So how much of breast and ovarian cancer is hereditary? A). 5 to 10 percent. B). 20 to 30 percent. C). 50 percent. Or D). 65 to 70 percent.

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1 Welcome. My name is Amanda Brandt. I am one of the Cancer Genetic Counselors at the University of Texas MD Anderson Cancer Center. Today, we are going to be discussing how to identify patients at high risk for hereditary breast and ovarian cancer syndrome. Up --- Upon completing this module, you ll be able to understand the importance of family history; be able to differentiate between hereditary versus sporadic cancer; increase the knowledge of BRCA1 and BRCA2 genes and its associated cancer risks; and how to identify appropriate testing candidates for BRCA1 and BRCA2. First, I want to go over a little bit of a pedigree nomenclature. So a pedigree is what we draw when we meet with a family and it helps us to draw both a maternal and paternal sides of the family and easily identify who s had cancer, who has not had cancer, and how old people are in their family, or how old they were when they are deceased. So to give you a little idea so you can follow through during this presentation, we wanted to give you a little bit of a key. So when you re looking at the family histories, you will see a square will represent a male, a circle will represent a female. Anyone who is shaded in will show that they ve been affected with cancer. Someone who has a line through them are a deceased individual. The person who has the arrow pointing to them is considered the proband: this is the person in the family who presented first for genetic counseling. Someone who s connected to another individual shows that they are a mating. You can see siblings are attached at the very top of their symbol. Anyone who is adopted will have brackets around their symbol. If we don t know the gender, we will just use a diamond, and the dx that we have in the --- in the pedigrees just let us know they ve been diagnosed. And so that, in following the dx, you will indicate whether it was breast cancer or ovarian cancer so that you are able to follow through the pedigree. We also want to go over a little bit about who is related to everybody. So a first degree relative includes your parents, your siblings, and your children. A second degree relative are your grandparents, your aunts and your uncles, and your nieces and your nephews. Your third degree relatives are your cousins, your great-aunts, your greatuncles, and your great-grandparents. And this will come into play when you re considering what the risk is for your patient to have hereditary cancer syndrome, depending on what degree of relationship that person in that family might have had cancer. When you re recording the family history, what we do for each family member, we re going to specify their gender, if they re living, what year are --- were they born or old are they today. If they re deceased, we will record how old they were when they passed away and what was their cause of death. We ll ask about any medical problems that that individual might have, particularly pertaining to cancer, and we ll ask about if there s been any prophylactic surgery. So did someone undergo a total hysterectomy and bilateral salpingo-oophorectomy? And then, reducing their ovarian cancer risk would be important information to capture. And whenever it is possible, it is ideal to be able to ob

2 --- obtain the medical documentation confirming the cancer diagnoses so that we re really aware of the cancer that we re diagnosing in that family and can confirm that with absolute. For each family member with cancer, we are going to ask that you specify what type of cancer the patient was diagnosed with, how old were they when they were diagnosed, did they have more than one cancer? So did someone have breast and ovarian cancer? Or did someone have breast and brain cancer? And when you ask a little bit more questions, you ll realize that the brain cancer is really a metastasis from the breast cancer, and we want to be able to differentiate that. We ll also ask about any lifestyle factors. So smoking, obesity, occupational hazards which may be a risk factor for the cancer that that patient might have developed. For example, if someone had lung cancer, were they a smoker and which would have placed them at risk for that cancer? It is really important to gather an accurate family history, and we really rely on this the most in cancer genetic counseling. It enables the health care provider to accurately perform a risk assessment regarding the likelihood of a hereditary cancer syndrome in the family. You might ident --- identify other cancer risks. So maybe they just have breast cancer in the family at this point but if you identify if they re at high risk for breast and ovarian cancer. You are going to manage those people much differently. You re going to recommend appropriate cancer risk management based on what that family history is telling and showing you, and it allows you to accurately interpret the genetic test results and make the best recommendations for the family. So making sure that the family history is accurate and has all the pertinent information in there is really going to help you in this risk assessment. So how much of breast and ovarian cancer is hereditary? A). 5 to 10 percent. B). 20 to 30 percent. C). 50 percent. Or D). 65 to 70 percent. So 5 to 10 percent of breast cancer is inherited. In those family histories we will tend to see particular patterns including early onset breast cancers, usually diagnosed premenopausally. You ll see individuals diagnosed with more than one type of cancer, and you ll see multiple generations affected. About 15 to 20 percent of breast cancer is considered familial. In those family histories, you ll see more than two individuals diagnosed with breast cancer. But they ll tend to be later ages of onset, more representative of the general population ages of onset. And there won t be a clear pattern of inheritance. So you might see a great-aunt diagnosed with breast cancer in her seventies, and maybe your patient was diagnosed with breast cancer in her sixties, but there s nobody else in the family diagnosed. It may just be a familial component leading to the breast cancers that we are seeing. Seventy to 80 percent of breast cancers are not inherited. They re considered sporadic. Basically, they re just happening by chance and chance alone. And it really composes the most of the breast cancer that we see diagnosed each year. So ovarian cancer, about 10 to 15 percent of ovarian cancer is inherited, particularly if it s a high-grade serous-type ovarian cancer. You ll see those same similar patterns in

3 the family history. Otherwise, about 85 to 90 percent of ovarian cancer is considered sporadic, hopening --- happening purely by chance, and happening at the general age of onset in the mid sixties. So to quickly compare a family history that might have a sporadic cancer versus a hereditary cancer pattern, we re going to talk about this here. So you can see in this sporadic family history, you have a patient who s been diagnosed with breast cancer at the age of 60, but nobody else in her family, either on her maternal or paternal side of the family have a history of cancer. For this patient, we would tell them she has a sporadic cause to her breast cancer. And her family members would not be at a significantly increased risk to develop this cancer. If we compare that to the hereditary family history that we have, we see that a grandmother was diagnosed with breast cancer at the age of 42 and is now deceased. She had a daughter who was diagnosed with breast cancer at the age of 47. And this individual had a daughter who was diagnosed with ovarian cancer at 50 and a daughter with breast cancer at 45. What we re tending to see in these families are multiple generations affected. We see the grandparents, parents, and the grandparents --- [speaker intended to say grandchildren] affected. We see early ages of onset, so cancer diagnosed before the age of 50. And all of these patterns make us concerned about family history is due to something inherited from the maternal side of the family. Some of the red flags for hereditary breast and ovarian cancer when you re reviewing a patient s medical and family history include premenopausal or early onset breast cancer, usually diagnosed under the age of 50. If you re seeing many relatives with breast and/or ovarian cancer on the same side of the family; both breast and ovarian cancer diagnosed in the same person. A woman who has bilateral breast cancer; even men who can diagnose with breast cancer be concerning that it might be hereditary. Is there a known BRCA mutation identified in a family member or is anyone of Ashkenazi Jewish ancestry, particularly pertaining to the central or eastern Euro --- European geography? So who are you going to refer and who are we testing? So, there are many professional guidelines out there that ll help you identify who s at risk and who s really the appropriate person to test, given a person s personal or family history of breast and ovarian cancer. These include, but are not limited to, the National Comprehensive Cancer Network, or the NCCN. We ve listed the website here so you can go and read a little bit more. It ll also be included in the appendix which we will review at the very end. And these review who should be referred for genetic counseling and risk assessment and who should be tested for hereditary breast and ovarian cancer. You might also check out the American Society of Clinical Oncology, or ASCO, as well as the American Congress of Obstetricians and Gynecologists, or ACOG. So when we re thinking about hereditary breast and ovarian cancer, the two genes that are most normally associated as a cause are BRCA1 and BRCA2. They really are responsible for the majority of hereditary breast and ovarian cancer that we will see. These are large tumor suppressor genes that are likely revolved --- involved in DNA

4 repair. So we want these genes to be working properly so that the repair of the DNA can be performed. But, if there is a problem or a mutation in either of these genes, they no longer can suppress cancer, which is why we see very high risk of cancers in these families when these mutations are inherited. About one in 500 to one in 800 individuals in the general population are estimated to have a BRCA1 or BRCA2 mutation. Individuals who are Ashkenazi Jewish actually have a higher chance of having a mutation, with that being one in 40 individuals. And they actually have one of three common Jewish mutations that are listed here, 185delAG, 5382 insertion C, and 6174 deletion T. These are the three common mutations that you will test a Jewish person for, if they have hereditary breast and ovarian cancer. So how are these mutations inherited? So if a parent has a mutation, and this is highlighted here in the small m that s the color red, they have a 50% chance to pass that mutation onto a child and an equal 50 percent chance to pass on the normal copy of the gene, and this one is designated with the capital M in black. And it --- it can equally be inherited from either a mother or a father and passed onto a son or to a daughter. So once again, it s a 50 percent chance that if a parent has the mutation that they have a chance of passing that on to a child. What is the breast cancer risk associated with a BRCA mutation? A). Up to 25 percent. B). Up to 55 percent. C). Up to 85 percent. Or D). Up to 100 percent. The answer is C) Up to 85 percent. Here, I m going to review the cancer risk and BRCA1 mutation carriers. In the green, we ll show you the individuals who have a mutation, the risk for primary breast cancer is between 60 and 85 percent chance over that woman s lifetime, and that s compared to about a 12 percent risk in the general population. Below that you ll see that there s a secondary primary breast cancer risk that a woman might have, and that is up to a 40 to 60 percent chance to develop breast cancer, and that s compared to about a 5 percent chance in the general population. A woman also has an increased chance to develop ovarian cancer up to 45 percent chance over her lifetime, compared to about a one and a half percent chance in the general population. There are some other cancer risks associated with a BRCA mutation. For men, they would have an increased chance for male breast cancer. There s a slightly increased risk for prostate cancer. And we can see and reported in the literature, a slightly increased risk of pancreatic cancer above that of the general population. But, the associations with BRCA1 are a little bit less clear. In individuals who carry a BRCA2 mutation, the risk for a primary breast cancer would be similar, about a 60 to 85 percent chance to develop breast cancer, compared to about a 12 percent risk in the general population. They would have between a 40 and 60 percent chance to develop a secondary breast cancer, compared to about a 5 percent risk in the general population. Women who have a BRCA2 mutation actually have a little bit lower risk of ovarian cancer compared to BRCA1, with that risk being up to 27 percent chance in their lifetime, compared to about a one and a half percent

5 chance in the general population. Male breast cancer risk is a little bit more clear here. It s up to a 6 percent chance. The prostate cancer risk for men would be up to 20 percent, compared to a 16 percent chance in the general population. And we know the pancreas cancer risk is elevated above that of the general population with a little bit more certainty than we knew for BRCA1, and that s up to about a 7 to 8 percent risk. In the literature there have been various other cancers that have been reportedly associated with BRCA1 and BRCA2. These include melanoma, colon cancer, larynx cancer, esophageal cancer, and gastric cancer. However, the clear associations and the accurate risk assessment and the risk number is not very clearly associated with either of these mutations. So we do not screen closely for individuals who have BRCA1 or BRCA2 mutations for these cancers. If there s a family history, we might recommend different screening based on that alone. So over time, these risks will gradually increase, and that s what we show here comparing BRCA1 and BRCA2 mutation carriers. This is a cumulative risk for them to develop breast cancer, which will be the green line, and ovarian cancer, which will be the blue line. So if you can kind of look, in a woman who s 30 years old, her risk to develop either breast or ovarian cancer is close to about 0 percent. But, you can see over her lifetime that number dramatically increases over her lifetime. And that s why we start screening at much younger ages so that we re capturing these cancers at their earliest ages of onset, because we tend to see that they re diagnosed at young ages. So there re some various discrepancies in terms of the actual risk associated with a BRCA1 and BRCA2 mutation in the literature. And this may be attributed to the ascertainment of the study population. In the initial study, some of these families were picked up based on their very strong family histories of cancers. You know, they might ve had multiple women in the family with very young breast cancer that it s hard to ignore there was something hereditary there. So the risks in those studies are probably higher because you are ascertaining families that have a higher chance to develop those cancers with as many people as you re seeing in those families. Compared to a population-based study where we re testing all comers who present to the study with breast cancer or ovarian cancer, and testing everybody. That s going to give you a little bit better and accurate number in terms of the risk. Because you re testing everyone, whether it s a more lower penetrant type of mutation and --- in the families where they have a little bit lesser cancer risk potentially, and so, that s why we give you a range of breast cancer risk, anywhere from 45 to 85 percent, because it s depending on which study you re looking at and what population they were testing. The ovarian cancer risk might range from 30 to 45 percent for a BRCA1 carrier and 10 to 27 percent for BRCA2, depending on which study you re looking at. Over time, we ve really noticed that there re particular pathology and histology trends of hereditary breast cancer and first, we ll discuss BRCA1. So these breast cancers tend to be hormone receptor negative. So ER/PR will be negative, and they will also be HER2 negative. So it s something that we look and evaluate for in the pathology when we re assessing a family history for hereditary breast and ovarian cancer. And we look

6 closely at the pathology to give us a little bit more information. We tend to see increased frequency of medullary breast carcinomas. These cancers tend to be high grade. And you can also observe ductal carcinoma in situ, or DCIS, as well as ductal and lobular carcinomas that are invasive. And so, making sure that you re testing the patients even though they have DCIS, is something to be aware of. In BRCA2 carriers, their breast cancers tend to be hormone receptor positive, so ER and PR positive. They are still going to be high grade. And you will also observe ductal carcinoma in situ as well as ductal and lobular invasive carcinomas. For ovarian cancers that are hereditary associated with BRCA1 and BRCA2, you will most frequently see serous type carcinoma, composing about 63 to 93 percent of patients, followed by endometrioid type ovarian cancer. It s associated with a high grade and stage. Oftentimes, patients are diagnosed at Stage III or Stage IV of their disease. And overall prognosis may be better for women who have BRCA mutation and ovarian cancer compared to sporadic ovarian cancers. They tend to have longer survival and longer times between recurrences, compared to sporadic carriers with ovarian cancer. Non-epithelial ovarian cancers have no known association with BRCA1 or BRCA2 mutations and should be considered when you re performing the risk assessment when you have the patient in front of you. If she has a non-epithelial cancer, you can reassure her that she is not at risk for a BRCA mutation. And BRCA1 and BRCA2 mutations are quite rare in borderline or low malignant potential, otherwise called LMP ovarian tumors and mucinous type ovarian cancers, which should also be, you know, considered when you re reviewing the pathology of your patient with ovarian cancer and considering whether or not to do genetic testing. So here we have a pedigree for you. So who in this family should be tested first? Your patient with the arrow is 24 years old with no history of cancer. But, she reports that her mother was diagnosed with ovarian cancer at the age of 48. Her grandmother was diagnosed with breast cancer at the age of 49 and is now deceased. Her aunt was diagnosed with breast cancer at the age of 37 and is now deceased. And her cousin was diagnosed with breast cancer at the age of 33. So clearly, this is a family that would be highly concerning for hereditary breast and ovarian cancer. But let s decide who should we test? Should it be A your proband, your patient who is 24 years old with no cancer history? Is it B the mother, 49 years old, diagnosed with ovarian cancer at age 48? Or C the maternal cousin who is 33 years old, diagnosed with breast cancer age 33? In this family, the ideal testing candidate would be the mother of your patient diagnosed with ovarian cancer at 48. This is because the most informative person to do genetic testing on is someone who has been diagnosed with cancer themselves, so, either breast or ovarian cancer. In that pedigree the mother is the ideal testing candidate because she s the most closely related to your patient, the 24-year-old unaffected woman. But, she s also been diagnosed with ovarian cancer and --- and really particularly at a younger age than we

7 tend to see in the general population. If we test that mother and we find that she has a mutation in BRCA1 and BRCA2, we can clearly see that there is hereditary cancer in the family and it better allows us to test other at-risk family members. If, let s say, we test the person who has cancer and she is negative, we really are not going to know what to do very much in that family because we ve tested the ideal --- ideal testing candidate and she does not have a hereditary form of breast and ovarian cancer due to the BRCA1 or BRCA2 genes. And in that scenario, we would not test the unaffected woman because we would anticipate that her testing would also be negative if her mother s was negative. So a negative test result in someone without cancer. So if we had tested the 24-year-old woman before testing anybody else, maybe it can offer a false reassurance, and it does not entirely rule out hereditary cancer in the family. You might have just tested the wrong person and so, this is really why it s key when you re meeting with families and meeting with patients that you re testing the most appropriate candidate in the family, and those are going to be the individuals who have cancer themselves. So, in summary, the majority of cancer is not inherited. Approximately 10% of breast and ovarian cancers are the result of mutations in BRCA1 and BRCA2. There are various red flags that you can use to help identify individuals and families at risk for hereditary breast and ovarian cancer, and there re multiple guidelines and recommendations regarding who is appropriate to perform genetic testing. The family history is an important tool in the genetic risk assessment and providing accurate risk assessment, risk management strategies, and interpring --- interpreting the genetic test results. Making sure that you re gathering a family history and always updating it on an annual basis is probably the best strategy because we know that these family histories change over time and you want to make sure that your risk assessment and how you re screening these family members isn t going to change over time. You want to make sure you re appropriately identifying the ideal testing candidate in the family, and it enables you to have a more accurate interpretation of a genetic test result and --- and be able to identify who else in the family might also be at risk for hereditary breast and ovarian cancer. Here, in the Appendix, is the National Comprehensive Cancer Network Referral Guidelines for who should be considered for hereditary breast and ovarian cancer syndrome testing. And I have them here for your reference. So you can take some time now and review those particular individuals who we would at --- identify as someone who might be high risk and should consider genetic counseling and testing. And they re going to continue here on the second page. And so, if any of your patients or your family members of patients fall into any or meet any of these criteria, it might be something that would be appropriate for them to be counseled, perform a risk assessment, and possible genetic testing. So I thank you for listening today to our talk

8 about hereditary breast and ovarian cancer and identifying individuals who are at high risk, and I welcome any of your feedback.

So, now, that we have reviewed some basics of cancer genetics I will provide an overview of some common syndromes.

So, now, that we have reviewed some basics of cancer genetics I will provide an overview of some common syndromes. Hello. My name is Maureen Mork and I m a Certified Genetic Counselor in the Clinical Cancer Genetics Program at The University of Texas MD Anderson Cancer Center. I ll be lecturing today on the Cancer