testing, the preventive surgery or reconstructive surgery is out of the question, therefore, all I can do is sit and worry about when and if I get cancer, I try to not let it consume my everyday living, but this is a scary situation, with no one to talk to about, I don’t want to burden my sister with this considering what she is already dealing with, and my other two sisters don’t seem too concerned with the fact that they could also carry this gene, needless to say, it adds to my anxiety level. has anyone else found someone who helps with getting the genetic testing?,

    1. I recently posted a blog on this very topic regarding Medicare patients not having access to preventive BRCA screening. Please call our cancer information service to discuss your concerns. Phone number is 800 227 2345.

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