Hi, my name is Darcy Thull and I’m a Certified Genetic Counselor and so my role here at UPMC is to provide cancer risk assessment and genetic counseling for individuals and families who may have a hereditary predisposition. And so today I’d like to talk to you about cancer risk assessment and genetic counseling particularly with regard to hereditary breast and ovarian cancer.  I have no financial relationship to disclose and today the goals and objectives of my talk are for you to be able to identify features of a hereditary cancer predisposition, to be able to define autosomal dominant inheritance and reduced penetrance and to recognize the implications of genetic testing with regard to cancer risks for your patient and their families.

So the purpose of risk assessment and testing is to identify high risk individuals who may benefit from cancer prevention strategies that are either medical or surgical. And in these individuals we can also initiate heightened cancer screening and early detection programs in an attempt to find something at an early stage. Also when we identify a gene mutation in these families we can then offer up testing to other people in the family and identify average risk individuals who do not need to undergo heightened screening and who in whom have the general population cancer risk.

So when we think about cancer how much of it is actually inherited?  So this is a pie chart that we frequently use and you’ll see that the majority of cancer is sporadic or happens for reasons we don’t understand, about 30% of the time we have a familial situation where we may have a few members who have been diagnosed but not a clear inherited situation and in these families we are probably dealing with the combined effects of both genetics and environment. And really in the smallest portion of the families 10% of the time we have an inherited susceptibility where we have one gene that’s not functioning properly that’s really creating risk.  And so when we look specifically at breast and ovary cancer the majority of risk is conferred by mutations in these two genes, BRCA 1 and BRCA 2.  Some people call them BRCA 1 and 2.  BR simply stands for breast, CA for cancer, 1 and 2 is the order of discovery. And it’s important to know that we all have these BRCA genes and they have an important role in our body, and although they account for the majority of hereditary breast and ovarian cancer they don’t account for all of it. And so there are some families in which we may find a different genetic predisposition or we are unable to find the genetic predisposition at all.

So some of the other causes of hereditary breast and ovarian cancer with regard to breast cancer, we have Cowden’s Syndrome, also associated with thyroid and uterine cancer; Li-Fraumeni Syndrome, relatively rare may account for about 1% of hereditary breast cancer; also associated with sarcoma, brain tumors, adrenal cortical cancers and leukemias. There are some moderate risk genes like CHEK2 and PALB2, these are genes that testing is available for but at this point in time medical management with regard to identifying a gene mutation is questionable. So it’s not something that’s widely done.  We also know that with regard to ovarian cancer risk we can see higher rates with Lynch Syndrome, also associated with colon, endometrial and urinary tract cancers and Peutz-Jegher Syndrome, associated with colon cancer and also breast cancer.

These BRCA genes are tumor suppressor genes and so their role in our body is to maintain the genome. They are supposed to identify double stranded DNA damage and initiate the repair. We know that mutations in these genes in the general population are not very common and probably occur in somewhere between 1 in 300 to 1 in 500 individuals. We do need to know though that in individuals of Eastern European descent or Ashkenazi Jewish descent have a higher rate of mutations in these genes, and so in the Ashkenazi population we may find a mutation in about 1 in 40 people, which is about a 2 ½% risk. 

When there’s a mutation in BRCA it significantly increases the risk for breast cancer, and based on this graph you can see that that increase in risk accounts – occurs across all ages with lifetime risks for breast cancer that may be between 56 and 87%.  More recent data is suggesting that on average these families have about a 56% lifetime risk for breast cancer but in some families that risk may be as high as 87%.  And we need to compare that to the general population risk of about 12%.  These women also have significant risks for ovarian cancer, the risks do differ a little between BRCA 1 and 2 with the highest risk for BRCA 1 being 44% and with BRCA 2 being 27%.  Again a striking difference as compared to the general population risk of 1 ½% and clearly identifying a mutation would have implications for your patient’s medical management.  

We know that those women who have already been identified as having breast cancer and who carry a BRCA mutation they also have an increased risk for second cancers, so ovarian cancer following breast cancer and that that risk might be as high as 16%.  And then increased risk for breast cancer in the contralateral breast, and this risk may range somewhere between 50 and 60% in their lifetime; again, a very significant implication with regard to surgical management at the time of initial diagnosis, or with regard to screening moving forward.

We know that there are other associated cancers with BRCA mutations. Males do have some risk, they can have upwards of a 6% risk for breast cancer. There’s a higher risk for fallopian tube cancer in women, prostate cancer maybe a 20 to 30% in a lifetime in men, and that’s as compared to the 14 to 16% risk in the general population, and then also somewhat increased risks for pancreatic cancer and melanoma. You’ll see that associated with a number of these malignancies.  I’ve underlined one of the genes and that’s because BRCA 2 in this situation has a somewhat stronger correlation with those malignancies. 

When we think in terms of risk assessment what is the role of the genetic counselor?  So we are trained to obtain family histories or pedigrees and analyze that information and to discuss the benefits, limitations, possible results, implications of genetic testing, cost of genetic testing with patients and their family members. We also coordinate the testing, can interpret the results within the context of the family history which is really important and we’ll talk a little bit more about that in a few minutes, to disclose that information and then to educate the patient, family and physicians with regard to the implications of that information. When we take a family history and evaluate a pedigree we try to obtain information about first, second and third degree relatives. And so if you see here the circles represent females, the arrow is pointing to the individual who’s of interest, our patient, and all of the symbols have numbers inside them. And that’s because that tells you what the degree of relationship is so all of those number ones are first degree relatives, the number two are second degree relatives and you’ll see that we try to go out as far as first cousins.

When we obtain a pedigree we try to get the ages, current ages of all of the individuals, age of death, cause of death, whether or not individuals have been diagnosed with cancer and if so how old were they and where did that cancer start.  We do try to obtain medical records to confirm the cancer diagnoses and we do that because aside from breast cancer which is a relatively reliable report, cancers like stomach cancer or female cancer tend to get a little murky and to have the information about exactly what was diagnosed is  helpful with regard to our risk assessment. 

We do ask about both maternal and paternal sides of the family and we also get information about the healthy individuals in the family, those people who’ve not been diagnosed with cancer because they give us a balance and a better view of the whole family.  We also ask about exposures and with regard to breast cancer particularly has there been any radiation exposure to the neck or chest in childhood or in the teen years because we know that that does increase the risk for breast cancer.

We also need to know that sometimes family history is limited either due to a very small family or because our patient has been adopted and we don’t really have any information about the biologic relatives.  When we look at a family history the features that are concerning for hereditary predisposition to breast cancer are two or more cases of breast cancer prior to age 50 particularly across several generations of the same side of the family.  We look for people who are diagnosed with an epithelial type of ovarian cancer, women who’ve had both breasts and ovary cancer, women who’ve been diagnosed with breast cancer in both breasts prior to age 50 and more recently we  have realized that women who have what we call triple negative breast cancer have a higher chance to have a BRAC1 mutation.  And so triple negative breast cancer refers to breast cancer that’s estrogen progesterone negative and HER2/neu negative. We also talked about the fact that in the Ashkenazi population that there’s a higher rate of BRCA mutations.  Is there anything unusual in that family like a male with breast cancer that might raise our level of concern about a genetic predisposition?  And it’s important to ask if any other family members have already undergone genetic testing because it’s not that uncommon for us to encounter families in which we’ve already identified a gene mutation and simply need to place our hand on the copy of that  result so that we can know what to test for in our patient.

We’re also looking or an autosomal dominant pattern of inheritance.  So remember autosomal means that these are genes that are not sex-dependent.  Dominant meaning we need inherit only one copy of the nonfunctioning gene to have that increased cancer risk. And so if you look to the right here you see a little pictogram of an autosomal dominant inheritance in which the man carries the mutation represented by the little white square.  So each time this individual parent to child there’s a 50-50 chance for him to pass either the functioning copy of the gene or the nonfunctioning copy of the gene. Which means that each child has an independent 50-50 risk and that males and females can be equally likely to inherit that gene mutation.

So when we look at a pedigree of an autosomal dominant inheritance we see generation to generation type of pattern. So here we have all of these purple individuals have the mutation and have been diagnosed with an associated cancer. We see a man to man transmission and we also see that there’s incomplete penetrance meaning that not everyone who inherits that gene mutation will develop cancer and that’s because you inherit the predisposition to cancer not the cancer itself.  And so these individuals with the stripe through their symbol represent people who we know based on genetic testing to carry the gene mutation but in whom cancer has not developed.

When we think in terms of testing we want to make sure that our patient  has a reasonable likelihood of carrying a mutation. And so typically that means that we want to start the testing process in someone who’s actually had the cancer diagnosis because these gene mutations really account for such a small proportion of the cancers.  If we fail to find a mutation in that individual who has cancer then we’re less likely to find anything in their unaffected family members and testing may not be warranted in those other individuals. 

We also want to make sure that the patient is meeting some type of testing criteria and so there are a number of criteria that have been established.  We tend to use the NCCN criteria though there are others like the USPSTF criteria.  It may be relevant to know that your  patient meets some sort of criteria because a number of the health  insurers do follow these guidelines with regard to coverage.

And then other questions to ask is do we have a test step available that can be interpreted. Will the results impact medical management and does our patient want the information?  So that although we can identify these gene mutations and hereditary risks we’re not yet able to fix those gene mutations and so some people may not want to have that information.

A frequent question is with regard to genetic discrimination and so I think it’s important to know that there are laws in place to help prevent this from happening.  There are a number of states who have enacted non-discrimination legislation and those laws vary from state to state. On a federal level we have HIPAA which does provide some protections with regard to group health insurance and the Americans with Disabilities Act provides protection against employment discrimination. More recently we have GINA which is a federal law that makes it illegal for employers to use genetic information with regard to hiring and/or health insurability.  And so there are a number of laws in place to help protect against genetic discrimination.

I think it’s also important to note that as of date we don’t really have any liability cases that we can identify relating specifically to genetic discrimination. We also are asked frequently is genetic testing covered by health insurance and in general it is, there are some exceptions, some of the Medicaid policies do not cover, some of the self-insured groups do not cover, the level of coverage is really dependent upon the policy and some of the insurers actually have specific eligibility criteria.   NCCN guidelines are followed by Medicare and also a number of other insurers. 

Genetic testing right now for comprehensive genetic testing at Myriad Genetics who have the patent on the test, it costs over 3000 dollars and that comprehensive testing picks up about 85%  of the mutations in the genes.  More recently, additional testing has been added to look at BRACA1/2 for large rearrangements, that’s called BART. And that testing is not automatically done in all situations when you order comprehensive testing so it’s important to know that that may be something in addition that you need to order. 

And then you’ll see the first test listed is the Multisite 3, that’s testing that’s specific to the Jewish  population because we know there are specific mutations that account for the majority of the hereditary risk. Also I mentioned once we identify a mutation in a family, we can do what we call single site testing in other family members which evaluates for the specific mutation that was found in that family and really narrows down the testing and helps reduce cost.

So now we’re going to talk a little bit about why we need to know the whole family history because it does help us with our overall assessment and result interpretation.  So we can have two women  who report the same history but in who the risk for having a hereditary predisposition is very different. So in this scenario we have two women who are diagnosed with breast cancer at age 48 and who report having a maternal aunt with an early-onset breast cancer.  So when we look at the first pedigree we see that our patient with the arrow down here at the bottom was diagnosed with breast cancer at 48 and her maternal family is actually quite large with many women who do not have breast cancer and we see the report of the breast cancer in the maternal aunt.  So in this family although we have two women diagnosed with breast cancer before age 50, we have many women who have not been diagnosed with breast cancer and when we look at this family as a whole we’re less likely to believe that it’s due to an inherited predisposition.  And in all reality the risk to carry a mutation in this family is about 1%.  Whereas when we look at this family, same scenario, patient and maternal aunt with breast cancer at a young age, we see a different story.  The patient’s mom never had breast cancer but she did have her ovaries removed at a young age which would reduce her risk for ovary cancer and also reduce her risk for breast cancer.  And then if we go up another generation we see that through the maternal grandfather we  have a woman who had young breast cancer and another who had ovary cancer.  So in this family we have a hereditary predisposition to breast and  ovary cancer.  We have three generations of women, all related through the same blood line with early onset breast cancer and/or ovarian cancer and the risk for a mutation in this family is about 50%.

When we do testing there are actually three possible outcomes.  We can get a positive result in which we found a mutation and we know that this individual and family has a hereditary predisposition  that’s been identified.  We can offer testing to other family members and we know they have an increased risk to develop cancer.  In this situation we would follow published guidelines for management, again NCCN.  In the second scenario we can fail to find a mutation and so we need to recognize that our genetic tests do not pick up 100% of the mutations and therefore we have ruled out the majority of the chance that this person has a predisposition to breast and  ovary cancer as a result of the BRCA mutation, but we can’t exclude that possibility. And so we need to manage that individual on her medical history and her family history. 

And then the last result that we could possibly get which happens about 3 to 5% of the time in the Caucasian population is a variant of uncertain significance which simply means that we found a very subtle change in the DNA and we have insufficient evidence to determine whether or not it’s harmful or benign.  The majority of these will ultimately be determined to be benign but that may take quite some time, years in fact, before we get that updated information. And so we need to follow these families based on their family history.  And the medical management should follow along that line. 

So in this scenario both of our women undergo testing and we failed to find a mutation in either of them. But I think that it’s important to realize that these have different implications. So in this first case where we have these many women in this family who are unaffected, this is actually a very reassuring result.  We ruled out the majority of the chance that this patient has a single gene predisposition to breast or ovary cancer.  It means that other women in the family are unlikely to benefit from BRCA testing and in all actuality we may be dealing with a sporadic or at most a familial predisposition. So we need to realize that other women in the family are at somewhat higher risk to develop breast cancer but not to the same degree as if we were to find a mutation.  And so those women do need to follow screening based on the American Cancer Society guidelines. 

In this scenario if we fail to find a mutation we’re really not reassured, we still have these three generations of women, we have multiple cases of young breast cancer and ovary cancer and this family history is consistent with a  hereditary predisposition and therefore this family and this  patient should be followed based on current guidelines for hereditary breast and ovarian cancer and screening and management should follow NCCN. 

And so when you’re thinking of terms of risk assessment and counseling and testing there are genetic counselors all over the country that can help you so if you’d like to refer to a cancer genetic counselor and need to find one in your area, you simply go to the National Society of  Genetic Counselors, put in your zip code and find a cancer counselor and you’ll be able to find one within your area. 

So I hope that we were able to convey some information to you to help you identify hereditary breast and ovarian cancer families to understand implications of genetic testing and how these genes are passed in an autosomal dominant manner.  Thank you.