Banu Arun, M.D.
Breast Medical Oncology
Co-Director Clinical Cancer Genetics
The University of Texas, M.D. Anderson Cancer Center
Dr. Arun: Dr. Banu K. Arun: I would like to welcome you to our session, "Risk Assessment and Management of High Risk Women." I'm Banu Arun. I'm one of the faculty members at the University of Texas M. D. Anderson Cancer Center.
Today I would like to discuss with you risk assessment of breast cancer and go over [the] risk management options we have for our high risk patients. That would include screening, chemoprevention and surgeries.
Just a quick reminder about breast cancer risk factors, age certainly is a very important risk factor for breast cancer. We know that with increasing age, the risk for breast cancer increases significantly. Gender obviously is a risk factor, so being a woman, in itself, increases the risk of developing breast cancer compared to male. Endocrine risk factors - we will go over that in a minute - include the use of hormones or any other endocrinologic factors. I will also mention, briefly, some of the pre-cancer lesions or the benign lesions that can also contribute to subsequent development of breast cancer. Today we will not have time to talk about dietary factors and lifestyle, however, I would like to mention that, at this point, we do not have definitive long-term prospective trials that tell us definitely that certain food groups or a certain lifestyle decreases or increases breast cancer risk. However, we tell our patients to adopt a healthy lifestyle and follow the guidelines of the food pyramid. That would also reduce the risk of some other diseases, heart problems, diabetes and other cancers besides breast cancer. I will, then, go over a little bit more in detail, about the importance of families who do have breast cancer and then, furthermore, go into details about breast cancer -associated hereditary genes and risk factors and what can be done about that.
So as I just mentioned, age is an independent risk factor for breast cancer. We actually know from large databases such as the SEER database, that breast cancer is a disease of elderly patients. You can see here, after age 50-60, there is a steep increase in the prevalence of breast cancer. And actually more than half of all breast cancers are diagnosed in women above age 60 or 65.
I had mentioned the importance about endocrine factors, hormonal factors such as estrogen. So we know that estrogen exposure can increase breast cancer risk. We see this in individuals who have early menarche, late menopause. For example, studies have shown that if women undergo oophorectomy in a pre-menopausal setting, and the source of huge estrogen production is eliminated, that decreases in itself, breast cancer risk by more than 50 percent. We also know that having no children or children after age 30-35 also increases risk of breast cancer risk. And, furthermore, we know that using hormonal replacement therapy increases subsequent breast cancer risk.
And I just want to point out one major study here, the Women's Health Initiative Study, that randomized post-menopausal women to either nothing or the combination of estrogen and progesterone or estrogen alone. This study looked at many outcomes that included cardiovascular events, pulmonary embolisms, thromboembolic events, several cancers including breast cancer, colon cancer, hip fractures. But at the end, it was aiming to look at the global index of taking the hormones or not. And here you can see that, in women who took in post-menopausal, otherwise healthy woman, who took the combination of estrogen and progesterone, breast cancer risk was increased by about 1.26 fold. Colon cancer risk was decreased but cardiovascular events and strokes were significantly increased. And at the end, when we looked it did not really have an impact on death so it did not increase or decrease deaths. So the global index was around 1. So, overall, there was basically no overall beneficial impact of taking the estrogen. It, yes, decreased the risk of osteoporosis and fractures, increased the risk of breast cancer, decreased colon cancer, but at the end it did not make a difference. So at this point our approach is to individually counsel patients regarding post-menopausal hormone replacement therapy and identify the ones who would will really benefit from that and would not have the side-effects. It is also recommended that hormone replacement therapy is considered, rather in the peri-menopausal or immediately at the beginning of the menopausal stage, for several years and not for a prolonged time.
I had mentioned, in my previous slides, that certain pre-malignant benign breast lesions can also increase breast cancer risk. For example, patients with a previous history of ductal carcinoma in situ or lobular carcinoma in situ have a 2 to 3 fold increased risk of developing breast cancer subsequently. Again, patients with a previous history of atypical ductal or atypical lobular hyperplasia also have an up to 4 fold increased risk of developing subsequent breast cancer.
Now, we also now know more and more about the importance of personal and family history of breast cancer. In terms of personal history, if we have a patient who already developed breast cancer on one side, and she's cured from that disease, we know that the risk of developing a new breast cancer in the opposite breast is about 0. 5 to 1 percent per year. So even though this patient had developed breast cancer and is cured from this disease, the risk of developing a new breast cancer in the opposite breast is high. So she should be managed accordingly. We know also that family history plays a very important role. Earlier studies showed that if an individual has 2 first degree relatives with breast cancer, that unaffected person's risk is about 20 to 30 percent, so 2 to 3 fold increased risk. If the first degree relatives, for example mother and sister, develop breast cancer at a younger age, or pre-menopausally, that lifetime risk actually goes up to 40 percent. So the age onset of the relatives' breast cancer is also important in our assessment. Furthermore, now - more than 15 years ago now - we have more information about hereditary breast cancer risk and quantify even better. With the identification of the BRCA1 and BRCA2 gene, we know that individuals who have a deleterious mutation in these genes carry up to 80 percent risk of breast cancer.
This chart gives you a summary of what I have just told. As you can see, individuals with the BRCA1 or BRCA2 mutation have the highest risk, up to 10 fold increased risk. That is followed by the second category of increased risk, that is individuals with benign breast disease: DCIS, LCIS and ADH. Then we have the other risk factors I just mentioned that have a 1.5 to 2 fold increased risk,again taking hormones, having late children and other endocrine- related factors.
Having said that, individuals with the BRCA1 or 2 mutation carry the highest risk. I also would like to add to that, fortunately, only about 10 percent of all breast cancers are due to gene line mutations. The rest, 90 percent of the breast cancers , are actually sporadic. Of these 10 percent hereditary breast cancers, about 80 percent are due to gene line mutations in the BRCA1 or BRCA2 gene. Then that is followed by mutations in the p53 gene, and if an individual has that, then the diagnosis is the Li-Fraumeni syndrome; or mutations in the PTEN gene , P10 gene, that is the clinical syndrome Cowden's syndrome; or mutations in the ATM gene. And breast cancer risk can vary anywhere between 20 and 50 percent in these individuals as well as some other cancers.
A little bit more information about individuals who carry the BRCA1 or BRCA2 mutation. So I had indicated that an average woman's risk to develop breast cancer is about 10 to 11 percent. If that individual carries a BRCA1 or BRCA2 mutation, that risk goes up to 80 percent lifelong. However, if we go down and look at the risk of breast cancer in women around age 40, that fold increased risk is actually more than 10. It's anywhere between 20 to 40 fold increased risk because in the average population breast cancer around age 40, or before 40, is see very rarely. As you will remember, it's a disease of an older age. So, therefore, relatively speaking, a mutation carrier has actually more than 10 fold higher risk to develop breast cancer if she's young compared to a woman who's age 70.
Having a BRCA1 or 2 mutation also increases risk of other cancers. The main second group of cancers we counsel our patients for, and discuss risk management options, include increased risk of ovarian cancer. Again, there is a 10 fold increased risk of developing ovarian cancer with the lifetime risk of at least 16 percent. Very importantly for us, it is also important to know that individuals who have a BRCA1 or BRCA2 mutation also have an increased risk to develop a second new breast cancer in the opposite breast. And based on several studies now, it's up to 65 percent.
We know, also, that when males have a mutation of BRCA1 or BRCA2 gene, their breast cancer risk is also increased; that's up to 6 percent. It's certainly less than a woman's average risk- woman's breast cancer risk- but it's a significant increase for males or men because their breast cancer risk is actually very, very low. We also know that in males, prostate cancer risk is increased. There's a 3 to 7 fold increased risk and if a man carries a BRCA1 or BRCA2 mutation. And it also appears that these cancers appear at an earlier age, about 10 years or so younger. We are getting more and more reports in, that in families who have BRCA2 mutations, we also see an increased of pancreas cancer and also melanomas and some GI cancers, colon cancers. However, the studies are currently being conducted and data is being collected so we can not definitely quantify the risk for those other cancers.
So after this introduction, who are the appropriate individuals that we can consider for genetic counseling and testing?
So this is a chart or a list of scenarios that would make us think about a hereditary problem and make us think that the person maybe should be referred to a genetic counselor, during which session the indications for genetic testing is discussed. So, for example, any woman with a history of breast cancer diagnosed before age 50 could be considered for genetic counseling. Whether this patient will end up doing genetic testing really depends on the interpretation of the counselors after obtaining a detailed family history of that individual. Secondly, if we are dealing with a family history of multiple cases with young breast cancers, that is certainly an indication to consider genetic counseling. If there is ovarian cancer with multiple family members in the family, that's also an indication. If a woman has breast and ovarian cancer, the likelihood of that person having a deleterious mutation in the BRCA1 or BRCA2 gene is up to 88 percent, so very high. Certainly, that woman is a candidate for genetic counseling and testing. We also like to refer and see patients with bilateral breast cancer, especially if the initial breast cancer was diagnosed before age 50. Also, certain mutations are seen more commonly in certain ethnic backgrounds such as certain Ashkenazi Jewish mutations. So we also pay attention to the ethnic background and cancer history in that individual as well as the family. And as I have mentioned, if there is a family with male breast cancers, that also certainly needs more attention and genetic counseling might be indicated.
So this is an example of a pedigree we obtain when we see our patients for genetic counseling. The arrow here shows this 40 year old woman who does not have cancer at this point, but she comes in for genetic counseling and testing because she's concerned. She has a 37 year old sister with breast cancer and another, [a] 42 year old young woman with breast cancer on her paternal side, so that's her father, father's mother was diagnosed and died of ovarian cancer, died at age 52. So this family history is very significant. Obviously we should do genetic counseling and testing but we like to test, not the unaffected person, but to test the affected person first. So always test the youngest person who is affected with cancer.
It would be this patient. And let's say this patient has a deleterious BRCA1 mutation, then we can go ahead and test the rest of the individuals. And let's say the sister is tested now and she has a 50 percent risk of carrying a mutation and she tests positive.
So what do we recommend this [for] young woman at age 40 who came to us [and] was found to be positive and does not have breast cancer yet? We discuss with her surveillance, screening. We discuss preventive surgeries, mastectomies, oophorectomies. And we discuss prevention with a drug.
So in terms of surveillance, this is just a summary of some of the important studies that compare MRI - breast MRI screening, to mammograms and ultrasounds in clinical breast exams. And without going into further detail, I just want to summarize the results and the comments , that MRI in all of these studies was always found to be more accurate and more sensitive when it was used in addition to mammograms, ultrasounds and clinical breast exams.
And indeed, based on these studies the American Cancer Society guidelines changed in March of 2007. And now breast MRI screening is indicated for women or individuals who have a deleterious mutation in the BRCA gene, p53 or PTEN gene. Or if an individual has a first degree relative that is known to have the mutation, then we can do MRI in that untested person also until she's tested and ruled in or out to have the mutation. And lastly, if we calculate the woman's life long risk to be greater than 20 percent, that is also an indication to add MRI breast screening to standard yearly mammogram screening.
Now how about preventive surgeries? So we can do screening but how about the mastectomy? Prospective studies have shown that if women with BRCA mutations undergo total mastectomy, their subsequent breast cancer risk is decreased more than 90 or 95 percent. These women are also offered oophorectomy because of the ovarian cancer risk. While oophorectomy reduces ovarian cancer risk by more than 90 percent, we have also seen again in prospective studies that doing oophorectomy also reduces breast cancer risk by about 50 percent. So that's an additional benefit for undergoing oophorectomy.
This is a study we did in our clinics and published some years ago because we wanted to see how our patients decided to undergo mastectomies because it is a rather aggressive and nonreversible approach. We at that time, even though we now have close to 2000, but at that time looked at 550 women who have had genetic counseling. And it appeared that women who were BRCA- positive, had the previous diagnosis of invasive cancer or DCIS, or had a family member with ovarian cancer, those individuals tend to do more mastectomies. However, women who have had advanced breast cancer and advanced ovarian cancer, tend not to do mastectomies. Most probably because they already had a life threatening disease and doing preventive surgeries would not add anything to their survival.
So after we discuss screening and surgeries with the patient, we also discuss chemoprevention, reducing the incidence with a drug, an intervention.
This slide summarizes the performed and completed studies looking at Tamoxifen versus placebo in high risk women. We have two studies from Europe, when Tamoxifen was compared to placebo in high risk women, that did not show a reduction in the incidence of invasive breast cancer. However, there are also two studies, especially the NSABP, which was done here in the U. S. on 13,000 women, that did show a reduction in the incidence of invasive breast cancer. That reduction was about 50 percent. Subsequently, Jack Cuzick et. al., also published another one, the IBIS one, that also looked at tamoxifen versus placebo in 7000 women, and again in this study, there was a 30 percent reduction in the incidence of invasive breast cancer. And very recently the NSABP P2 study, or [the] other name is the Star Trial, compared Tamoxifen to Raloxifene, which is a very similar drug, in 19,000 women, and both the drugs reduced the incidence of invasive breast cancer in high risk women.
Raloxifene in that study was found to be a little bit more safer. It had less thromboembolic events and uterine cancer. But one question mark it left was, that Raloxifene was about 35 percent less effective in reducing the incidence of pre-cancer lesions such as DCIS, LCIS and ADH.
Here are the side effects of Tamoxifen. As I had mentioned, pulmonary emboli, thromboembolic events, endometrial cancer, deep vein thrombosis, and again, if you are talking about these side- effects in an otherwise healthy individual, many women might not want to go through these side- effects. And in fact, several reports have suggested that only 30 percent of high risk women like to take Tamoxifen because of the side-effects. And 70 percent actually say no to this agent as a prevention drug.
The other problem with Tamoxifen is that it only reduces the risk of estrogen receptor- positive breast cancer. It does not reduce the risk of estrogen receptor- negative breast cancer.
So, therefore, the interest at this point in developing new chemopreventive agents lies in also finding effective agents that can also reduce the incidence of estrogen receptor- negative breast cancer. Obviously trying to identify less toxic agents with less side- effects. Again Tamoxifen's acceptance is rather low. And one way to study these agents, instead of accruing 19,000 women, is perhaps doing pilot short term prevention trials, to see if that agent should move forward to larger studies that really take more than 10 years to complete and get the results.
And these are some of the potential targets many, including us, have looked at and are currently looking at: for example, Cox-2 inhibitors, tyrosine kinase or small molecule tyrosine kinase inhibitors, retinoids, some transcription inhibitors, and then aromatase inhibitors, but that's more for estrogen receptor-positive in prevention. And these can be actually considered for estrogen receptor -negative breast cancer prevention.
Now let's go back to our patient as you -know- have heard. We initially saw this patient. She was positive and we discussed management options for this one. But what do we tell her sister who also has a mutation but already had breast cancer? How would that information help that individual?
Well first, as I mentioned and I want to stress it again, it is important to test the person in the family who had breast cancer at the youngest age. So that way we are increasing our likelihood in finding the mutation. Once we find the mutation, it can affect, for example, surgical decisions because we know [that]the risk of a second contralateral breast cancer is higher. Perhaps that person would benefit from double mastectomies when she is diagnosed with breast cancer, to also reduce the potential risk of a second breast cancer in the opposite breast later. Furthermore, because of the risk of ovarian cancer, we can offer oophorectomy to these patients. If these patients undergo oophorectomy, they can be candidates for other certain and better endocrine therapy. So that is another indirect benefit, if you will. And finally, which is very new and very exciting, for the first time there are now targeted agents, for example, the PARP inhibitors, that are being tested right now. They're in clinical trials, that target hereditary breast cancer: two recent breast studies have been completed with two PARP inhibitors and one in ovarian cancer, and the results are very, very promising.
What I would like to stress again and conclude is that genetic risk assessment and management is a multi-disciplinary and coordinated effort that usually takes place in cancer centers where the use is optimal and the benefit is optimal too. We, further, have to refine risk models to seek which persons should undergo genetic testing. The other important question is when a person undergoes genetic testing, and we do not find a BRCA mutation, so what's next? What's then? That person is still at high risk, still has a significant family history. We could not find a mutation but there's something else going on. So again, we need to have models and other research going on to identify these individuals, perhaps genetic modifiers. As I mentioned, at this point, we really don't have an approved agent besides Tamoxifen and Raloxifene that reduces the incidence of estrogen receptor- positive breast cancer but we don't have anything to reduce the incidence of estrogen receptor -negative breast cancer. So research in that area is also continuing. And finally as I mentioned, breast MRI screening was introduced recently in addition to yearly MRIs -- yearly mammograms. However, it's new. The frequency still needs to be determined. Currently we are doing it once a year. Perhaps it should be done every 6 months. Plus, we do not know the long term outcome either [of] side-effects or the benefits ,such as, does it add a survival benefit? So these questions are being intensely studied by us and several many, many other groups. And hopefully we'll have some answers soon. Thank you very much.
Risk Assessment and Management of High Risk Women video
©2010 The University of Texas M. D. Anderson Cancer
1515 Holcombe Blvd, Houston, TX 77030
1-800-392-1611 (USA) / 1-713-792-6161