BRCA gene mutations and ovarian cancer: an interview with Dr Matulonis, Harvard Medical School

Ursula A. Matulonis, MDTHOUGHT LEADERS SERIES...insight from the world’s leading experts

What is a BRCA gene mutation and how many types are there?

The BRCA gene encodes for the BRCA proteins, BRCA1 and BRCA2. These proteins are very important in repairing DNA, which they do by correcting double-stranded breaks.

If one copy of the BRCA gene is mutated and then the other copy also becomes abnormal, there is either a reduction in the amount of this DNA repair protein or the protein is dysfunctional. The DNA then can't repair itself and relies instead on more error-prone ways of repairing that sometimes work and sometimes don't. If it does not work, more genetic abnormalities arise and then cancer develops.

Most BRCA1 and BRCA2 cancers are breast and ovarian cancers, but a BRCA2 mutation may also be associated with a wider variety of cancers including melanoma, pancreatic cancer, prostate cancer, and more rarely, gastric and uterine cancers.

The BRCA gene is therefore very important. The mutation may be what is called a germline mutation, where every cell in the body contains that mutation, or it may be a somatic mutation, where the mutation is only found within cancer cells and not in the blood or skin cells, for example.

Somatic BRCA mutations are rarer and probably only account for 10% of genetic abnormalities across the whole spectrum of BRCA mutations.

How are BRCA gene mutations inherited?

They are inherited in a dominant pattern. We inherit one copy of the gene from each of our parents. If one of the copies in a mother is abnormal, there is a 50% risk that she will pass on the abnormal copy to her offspring.

Many women are aware that having a variant BRCA gene can greatly increase their chance of developing breast cancer, but how much does having a BRCA1 or BRCA2 gene mutation increase a woman's risk of ovarian cancer?

It depends on the specific gene. Certainly for breast cancer, the risk is increased by up to 80% over a person's lifetime. For ovarian cancer, the lifetime risk is up to 40%.

Having a BRCA1 or BRCA2 mutation would certainly be enough reason to perform risk-reducing surgery by removing the ovaries and fallopian tubes.

What tests are available for BRCA mutations?

There are many tests available to women. Certainly in the United States, since the Supreme Court struck down Myriad's hold on genetic testing and basically said “No one can own a gene,” several companies have started offering genetic testing to women.  One can hope that this will make testing more accessible by lowering the price but also maintaining the quality of the testing.

How much does testing for BRCA1 and BRCA2 cost and is this prohibitive for many women?

It depends on how many genes are being tested. If it's a very basic BRCA1 and BRCA2 test looking at very few mutations because, for example, somebody knows their mother has a BRCA mutation, it is not necessary to perform an expanded panel which covers many more potential high risk genes.   You basically look for that gene to see if they have it or not.

Another example would be if somebody had a family history of breast or ovarian cancer, yet their family members were all negative for BRCA. In that case, other genes would obviously be involved. Therefore, expanded panels of genes can now be tested rather than just BRCA1 and BRCA2.

There are other genes that are purported to be important in DNA repair and may confer a risk if they are mutated, but not enough is known about women who carry these mutations to be able to say with any certainty what their risk of developing cancer is. At this point, there is a lack of concrete information about risk reduction.

The risk associated with BRCA1 and BRCA2 mutation is very well-established and if somebody has a mutation of one of those genes, they should be referred for risk-reducing surgery or at least to discuss those surgeries, which include bilateral mastectomy and removal of the ovaries and fallopian tubes.

Who should consider getting tested for BRCA mutations? What are the main advantages and disadvantages?

The NCCN breast and ovarian high-risk genetics guideline recommends that  any woman who has ovarian cancer should be referred to undergo testing, regardless of her age, family history and the type of ovarian cancer she has.

A better understanding of the BRCA mutation is really important because discovering the mutation provides a way of identifying someone who is at high risk of developing ovarian cancer so they can be treated with risk-reducing surgery.

Secondly, if someone did develop ovarian cancer and we found out they had a BRCA mutation, they could be treated with PARP inhibitors because these drugs have now been FDA approved.

The other exciting point is that among women who don't have a germline BRCA mutation, their cells can potentially be made more sensitive to PARP inhibitors through a variety of different therapy combinations which are undergoing testing in cilnical trials but so far have quite exciting results.

BRCA is hugely important in terms of ovarian cancer ideology and development, but it's also very important from a therapeutic standpoint as well. The more we understand the gene and also the whole concept of DNA repair, as well as the level of genomic instability within an ovarian cancer cell, the more likely we are to move in the right direction in terms of improved treatment options for women who do have the cancer and in terms of continuing risk-reducing strategies that could lead to the cancer being caught early or even prevented.

What options are available for women who test positive?

Once a woman is identified as having a high-risk mutation, she would then need to consider two decisions:   how does this mutation impact her and what can and will she to do about it?

She would also need to share the information with her family and assess the family tree to identify whether the mutation had come from her mother's or father's side. The presence of a high risk family will likely have a significant impact on family members.

She would need to consider whether to undergo a bilateral mastectomy and then ovarian and fallopian tube removal. She could take tamoxifen, but the  impact of taking a drug like tamoxifen in somebody who has a high-risk mutation is really unknown.

The standard of care offered would be either to perform these surgeries or increase the patient's screening. However, we don't currently have a good ovarian screening test that detects ovarian cancer early.

For breast cancer, women who have decided not to have surgery should be getting a yearly mammography, as well as a yearly breast MRI scan.  The exact optimal age to remove the fallopian tubes and ovaries needs to to be discussed with the patient's medical team.

Some physicians will say a person needs to start thinking about surgery ten years before the youngest family member has developed cancer, but I'm not sure we have any data to really support that. I think the patient should make their decision independently of when her other family members developed cancer. It has to be individualized around her.

Angelina Jolie recently spoke out about her decision to undergo preventative surgery to remove her ovaries and fallopian tubes. What are your thoughts on this?

Overall, I think it's good and empowering. She has turned the topic of BRCA testing and having a BRCA gene from one that women didn't want to talk about into one that they are not afraid to openly discuss. Now people are saying “What can I do to empower myself, to reduce the risk of cancer in me personally and how can that knowledge impact other family members?”

By making such a public disclosure about medical information, she has taken away the stigma of having a BRCA mutation. She has also been very eloquent at discussing the complexities of the decision-making process and how these risk-reducing strategies do need to be individualized.

What are the main signs and symptoms of ovarian cancer?

The problem is that if someone starts to display signs and symptoms of ovarian cancer, unfortunately this usually means the cancer has spread. Symptoms such as abdominal bloating, pain and swelling; difficulty with digestion; constipation; diarrhea and pelvic pain often mean the cancer is no longer in the early stages and confined to the ovaries, but has spread to the upper part of the abdomen, around the intestines and to different parts of the abdominal cavity.

The signs and symptoms are, of course, important because you want someone to be diagnosed as soon as possible, but unfortunately you can't detect early stage ovarian cancer through signs and symptoms.

Other symptoms may be shortness of breath because the fluid in the cancer pushes up against the lungs, which then fail to fully inflate. There may also be fluid in the abdomen (ascites) or pleural fluid, where fluid accumulates between the chest wall and the lung.

Where can readers find more information?

The National Cancer Institute (NCI) website is very good. It provides a good level of understanding, really delving into a lot of different topics including the risk-reducing surgeries available and information about breast cancer genes.

Our website, also has useful information about those topics and there is a Lynparza website, which provides specific information about the drug Lynparza.

About Dr Matulonis

Ursula A. Matulonis, MD is Medical Director and Program Leader of the Medical Gynecologic Oncology Program at Dana-Farber Cancer Institute and Associate Professor of Medicine at Harvard Medical School. Her research focuses on targeted therapies for gynecologic malignancies, with a specific interest in the genetic changes in ovarian cancer and how that can lead to rationale targeted drug selection. Dr. Matulonis is the Principal Investigator of several clinical trials and translational studies for ovarian cancer. Dr. Matulonis is a Co-PI on an ovarian cancer SPORE project entitled “Identification of Oncogenic Mutations in Ovarian Cancer,” and a Co-PI on the project “Genetic relationships between breast and ovarian cancer” that is funded by the Breast Cancer Research Foundation. She is also a past recipient of a DF/HCC Ovarian Cancer SPORE Developmental Grant entitled “Genetic Fingerprinting of Ovarian Cancer.”

Dr. Matulonis serves on the National Comprehensive Cancer Network Ovarian Cancer Recommendation and Guideline Committee for both ovarian cancer and for the treatment of anemia, the Gynecologic Oncology Group Quality of Life Committee, a member of The Cancer Genome Atlas Project (TCGA) Endometrial Analysis Working Group, and is Medical Director and Board Member for the non-profit organization Ovations for the Cure. She is a recipient of the Dennis Thompson Compassionate Care Scholar award, the Lee Nadler “Extra Mile” Award, and was named one of Boston's Best Physicians in Medical Oncology by Boston Magazine numerous times. She serves on the editorial board of the Journal of Clinical Oncology.

April Cashin-Garbutt

Written by

April Cashin-Garbutt

April graduated with a first-class honours degree in Natural Sciences from Pembroke College, University of Cambridge. During her time as Editor-in-Chief, News-Medical (2012-2017), she kickstarted the content production process and helped to grow the website readership to over 60 million visitors per year. Through interviewing global thought leaders in medicine and life sciences, including Nobel laureates, April developed a passion for neuroscience and now works at the Sainsbury Wellcome Centre for Neural Circuits and Behaviour, located within UCL.


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