Decoding Breast Cancer Risk: BRCA and Beyond

Lidia Schapira, MD; Leif W. Ellisen, MD, PhD


October 16, 2014

Editor's Note: BRCA gene mutations put women at high risk for breast and ovarian cancer, but who should be screened for these mutations? A study published in the Proceedings of the National Academy of Sciences of the United States of America,[1] and a viewpoint by the same authors,[2] support widespread screening for BRCA1/BRCA2. Yet this recommendation has raised concern among experts, as reported by Medscape. Further complicating the discussion is the role that other genes play in raising a woman's risk of developing these cancers.[3] Clippings in hand, patients are coming to their doctors with questions. How should clinicians advise them?

To help answer these questions, Lidia Schapira, MD, associate professor at Harvard Medical School, spoke to Leif W. Ellisen, MD, PhD, program director of breast medical oncology and clinical director of breast/ovarian cancer genetics at the Massachusetts General Hospital, Boston, Massachusetts, about the practical issues regarding risk assessment in women concerned about their potentially increased risk for breast and ovarian cancer.

Red Flags in the Family History

Dr Schapira: BRCA testing is appropriate for women who are at high risk for breast or ovarian cancer. What key features of family history do clinicians need to ask about to determine whether a woman is at higher-than-average risk of developing breast or ovarian cancer?

Dr Ellisen: There are what we might call "key features" or "red flags" in the family history that increase the likelihood of genetic predisposition. One red flag is the presence of breast cancer in the patient or family members before age 50 years. There is a very strong association with age and genetic predisposition—the younger a woman is when breast cancer is diagnosed, the more likely it is that the breast cancer is genetic.

Probably the most powerful sign would be breast and ovarian cancer on the same side of the family, and in particularly if both cancers are found in a single individual. A history of male breast cancer is often associated with genetic risk, as are multiple primary breast cancers in the same individual.

Similarly, patients who are of Ashkenazi Jewish ancestry can have certain so-called "founder mutations," particularly of BRCA1 and BRCA2. Breast cancer, and particularly breast cancer in young women, in the context of Ashkenazi history, would be something to consider in terms of referral for genetic counseling and testing.

Another thing that is quite important to consider, and is sometimes overlooked, is the paternal history—the father's sisters and father's mother. As we know, genetic breast cancer predisposition can be equally transmitted from the paternal or the maternal side of the family. Breast cancer is much less common in men, so the genetic predisposition might not be as evident when only taking the history of first-degree relatives.

Genetic Testing: Trickle to Watershed

Dr Schapira: If a patient is identified and referred for genetic evaluation and testing, what is involved in the risk assessment? And what kinds of mutations are we routinely testing for?

Dr Ellisen: If the patient who is being considered for referral is not affected by cancer but has a family member who is affected, it is often much more useful to start the genetic referral, if possible, with the affected family member. This is because the genes are transmitted in the manner of autosomal dominance, so there still could be a mutation in the family that the unaffected patient did not inherit. That's why testing a family member who actually has had cancer, particularly an early cancer, is often the best place to start.

As for specific tests, we have seen watershed growth of testing for hereditary breast and ovarian cancer risk over the past year, in part as a result of patents on BRCA1 and BRCA2 gene testing being overturned. Before last year, one company, Myriad Genetics, had a patent for testing those genes. There was only one test in the country that you could order commercially for BRCA1 and BRCA2. If there were other genes of interest, testing was usually done through other laboratories. Now that the patents have been overturned, several laboratories are offering testing for gene panels that include BRCA1 and BRCA2 as well as a group of other cancer risk genes.

In the future, there will be less testing of patients selectively for BRCA1 and BRCA2 mutations, and instead we will be doing more testing using a panel of as many as 20 or more genes. There are potential pros and cons of this "multigene panel approach" vs the traditional single-gene testing that we have been doing now for more than 15 years.

Dr Schapira: How many patients in the United States have breast or ovarian cancers that are associated with a recognized mutation?

Dr Ellisen: It is believed that 5%-10% of all breast cancers have a major hereditary component. Most breast cancer is generally sporadic, as are many other cancers that are associated with aging. Of the 5%-10% of cases that are hereditary, only about one fourth involve single-gene conditions. The strongest drivers of genetic cancer risk for breast and ovarian cancer are BRCA1 and BRCA2. There are several others, with variable penetrance or risk of causing cancer, but it's a relatively small percentage.

Nonetheless, it is quite important to recognize families who have striking histories and are more likely to have the high-penetrance or high-risk genes. For these cases, once a mutation is identified, we have specific high-risk management guidelines and data about improved outcomes.

It's Not Just BRCA1 and BRCA2 Anymore

Dr Schapira: In light of recent articles in the medical[1,2,3,4] and popular press[5,6] on genetic testing for breast cancer, as well as coverage by National Public Radio,[7] I have had patients come in and ask me about specific genes that I didn't think the public had heard about. Can you tell us about genes other than BRCA1 and BRCA2—perhaps PALB2, CHEK2, and p53—and how we should think about them clinically?

Dr Ellisen: It is a rapidly evolving area. Many of my patients brought me the article from the New York Times[5] about how more gene testing providing more information but less knowledge. That alludes to this multigene testing rather than just testing for BRCA1 and BRCA2.

Classifying genes into three categories of cancer risk is probably the easiest way to talk about the issue. The first category is high-risk breast and ovarian cancer, and those genes are the big players that we know of: BRCA1 and BRCA2. These genes are associated with high risk for breast and ovarian cancer, and are not particularly high-risk for other cancers. There is some potential risk for prostate cancer and male breast cancer, but mainly the risk is for breast and ovarian cancer. We have comprehensive National Comprehensive Cancer Network (NCCN) management guidelines for patients with those mutations.

In the second category are so-called high-risk cancer genes associated with other cancers in addition to breast and ovarian cancer, for which there are also management guidelines. In this category are four genes: PTEN, p53, CDH1, and STK11. PTEN is associated with Cowden syndrome (associated with breast cancer), thyroid cancer, endometrial cancer, and colon cancer. The second gene, p53, is associated with breast cancer and brain cancers, particularly early childhood cancers as well as adult and childhood sarcomas. The third, CDH1, is associated with lobular breast cancer and diffuse gastric cancer, and the fourth, STK11, or the Peutz-Jeghers gene, is associated with breast cancer risk and intestinal polyposis in colon cancer risk. Those are the two high-risk categories of cancer genes.

In the third category of cancer risk are moderate- to low-penetrance breast cancer genes. These are the genes that are now included on these new multigene panels that virtually all of the diagnostic companies are offering, but for which there are no consensus management guidelines about what to do for patients who are found to have these mutations. As you can imagine, this creates a quandary for clinicians, even the most expert, in counseling patients who are found to have these mutations.

Among the most important genes in the third category of low- to moderate-penetrance genes is PALB2, which has recently been shown to be associated with up to a 40% lifetime risk for breast cancer. It almost approaches the breast cancer risk associated with BRCA2—so it appears to be an important driver. It is unclear whether it is associated with ovarian cancer risk.

In addition to PALB2, there is CHEK2, which is associated with a 25%-35% lifetime risk for breast cancer. Finally, in terms of the common genes, the third gene is ATM, the well-known ataxia-telangiectasia mutated gene. This is not the biallelic mutation that gives rise to the childhood syndrome, but a monoallelic mutation that is associated with perhaps a 20%-30% lifetime incidence of breast cancer.

The important point about these low- to moderate-penetrance genes is that the penetrance or the risk associated with them is very closely tied to the patient's family history. In other words, if there is a strong family history of breast cancer associated with the mutation in that family, their risks might be relatively elevated, but in a patient who has never had breast cancer or who has a very unimpressive family history, it's not clear how high the risk estimates would be. That is the big challenge that we face in interpreting the findings of a mutation in those genes when we do multigene panel testing—telling the patients what their risks are, and what they should do about those risks.

Choosing Preventive Therapies

Dr Schapira: I can see challenges here. When you see a woman who has one of these mutations and an indeterminate family history, but you don't have consensus guidelines, do you recommend screening with perhaps MRI in addition to mammography? Do you talk about bilateral prophylactic mastectomies? How far do you take this conversation? What seems reasonable?

Dr Ellisen: Let's just remind ourselves for a moment what the consensus recommendations are for the highest-risk genes. For BRCA1 and BRCA2, the current consensus management guidelines state that patients can choose either aggressive screening with annual mammography and annual bilateral breast MRI, or they can choose cancer prevention with surgery.Currently, we don't have long-term outcome data to say that breast cancer prevention definitely leads to better outcomes than does aggressive screening and early detection. It's possible that someday we may have those data, but currently we don't. That is because when breast cancers are found, most are curable. For the highest-risk setting, prophylactic surgery is on the table and is quite effective.

However, for the other genes, and particularly those in the third category of cancer risk (PALB2, CHEK2, ATM), most people would say that prophylactic mastectomy should not be a consideration because the risk would not warrant it. If you extrapolate from other conditions, such as atypical ductal hyperplasia, which might have a similar type of risk, we don't recommend that those women have prophylactic surgery. PALB2 conveys a risk for breast cancer that is somewhat higher than that for ATM and CHEK2, but not quite as high as that for BRCA2.

Similarly, for such genes as PTEN or CDH1, for which the risks are in the 20%-40% range of developing breast cancer over a lifetime, most women would not choose bilateral mastectomy, except in the setting of a striking family history.

Some women just don't feel comfortable with this risk, and we know that surgery is effective and they might choose that approach. But for the women who don't choose surgery, we're talking about increased screening with MRI in addition to mammography; this is most useful in younger premenopausal women, because the breast density of young women makes mammograms harder to read. There is also the consideration of taking hormonal agents to prevent these breast cancers.

The unplanned subset analyses from large randomized trials[8] of breast cancer prevention have suggested a benefit for the breast cancer preventive agents (such as tamoxifen) in women who have BRCA2 mutations, and possibly BRCA1 mutations as well.However, we don't have data that these hormonal breast cancer preventive agents are effective in the setting of these other genes. Because most of these genes give rise to estrogen receptor-positive breast cancers, the thinking is that probably these hormonal agents would have an impact on breast cancer risk. It's a consideration, but not a standard recommendation as a risk-modifying strategy.

Dr Schapira: I know you have had patients who have opted for prophylactic bilateral mastectomies. In your experience, what makes them choose this option?

Dr Ellisen: The number one driver—this is true in my own practice and also true in studies[9,10,11] of this question—is the patient's own personal and family history. In my experience, women who have a high-risk gene—BRCA1 or BRCA2—and who have had cancer are much more likely to opt for bilateral surgery; in that case, it is not fully prophylactic, but it is prophylactic against future cancers.

Women who have a BRCA1 or BRCA2 mutation and a very strong family history of breast cancer are also more likely to opt for surgery. In my own practice, I have observed that for a woman who has experienced the breast cancer death of her mother, sister, or other family member, that history is a major driver of the woman's decision to undergo mastectomy. In other cases, a woman who has anxiety over the possibility of developing a cancer—even though it might well be curable—and who doesn't find it acceptable to live with that risk or the inconvenience associated with screening, particularly if she has undergone multiple biopsies along with screening, may opt for mastectomy. These are all reasons women may choose prophylactic mastectomy.

Studies have shown that most women who choose mastectomy are happy that they did so. This is particularly the case where women take time to consider this decision. An important statistic that I share with patients is this: The highest risk for developing breast cancer, even in cases associated with BRCA1 mutations in a family with a lot of early breast cancer, is only in the range of 2%-2.5% per year. If a woman came to me and asked, "Do I really need to have the surgery immediately?" I would tell her, "In a year, you have two chances in 100 of developing cancer. In the next 5 years, you still have a 90% chance of not developing breast cancer."

In my clinical experience as well as what is shown in studies,[8,9,10] when women take their time and think carefully about the decision and make what seems to be the right decision for them, most of those women are happy about the path that they have chosen, whether it is screening or preventive surgery.

Is Universal Genetic Screening in Our Future?

Dr Schapira: Do you see us moving towards universal screening of all women, regardless of family history and ethnicity?

Dr Ellisen: There has been a lot of debate about this, and there will continue to be. With any screening test, the risks and benefits are dependent on the prevalence of the condition that you are screening for in the population. That is true for genetic testing and for breast cancer screening. If you are screening in a population with a low prevalence, you could find mutations in the setting of no significant family history, and it may be quite difficult to interpret what that mutation will mean for a woman's risk. That is the concern that is being raised about the possibility of universal screening in the absence of any family history—that we might be overtreating women, because, as we know, the management guidelines that exist now were developed in the setting of women who had family histories.

The debate is going to continue over the next few years, particularly with more genetic sequencing, more access, and more genes being tested. It's an issue that we are going to have to grapple with.

The counter-argument has been that there are women in whom the family history is not apparent. A woman develops a cancer that we find out is genetic, but the family history was either unknown to the woman, or it was transmitted through the father. That is an unfortunate situation, and all of us are very concerned about those situations. This point brings us back to where we started the conversation, which is that we need primary care and other front-line providers to do the best that they can to elicit these types of family histories that might guide women to an appropriate genetic diagnosis and prevention, if that's possible.


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