Educational Programs: Current
Topics in Oncology
Dr. Banu K. Arun
Session 1: Risk Factors & Prevention
Date: September 8, 2009
Time: 29:04
Banu K Arun, M.D.
Associate Professor, Breast Medical
Oncology
The University of
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Dr. Banu Arun: Welcome to the global academic programs. I'm Banu Arun, M.D., one of the breast medical oncologists at the University of Texas M. D. Anderson Cancer Center. Today I will be talking to you about risk factors and prevention for breast cancer. Today we will cover risk assessment and review risk management options including screening, chemo prevention and risk reductive surgeries.
Let's start with risk factors first. As you all know there are several risk factors that are associated with the increased risk of breast cancer. Gender, obviously being female is one of the major risk factors. Age is a risk factor as well, as we know that with each increasing year breast cancer risk increases. We will touch base a little bit on endocrine factors. I will mention that some certain benign, high risk lesions also confer an increased risk, subsequently. We will not have time today to talk about dietary factors and lifestyle, however studies are ongoing to evaluate whether certain diets and lifestyle changes might decrease or increase breast cancer risk. We will also touch base on the personal history of breast cancer and family history of breast cancer and we will touch base on the breast cancer genes BRCA1 and 2, how those play a role in the assessment and subsequent risk of breast cancer.
I have mentioned that age is an independent risk factor. As you can see from this slide, breast cancer incidence increases dramatically after age 45, 50 and in fact data-SEER data-indicates that about half of all of breast cancers appear in women who are above age 65.
I also had mentioned that endocrine risk factors play a role, especially estrogen exposure. When individuals have early menarche and/or late menopause-in other words if a woman's body is exposed to estrogen for a prolonged time, that can increase subsequent breast cancer risk. Some studies have shown that when women undergo premenopausal oophorectomy for some other medical reasons, breast cancer risk is decreased by about half. We know from studies that having no children, or giving childbirth after age 30, that increases breast cancer risk also. And finally, several studies have shown that using hormonal replacement therapy increases subsequent breast cancer risk.
This slide summarizes two of the major studies performed. One is the women's health initiative study which randomized postmenopausal women to: either estrogen and progesterone, estrogen alone, or a placebo. And to summarize the findings, breast cancer incidence was increased in women who took the combination of hormone replacement therapy compared to either placebo or estrogen alone. A very similar increased risk was also seen in the HERS study where again postmenopausal women were randomized to estrogen plus progesterone-again a 1.3 fold increased risk. If you look at all of the other end points in that study, we see that certain cardiovascular events were increased, such as strokes, coronary heart disease, and pulmonary embolisms were increased. Some other end points such as colon cancer, hip fractures, were decreased, but overall the death rate and the global benefit index were not different. So in some areas there was improvement and in some areas there was actually a worse outcome, indicating that in the end, the global benefit was close to one. So at this time it still remains an individual decision whether a high risk woman should do hormone replacement therapy for post menopausal symptoms or not and it requires a very careful discussion and informed decision making with the patient.
I also had mentioned that certain premalignant or benign breast lesions increased subsequent breast cancer risk. For example, women with a history of previous ductal carcinoma in situ or lobular carcinoma in situ or atypical hyperplasia have a higher risk of developing breast cancer subsequently. The risk ranges anywhere from two-to-fourfold. So if a woman comes in with a history of ADH maybe 10 years ago and it was excised, we can tell the patient that her subsequent breast cancer risk is at least fourfold increased and appropriate risk management options can be discussed. Another category is having a personal and/or family history of breast cancer.
We again know that when women develop breast cancer their subsequent breast cancer risk to develop breast cancer, for example, in the opposite breast-a second primary-is about .521 percent per year. So if we are dealing with a young, for example, 30 year old woman with stage I left breast cancer, her risk to develop a new primary in the opposite breast is .521% per year. So with a life expectancy of 75 to 80 years, her risk-subsequent risk-of new primaries would range anywhere between 25 to 50%. Certainly this woman, even if she's cured from her stage I breast cancer, is at increased risk for opposite breast cancer.
We know from studies that individuals who have first degree relatives with breast cancer are at higher risk. For example, if an individual comes in with a family history of breast cancer-for example in two first degree relatives, we can say that that person's breast cancer risk is about 20 to 30%. Now we can better quantify that risk if we know if that individual has a deleterious mutation in the BRCA1 or BRCA2 gene. The lifelong risk of breast cancer ranges from 50 to 80% in those individuals. And this chart summarizes what we just talked about. As you can see, early menarche, late menopause, late age at first birth or nulliparity, and hormone replacement therapy all increase breast cancer risk maybe anywhere between one-and-a-half to twofold. Then the next higher risk category are individuals with benign lesions such as ductal carcinoma in situ and atypical hyperplasia. But as you can see, the highest risk is actually indeed in individuals who have a mutation, a deleterious mutation in the BRCA1 or BRCA2 gene, and they have up to tenfold increased risk of breast cancer.
Now luckily not all of the breast cancers are hereditary. It's actually only 5 to 10% of breast cancers that are due to germ line mutations and out of these, about 85% are due to mutations in BRCA1 or BRCA2 genes. And then the remaining 10 to 15% of hereditary cancers are due to mutations in the P53 gene, such as in the Li-Fraumeni syndrome, in the PTEN gene such as in Cowden syndrome, and the ATM gene. If we have an individual with a known BRCA1 or 2 mutation, we definitely can tell the patient that her lifelong risk for developing breast cancer is up to 80%-let's say an eight-to-tenfold increased risk. But we can also tell this individual that even at earlier ages, for example by age 40, her risk is already anywhere between 10 to 20% compared to .5% population risk. That's a dramatic, more definitely tenfold increased risk, so younger women are especially at higher risk if they have a BRCA1 or BRCA2 deleterious mutation.
We also counsel our patients regarding the risk of other cancers if they carry a deleterious mutation in the BRCA1 or 2 gene. For example, ovarian cancer risk is increased in these women as well. There's a tenfold increased risk of developing ovarian cancer with a lifetime risk of 16%. As in sporadic breast cancer (the non-genetics), the risk of a second new primary in the opposite breast is also increased in women with BRCA mutations. The lifelong risk is up to 64% by age 70 in mutation carriers, and that leads to the discussion, which we will be discussing later, to preventive contralateral surgeries or mastectomies in women with the BRCA mutations who already have one breast cancer.
To continue with a risk of other cancers in mutation carriers, we also tell our patients that males who also carry the mutation are at increased risk for some cancers, for example male breast cancer. Even though the incidence is low, it's still higher than the average population-about 6% lifetime risk by age 70. We also tell them that their prostate cancer risk is increased by anywhere between three-to-sevenfold and that the prostate cancer onset might be actually a decade earlier, so earlier screening is recommended to males who have a BRCA mutation.
There is not that much data out there in regards to pancreatic cancer, however we see more and more individuals with pancreatic cancer in BRCA families, and it is thought that the increased risk is about three-to- fourfold. And then there are also associations with melanoma and other GI cancers in BRCA families.
So who are the appropriate individuals for genetic testing? Is any person who perceives her risk as high and comes into our clinic appropriate for genetic counseling and testing? So there are some practical, clinical red flags here we consider when we see a patient and evaluate for genetic counseling and then testing. For example an individual with a personal history of breast cancer before age 50 could be considered for genetic counseling if there is also a significant family history. So if that individual has several other family members with early-onset breast cancer or ovarian cancer, that's significant. However if this person has multiple, healthy, female relatives who lived up to ages 70 and 80, most probably there is no hereditary form of cancer in their family and maybe this person is not a great candidate for genetic counseling and testing. However, as I mentioned, if it's a family with multiple cases of early onset breast cancer, that is significant. If it's a family with ovarian cancer and breast cancer, that's also a significant family. And if there's breast and ovarian cancer in the same person, the likelihood of finding a mutation in that person, a deleterious mutation in the BRCA1 or 2 gene, is actually up to 80%. It's pretty high. We also know that individuals who have bilateral breast cancer, and especially if one of the cancers occurred at early age, is a risk factor and should be alerting.
We know that certain mutations are seen as a higher prevalence in certain ethnic background individuals such as Ashkenazi Jewish, so again breast cancer in Ashkenazi Jewish background is also indication to look at the family closer and consider genetic counseling and testing. And as I mentioned in the previous slide, male breast cancer incidence or risk is higher in these families. If we are dealing with a male breast cancer patient we also should look at the family a little bit closer and think about genetic counseling and testing.
So just as an example, let's say this 40 year old unaffected individual comes in and is concerned about her family history because her sister, one of her sisters was diagnosed with breast cancer at age 37, another sister at age 42 and then a healthy mother and father-but father's mother diagnosed with ovarian cancer. So obviously that's a very suspicious family history. But we would tell the patient-this unaffected individual-what really makes sense and the appropriate person for testing should be the youngest affected person in the family. We like to always start with the affected person in the family if possible and would offer genetic testing to this individual. And let's say we test this patient and her results come back as having a deleterious mutation, the BRCA1 gene. Then we can start offering predictive testing to these individuals because now we have identified a specific mutation in the BRCA1 gene and we can test for that specific mutation in these individuals and that is called predictive testing.
And let's say this unaffected individual has the same mutation. So what are the options we can discuss in terms of risk and risk management for this patient? So again we discussed with this unaffected person surveillance options, preventive mastectomy and oophorectomy options, and prevention with drugs. In terms of surveillance, several studies have shown that adding an MRI to a mammogram might yield a better result in detecting cancers. Some studies- earlier studies-have shown that breast cancers in mutation carriers, when they are followed up with mammograms, are not detected well enough, and that actually half of the cancers that are detected are interval cancers. They are detected in between mammograms. So therefore, studies have looked at adding a more sensitive way, looking at MRI's but also maybe doing screening every six months.
So these are some of the studies which looked at high risk individuals and this last study by Warner et al, looked actually at 236 patients who had a known genetic mutation and they compared yearly mammogram to MRI to yearly ultrasound, with every six months clinical breast exams. And they concluded that MRI was more sensitive and that's the conclusion of most of the studies, actually. And based on these and some other studies, the American Cancer Society guidelines were revised in March of 2007 and now these guidelines recommend MRI screening for individuals with the BRCA1, P53, or PTEN mutations, or untested first degree relatives.
So if you have a woman whose sister is a known mutation carrier, then the sister can undergo MRI breast screening in addition to mammogram until she's tested and until it's proven that she does not have the gene. And also there's another category where we can offer MRI screening in addition to mammogram: individuals who have a lifelong breast cancer risk greater than 20%. However, that risk needs to be calculated not simply on the Gail model but more on models that are heavily based on family history, such as the Claus model or the Parmigiani model.
The second option after screening that we discuss with our patients is prophylactic surgeries. So prospective studies have shown that mastectomy appears to be effective in reducing the risk of breast cancer by more than 90% in BRCA mutation carriers-so the risk reduction rate again is more than 90%. These prospective studies have also shown that, especially if done in premenopausal women, doing bilateral oophorectomy - removing the source of estrogen can reduce breast cancer risk by 53%. Again these patients also get another benefit out of undergoing oophorectomy because as we discussed, they have a higher risk of developing ovarian cancer. So ovarian cancer risk is also decreased by more than 95%, and by removing the ovaries, breast cancer risk is also reduced by more than 50%. And we share this data with our patients in helping them with decision making.
It is interesting to see how different patients, even though they have the same risk scenario, end up at different or complete opposite decisions. We might have a 40 year old woman who has a BRCA mutation who indicates that she definitely wants a mastectomy and we might have the same scenario in another woman where she says, "I never want to do a mastectomy". So we did a study looking at about 550 patients who've had genetic counseling at our institution and we wanted to see what affected the decision for mastectomies. And it turned out that having a BRCA positive mutation, or having a diagnosis of DCIS or invasive breast cancer, or having a family member with ovarian cancer was associated with risk reduction surgery- so individuals who had these characteristics were leaning more towards surgery than the individuals who did not have that. More women with advanced breast cancer or advanced ovarian cancer actually opted for surveillance, which make sense because if they have advanced breast cancer they really don't really worry about the new opposite breast cancer. They are more concentrated on treating their current problem, advanced breast cancer or ovarian cancer.
The third option we discuss with our patients after surveillance and risk reduction surgeries is chemo prevention. So in our high risk individuals, what drugs can we offer them that would reduce the risk of breast cancer? There have been a number of studies done in high risk women looking at the reduction of breast cancer incidence.
As you will see here, most of the studies were done with a selective estrogen receptor modulator, Tamoxifen, compared to placebo in four of these trials. The biggest trial is the NSABP-P1 trial which randomized 13,000 high risk women to five years of Tamoxifen or placebo, and at the end of five years it was shown that ER positive breast cancer incidence was reduced by 50%.
The second positive study is from the
After the two positive studies, especially the P1 study, another larger
prevention study was undertaken in the
So even though Raloxifene was a little bit safer when compared to Tamoxifen, compared to placebo (which is another acceptable option), obviously there were still thromboembolic events seen and still uterine cancer seen. However, and more importantly (and also a little concerning) was the fact that Raloxifene was about 35% less effective in reducing the incidence of premalignant or pre-invasive lesions such as DCIS, LCIS and ADH, and that barely missed statistical significance with a P value of .058.
And the reason why a number of women-about 70% in the U.S-do not want to take Tamoxifen or SERMS is that these women have otherwise no problems and are healthy and don't want to go through the potential side effects of this drug. Obviously it is concerning that pulmonary embolism risk is increased and endometrial cancer risk is increased by 2.5 fold and PE risk by threefold. I have to point out though that these risks are higher in the elderly population-in women about age 55. However in an otherwise healthy woman, these side effects might not be acceptable.
Then there are other, not threatening but unpleasant, side effects. Because Tamoxifen reduces or blocks estrogen, it can induce menopausal symptoms, hot flashes, fluid retention, muscle aches and pains and maybe cognitive alteration and cognitive functions, which again in an otherwise healthy woman is not acceptable. What we also saw in the P1 trial as well as the P2 trial is that even though Tamoxifen reduced the incidence by 50%, it did not touch the incidence or the development of ER negative breast cancer. So the benefit was only seen in the prevention of estrogen receptor positive breast cancer. So in other words, we don't have anything that can prevent estrogen receptor negative breast cancer.
Therefore, current research in this area is concentrating on the identification of new chemo-preventive agents that are also effective against estrogen receptor negative breast cancer development, that have a better toxicity profile. And maybe instead of running 10 year studies in 20,000 women, where the patients would take the drug for five years, it makes sense to maybe prescreen potential agents in short term prevention trials, and that's what we and many other investigators in this field are doing. Potential targets, besides targeting the estrogen receptor positive pathway, besides Tamoxifen and the aromatase inhibitors are for example, Cyclooxygenase-2 inhibitors, retinoids, tyrosine kinase inhibitors or the small molecule tyrosine kinase inhibitors and some other targets.
So now let's switch gears a little bit because I think this is important. We have discussed management, risk management, for this high risk unaffected person. We went over screening, preventive surgeries and chemo prevention and discussed Tamoxifen. So what do we tell the patient who has a BRCA mutation and who already has cancer? Obviously we cannot talk about prevention anymore because she already developed breast cancer, but it's still very important to first of all know the mutation because it might have some treatment implications.
As I mentioned, we want to test the person in the family with cancer first. It might affect the treatment. For example, if the patient has a BRCA1 mutation or 2, she might want to do instead of segmental, she might want to do bilateral mastectomies, one being for prevention. Because of the increased risk of ovarian cancer she might want to remove her ovaries, which will then maybe make her eligible for aromatase inhibitor therapy. As you know we don't use aromatase inhibitors for breast cancer treatment in premenopausal women. However if a 40 year old women undergoes bilateral oophorectomy she might become eligible to take aromatase inhibitors for adjuvant hormonal therapy.
Then very recently, for the first time ever, a new class of drugs has been developed, the PARP inhibitors, which target especially cells that have DNA repair problems and that is individuals or cells with BRCA1 and BRCA2 mutations. Some of these drugs are oral. Some of them are IV formulations and as you might have heard from the recent ASCO trials, these are now, or ASCO meetings, these agents have now been tested, either a single agent or in combination in triple negative but also BRCA1 or 2 positive breast cancer and actually also ovarian cancer patients, so these are very promising agents. So in the near future we might be actually offering genetic testing for patients with cancer, not for risk but to determine if they're eligible for certain targeted agents.
I would like to conclude by saying that high risk assessment and risk management requires multidisciplinary coordination in cancer centers. We are still working on refining the risk models to identify who the best individuals are to undergo genetic testing, or the ones who don't undergo genetic testing, what indications or what predictors are there to call that person a high risk person. We need to work on identification of safer agents that can also prevent estrogen receptor negative breast cancer and as I mentioned in the screening sections, we now add MRI to mammograms in really high risk individuals but we still don't know the frequency and we don't have long term outcomes and whether it improves survival if we do this approach. So with this I would like to conclude and thank you very much for your attention.
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