Anna Villa, MS, CGC, and Kristin Wiley, MS, CGC, Comprehensive Cancer Center at Wake Forest Baptist Medical Center, provide an overview of indications for genetic risk assessment. They also discuss high-risk hereditary cancer syndromes, hereditary cancer panel update and the current state of insurance coverage.
Submit a question to Anna Villa and Kristin Wiley ANNA VILLA: I'm Anna Villa. And I'm a genetic counselor at Wake Forest Cancer Center. And today, I'm going to be working with Kristin Wiley to talk with you all about hereditary breast cancer syndromes, and our use of hereditary cancer panels to assess men and women who are at risk for hereditary cancer syndromes. So as an overview, I wanted to talk about some of the indications for a further genetic risk evaluation, and how those differ from that of actual genetic testing. Then we'll go over the components of a genetic risk assessment, discuss some high risk hereditary cancer syndromes. And then Kristin will take over to talk about hereditary cancer panels, the current state of insurance coverage, and then give some final thoughts and resources. So any genetic counseling session that focuses on hereditary cancer syndromes will include the statement that most cancer is not hereditary. In fact, only about five to 10% of cancers are. And that's true of cancers as a whole, and breast cancer specifically. So then the question becomes, because this is such a fairly small percentage of patients who are truly at risk for a hereditary cancer syndrome, how do we identify those people who should get further risk assessment? And the answer to that is we consider their personal and family history of cancers. So the American College of Medical Genetics and the National Comprehensive Cancer Network have published guidelines for when to consider further genetic risk evaluation for your patients. They're pretty similar to one another. And you can see ACMG's guidelines here. It might be hard to read, but just know that they exist. They can be found on their website. But both ACMG and NCCN are similar. They both consider age at diagnosis, the patient's ethnicity, tumor characteristics, and also the pattern of cancers in a patient's family. These are the NCCN criteria. These really just add one thing to ACMG criteria, which is it also includes people who have no personal history of cancer. So it says that if a person has no personal history of cancer but has a close relative that meets the criteria there on the left, then they can also be considered for further genetic risk evaluation. And again, these can be found on NCCN's website. So it's important-- oh, I've been using the term genetic risk evaluation. And I went to distinguish that from genetic testing. A genetic risk evaluation is really just a risk assessment that we do based on what we can observe in the patient's personal and family history. Then genetic testing is the actual analysis of the patient's genes. And it's important to distinguish between those two, because their criteria are different. So an example of this is a woman who is diagnosed with breast cancer prior to the age of 50. And that alone does not qualify her for genetic testing. Qualifies her for further risk evaluation, but not testing. In order to meet criteria for testing, she would have needed to have been diagnosed at or before the age of 45, have a triple negative tumor, be of a high risk ethnicity, or have additional family history suspicious for hereditary cancer syndrome. So this may be kind of-- might seem redundant. You may be asking, why have two different sets of criteria? And the answer to that is testing criteria are quite detailed and oftentimes complicated. And they're going to differ by cancer syndrome. So I've listed an example of criteria for just one hereditary cancer syndrome. It's hereditary breast and ovarian cancer. This syndrome is caused by mutations in just two genes, either BRCA1 or BRCA2. But we know that there are more genes that can cause a high risk for breast cancer. And each of those syndromes have their own complicated criteria that I'll tell you are usually more involved than what you see here. So the point of the guidelines for a genetic risk evaluation is to really provide a tool for health care professionals to quickly screen their patients. So it's going to cast a wide net, but it's going to let them quickly decide if their patient should be referred for further genetic risk evaluation, or if they're at a pretty low risk of having a hereditary cancer syndrome. So then that genetic risk evaluation is where we take a detailed history and figure out, is this patient truly appropriate for testing, or is there a very low risk that they actually have a syndrome? And during that genetic risk assessment, we take a detailed family history to distinguish those patients who might benefit from testing from those who it's probably not as appropriate. And the thorough family history includes the things you'll see listed here. So it's a three generation pedigree. It includes first, second, and third degree relatives to the patient and includes both maternal and paternal relatives. They're equally important in assessing a patient. We also want to know about all family members, not just those who have had cancer, or not just those who are living or deceased. We need to know about all of them. And we usually at least want to know their current ages or their age at death. For those family members who have had cancer, we need even more information. We need to know what age they were diagnosed. Sometimes we need the pathology of their cancer. We also want to know about their family member's ethnicity. And for those people who have had multiple cancers, we need to know if they were two truly, two separate primaries, or if they were perhaps cancers that had spread or recurred. So that's a lot of information that we need to get. And as you can imagine, that takes a long time. It's time consuming for both the patient and the provider taking it. And lots of times, it also requires a lot of extensive follow up. Because this information may not be available during that first meeting with the patient. But it's worth the time investment, because it allows us to do three really important things. The first is that it allows us to identify the most informative family member to test. That's not always the patient in front of us. We always want to test a family member who has a personal history of cancer, if at all possible. Secondly, it allows us to be sure that whatever testing we do order, it covers all of the genes that might be an explanation for the cancers we see in the patient's family. So it helps us to order the most comprehensive testing, and also the most appropriate testing for a patient. And finally, that family history allows us to know if the patient even meets NCCN criteria for testing. But it also helps us know if they meet their insurance company's criteria for testing. And that's actually a really important question that patients have for us, is my insurance at least going to help with the cost of this test? So to illustrate the importance of the family history, I wanted to share a case example. This example is a woman who is diagnosed with a new breast cancer at the age of 47. Her diagnosis alone does not qualify her for genetic testing, though it does for further risk assessment. So in-- her tumor was not triple negative. She wasn't of a high risk ethnicity. And she wasn't diagnosed at or before 45. So she needed some help from her family history. And at first glance, it doesn't look like there's much there to qualify her. But when we look closely, her paternal family history, it looks like it has a limited structure. And that's actually one of the many criteria set by NCCN. And also, a lot of insurance companies will include that in their criteria. And a limited family structure is defined as having fewer than two first or second degree female relatives living beyond the age of 45 in either lineage. So that's true of her paternal family history. Her grandmother is the only relative who lived beyond 45. Her paternal aunt passed away in her 30s from an unspecified form of cancer. So this patient gets genetic testing. And the results show a mutation in a gene called ATM. For those of you who aren't familiar, we haven't been testing ATM all that long for breast cancer risk. And the risk we associate with a lifetime breast cancer risk is about 17% to 52%. And that may seem like a big range. I agree. It is. But then we can refer back to the patient's family history to try to narrow that range. So for example, if she had a very large family and very few cancers, we might think she might be towards the lower end of that risk. If she has a lot of breast cancers in her family, she might be towards the higher end. So that's just the way the family history can also be helpful once testing is complete. And so even though testing was ultimately informative for us for her for her family members, I was surprised by the results for a few reasons. The first reason is that I think her family history really looked like she had a sporadic cancer. And statistically, that's the most likely result. And then the second reason is that of breast cancers that are due to an inherited predisposition, most occur, or at least half occur, due to two genes, BRCA1 and BRCA2. So you can see there, BRCA1 and BRCA2 account for about half of all inherited breast cancer syndromes, which means the other half are caused by mutations in other genes, such as ATM. But because BRCA1 and two are still the most likely candidates when we're testing a patient, thought we could start there with their risks and management. So in this table, we've compared the lifetime cancer risk for patients who have a BRCA mutation to those of the general population. And the breast cancer-related risks are highlighted in pink. But you can see there's risk for other types of cancers as well. But you can see the risk for a first breast cancer over a woman's lifetime if she has the mutation is between 40% and 80%. The risk for a second breast cancer within five years can be as high as 27%. And the risk for male breast cancer can be as high as 10%. So because we know that these risks are increased, we use that to help guide our management of these patients. And management can fall into three main categories. Those are surveillance, surgical options, and chemoprevention options. Again, I've highlighted the ones that apply to breast cancer in pink. So any woman who has a BRCA mutation can consider prophylactic bilateral mastectomy. If she chooses not to have that done, the NCCN recommends that she start annual breast MRIs at the age of 25, and continues those through at least the age of 75. Once she reaches the age of 30, it's recommended that she add an annual mammogram to her screening, and continue that through the age of 75. And then finally, these women can also consider use of chemoprevention options like tamoxifen to reduce their cancer risk. And though BRCA1 and two and hereditary breast and ovarian cancer syndrome are the most commonly mutated genes that you're going to see, there are other genes that increase cancer risk quite significantly. And they have a high risk of breast cancer, which is greater than 50% over a woman's lifetime. So those conditions are listed across the top there-- Li-Fraumeni Syndrome, Cowden Syndrome, Peutz-Jeghers Syndrome, hereditary diffuse gastric cancer. Each of those are caused by mutations in different genes, but they're managed pretty similarly to one another, and mostly reflect the management of BRCA1 and two mutation carriers. So for any woman who has any of these conditions, she could consider risk-reducing mastectomy. If she does not pursue that, it's generally recommended that she start increased breast cancer screenings through MRIs and mammograms-- excuse me, breathe-- MRIs and mammograms, usually between the ages of 20 and 30. Each of these conditions are also associated with other types of cancers, which we don't have time to address. But they're listed on the bottom row there. And a few important highlights I want to include are that people who have Li-Fraumeni Syndrome, it's recommended that they reduce their exposure to radiation whenever possible, because they've been shown to be at an increased sensitivity to ionizing radiation. So it increases the risk for a second malignancy. Also, for the breast cancers that are associated with hereditary disease gastric cancer, those tend to be of the lobular type. And so as you may have noticed from previous slides, a lot of these syndromes have overlap in their clinical presentation. I think that point is nicely illustrated by this image from Ambry Genetics. And because there's that overlap in clinical presentation, it had been a testing challenge for providers and genetic counselors in the past, because we used to test for each syndrome independently and in a stepwise manner. So it became a very long, drawn out, and expensive process. It was the emergence of hereditary cancer panels in the past few years that have really eliminated a lot of those issues. So they made testing more cost-effective and more efficient. It's done in a shorter amount of time. However, even though these panels seem like a great tool, they do have criticisms and limitations. And one of those limitations is really the lack of widely established guidelines for how to treat individuals who have mutations in some of these genes. So you can-- well, any hereditary cancer panel is going to include analysis of those high risk genes, like BRCA1 and two. And for those high risk genes, there are well-established guidelines for how to care for these patients and try to reduce their cancer risk. But the problem is a lot of these panels will also include some more moderate risk genes or newly described genes, for which cancer risk is not as well-defined. And what we should do to manage that risk has also not been well-established. So because of that complication, providers, when we're testing patients for some of these other genes, providers have to rely more on maybe the patient's family history or their professional experience and expertise to put together an appropriate screening plan for these patients, or management plan. Our hope is that as more people are tested and more data is gathered, we'll be able to better define these cancer risks, and also how to manage these individuals. But for now, this is still a work in progress. And as I transition over to Kristin, she's going to further address the availability of these panels, talk about some of their limitations, and also what we're doing to address those limitations. KRISTIN WILEY: So like Anna said, I'm going to be describing the genetic testing options that are currently available for hereditary cancer syndromes. The development of next generation sequencing, also known as massively parallel or deep sequencing, has revolutionized genomic research. The vast majority of laboratories are now utilizing this technology, and are therefore able to offer multi-gene panels for the price of what it used to cost to test one or two genes. [AUDIO OUT] Patients diagnosed at a younger age were more likely to have a BRCA mutation, but that chance of finding a mutation in a different gene increased as the patient's age of diagnosis increased. And relating this back to the family history aspect of a genetic risk assessment, this highly-- or this finding serves as a reminder that a diagnosis of postmenopausal breast cancer doesn't necessarily rule out a genetic predisposition, especially if there's still a family history of-- or a significantly family history. [AUDIO OUT] And therefore, it's been questioned that whether or not knowledge of mutations in these additional genes would actually alter the patient's management, since many of them are already considered to be at a high or a high risk based on their personal and family history alone. [AUDIO OUT] Anna and I have both mentioned this more than once, but I do want to bring it up again because we have seen patients who, after being told about these limitations, state that they're unable to handle that level of uncertainty and opt to not pursue genetic testing through a panel because of these limitations. And while there are other aspects of the risk-- or of the tests that we cover in a typical genetic counseling session, we really do emphasize these two points so patients have more realistic expectations of what information can be gained before pursuing genetic testing, especially through a hereditary cancer panel. [AUDIO OUT] And also, Anna and I can be reached at the email addresses and phone numbers listed here. And we would really love to answer any questions you may have in the future or right now. Any questions? [APPLAUSE]