Breast Cancer Screening, Risk, and Options for High-Risk Women

In light of the recent public discourse on breast cancer risk and options available to women who are at high risk for breast and ovarian cancer, we are speaking with Dr. Anne Wallace, team leader of the Moores Cancer Center’s breast program at the University of California, San Diego. Dr. Wallace is a surgeon who helps women with screening and preventive decisions. Joining us also is Professor Lisa Madlensky, the director of the Family Cancer Genetics Program, also at the University of California, San Diego.

-Interviewed by Anna Azvolinsky, PhD

Cancer Network: Professor Madlensky, you help patients assess their breast and ovarian cancer risk, and provide genetic consultations, so that women can make informed decisions about their health. Who are the women you typically see with concerns about breast or ovarian cancer risk? Are they mostly those with a family history of breast or ovarian cancer?

[[{"type":"media","view_mode":"media_crop","fid":"18055","attributes":{"alt":"Lisa Madlensky, PhD","class":"media-image media-image-right","id":"media_crop_5983174456752","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"1217","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":"Lisa Madlensky, PhD","typeof":"foaf:Image"}}]]Prof. Madlensky: Most of the patients we see in our Family Cancer Genetics Program are either patients themselves who may have just been diagnosed and are seeking genetic testing, or they could be patients who have a fairly strong genetic history of breast and ovarian cancer or other cancers and want to learn more about their personal risk of cancer and if genetic testing is appropriate for them. Maybe they want to know if they are following current screening and surveillance guidelines. Basically, what we want to do is to assess their genetic risk factors by looking at their family history. We want to know if anyone in the family already had genetic testing, if there already is a known gene mutation present in the family. Then we want to help them get a sense of what their personal cancer risk is and what they can do about it.

Cancer Network: Could you briefly describe the tests available to assess both breast and ovarian cancer risk?

Prof. Madlensky: The one that we test for most commonly is the BRCA1 and BRCA2 genes. It is a fairly straightforward test, but there are some nuances involved. For example, women who already know that they have a mutation present in their family, they get a much simpler test compared with someone who is the first person in their family getting tested-those patients get a more complete test. For people who have Jewish ancestry, there is a separate test that we start with. There are different technologies used to do the BRCA test; even though it is labeled as just getting BRCA testing, there actually are nuances involved in ordering the correct test. There are other tests also available. For families that clearly show a hereditary breast cancer predisposition, there are now newer next-generation types of tests that look at other genes besides BRCA1 and BRCA2. We are just starting to offer those now for very select families.

Cancer Network: Could you just elaborate on the initial BRCA testing that is done, and then the more elaborate testing, what do these mean exactly?

Prof. Madlensky: Ideally, we want the first person in a family who gets tested to be someone who has had breast or ovarian cancer because we want to be able to figure out if their cancer is related to a BRCA mutation. So, the first person getting tested will get full sequencing of both genes. The analogy I like to use is, it is kind of like doing a spell-check in two books to try to find a small spelling mistake in there.

There is another level of BRCA testing, called BART, which stands for BRCA rearrangement testing. That is the equivalent of looking for a chapter that is missing from one of the books, and the sequencing technology can’t pick up that type of change. That test was not routinely done for women, and now it is increasingly routinely done as part of BRCA testing. There are different layers of BRCA testing, and we want to make sure the appropriate women get the appropriate layer of testing that is right for them.

Cancer Network: Based on the increased frequency of women who are getting the more detailed BART analysis, do we know how many women have these lower penetrance gene mutations that are not the canonical mutations in the BRCA genes?

Prof. Madlensky: We don’t really know if they are lower penetrance, they are probably the same level of penetrance. But the key population that we focus on are women who are of Hispanic or Middle Eastern ancestry; those are the two groups that seem to have a higher rate of these large rearrangements.

Cancer Network: The actress Angelina Jolie publically disclosed her decision to have a double mastectomy because she found out she is a carrier of the BRCA1 mutation that makes it more likely to be diagnosed with breast and ovarian cancer. What are all of the options women have who are at higher risk, either because of genetic predisposition, or other circumstances? Dr. Wallace, let’s start with you.

[[{"type":"media","view_mode":"media_crop","fid":"18058","attributes":{"alt":"Anne Wallace, MD","class":"media-image media-image-right","id":"media_crop_6241752641750","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"1218","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":"Anne Wallace, MD","typeof":"foaf:Image"}}]]Dr. Wallace: Basically, there are three main options for women who are high risk, with the BRCA-mutated patients considered to be the most high risk. The first one is very close observation. BRCA is one of the strong and one of the only indications for yearly breast MRIs, or magnetic resonance imaging, together with yearly mammograms. Currently, the recommendations are for women with a BRCA mutation over the age of 25 to begin that yearly screening and a yearly check with a breast specialist, and then an off-yearly check with a primary care provider as well. That is what we call close observation, and that close screening seems to be able to detect breast cancers in its earlier stages and that makes treatment easier.

The next option is chemoprevention, which means taking some sort of drugs to change the hormonal environment of the patient. Typically, chemoprevention means the drug tamoxifen for premenopausal women or raloxifene for postmenopausal women. Now the data in the BRCA population is weaker for the chemoprevention because those trials that were run did not specifically randomize for BRCA patients, but there has been enough time and retrospective analysis of the studies that we think that there is probably a significant risk reduction in those BRCA patients. Together with that, if you add ovarian oblation, or removing the ovaries, these are another type of chemoprevention because this results in depletion of estrogen. If you add that together with drug therapy, we can increase risk reduction. It is very hard to predict the number, but it is probably somewhere between 30% and 80% risk reduction with those two approaches together.

The third option is surgery, and that is a bilateral mastectomy, double mastectomy, and we know that reduces risk of breast cancer by about 90%; you are never at 0%. We also know that several studies have shown there is actually no survival benefit when you do a double mastectomy. You do reduce the risk of getting the cancer and the need to have to screen frequently, you reduce the risk of having to treat it, but you don’t actually reduce the risk of dying from it. That is a very clear distinction that we do need to make for our patients. However, in that patient population, if they remove their ovaries when they are young-meaning between the age of 35 to before menopause-you do actually reduce death rate from breast cancer.

Cancer Network: For women who are diagnosed with early-stage breast cancer, is the goal to minimize the amount of tissue removed? I think there has been a trend recently for women to opt to remove their healthy breast as well.

Dr. Wallace: So, this is a very complex discussion actually. We are in a little bit of a wave in the last half of a decade in women wanting to have fairly radical surgery for low-level disease. There are appropriate women for bilateral mastectomies who have a large breast cancer in a small breast, or those women who have other risks to their opposite breast or have severe proliferative changes on their opposite breast, meaning a lot of MRI abnormalities and a lot of previous biopsies and things like that. Or cosmetically, it may make sense to do it. But, the majority of women do not need a bilateral mastectomy if they have a single breast cancer. It does not change survival, and it does not change the need to treat their breast cancer. That is a misconception that women have-they think if they have radical surgery, that they can avoid the systemic treatment of their breast cancer, and that means the anti-endocrine therapy, the anti-estrogen therapy, the chemotherapy, and radiation for larger tumors. Women sometimes think that if they remove both of their breasts, they can stop there and not have any other therapy, but that can actually be harmful because they may be undertreating their breast cancer. Explaining to patients what their true risk is and the treatment they need, and that too much surgery is radical is an important role of the breast surgeon.

Cancer Network: And just briefly, women who are at normal risk for both breast and ovarian cancer, what are the current guidelines for screening and genetic testing?

Prof. Madlensky: Right now, the US Task Force is actually revising and developing their statement for recommending who the appropriate candidates for BRCA testing are, and we always want to make the point that this is not what one would consider a routine test. All of the guidelines emphasize appropriate risk assessment ahead of testing, so that means an evaluation of a full family history. Really whenever possible, we try to get medical records on family members as well. It doesn’t always work out, they are not always available, but we do try to confirm as much family history as we can to make sure we are giving the patient accurate risk assessment. In general, the types of things we look for in a family history that indicates testing is appropriate is women with premenopausal breast cancer and women with ovarian cancer, and it is important to note that it is specifically epithelial subtypes of ovarian cancer. There are a lot of ovarian cancers that are not associated with the BRCA genes, for example, germ cell tumors of the ovaries, so it is really focused on epithelial cancer of the ovaries. Families that have male breast cancer, which is very rare, is an indicator that a BRCA mutation may be genetic.

Increasingly, we are learning that especially for BRCA2 families, there may be elevated rates of pancreatic cancer and early-onset prostate cancer, meaning much younger than average prostate cancer. All of these are indicators in a family tree that BRCA testing might be appropriate, but we really do want to do a full and complete evaluation of the family history to make that determination. The other point is that we hope the first person in the family getting tested is someone who has breast or ovarian cancer, which makes testing for others in the family much more accurate. If the patient in the family who has cancer doesn’t carry a BRCA mutation, then there is no need for the other relatives to go ahead and get BRCA testing; it doesn’t make sense. So, as far as guidelines, there is not one overall guideline to determine who should consider testing. It is really for primary care doctors to look at the pattern in the family and get data on which cancers are present, and then refer to genetic counseling or cancer genetics specialists for a full evaluation.

Cancer Network: Do either of you have anything else about this topic overall that we have not discussed yet?

Dr. Wallace: I think the big thing to understand is the difference between a very high-risk woman making a decision and a breast cancer patient being treated and making decisions. In Angelina Jolie’s case, a lot of her decision was driven, I am sure, by her wanting to reduce her risk and not wanting to, as much as possible, go through cancer treatment ever and simplifying her life. That is a lot of it for BRCA patients-having to go through intense screening for years is intensely stress-provoking and even though it seems like radical surgery, double mastectomy for BRCA carriers is something within the standard of care and something we do fairly regularly. I would say that 50% of my patients elect to do it. It is not done the next day after testing-the patients are counseled, they see other clinicians, they think about it and hear about all of the risks and benefits, and then they go forward with it. This is a very small, select group that is very different from the majority of women who are at regular risk or even those who have breast cancer.

Prof. Madlensky: The only thing I would like to add is that the genetic counseling community is here, as consultants, to work with physicians who have a lot to do and have very busy days. Our consultations are typically 60 to 90 minutes long because we are going through a lot of information with these patients. I just want to make sure that physicians are aware that there are genetic counselors out there, who are available and can help with the risk assessment process and with coordinating genetic testing, going over results, making recommendations for families. This is what we are here to do, to partner with physicians in that effort.

Cancer Network: Thank you both so much for joining us today!

Prof. Madlensky: Thank you!

Dr. Wallace: Thank you!