Twenty Years after BRCA Discovery, Progress in Prevention and Early Detection

By Andrea Peirce

on Monday, May 5, 2014

Pictured: Kenneth Offit Clinical Genetics Service Chief Kenneth Offit
Summary

Memorial Sloan Kettering Clinical Genetics Service Chief Kenneth Offit discusses ways for women to clearly assess their risk for breast and ovarian cancers.

To commemorate the 20th anniversary of the discovery of the BRCA1 gene, Kenneth Offit, Chief of Memorial Sloan Kettering’s Clinical Genetics Service, revisited last year’s Q&A on BRCA testing and cancer risk. See our updates and information on the latest advances in genetic testing below.

Actress Angelina Jolie ignited a national dialogue on breast cancer risk and genetic testing in May 2013 with an op-ed in the New York Times, in which she described her choice to undergo a preventive double mastectomy after learning she carries a mutation in a gene called BRCA1.

Certain inherited gene mutations are associated with an increased risk of breast and ovarian cancer. BRCA1 was first discovered 20 years ago; BRCA2 followed later. BRCA1 and BRCA2 mutations both are more common among people of Eastern European (Ashkenazi) Jewish ancestry. Memorial Sloan Kettering cancer geneticist and medical oncologist Kenneth Offit led the research team that identified the most common mutation in BRCA2, observed in those of Ashkenazi heritage.

Today, testing is available for mutations in BRCA2, as well as in BRCA1 and in other genes that have been linked to an increased risk for breast and ovarian cancer. Women can use the results of such genetic tests to make informed decisions — such as whether to surgically remove the breasts (preventive mastectomy) or ovaries (preventive oophorectomy) — to reduce their cancer risk.

In an interview, Dr. Offit notes that there have been great strides in prevention and early detection of breast cancer since the BRCA1 and BRCA2 mutations were identified. He encourages women and their families to take these factors into consideration when weighing their options.

Who should undergo genetic testing for breast cancer?

It’s very important that women speak to their physicians if they have a personal history of breast cancer or close relatives who have had breast, ovarian, or prostate cancer, or some other types of cancer. Other strong risk factors include having had breast cancer at an early age (before age 50), having both breast and ovarian cancer, having a male relative with breast cancer, and being of Eastern European Jewish ancestry. In addition all women with a personal history of ovarian cancer — regardless of their family history — should have BRCA testing.

While a significant number of women with breast cancer have a family history of the disease, only a small number may be advised to get genetic testing. Only about 5 to 10 percent of women with breast cancer will have an inherited risk of the disease due to BRCA mutations or other mutations.

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What is involved in getting tested?

Genetic testing is not just a blood test — it’s a process of genetic counseling that often involves the family. We like to see individuals with their sisters, their mothers, their significant others, both as a support and to enable women and their family members to make mutual decisions about screening and prevention.

Women meet with a genetic counselor to review all the options available should a test turn out to be positive, and also visit with a doctor to go over their family history of cancer and other risk factors in more detail. Only at that point is the actual test given (if a woman chooses to have it). Results take a few weeks to come back.

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What kind of information does genetic testing provide to women and their families?

If a woman tests positive for a BRCA mutation, she is not only at increased risk for breast cancer but also at increased risk for ovarian cancer. In fact, while the BRCA test is named after breast cancer, it is the ovarian cancer risk that we pay close attention to because we don’t have a means to screen for ovarian cancer to find it early, when it’s potentially curable.

When we first started doing genetic testing, we were very concerned about the negative impact that results might have. But we have found that genetic testing is in fact a very empowering experience both for women and their families, as there are now proven means for prevention and detection of some of the associated cancers.

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If a genetic test shows that a woman has an increased risk for breast or ovarian cancer, what are her options?

There are at least three options available upon testing positive for BRCA mutations. Surgery is one of them, and it’s the most effective means of breast cancer prevention. And while the surgical option for breast cancer is just that — an option — we strongly recommend surgical removal of the ovaries to reduce the risk of ovarian cancer for women who no longer expect to have children.

Doctors at Memorial Sloan Kettering and other hospitals now have a very powerful means of screening for cancerous changes in the breast with magnetic resonance imaging, or MRI, which is more precise than mammography in finding early breast cancers. While most women in the United States choose screening over surgery, this is a discussion that needs to be individualized.

In addition, we can offer preventive treatment with drugs such as tamoxifen that for some women can cut the risk of breast cancer in half.

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Do you foresee any new advances in genetic testing for breast or ovarian cancer?

Up until now, we have only been able to tell a woman who tests positive for a BRCA mutation that her risk for developing cancer ranges from 40 to 90 percent. But over the last several years, researchers at Memorial Sloan Kettering and elsewhere have discovered that there are genetic variations that will allow us to more closely pinpoint this risk. We hope to make these more-precise testing options available to women as part of our continued research.

Another research study now open at Memorial Sloan Kettering involves testing for genes other than BRCA1 and BRCA2 in women with family histories of breast and/or ovarian cancer who have already tested negative for BRCA1 and BRCA2. In this study we offer a “panel” of tests for other genes (for example PALB2, CHEK2, etc.) that have more recently been discovered, and about which little is known regarding preventive care that is required.  Individuals have the option in this study to get results only on genes they wish to learn about. As part of this research, there is no cost for the testing. Eventually, we anticipate that these “panel” tests will be more widely available and covered by insurance.

Finally, as part of longer-term research, we are also using next-generation DNA sequencing to discover new genes associated with hereditary risk for breast or ovarian cancer.

To make an appointment with our Clinical Genetics Service, call 646-888-4050.

To make an appointment with one of our breast cancer specialists, call 646-497-9064.

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Comments

Why has there been so little progress for BRCA patients since the gene was discovered 20 years ago. Young daughters today have exactly the same draconian options their mothers did, no better - (1) extreme life altering surgery (preventative mastectomy and oopherectomy) (2) tamoxifen, which has only partially effective and makes young women likely have menopause like symptoms (3) surveillance, which is only partly effective in finding bad news, not averting it. I am sure you can understand the frustration and sorrow of the BRCA mutation community. Is there anything in the pipeline that they can hope for - gene therapy, immune therapy, parp inhibitors or other PREVENTATIVE treatments ?

Salome, thank you for your comment. We sent it to Dr. Offit, and this was his response:

"When we first started BRCA testing two decades ago there was the real fear that the measures we would offer might not actually make a difference in women's lives. We did not know if our 'preventions' and interventions would work to save lives. Now, the reassuring news for BRCA mutation carriers is that we have 20 years of data to support the effectiveness of these interventions -- preventive surgeries, anti-estrogens, and screening. The advent of MRI breast surveillance, not available 20 years ago, has allowed many women to elect not to have preventive surgery. And we have shown that 'preventive' ovarian surgery -- after childbearing -- indeed saves lives. We agree with you, Salome, that no medical intervention is always succesful. We also agree with you that there is a need for more 'targeted' drugs such as PARP inhibitors to be used in prevention.

A final point I like to point out is that preventive surgeries were being done for many years before the BRCA genes were discovered. Once we did start testing, we were able to define those 50% of daughters of mothers with BRCA-associated breast cancer who did not need to worry about increased risk.

So, while much work remains to be done, considering that some of these BRCA mutations have been in families for more than 1,000 years, the past 20 years should be viewed as a real turning point in our effort to decrease the burden of hereditary cancer."

What are your current recommendations for screening/prevention for someone who has a mutation in the ATM gene? If a woman had radiation treatment before the gene was identified what precautions would be helpful to prevent a radiation induced cancer?

Sharon we suggest you contact our Clinical Genetics Service at 646-888-4050. They should be able to help you with these questions or guide you to the correct resource.

This is sent with the utmost respect to this department. I understand that the current risk (not life time risk) of ovarian cancer in a BRCA2 positive 40 year is around 3%. Given the latest research that is currently distinguishing the risks between BRCA1 and BRCA2 patients along with the hope of future strides in ovarian cancer screening what is the rush to recommend an oopherectomy. Would the notion of waiting for 2-3 years for possible less drastic guidelines not make sense. Should one consider there current physical health (diet, alcohol, smoking, over weight, exercise) in assessing their risks before considering such a radical surgery. In light that ACOG's current guidelines graded the recommendation of an oopherectomy for women with BRCA as LEVEL B (recommendation based on limited or inconsistent evidence) are there any oncologists that don't support an oopherectomy for BRCA2 patients. Can you help me find them.

Gil, we are looking into getting answers to your questions and will respond as quickly as we can. Thank you for your comment.

Gil, we passed your question on to Noah Kauff, MSK Director of Ovarian Cancer Screening and Prevention, who responds:

The question you ask is an important one. The optimal time for risk-reducing surgery depends on a number of factors: What are a woman's current age, reproductive desires, personal history of cancer, and current strategy for breast cancer risk-reduction. As you point out, in the setting of a BRCA2 mutation, a woman's risk of ovarian cancer is only 2-3% by age 50. However, her risk of breast cancer by age 50 is 26-34%. If oophorectomy is deferred until age 50, a women will not receive the 40-70% reduction in breast cancer risk that oophorectomy confers.

The best way to determine what is the most appropriate time for an oophorectomy in an individual woman with a mutation in either BRCA1 or BRCA2 is likely in the setting of a consultation with a gynecologist, gynecologic oncologist, or geneticist experienced in the care of women at inherited risk.

Thank you for taking the time to reply to my post. I fully understand your answer and have a follow up question. If a healthy BRCA2 40 year old undergoes a prophylactic bilateral mastectomy thereby reducing her inherit risk of breast cancer is it then reasonable to defer a prophylactic oophorectomy until 50. Is it necessary and advised to undergo both a prophylactic bilateral mastectomy and a prophylactic oophorectomy for BRCA2 women in their early 40s. While accepting the life time risks for BRCA2 mutation carriers it seems redundant to have both prophylactic surgeries simultaneously in your early 40s. In the setting of BRCA2 mutations, with a woman's risk of ovarian cancer being only 2-3% by age 50, I don't see any additional benefit to undergo a prophylactic oophorectomy after a prophylactic bilateral mastectomy has been performed at age 40, as there will be no additional benefit of breast cancer risk reduction. Thank you for your time and insight.

Gil, thanks for following up. For these kinds of specific questions with many factors to consider, we recommend you consult with a genetics counselor who can guide you through the decision process. You can find out more information from our Clinical Genetics Service at

http://www.mskcc.org/cancer-care/hereditary-genetics

Thank you for your comment.

If someone has both the BRCA 1 and BRCA 2 mutations, is there a strong chance that there is Ashkenazi Jew genetics in their family? What percent of people carry both mutations?

Dear Rita, we reached out to Dr. Kenneth Offit with your question, and he had this to say: "Yes -- if a person had both a BRCA1 and a BRCA2 mutation there would be a good chance that person is of Ashkenazi ancestry. It would depend on what the actual mutation was. There is a particular BRCA1 mutation called 185delAG and a particular BRCA2 mutation called 6174delT and if the person had these that would indicate their ancestry. Each of these individually is seen in 1/100 persons of Ashkenazi ancestry. So the chance of one person carrying both would be 1/100 x 1/100 = 1/10000. There are other populations with common BRCA1 and BRCA2 founder mutations. These populations are from Scandinavia." Thanks so much for your comment.

If a patient has already has and is being treated with chemo for ovarian cancer, will a BRCA test automatically be positive? And if the test is positive, what are the chances that it is breast cancer related, not ovarian related? Thank you.

April, BRCA tests look for mutations that occur in every cell in your body (and have been inherited from your parents), not for mutations that occur only in the tumors themselves. People are born with these mutations and carry them for their whole lives, so they do not change based on treatment.

A diagnosis of ovarian cancer or breast cancer does not mean that a person has BRCA mutations. There can be many other causes as well.

If you'd like to speak to a clinical geneticist at MSK, you can go to http://www.mskcc.org/cancer-care/hereditary-genetics for more information.

Thank you for your comment.

My 58 y/o sister is a 15 year survivor of ovarian cancer. She was recently diagnosed with triple negative breast cancer. Had mastectomy of that breast 2 weeks ago, and port and chemo to begin next week. She will be tested for BRCA gene on Tuesday. If she is positive, what are the chances for me and my daughter and 2 son to be a carrier?

Sandy, we are not able to answer individual medical questions on our blog. If you'd like to make an appointment to speak with someone on our Clinical Genetics Service, you can call 646-888-4050 or go to http://www.mskcc.org/cancer-care/hereditary-genetics for more information. Thank you for your comment.

All my mom's 4 sisters have had breastfeeding cancer. My mother now has it. What are my chances and my sisters chances of developing breastfeeding cancer also

Mya, unfortunately we are not able to answer individual medical questions on our blog. If you have a family history of breast cancer you may want to make an appointment to speak with someone on our Clinical Genetics Service. You can call 646-888-4050 or go to http://www.mskcc.org/cancer-care/hereditary-genetics for more information. Thank you for your comment.

What are the risks of having your ovaries out pre-menopause and are BRCA1 positive women eligible for hormone replacement therapy?

RNLA, we forwarded your questions to Noah Kauff, who is an expert in BRCA mutations. To your first question, he responded, "For women with mutations in BRCA1 or BRCA2, removing the ovaries before menopause reduces the risk of ovarian cancer by 80-90% and the risk of breast cancer by 40-70%. However, removing the ovaries prior to menopause is clearly associated with symptoms such as hot flashes, night sweats, and vaginal dryness. It is also associated with an increased risk of osteoporosis, and it may be associated with an increased risk of heart disease later in life. For most women with an inherited predisposition to both breast and ovarian cancer due to a mutation in BRCA1 or BRCA2, the benefits of removal of the ovaries on cancer risk outweighs the possible adverse impact on other chronic health risks. However, the pros and cons should be carefully weighed with your doctor."

For your second question, he responded, "For women with a BRCA1 or BRCA2 mutation who have not had a hormonally responsive breast cancer, hormone replacement after removal of the ovaries is an option. Hormone replacement is, however, associated with both risks and benefits. Women considering hormone replacement following removal of the ovaries should discuss these risks and benefits with their doctor, taking into consideration an individual woman's history and specific menopausal symptoms."

Thank you for your comment.

My 22 year old daughter and I both have tested positive for the BRCA1 gene. I am 55 and a 19 year ovarian cancer survivor. We are looking ahead to genetic counseling, more for her benefit. Is 22 too soon to have a mammogram? Thank you for your response. I am finding this blog very informative.

Dear Nancy, we can't answer personal medical questions on our blog, but you may be interested in learning more about breast cancer screening guidelines for women at increased risk here: http://www.mskcc.org/cancer-care/adult/breast/screening-guidelines-brea…

In addition, you and your daughter might be interested in learning more about our Screening Program for Women at Increased Breast Cancer Risk: http://www.mskcc.org/cancer-care/screening-services/screening-women-inc…. To make an appointment for a consultation and personalized screening recommendations, please call their office at 646-497-9064.

We hope this is helpful. Thank you for reaching out to us.

As of today, are the Next Gen panels for breast cancer risk considered "standard practice" for BRCA negative women who are considered high risk due to family history (>20%)? Are these tests of clinical utility at this point? I am as concerned about the harms that result from these tests (over diagnosis and over treatment) as I am about breast cancer. Genetic testing companies stand to make a lot of money off of these tests, even though there are no clinical guidelines for how to manage those who turn up positive. I am concerned that breast surgeons see so many cancer patients that they are swayed emotionally by the (perhaps false) hope of gene testing. Concerns about liability may also motivate referrals for panel testing now. Even if they aren't sure of the clinical utility, doctors need to alert patients to the test, because it's there.

Frankly, I don't know who to trust. I am fearful of pursuing medical care in uncharted waters. Do you have a standard approach at this point?

Marie, we sent your questions to clinical geneticist Mark Robson, who said, "It is difficult to say whether additional genetic testing would be useful for her as an individual. Further testing, with a panel or by some other means, can be helpful for some individuals and families, but she should meet with an experienced counselor to discuss the pros and cons in her own specific circumstance." If you'd like to find out about arranging a consultation with MSK's Clinical Genetics Service, you can call 646-888-4050 or go to https://www.mskcc.org/cancer-care/risk-assessment-screening/hereditary-… for more information. Thank you for your comment.

My 55 yr. old sister just participated in a study at Einstein Montefiore in The Bronx. They are testing Ashkenazi Jewish women for BRCA even if they are low risk. My sister just learned she has BRCA2 (617delT). I am 58; no history of breast/ovarian or prostate cancer in the family. But, my father was born in 1921 and his mother was born in 1880. Father's family was extremely poor in Czechoslovakia, medical care was virtually nil. My father said his mother died of bone cancer. I can guarantee they would have no idea if this was a metastasis from breast or a primary cancer. How should I treat my family history? We really cannot say with any certainty whatsoever what the paternal grandmother had. Our first cousin (a female who had the same paternal grandmother) was diagnosed with breast cancer at age 64. I see no point in having myself tested unless I know that insurance will cover a prophylactic oophoerectmy..otherwise, why bother? How should I present my family history with so many unkowns about my paternal grandmother? Thanks

Ramona, thank you for reaching out. Family history, genetic risk, and decisions about being tested are indeed complex topics, and it is very valuable to have counseling on these questions. Our Clinical Genetics Service offers hereditary cancer risk assessment, genetic counseling, and genetic testing by specially trained genetic counselors and physicians.

You can learn more here:

https://www.mskcc.org/cancer-care/risk-assessment-screening/hereditary-…

58 yo female, BRCA 2 positive. No personal or family history of breast/ovarian cancer. Just had RRSO at Sloan. Can you tell me about peritoneal cancer and the theory as to why that my occur? I read that it is very similar to ovarian cancer.

Hi, we recommend that you discuss this with your MSK treatment team. Thank you for your comment.

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