Chapters Transcript Video Cracking the Code: Genetics in Modern Oncology In the early 90s, the identification of the BRCA1 and BRCA2 genes revolutionized our understanding of genetic predisposition to breast and ovarian cancers. Although we had long known that all cancers are associated with genetic changes, these discoveries introduced a new concept, being born with a genetic change that increases the risk of cancer, which opens the door to prevention and early detection. Since then we have identified other genes linked to various types of cancers. The approach has shifted from focusing on single gene syndromes to using multiple gene panels. Most recently, we have learned that adhering to traditional criteria for genetic testing may lead to mis testing individuals who carry mutations that could increase their cancer risk. Welcome to Baptist Health Doctor Doc, a podcast built for innovation and collaboration by physicians for physicians. Hello, I'm Doctor Venkatappa, an oncologist, hematologist at the Miami Cancer Institute, a part of Baptist Health South Florida. And joining us for our discussion is Doctor Martin Negron, a medical geneticist at Baptist Health Miami Cancer Institute. Doctor Alis Martin Neron is a highly qualified expert in clinical genetics. She did her medical school in Guadalajara, Mexico, an internal medicine residency in Puerto Rico, and followed that with a residency in clinical genetics and genomics at the University of Alabama in Birmingham. She topped off her educational career with a fellowship in cancer genetics in the City of Hope Comprehensive Cancer Center in Duarte, California. After that, she moved to Miami, worked at the Miami Children's Hospital for a few years before joining us at the Miami Cancer Institute 8 years ago. Welcome, Mireles. Hello. Let's start with an overview on clinical genetics. Tell us a little bit about clinical genetics. In genetics, um, what we try to see is if the patient is born with a genetic predisposition that in the case of cancer genetics put them in an increased risk for cancer. We all have genes uh that genes manage every function of our body, including the protection against cancer. These are called tumor suppressor genes and those are the majority of the genes that we test. When people are born with a genetic predisposition they are in an increased risk compared to the general population. Understand that we all have a risk of developing breast cancer, but people that are born with a genetic predisposition are in an increased risk compared to the general population. So what we do is we test not to see if the patient has the genes everybody had the genes is we look for defects in the genes. Excellent. That's such a simple but very effective way of explaining what clinical genetics is all about. So, explain to our audience the difference between germline and somatic mutations. Germline genetics. Our germline are changes that we're born with, so the, the germline are changes that are in the majority of our body in our body cells. There's some nuances, but I'm gonna keep it simple, and that can be passed down. Somatics is a change in a cell that in the case of cancer begins to grow and not stop because all the processes that are supposed to be in place for some reason are not working. What could be the reason? It could be environmental factors or maybe something that we're doing that is increasing the risk or maybe, uh, and I said that to patients when I see them, they could be a gene that we're yet to identified. Excellent. So, Am I correct in saying that germline mutations can be passed on to children? And can exist in the larger family among siblings where somatic mutations are unique to the individual and cannot be passed on to other uh people in the family. Correct. A general mutation was passed down to the individual in the majority of cases, although there's changes that begins in the individual, but then they're passed down to other generations. Excellent. Thank you. So tell me a little bit about the genes and the syndromes that have been identified in the recent years. As you discussed, the BRCA1 and BRCA2 basically created the My Specialty cancer genetics. Um, these two genes are are high penetrance genes, meaning that if you carry a mutation, your risk for cancer is highly elevated. Uh, but then recently we have noticed moderately increased risk, low penetrance risk, meaning they're associated with breast cancer, but the risk is lower, but it still is important. So when I see a patient with one of these genes, I said this mutation contributed to your cancer is likely not to be the only cause because the risk is not as high, but it definitely. contribute contributed so this has been very important because we started with 2 genes and now we have 13 genes associated with breast cancer but these are not the only genes we we there we know about genetic predisposition for colon, uterine, ovarian, hematological conditions, pancreatic cancer, so that's why we have the multi-cancer panel. Excellent. Thank you. So, at the Baptist Health Miami Cancer Institute in Miami, we are now offering universal germline testing. Can you expand on that offering and what should the South Florida community community know about this? Yes, in the last uh few years we have noticed that we are missing individuals who carry mutation. If we follow the guidelines, it's usually the NCCN guidelines, National Comprehensive Cancer Network guidelines, we will miss many individuals and we know that because when we. especially in multi cancer panel, we noticed that people are carrying a mutation in a gene that is not associated with the cancers in the family so the research start in looking into this and not many not many um hospitals are doing this, uh, is, uh, offering testing to. All net new patients is only at NCI. It's a pilot program, but we have been already seeing cases. I have seen multiple patients that had test positive for and would have not meet criteria for genes that will change medical management and that is not only important for them but it's also important for the family. You know, I looked at the, um, the data on universal genetic testing and how you and your team have improved the testing opportunities for patients at Miami Cancer Institute. Um, a year ago, we had about 1400 people who Accepted genetic testing. And I see that in the three months of the pilot that you and your team have started, um, the uptake has increased by 30% already. So congratulations to you and your team, um, and to hear from you that amongst the 30% who accepted genetic testing, even though they did not meet any national criteria, that you were able to find mutations that played a significant role in why they developed cancer. And played a role in their treatment decision making is indeed something uh really remarkable. So, uh, I believe that our South Florida community is, is, uh, blessed to have this sort of an opportunity to get the universal genetic testing for net new cancer patients. And I hope that you and your team will be able to expand this to other affiliated facilities with Miami Cancer Institute. So continuing the conversation, tell me, what are the potential benefits and risks of implementing universal germline genetic testing in oncology patients? The main benefit is not well, I always said the patients there are 4 reasons to do genetic testing. Uh, the first is to know why we're humans. This is something in our nature we know we want to know why. Uh, the second is for treatment purposes. It could be surgical, it could be, uh, medication, it could be an addition to the chemotherapy. Then the third one will be, these are syndromes. This is associated with more than one cancer is what is my risk for other cancers and what can I do to prevent. And then the last one that is I'm telling you maybe the most important for the patients is to know how, how the, the individual can help the family. They always many cases I see patients saying. I already have this. I'm older. I'm doing this for my children, so it's very important for the patients. So those are the reason when a patient get the genetic testing is is right away after they see the first, uh, physician at MCI, they get the testing this the process starts and by the time that the other workup is done, the results are in place and the the management can start easier. Thank you for that. So, to summarize what you just said over there, there are 4 reasons why people should get tested. One is to understand why the cancer happened in the first place. 2, Because we know that mutations can affect treatment planning and can have a significant impact in, in, in deciding what drugs to use and what surgical options can be exercised. And number 3 is, uh, to check and see if there are mutations, because we now have multi-gene panels that can increase the risk for other cancers. So this can be preventive in nature. And 4th, like you said, most important, you can then relay that information to your family and educate them and help them take preventive measures ahead of time. Correct. The in in terms of uh treatment, there's specific medications such as PARP inhibitors, medications that are specific for patients who carry BRCA1 and BRCA2 mutation is part of the precision medicine. Uh, for, for example, Lynch syndrome that is associated with colon, uterine ovarian, they can use, uh, medications such as pembrolizumab, uh, for any cancer in the individual even if it's not specifically associated with Lynch. So there is, um, many benefits and in terms of surgical. Uh, management, if somebody is born with a genetic predisposition for breast cancer, there is an increased risk for a second breast cancer, so maybe the patient would want to be more proactive and have a risk reducing mastectomy, and that is one of, uh, one of the uh recommendations provided to the patients who carry a genetic predisposition. You know, as a breast medical oncologist, um, who've been, who's been practicing for over 20 years now, I have seen in my lifetime how our treatment of breast cancer has evolved from being focused on the site of origin to now being agnostic to the site of origin. Because of the benefit that we get from these multi-gene panels, we can, as you mentioned very clearly, in cases of Lynch syndrome or in cases of BRCA 1 or 2, there are so many drugs that we can use now like PARP inhibitors, uh, like Olapari. Um, or Lynch syndrome, the, the immunotherapy options that are now open to patients who have a molecular abnormality, irrespective of where the disease started from. This has um made a significant change in how we treat our patients. And I believe, uh, with the advent of artificial intelligence techniques, technology, we will see a rapid improvement in our ability to continue to do so. Tell me, what role can general physicians play in identifying patients who might benefit from broader genetic testing even if they don't meet traditional criteria? Well, it, it is possible that um many physicians in our audience have patients that has asked about it because people are aware of it because of the news, um, Angelina Jolie had an effect and many people are aware of the BRCA1 and BRCA2 gene commonly known as BRCA1 and 2. they are maybe not know that there are other genes, but they will go to the physician and ask for the test. The being proactive is, is by, is, is a reason to maybe refer to genetics. Ask questions about family history, um, not just um very close relative but ask about obviously father, mother, children, but ask about uh uncles, aunt, grandparents because that is important. Um, also the ethnicity individuals with Ashkenazi Jewish descent and individuals of Bohemian ancestry, they are in an increased risk for certain mutations. Uh, look at the family history, the way that the guidelines are written, the age is taken into consideration, but maybe, um. Um, based on the amount of individuals that will be enough to consider genetic testing and I think that if the patient prompt you it's a good idea to refer to genetics. Excellent. Thank you for that information. So to, to summarize what you just said. For the general physician, for the primary care doctor. What you're telling us is go beyond the national guidelines. If a patient asks you for genetic testing, please go ahead and order that because there's a lot of value from the information that we obtained from these multi-gen panels, correct? Well, the phys the physician can um order, but it's. The ideal if it's possible to refer to a genetic providers uh for example in Miami Cancer Institute, uh, we have genetic counselors this is uh master degree specialty that um are able to get the family history and provide pre-counseling to the patient. Uh, so that would be ideal if a doctor decide to do the testing, there have to be aware that there may be some genes that, uh, some panels offer that maybe the patient doesn't want the information. And uh it's it's a good idea to maybe contact the labs and are more questions but ideally is to refer to genetics however we're not many so it's possible that you will need to order the test and not um have uh somebody involved in genetics. If the test is positive, the patient should be seen by a genetic provider uh there are many nuances and. For example, in genetics we have 3 possible results positive meaning that there is a genetic predisposition, uh, negative means that there was no defect found, however, there's still some recommendations based on family history. Uh, for example, if somebody has a negative result but they have a first degree relative with colon cancer, then this patient needs to be followed as a high risk colon cancer patient and needs to have colonoscopy more frequently. That is one example. And then we have a third result, a variant of uncertain significance, and that is to have a change in the gene that we don't know for sure if it's caused problems or not. Statistically speaking, the majority of these changes are benign changes, so we don't do any changes in management. And this can be very difficult to discuss with the patient and in some cases maybe it can lead to misinformation and then the patient to do some follow up that is not necessary so it's very important that the person who ordered the test is aware of this uh nuances in genetic testing. OK. So, that was a lot of information in your answer. I'm gonna try and summarize that. Um, the first point that you, you hit upon was That while it's easy to order the test, it is better to refer patients to an expert like you. Um, and the second point that you clarified was that there are very few people with the expertise that you have and with the, with the, the, the bandwidth that your team has. Um, so let me ask you a question before I summarize the rest of the answer that you gave. Um, and that is that can general physicians outside of Miami Cancer Institute refer to you and your team? Any patient who's interested in clinical genetic testing. Yes, that is a possibility. We have, um, we received many doctors, many uh many patients from physicians in the community and because this is a physician, um, practice is very easy, um, for the insurance to approve and the majority of the test is covered by insurance if the patient meets criteria but also very affordable. Excellent. Thank you. So it's, it's really good to know and it's, it's important for our audience to understand, especially in South Florida, um, that they can refer to Doctor Alis Martin Negron and her team, even if they're not part of Miami Cancer Institute. Um, yeah, I believe that this is one of the services that sets Miami Cancer Institute apart from everybody else because this is such a A unique department and like you mentioned, is, is offered in very few comprehensive cancer centers, um, all over the United States. So coming back to your answer, you mentioned that there are 3 possibilities in when, when a multi-gene genetic testing is done. One is it could come back negative. 2 is it could come back showing a variant of unknown significance, and 3 is it could come back positive. And then you emphasize that a patient with a positive genetic panel testing must be seen by a genetic expert like you, correct? Excellent. And with variant of unknown significance, uh, would you say that if the patient is anxious or confused, they should still come and see you or one of your counselors? I think yes, uh, because a variant of uncertain significant can be the patient could believe is positive and in in the hands of somebody that is not well versed in genetics they may do some surgery or treatment that is not necessary. A variant of uncertain significant also cause distress to the patient because they believe this is gonna be eventually positive when in reality the statistics doesn't apply it, it's not our experience so it's very important it cause a lot of distress and um this. This is when our testing many people uh helps to lower the numbers of variant of uncertain significant this is when for example AI is also helping creating models that uh give us an idea if this is something to be worried about or not. Uh, so I, I think that one of the big changes that I have noticed recently with the variant of uncertain significance is that addition of RNA to testing and AI and more people being tested because in the past we only have um the ancestry but now with more information. Those numbers are getting lower, less variant of uncertain significant but it's very important they take away is is a change that it doesn't uh affect management. And coming back to your, uh, the, the previous question that you answered so eloquently, uh, and you mentioned very clearly that even if the test is negative, if there's a significant family history of cancer, then that patient needs to be monitored more aggressively as a possible high risk, uh, patient. And then you alluded to the fact that there are certain ethnicities who are known to have high risk um for cancers. You talked about the Ashkenazi Jewish ancestry. You talked about Bahamians. Um, South Florida, as you know, is, is a melting pot of people from multiple countries, mainly from the Caribbean and South American countries. So tell us a little bit about, um. The population in South Florida and are there any unique characteristics of this population from the Caribbean, from the Bahamas, uh, from South America that puts them maybe at a different risk uh compared to the European ancestry people? Yeah, we are learning, uh, that is the that is the the the situation in at the beginning of uh genetic testing, the majority of patients were Northern European and individuals of Ashkenazi Jewish descent. Uh, this is what we know of the increased risk for mutations in the Ashkenazi Jewish population. Uh, that is one that I, I mentioned the BRC1, BRCA2. There is a mutation in the APC that is a very mild mutation compared to the general population in terms of the bohemian is because there is some BRCA mutations that we have learned from our, uh, Hispanic population. Uh, we're still learning in Latin Americans sadly, uh, genetic testing is, is not offered as often as here, and, um, there is a need for more um testing in individuals of that and of um. Hispanic ancestry and this is why for example when when we do universal testing is just add to the information that we need to better know what is the the actual risk for now the recommendation is the same as the general population there are some founder mutations meaning mutations that we see common in certain populations that we have noticed, but we need to learn more about that. Excellent, thank you. So from, from what I hear you saying. That the more the people get tested, the more data that is available, and that will lead to a reduced number of variants of unknown significance that will lead to more valid information and You believe that AI is going to make a huge difference, is that correct? How are we improving our ability to interpret these test results? Yes, um, there is something called genome wide association in that you get many uh changes that are common in the population and you get it together, so AI because it manage large amount of information. And together with testing more people we're gonna gather more information to fill those gap in information. Uh, by having this extra information, not only we're gonna learn about our risk of cancer gene but other conditions such as diabetes, uh, hypertension, high cholesterol, so, um, this that they don't have a single mutation, but they may they may be more people that are in an increased risk for, um, having, uh, these issues compared to the general population so it it's just. Getting testing more people is just enrich the data and again because it's a large data AI is helping already. Excellent, thank you. So before we conclude, tell me a little more about the impact of genetic testing in the treatment of patients. Yes, so, uh, for example, let's let's take an example of a patient that come with breast cancer to our, to the Miami Cancer Institute. Uh, when they get tested, if they test positive for a BRCA mutation, then the surgeon is gonna discuss the probability, the, the option of removing the other breast prophylactically. Why? Because the risk of a second cancer could be up to 40%. So then the patient can do that and then is followed with clinical examination only. If the patient, for example, is triple positive, then we know that maybe the addition of platinum to the, to the chemotherapy is helpful. So it's another way that we're helping the patient. Uh, because there is an increased risk for ovarian cancer, eventually when the patient is done with the with the acute phase of the treatment for breast cancer, then the patient will see the gynecology oncologist to discuss removal of the ovaries because we don't have good screening, so it, it can help in many phases of the process of uh the treatment. Um, there is, um, individuals who have metastatic breast cancer PARP inhibitors like Lyarsa, for example, it has been used with a, a good. Is is good response and by also knowing more about genes we may learn about other treatment treatment options in the future it it can help the patient at the moment of the treatment after the treatment and for screening purposes. Excellent thank you very much for joining us this afternoon. As clinicians, researchers, and patients, we are standing at a turning point where understanding our DNA is no longer a distant concept but a tool that has already changed lives. The challenge now is making sure we translate that knowledge ethically and responsibly. Here in Florida, we're seeing remarkable growth in research, clinical trials, genomic research, biotech innovation, and the integration of AI driven tools in healthcare systems from Miami to Palm Beach. Baptist health institutions are harnessing this data from genetic testing, population health studies, and precision therapeutics to deliver more personalized predictive care. The momentum is real and it's local. Thank you for joining us, Dr. Martin Negron. I really enjoyed this conversation. Thank you for the invitation. To find out more about the topics covered on Baptist Health. to doc, please visit physiciansources.baptisthealth.net. Created by
