Hello, I m Banu Arun, Professor of Breast Medical Oncology and Co-Director of Clinical Cancer Genetics at the University of Texas MD Anderson Cancer Center. Today I will be discussing with you Hereditary Breast and Ovarian Cancer Syndrome: Management of Breast Cancer Risk. Upon completion of this lecture, participants will be able to describe breast cancer risk management option including screening, chemoprevention, and surgery for individuals with a BRCA1 or BRCA2 mutation; understand the benefits and limitations of current chemoprevention options, and ongoing studies for novel chemoprevention agents; recognize complex cases; and consider referral to high-risk programs for participation in screening protocols and clinical studies. This table illustrates risk factors for breast cancer. As seen here, the highest risk is conferred by having deleterious mutations in the BRCA1 or BRCA2 gene. Individuals with this mutation have a up to ten-fold increased risk or a lifetime risk of up to 80% of developing breast cancer. But the second group that increases breast cancer risk are individuals with a known pre-malignant breast disease, such as ductal carcinoma in situ, lobular carcinoma in situ, or atypical hyperplasias. These individuals have --- can have a up to four-fold increased risk of developing breast cancer. Then there are other risk factors that are related to endocrine factors or diet and exercise-related factors, such as early menarche, no pregnancies or later pregnancies, hormone replacement therapy. As you can see here, the increased risk is in a two-fold risk level. I would like to now talk a little bit about BRCA1 and BRCA2 mutations and the risk it confers. As you can see her --- here, the first example is population risk. A woman s lifetime risk to develop breast cancer by age 70 is anywhere between 10 to 11 percent. However, individuals who have a deleterious mutation in the BRCA1 or BRCA2 gene have a[n] up to 80 percent risk of breast cancer or up to tenfold increased risk. Having BRCA1 and BRCA2 mutations also increases risk of second and other cancers. For examples, these women are at a higher risk, ten-fold increased risk, to develop ovarian cancer, with a lifetime risk being at least 16 percent, even up to 40 percent. And, very important for a patient who already has one breast cancer, if that individual has a deleterious mutation in the BRCA1 or BRCA2 risk, her risk to develop contralateral breast cancer, so a second primary cancer, is up to 64 percent, based on two prospective trials, by age 70. So, Who are the appropriate individuals that should consider genetic counseling and genetic testing? This slide lists for us the red flags where we should pay closer attention to the family history and consider referring patients or individuals for genetic counseling and then potentially testing. For example, an individual with a personal history of breast cancer diagnosed before age 50 should be considered for genetic counseling. Individuals with especially a certain subtype of breast cancer such as having triple negative or ER/PR-
and HER2-negative cancer, even without family history, should be considered for genetic counseling if they were diagnosed before age 50 or even before age 60. If there are --- there s a family history of multiple cases of early onset breast cancer, again, those individuals should be looked at closer. A family history should be taken and a referral for genetic counseling should be made. If there is ovarian cancer within the family history of breast or ovarian cancer at any age, should be considered for counseling. If a woman has a breast and ovarian cancer, her likelihood of having a BRCA mutation is more than 80 percent. This woman is certainly a candidate to consider genetic counseling and testing. Individuals with bilateral breast cancer, especially if the first breast cancer was diagnosed at a younger age, Ashkenazi Jewish heritage, and also a family history of male breast cancer should alert us to look at the family history a little bit closer and make a referral for genetic counseling and potentially subsequent testing. There is also more and more evidence that individuals, especially younger women with a history of ductal carcinoma in situ, even in the absence of invasive cancer with or without family, should be considered for genetic counseling and testing. The American Society of Clinical Oncology Guidelines recommend a cancer predisposition testing should be offered when there is a high likelihood of a positive test and if there --- if we can adequately interpret the test results, and if the test results will influence medical management. That means for unaffected individuals, so the individuals who do not have a diagnosis of cancer, risk management options. And for the affected individuals, that means individuals who already have a diagnosis of cancer, for example breast or ovarian cancer, treatment decisions. When we discuss risk management options we like to divide the --- our approaches into two different categories. One risk management option category is the ones that are affecting the unaffected individuals, the individuals without cancer. And then the other group is how to manage individuals who already developed breast cancer and how the genetic information could be used in those individuals. I would like to start our approach [with], how to discuss risk management options with unaffected individuals. The categories we discuss include surveillance, prevention with a drug, chemoprevention, and preventive surgery, such as prophylactic mastectomy and prophylactic oophorectomies. A few questions: Question number one, Breast cancer screening for a woman with a BRCA mutation should include monthly self-breast exams, semiannual clinical breast exams, and A) Annual mammograms, B) Annual breast MRIs, C) Annual mammograms and annual breast MRIs,. D) Annual mammograms and annual ultrasounds. The answer is C. Individuals with a deleterious BRCA mutation are candidates to undergo annual mammograms plus annual breast MRIs. The data supporting this comes from several studies that are either retrospective or prospective, as illustrated in this table. Several studies evaluated in high risk individuals either with known or unknown BRCA mutations, the value of adding MRI to standard screening, such as mammogram and some studies, ultrasounds and clinical breast
exams. And what all of these studies concluded is that adding an MRI to breast screening is more accurate, more sensitive, and more informative. And, indeed, in 2007, the American Cancer Society guidelines included breast MRI screening for individuals at high risk. And these guidelines are now in the NCCN screening recommendation guidelines for women with deleterious BRCA mutations. The guidelines include self-breast exams, training and education starting at age 18, clinical breast exams every six to 12 months starting at age 25, annual mammogram and breast MRI screening starting at age 25, or individualized based on earliest age of onset in family, and discuss options for risk reducing mastectomy on a case-by-case basis. And I will come back to the surgical intervention in a little while. Recommended risk reduction salpingo-oophorectomy should be ideally done between ages 35 and 40, and upon completion of childbearing, individualized based on earliest age of onset of ovarian cancer in the family. For those individuals who have decided not to undergo risk reducing salpingo-oophorectomy consider trans --- transvaginal ultrasound and C-125 levels every six months starting at age 35, or five to 10 years before the earliest age of ovarian cancer in the family. And also consider chemoprevention options that I will be also discussing in a minute. In men with BRCA mutations, self-breast exam training and education is recommended to start at age 35, clinical breast exams every six to 12 months starting at age 35, and also consider baseline mammograms at age 40, annual mammogram if gynecomastia or parenchymal glandular breast density on baseline study, and adhere to screening guidelines for prostate cancer. So now I would to switch gears and talk a little bit about chemoprevention for these individuals. This table summarizes for us the prospectively-run Phase III large breast cancer prevention trials. As you know, there are three positive, actually four positive new trials to date. The very first trial was done in high-risk women under the NSABP P-1 trial. That compared tamoxifen to placebo in 13,000 women and there was a 50 percent reduction in the risk of developing invasive breast cancer. The second larger trial was done in the UK, the IBIS-I trial, that also compared tamoxifen to placebo in 7,000 women, and there was about 30 percent risk reduction in invasive breast cancers. Then, the NSABP --- NSABP P-2 launched a second trial comparing now tamoxifen, the winner of the P-1 trial, to raloxifene, another selective estrogen receptor modulator, in high-risk but postmenopausal women, in about 19,000 women, and both agents were able to reduce the incidence of breast cancer. However, the benefit to reduce invasive breast cancer was about 20 percent more for tamoxifen over raloxifene. And finally, very recently in 2011, a Canadian NCIC study reported on the benefit of exemestane versus placebo, showing a more than 65 percent risk reduction in the incidence of invasive cancer in postmenopausal, high-risk women who took exemestane versus placebo.
So, our second question set, Tamoxifen is likely [to] be more effective for: A) BRCA1 mutation carriers, B) BRCA2 mutation carriers, C) Tamoxifen is equally effective for BRCA1 and BRCA2 mutation carriers, D) Tamoxifen should not be used for mutation carriers. The answer is D. Tamoxifen should not be used for mutation carriers because none of the studies actually looked prospectively in these mutation carriers so we do not have any prospective data. A few pearls about selective estrogen receptor modulators used in clinical practice as chemopreventive agents. As we know, acceptance for these agents is low. It s less than 20, it s less than 30 --- 20 percent, most probably because of the side effects that are not acceptable to an individual who is otherwise in good health. Increased risk of endometrial cancer, thromboembolic events, and most importantly, menopausal symptoms such as hot flashes, cognitive function problems, and weight gain. More importantly, these agents do not prevent the development of estrogen receptor-negative breast cancer. And about 70 percent of the BRCA1-associated breast cancer are estrogen receptor negative. Therefore, research in this area done by us and many others include to --- to try to find agents and targets that are effective in estrogen receptor-negative breast cancer development, such as a nonsteroidal anti-inflammatory drugs, COX-2 inhibitors, retinoids, small molecular tyrosine kinase inhibitors, and NF-kappa B inhibitors, and many others. There are currently smaller Phase II prevention studies going on at our institution, but also [at] other institutions, trying to evaluate potential chemopreventive effect of agents. Using a FNA model where we obtain tissue before and after treatment for three to six months to evaluate changes in the tissue, we and others have completed Phase II prevention studies using different agents such as anastrozole, celecoxib, vitamin A, Targretin, and some others that are either currently ongoing or pending. The idea is, again, to try to prevent ER-negative breast cancer but also find agents that can also prevent --- that also have less side effects and are not as toxic as tamoxifen so that the acceptance among high-risk women is high. There are also ongoing large Phase III trials, such as the IBIS-II trial, that is randomizing high-risk women in Europe to placebo versus anastrozole. There is a study that is called an Italian study in BRCA mutation carriers, evaluating letrozole versus placebo, an aromatase inhibitor. The NSABP-B35 has conducted a study in ductal carcinoma in situ anastrozole versus tamoxifen. And finally, a aromatase inhibitor, letrozole versus raloxifene study was going to happen but that study is at this point on hold. As you can see, though, these --- all of these studies include agents that only prevent ER-positive breast cancer and these agents are only indicated in postmenopausal women. So we really do not have anything at this time to prevent ER-negative breast cancer patients, especially ER-negative breast cancer especially in younger or premenopausal women. Question number 3, Prophylactic mastectomy reduces breast cancer risk by: A) 90 to 95 percent, B) Reduces risk by 100 percent, C) Reduce breast cancer risk by 75 to 80
percent, D) Should not be used for women with BRCA mutations. The correct answer is A. Prophylactic bilateral mastectomy reduces breast cancer risk by 90 to 95 percent in individuals who have a deleterious BRCA1 or BRCA2 mutation based on prospective trials. Mastectomies can be done either as simple mastect --- simple total mastectomies or subcutaneous mastectomy, even though the thought is that a total mastectomy appears to be more effective, and, as mentioned, in prospective trials, have been shown to reduce breast cancer risk by more than 90 percent. As I have mentioned individuals at incr --- with a BRCA1 or BRCA2 deleterious mutation are also at increased risk to develop ovarian cancer. Therefore, oophorectomy is also discussed with these individuals to reduce the risk of ovarian cancer. However, if done in the premenopausal setting, these individuals also benefit in terms of breast cancer. Prospective studies have shown that if women undergo oophorectomies in the premenopausal setting, their breast cancer risk is actually decreased by about 50 to 53 percent. However, some studies have shown that the benefit is only seen in BRCA2 carriers, even though this data needs to be approached carefully as the --- in the subgroup analyses, the number of BRCA2 mutation carriers was very low. But, overall, there is a benefit in terms of breast cancer risk reduction when patients also undergo oophorectomies. Now, I would like to switch gears a little bit and discuss with you very briefly the management options for individuals who already have developed breast cancer, who underwent genetic testing and were found to have a BRCA1 or BRCA2 mutation. It is important for us nowadays, because it might have treatment implications. For example, in terms of surgeries, if we have a patient with Stage I breast cancer, a young woman with a BRCA mutation, she might be eligible to undergo segmental mastectomy and have radiation therapy. However, if she has a BRCA mutation, because of the increased risk of contralateral breast cancer, she might opt to do bilateral mastectomies. So, therefore, she has these choices that she can discuss with her surgeon. If this individual has ER --- estrogen receptor-positive breast cancer and undergoes the oophorectomy, she might be a candidate actually to be treated adjuvantly with an aromatase inhibitor instead of tamoxifen. And, very excitingly, recently new targeted agents have been developed that for the first time ever can target cancer that are associated for --- with hereditary cancer. For example, the PARP inhibitors have been studied in Phase I and Phase II, and [are] now being studied in Phase III clinical trials for BRCA1 and 2-associated breast as well as BRCA1 and 2-associated ovarian cancer. And, furthermore, once we identify a mutation in the person with cancer, we know what the mutation is and we can do predictive testing in individuals in that family, especially first degree relatives, to identify if the relatives carry the mutation, and discuss with them risk management options that I just summarized for you. So, in summary, we really need to evaluate family history very carefully in patients with or without cancer. It is ideal if we perform the genetic testing first on the patient who has cancer and then once we identify a mutation, we should offer predictive testing to unaffected family members because if they are positive, they truly would benefit from risk reduction approaches. We should discuss screening, surgery, and
chemoprevention, what we know and what we don t know in this field. And, very importantly, refer for clinical trials and registries. Many research questions remain unans --- unanswered and we all need to work together. I would like to thank you for your attention and would like to encourage you please to give us feedback. Thank you.