Podcasts about cdh1

In partnership, the CGA-IGC Education and Research Committees are pleased to present the second episode of a three-part series focused on Research Collaborations. This episode is hosted by Emma Keel, MS, CCG, who spoke with Ophir Gilad, MD, the lead of the Gastric CDH1 Multicenter Consortium.This episode is essential listening for clinicians, researchers, and anyone interested in hereditary GI cancer syndromes research. Learn about this consortium's strategies for ensuring data quality and the goal of creating the largest cohort of CDH1 patients to date to better understand the syndrome. 

In this episode of The Clinical Research Coach, host Leanne Woehlke sits down with Stacy Martin, who shares her journey of entering a clinical trial. Stacy talks about her mother's stage 4 uterine cancer diagnosis, which led to genetic testing that revealed a hereditary mutation called CDH1. This mutation increased the likelihood of cancer in Stacy and her siblings. Stacy describes the moment she discovered she was CDH1 positive, the challenges she faced afterward, and the lessons she learned through the clinical trial process. No longer having a stomach, Stacy has to eat more frequently to keep her energy up. Becoming a "professional snacker" led her to turn her newfound snacking habit into a business and Seahorse Snacks was born. Seahorse Snacks makes healthy delicious roasted nuts with unique and unusual flavors.To Connect with Stacy:Stacy MartinStacy@seahorsesnacks.comLinked In:https://www.linkedin.com/in/stacy-martin-461b33a/Seahorse Snacks:https://seahorsesnacks.com/Instagram: @seahorse_snacksTikTok: @seahorse_snacks

Featuring perspectives from Dr Kevin Kalinsky and Dr Heather McArthur, including the following topics: Introduction (0:00) Case: A woman in her mid 80s with a 2.7-cm residual tumor after neoadjuvant pembrolizumab/chemotherapy for localized triple-negative breast cancer (TNBC) — Ranju Gupta, MD (3:31) Question and Comments: Approach to neoadjuvant therapy and defining residual disease; PD-L1 status and efficacy of pembrolizumab in the localized and metastatic settings — Kapisthalam (KS) Kumar, MD (8:04) Case: A woman in her mid 60s with node-positive TNBC and a single lung metastasis who receives neoadjuvant therapy based on the KEYNOTE-522 trial — Dr Kumar (17:18) Case: A woman in her early 70s with localized TNBC and residual disease after poorly tolerated neoadjuvant pembrolizumab/chemotherapy and lumpectomy — Dr Kumar (23:29) Case: A woman in her late 60s with widely metastatic ER-negative, HER2-low disease after multiple lines of treatment — CDH1 and ERBB2-V697L mutations, microsatellite stable, tumor mutational burden 3 mut/Mb — Dr Gupta (29:13) Question and Comments: Adjuvant therapy selection for patients with localized TNBC with a BRCA mutation and residual disease; risk of acute myeloid leukemia/myelodysplastic syndromes associated with PARP inhibitor therapy — Dr Kumar (40:52) Case: A woman in her early 70s who develops recurrent metastatic ER-negative, HER2-low breast cancer after nab paclitaxel/atezolizumab and receives sacituzumab govitecan — Dr Gupta (46:49) CME information and select publications

Professor Parry Guilford is known for successfully in identifying the first known genetic mutations in the CDH1 gene, leading to the description of a new cancer syndrome Hereditary Diffuse Gastric Cancer (HDGC). This discovery has conservatively saved 27,000 people from developing a severe form of stomach cancer. Parry is determined to continue to change the course of HDGC stomach cancer patients outcomes, he is invested in the CDH1 mutation families and feels their trials as if they were his own. We discuss genetic counselling, the age at which we test our children for hereditary cancers, his work on lobular breast cancer, bowel cancer and funding research. 

This episode is hosted by Josie Baker, MS, LGC, and features Jeremy Davis, MD, a National Cancer Institute (NIH) surgical oncologist.Together, they discuss Dr. Davis' recent article published in the Journal of Medical Genetics  titled “Decision-making and regret in patients with germline CDH1 variants undergoing prophylactic total gastrectomy.”This podcast was released during  Patient Experience Week.   Read our blog post to learn more about this podcast HERE

Dr. Shannon Westin and her guests, Dr. Jeremy Davis and patient advocate Kathryn Carr, discuss the paper "Costs of Cancer Prevention: Physical and Psychosocial Sequelae of Risk-Reducing Total Gastrectomy" recently published and printed in the JCO. TRANSCRIPT Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in depth on manuscripts that are published in the Journal of Clinical Oncology. I am your host, Shannon Westin, a professor of GYN Oncology at MD Anderson, and the JCO social media editor. I am so thrilled to have wonderful authors here today who do not have any conflicts of interest. We are going to be discussing the “Costs of Cancer Prevention: Physical and Psychosocial Sequelae of Risk-Reducing Total Gastrectomy.” This was published in the Journal of Clinical Oncology online on October 30, 2023, and in print on February 1st, 2024.  And I am excited. I am accompanied by the lead author, Dr. Jeremy Davis, who is an Associate Professor and Surgical Oncologist at the NIH, National Cancer Institute Intramural Research Program. Welcome, Dr. Davis.  Dr. Jeremy Davis: Thank you. Shannon Westin: If it is okay with you, I'll call you Jeremy. Dr. Jeremy Davis: Yes, please.  Shannon Westin: Fabulous. We also have patient advocate Kathryn Carr, who is a board member for No Stomach for Cancer. Welcome, Kathryn. Kathryn Carr: Thank you so much.  Shannon Westin: So let's get right into it. I think this is really thought-provoking work. First, I'd love to level set. So this was work around hereditary diffuse gastric cancer syndrome. Can we get a little bit of information about what causes this and how common it is? Dr. Jeremy Davis: So, hereditary diffuse gastric cancer syndrome, also referred to as the diffuse gastric cancer and lobular breast cancer syndrome, is basically early-onset diffuse gastric cancer and in women, lobular type breast cancer attributed to germline mutations in the CDH1 gene. If we look at all cases of gastric cancer in the United States, only about 1-3% may be considered hereditary in nature. But when we do study hereditary causes of cancer, it is by far the most common one that we are aware of. Shannon Westin: What is the likelihood that someone who is a carrier of a germline CDH1 variant will develop gastric cancer? Dr. Jeremy Davis: That's a good question. Early on, when the syndrome was first described, the estimates of cancer risk were quite high, probably upwards of 70-80%. The good news is that more current estimates published in the last few years suggest that that risk in a lifetime is probably in the 25-40% range. It's interesting, we do have our own data that are under review right now, where in some families where there's no history of stomach cancer, that risk of stomach cancer in a lifetime getting a CDH1 mutation might be as low as 10%. So I think the takeaway is that there's clearly a spectrum and that spectrum of risk is probably based on factors that we don't quite yet understand. Shannon Westin: What are the options for management of this hereditary syndrome, really focusing on the gastric cancer syndrome portion today? How good does it do to reduce the risk? Dr. Jeremy Davis: The options are really two. One is probably the prevailing recommendation that most people would be aware of, is to prophylactically remove the stomach, and we choose to use the term most often ‘risk-reducing gastrectomy', but to remove the entire stomach and really eliminate the risk of cancer from ever developing. The other option is enhanced surveillance, and people might think of this as akin to other high risk cancer syndromes. But for this we would do yearly or annual endoscopic surveillance. Many people think that that may not be the best option, but it is certainly an option. We discussed some of that in the paper about what are the risks and benefits of gastrectomy, and then what may be the benefit of enhanced surveillance for some people. Shannon Westin: Well, I would love to hear Kathryn. I think this is a perfect opportunity to hear a little bit about your journey with carrying this variant, as much as you are willing to share with our listeners. Kathryn Carr: Yeah, absolutely. So I found out that I have this spicy little gene back in 2019. My whole family got tested so the gene comes down from my paternal great grandmother. There are five of us who actually all had our stomachs removed by Dr. Davis. Within a year, he had five Carr stomachs. For me when I found out, I was extremely overwhelmed. I mean, “You want to take my stomach out? Like, what do you mean?” But after talking to Dr. Davis and his entire care team, I knew for me, having the total gastrectomy was the only option simply because I know my personality type enough that I was not going to be able to move forward with life unless I got rid of this overwhelming worry. Shannon Westin: Yeah, I think that makes sense. I'm a GYN oncologist by trade, so I often reference all things surgery around that. We have the same thing when we talk about risk-reducing surgeries for endometrial and ovarian cancers. This seems more like what we do in Lynch syndrome, where patients are at risk for endometrial cancer. Removal of the uterus is almost definitive in its ability to reduce that risk, but it's obviously a very large surgery. Jeremy, can you review the gastrectomy in general? What are the most common short-term and long-term adverse events? What did you have to discuss with Kathryn and her five family members around what they could expect from this surgery? Dr. Jeremy Davis: Yeah, I think this is a great question because it's the thing at the top of most patients' minds. When I sit down to talk to somebody about gastrectomy, usually a lot of the conversation initially centers around ‘how long does the operation take, how long am I at the hospital, and what are the most likely risks of the operation?' The good news is that as operations go, it can be done in two to three hours, and most people are in the hospital for maybe five to seven days. The risks of this operation, however, at least during the operation or immediately afterward have to do with how we have to reconnect everything and reconnecting the intestine to the esophagus so that people can continue to eat. Because I think a lot of people wonder, "Well, how am I going to eat?” The stomach's gone, but we recreate intestinal continuity. We put things back together in a way that people can eat and absorb their food.  But that connection we make between the esophagus and intestine is almost like the Achilles heel of this operation. It's the one thing that keeps surgeons up at night, and it's probably the one thing that causes the most trouble in terms of immediate risks, like leaking. If that connection leaks, it can lead to infection. There are other aspects of the operation that relate to any kind of intestinal surgery, such as leakage, blockage, or narrowing or something like that. So these are the things you need to worry about in the short term. But you mentioned the long-term consequences, and that was really one of the reasons why we wrote the paper. If you look in the literature, the focus is on the acute problems, things that happen within 30, 60, or 90 days of the operation. Which, yes, those are very, very important. But since we're talking about an operation that's supposed to prevent cancer and therefore allow the patient to live a long and happy life, I think it's important for us to think about what happens well beyond the time that the patient essentially heals from the operation.  Shannon Westin: It's so critical. And I think before we go into the work that you did and what you all found, Kathryn, I would love to get your perspective. Having gone through the procedure, what was your experience? Give us as little or as much detail as you want, whatever you're comfortable with. But also, what did you wish you had known? What surprises kind of came up during the course?  Kathryn Carr: I'm going to quote Rachel, who works with Dr. Davis at the NIH. She's the clinical dietitian. And my question to her was, "Seeing all the patients you've seen and knowing all that you know, what would be the advice that you would give me?" She told me to have the patience to get through the first year. I think that really set my expectation of, "Okay, this is not just a surgery where in a week or two weeks I'm going to be up skipping along." It is a marathon. I really worked hard with Dr. Davis in the hospital. I'm allergic to everything. I was convinced that my spleen was erupting. I think I scared many fellows, and they were like, "That's actually not where your spleen is. It's fine. You're okay. Stop getting on WebMD." But once I got home, those first eight weeks, they're hard. There were several moments where I would just sit and stare off into space and think, "Oh my gosh, what have I done?" But for me when Dr. Davis called to tell me the pathology report and that they did find some signet cells, I was 100% sure that I made the right decision. I would have been worried every second of every day that my body was going to turn on me. So once I kind of had that relief, it was like, "Okay, my body can do this. We're built to do hard things." Then it was just getting through the first six months, learning what I could eat, what I couldn't eat, working with Rachel on different strategies of, “Okay, I'm going to maximize my protein in the morning and then maybe get a little more adventurous as the day goes on.” But what I wish I had known before surgery, because I'm a planner, I want everything scheduled and figured out. I was in the hospital, I had a different outfit for every day, and I just wanted it to go perfectly. I think taking away the expectations of what your journey is going to look like would be the best advice I could go back and give myself. Because I am very competitive, and my dad and I were separated by seven months of this surgery. He can do things that I still can't do, and that's okay. Everyone's healing journey is going to look very different because everybody is going to respond incredibly different. It's like the body is doing roll call and the stomach is nowhere to be found, and everybody is going to respond totally differently to that. Shannon Westin: That's so insightful. I really appreciate that.  I guess now it's a good time to turn to the work that you did, Jeremy, and you kind of already hinted at what your objectives were, but can you maybe walk through your primary objectives in the way you designed the study. Dr. Jeremy Davis: You know, I think as somebody who trained to take care of people with cancer and do big operations to cure people, this was a little bit of a different experience in the beginning for me. Because here I was taking ostensibly normal people - Kathryn may argue with that statement - but normal people, and I was going to take them to the operating room and do something to them to prevent a problem. And this is not a minor thing, it's a big deal. What I learned pretty quickly was how much I was disrupting people's lives. And what I mean by that is that a patient comes to clinic three or six months after surgery. We all document the typical things. They are healing well, they are recovering as expected, their incisions are healed and all this stuff. But it was the stuff that didn't always go down in the medical record. The comments that the patients made to my team, the nurses, the dietitian, about how their lives were being disrupted. And this started to change my viewpoint on, “Oh my goodness, we're paying attention to important things, but we're really not paying attention to what's happening.” So, the idea behind the study was really to explore those consequences that don't get talked about a lot. That was the nature of the idea behind the study. It was easy enough for us to conduct the study because my research at the NIH is about gastric cancer, but more specifically, this hereditary form of gastric cancer. We have a natural history study that allows us to follow people for a long time, not just within three or six months of surgery, and then we're done. So that longitudinal aspect of the study is really what allowed us to accomplish that. Shannon Westin: What I thought was really interesting here is how many different types of questionnaires you were able to utilize to really assess beyond kind of the straightforward quality of life Yes/No. Can you speak a little bit about some of the questionnaires you chose and why?  Dr. Jeremy Davis: My concern going into this was that I had read a lot of the literature related to quality of life after gastrectomy for gastric cancer. There are certainly these validated questionnaires out there. And my sense was, having read those questions and papers, that those validated typical questionnaires- I'm referring to the FACT-G or the FACT-Ga might not capture the things that we wanted to capture. So, I spoke to our palliative care service here at the NIH clinical center, which is the hospital here on campus in Bethesda. They had developed a questionnaire many years ago that they called the NIH HEALS or Healing Experience of All Life Stressors. They designed that to identify stress causing changes associated with chronic illness. You might argue that having a germline mutation that puts you at risk for cancer is kind of a chronic condition. So, we thought we would use that.  And then the last part was we just sat around the table and we thought, “Well, jeez, what are all these things that people are telling us that would never be captured in almost any questionnaire?” And that's when we designed a series of questions that we thought were relevant to our patient population because we wanted to capture all the things that people had told us. Those were things like, “I had to change my job because I couldn't do the same work anymore, right?” Or, “My partner, our relationship changed substantially, and we grew apart, and we ultimately got divorced.” How do you capture that? So that's how we designed it. We basically looked at all the patients that we had done the prophylactic gastrectomy on and applied all of those validated and unvalidated questionnaires. Shannon Westin: That's so great. And I bet, Kathryn, you participated quite a bit in that, in addition to other people in the study. Kathryn Carr: I did, and I'm so grateful that Dr. Davis is doing this study because it is so important to look at what life is like without a stomach. You have this immediate thought of, “Okay, I just want to save my life. I want to make my life longer. But how is it going to change my life? How is it going to alter my day-to-day?” Because even Dr. Davis has said it would be weird if it didn't change your life. I mean, you're taking away a very important piece of the puzzle. So, I think this study is going to help people make more accurate decisions. I don't doubt my decision to have my gastrectomy at all, but this is beautiful information just so that you can be more well-prepared to walk into the surgery of, “Okay, now I have a very clear understanding of what my life could look like.” I've been very fortunate that I have not had a lot of the physical problems. I don't deal with a lot of bile reflux. My weight has stabilized, so I am very blessed in that way. But emotionally, this has been a really tough surgery. You start to feel misunderstood, like you have to walk into every day being very prepared of, “Okay, every two hours I have to eat something or else I get real hangry, not just a little hungry, real hangry. Also, my body will start to shake.” That's how I get my hunger signal. My whole body will start shaking, which is very scary. It's very unpleasant. I'm almost four years post-op, and so I lean into my schedule and routine.  One piece of advice for anyone walking into this surgery is to make sure you're anchored in something. For me, my faith anchors me, but if you're not anchored in something that is secure and true, like, you are going to float away, because this is a storm.  Shannon Westin: Jeremy, do you want to just pass on a few of the key findings? I encourage everyone to read the paper. There are so many different things that were explored and identified as part of this study. It's amazing with the number of patients that were involved, what the depth of the findings was. But perhaps you can kind of hit some of the major high points. Dr. Jeremy Davis: Yeah, I think the key takeaways for me, and obviously I'm still learning from all of this, is that I think we talk a lot about the surgery, in this case especially, but we don't talk enough about what life is like afterwards. I've started to talk to people about how much you think your stomach plays a role in your life, and you think about how much of our life centers around eating and drinking and holidays and family gatherings. And you have to imagine that means those activities are potentially disrupted. So for me, the key takeaways from this are, number one, we have to be aware. We have to be aware that risk reducing surgery of almost any kind has consequences. Yes, we want it to have a positive impact on the patient, but we have got to be aware of the negative impact. This is like systemic chemotherapy. It can do a lot of good, but toxicities are real. In terms of the specific findings from this study, listen, 94% of people in the study, 126 of people, 94% had some long term consequence. And it wasn't just like some long term, “Oh, I don't like my scar.” No, it was 94% of people had a long term problem, such as “I have daily bile reflux that interferes with my activities of daily living.” Something like that.   And I think the range of consequences is really important, too. And so, again, they range from things like GI symptoms, which you would imagine would be quite typical for a gastrectomy, but mental health, right? People talking about worsening symptoms of anxiety or depression, some substance abuse. Whether it was alcohol or otherwise, disruptions in relationships, I mentioned earlier, and even occupation change. I can't physically do the job that I used to do. So I think as clinicians, as surgeons that walk into this, yes, we need to focus on the surgery and the immediate consequences, but we also need to think, “How am I going to change this person's life? Not just for the better, but how might I really impair their life in the long term?” Kathryn Carr: Well, in one, just very simple example. So like going out to eat with people. There's a natural cadence of conversation. I take a bite, you talk and vice versa. But when you're chewing your food to the nth degree it interrupts that natural cadence. I avoid dinner dates because then I have to talk about my stomach on a first date or going out to dinner with friends. It's nice if there's a group of us because then other people can carry the cadence but then you kind of feel left out of the conversation because you're like, “Oh, well. I've got to eat, otherwise I'm going to pass out.” So that's just like a very simple, you wouldn't think of, “Okay, I'm going to dinner at 7:30 so I should probably eat a snack before I go because I might not get my food until 8:00 or 8:30.” So it's just like you're constantly thinking about, “Okay, I've got to make sure that I have food in my body.  Shannon Westin: It's so critical.  Well, this has been an awesome discussion and I'm sad that it's coming to a close. I guess just final thoughts around what's next in this space. Like what are you working on now, Jeremy? Dr. Jeremy Davis: I'm a cancer surgeon and a cancer researcher so my goal is to find a way for us to prevent stomach cancer that doesn't require me having to take out somebody's stomach. So in the laboratory that's what we're doing, right? We're working on finding a way to prevent stomach cancer so that I don't have to do this operation anymore. But on the clinical side of things, the next thing that we're exploring is how do patients think about, talk about, or express concerns to their physicians about reproduction - reproduction in the setting of a cancer predisposition syndrome. And I think that's going to be really important work.  Shannon Westin: That's great. Kathryn, any thoughts? Kathryn Carr: I know that being four years out, I'm not like an old timer, but I do just want to help anyone who's at the beginning stages of this journey and just making other patients feel less alone. I told Dr. Davis I just entered the world of TikTok to talk about gastrectomy and just opening up a conversation of what does life without a stomach look like? And just making people feel less alone and more understood throughout this process. Shannon Westin: Thank you both for the work you're doing, and thank you to all of our listeners for tuning in to JCO After Hours. Again, we were discussing the “Costs of Cancer Prevention: Physical and Psychosocial Sequelae of Risk-Reducing Total Gastrectomy.” Please do not be a stranger to our podcast. Check out our other offerings and reach out to us on X and Instagram if you have other topics you want us to cover. Have an awesome day. The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.     

Today we have a very special guest with a very special topic. We are honoured to have Jordan Ricks as a part of our show as she is such an amazing person who has a story that is just one big miracle. After falling pregnant, Jordan found that she started to vomit and get sick, which at first seemed normal, but eventually it grew to be completely out of control. She has a mutation in her DNA called CDH1 that causes her to be more prone to stomach and breast cancer, so when she let the doctors know she had this gene, a grave look crossed their faces and they discovered some terrible news. Jordan was in complete sorrow, but had this voice come to her that she was going to go through something similar to her dad, which would get her through this. “You knew this was coming. You've been prepared for this. Now go and be a miracle.”About Jordan and her genetic mutation 1:00Finding the cancer 9:40The cancer doesn't define who she is 21:00Having to share the trial with her child 26:00Her experience has helped her help others 33:00If you are going through the darkest of times 39:30“All 4 of the doctors came back and they all looked at me solemn and sad, and I was like ‘What's going on?' Then Dr. Ott, my surgeon, was the one who broke the news and told me ‘You are stage 4 with signet ring gastric cancer due to your CDH1 mutation.' There I was, 29 years old, 6 months pregnant, sitting in the hospital with bad news. It was so shocking to my system.” 10:55https://www.facebook.com/theirishmummy/https://www.instagram.com/the_irish_mummy/Pick up a copy of Journal to Joy. My NEW 90 Day Goals, Gratitude & Affirmation Journal to Create a Happy & Abundant Life.https://www.theirishmummy.com/Subscribe to Letters to My Sisters Newsletter. You will hear EVERYTHING here first.https://www.theirishmummy.com/

ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the voice of the world's oncology professionals. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guests' statements on this podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so data described here may change as research progresses. In this podcast, Dr. Allison Kurian and genetic counselor Kristen Mahoney Shannon talk about what people should know about genetic testing and hereditary breast cancer, including what to expect when meeting with a genetic counselor, ways to reduce your risk of developing cancer, and talking about genetic test results with family.  Dr. Kurian is a Professor of Medicine and of Epidemiology and Population Health at Stanford University School of Medicine, and Director of the Stanford Women's Clinical Cancer Genetics Program. She is also the 2023 Cancer.Net Specialty Editor for Breast Cancer. Ms. Shannon is a senior genetic counselor and Director of the Cancer Center Genetics Program and Director of Genetic Counseling for the Massachusetts General Hospital Department of Medicine. She is also a 2023 Cancer.Net Advisory Panelist. View disclosures for Dr. Kurian and Ms. Shannon at Cancer.Net. Dr. Allison Kurian: I'm Allison Kurian. I am a professor of medicine, oncology, and epidemiology and population health at Stanford University. And I am speaking today with my colleague, Kristen Shannon, who will introduce herself. Kristen Shannon: Hi, it's great to be here. My name is Kristen Shannon. I am a genetic counselor and the director of cancer genetics at Massachusetts General Hospital in Boston. And I have no financial relevant disclosures to report. Dr. Allison Kurian: Thank you, and I have no relevant financial disclosures either. Very good. So today we will be talking about breast cancer and inherited risk and genetic testing. And let me start by providing a definition of a genetic or hereditary condition. So the way we think about this is something that has a high risk for developing a disease, not a certainty, but a high risk, and runs in families, generally because of a genetic finding that we can identify. And that typically is identified through sequencing, testing of blood or saliva samples, and typically allows us to find a change that we know is clearly associated with disease. A good example for breast cancer are the genes BRCA1 and BRCA2, which some may have heard of, and we will talk about further. So that is just an example, and we will get into more of the details of this as we go on. But I think the point is something that runs in families often is seen with the trait, so for BRCA1 or BRCA2, that would be breast cancer or ovarian cancer, affecting people in every generation. And having what we call for these kinds of genes an autosomal dominant inheritance pattern, so inherited from either parent. And taking only 1 copy that is not functioning to give a person higher risk of the condition. So that's sort of a bit of the basics here on genetic or hereditary risk. And just to give a sense of how common hereditary breast cancer is, we think that in general this may account for, I would say, somewhere between 5% to perhaps 10% of cases of breast cancer. And Kristen, please jump in and tell me if you think differently. But that would be my ballpark. And I think probably the majority of those are the BRCA1 and BRCA2 genes that I mentioned, although there are others that we are recognizing are playing more of a role than we thought, and we'll discuss those, too. So let me give you a chance to continue and respond, Kristen. Kristen Shannon: Yeah, no, I totally agree. And I was thinking that maybe I could talk a little bit about some of the features that are suggestive that there could be one of these inherited breast cancers in the family, because recognizing these signs of hereditary breast cancer can be super important for early detection and prevention of breast cancer. So first, multiple cases of breast cancer within the family, especially among close relatives like parents, siblings, children, those can be a sign that the cancer is inherited. Another important sign is early age of onset of disease. So breast cancer diagnosed at a young age, typically before the age of 50, might point towards hereditary risk. And it's not always the case, but it's something to be aware of. Also, if there is a history of ovarian cancer in the family, especially if you see it in conjunction with breast cancer cases, that's a significant sign that there could be something inherited in the family. And while it's rarer, male breast cancer can also be associated with hereditary gene mutations. So if there's a history of male breast cancer in the family, it's definitely something to think about in terms of hereditary risk. Multiple cancer types in the family can also be another clue. It's not always just breast and ovarian cancer. If you see a family history of both breast and ovarian cancer or pancreatic cancer or prostate cancer within the same family, that also might be a sign of an inherited cancer syndrome. For individuals of Ashkenazi Jewish descent, it's worth noting that they have a higher prevalence of certain gene mutations in specific genes, specifically BRCA1 and BRCA2, which Dr. Kurian has mentioned before. So a family of history of breast or ovarian cancer in an Ashkenazi Jewish individual should be noted as a higher sign that this cancer could be due to an inherited gene. And lastly, if someone has had breast cancer in both breasts, that's called bilateral breast cancer, and that might indicate hereditary risk. It's important, though, to remember that it's not just about any single sign in isolation. You really need to take a look at the bigger picture and the bigger context of the family. So if you notice any of these signs in your family, it's a good idea to seek guidance from a health care professional, like a genetic counselor or a medical oncologist, and they can help assess the family's risk and recommend genetic testing if needed. Dr. Kurian, did I forget anything or leave anything off? Dr. Allison Kurian: Perfect as always. I will just add a little bit here in terms of the specific gene names that we think about, because sometimes it helps people to have sort of a list in their minds, not that we expect you to remember the whole alphabet soup of these different genes. And let me just say that I think it's always a bit of a hodgepodge, some of these names. I used to wonder how people come up with these names, and often there's a bit of a history there. But I will just go through a few of them. We now have some practice guidelines, and they are basically put together by a group of experts who review all the evidence frequently and come up with recommendations. And so there is a list in these guidelines of basically which genes we think are appropriate to test for breast cancer in families, because there's enough evidence to suggest that. And so in addition to BRCA1 and BRCA2, the ones that I think of as the most important, and I'll want to hear Kristen's thoughts about this, too, but the ones that we see most often are called ATM. Sounds like a cash machine, unfortunately not, but ATM. CHEK2, C-H-E-K-2, and then one called PALB2, which stands for Partner and Localizer of BRCA2, and is a lot like BRCA2 in its risks. There are some other genes that give breast cancer risks that are less common. One of them, CDH1, is a gene that also causes an increased risk of stomach cancer. There are a few others that we always keep in mind. There's one called PTEN that's very rare that causes a syndrome called Cowden syndrome that I certainly haven't seen much of. Kristen may have seen more, but it's not something we see often and goes with a lot of other features in families. There are 2 genes that I think we recognize more in recent years and like to be sure we test, called RAD51C and RAD51D, and those both give increased risks. And then another one that I always think of as important here is TP53, and that is a gene that causes something called Li-Fraumeni syndrome, which has probably the highest cancer risks of which we know. There's another one, STK11, that gives some risk, NF1. We see these as being less frequent contributors. Those are the ones that I kind of keep in mind. And again, there will not be a quiz on the alphabet soup, but just so you're aware of what kinds of names you might hear. Kristen, please jump in if I've forgotten any or anything else you want to say. Kristen Shannon: No, I think that that's important. I think the only thing that I would add is that some people think when they go in for breast cancer genetic testing, they only are getting the BRCA1 and BRCA2 gene. And it's just important for people to realize that that's not really a complete test at this point, as you mentioned, Dr. Kurian. Dr. Allison Kurian: Totally agree, and thank you. Kristen Shannon: Should we move into how to prepare for a genetic counseling appointment? Dr. Allison Kurian: Please, yes. Kristen Shannon: Sure, okay. So preparing for a genetic counseling appointment for breast cancer risk can be helpful. First and foremost, we suggest that you gather your family health history. So reach out to your relatives and compile as much information as possible about your family's health background. Pay special attention to any instances of breast cancer and ovarian cancer, prostate cancer, pancreatic cancer in the family. And if any family members have had genetic testing, it's really helpful to jot down those test results as well and bring them with you to the appointment. The other thing is to think about your own personal medical history. You know, think about if you've had any past diagnosis, any treatments, surgeries, or medical conditions, especially those related to breast cancer, your genetic counseling appointment will include a discussion of those. The other thing is, you know, if you've had any medical tests related to cancer, it's important to gather those records if they're not already in your hospital's medical record system that you are going to. Another good idea is to just prepare a list of questions that you might want to have answered. So what do you want to know? Are there specific concerns or specific things you're curious about? It's also important to understand what you want to get out of this genetic counseling encounter. Do you want to just clarify your risk of having a gene? Do you want to consider genetic testing? Or do you want to talk about just managing your risk for breast cancer? That's super important to have that in mind before you actually go into your appointment. Lastly, I would consider bringing along a person, a supportive person with you to the appointment. Having someone with you can help provide emotional support because sometimes these visits can get emotionally charged, but it also can help to have someone remember important details that you will discuss with your health care provider. So it's really important to just arm yourself with information, questions, and support so that the appointment is as productive and informative as it can be. Do you have anything else you'd like to add, Dr. Kurian? Dr. Allison Kurian: It's wonderful to have your expert perspective on this. And I guess any thoughts about really what's inside the box? I think sometimes people just sort of wonder what's going to happen when I go in that room. Sometimes we have patients come in and say, “What are you guys going to do to me? Will there be surgery done?” And we reassure them that we are not doing anything that wild. And so maybe just a sense of kind of walking people through what will happen when they go to meet with genetic counselors. Kristen Shannon: Absolutely, thanks for bringing that up. So during the initial meeting, first you'll probably discuss your personal health history, again, any past diagnoses, surgeries, medical conditions. And then typically a genetic counselor or a medical professional will dive right into your family health history. So they'll ask a whole bunch of questions about your close and extended family members to build a really comprehensive picture of your family and the cancer diagnosis in it. They'll want to know if anyone in your family has had cancer, and they'll also want to know what type of cancer that person has had and also the age at which that person was diagnosed. So those are the 3 pieces of information that your health care provider will want to get from you. The genetic counselor will also probably ask you about what you want to get out of this encounter to make sure that you're both on the same page. Again, do you want genetic testing? You know that already. Or do you want to just talk through the process? So the big part of the initial meeting is really education. The genetic counselor will explain what Dr. Kurian described at the very outset of this discussion, what's the genetic basis of hereditary breast cancer, including all the specific genes that Dr. Kurian—the alphabet soup that we talked about. Talk about inheritance patterns and the implications of having a genetic mutation. The genetic counselor will probably also first assess your risk of having a mutation in one of the genes, and then they'll also talk to you often about genetic testing. So if genetic testing is on the table and you and the genetic counselor both agree that it's a good step, they'll walk you through the process of informed consent. And so this ensures that you understand what the testing entails, the potential outcomes, the implications of the test results. And then if you decide to go through with genetic testing, you will provide a blood or a saliva sample. And then it's a waiting game because these test results can take several weeks, usually about 3 to 4 weeks to get the test results back. When the test results come back, you'll typically have a follow-up appointment, either in-person or on the phone with your genetic counselor. And that's when they spend a lot of time interpreting the test results, explain what they mean for you and your health, as well as discussing the appropriate risk management strategies, if necessary. And if a gene mutation is identified, a genetic counselor will guide you on how to manage these risks. But it will depend on the specific mutation that is identified. And then the other thing that the genetic counselor can help with is just the emotional support. Some people have a harder time than others hearing this information. And also to talk about how to tell your family members about this. So in a nutshell, the initial meeting with the genetic counselor is about gathering information, assessing risk, and potentially deciding on whether or not you're going to have genetic testing. And then after that step, it's about interpreting the test results, talking about next steps, and providing emotional support. Dr. Allison Kurian: Thank you, Kristen. That was wonderful and very complete. And as I was listening to you, first of all, I was thinking about my general admiration for genetic counselors, which is huge. They taught me everything I know about this field. But so also kind of highlighting the key things that a meeting with a genetic counselor will do for you, as you so nicely did. And I think it's getting the right test ordered, making sure that the results make sense to you, and going beyond the patient. But I think those are sort of the key aspects that you communicated really well of the things that we want to get done there. Kristen Shannon: Well said, well said. And I couldn't agree more. Dr. Allison Kurian: And what do you think about the family part in terms of how that gets done? Kristen Shannon: Right, so discussing your genetic test results with family members can be hard and challenging, but it's really, really important. In terms of talking to your family members, I think first, determine the way you're going to notify your family members. So are you going to talk to them? Are you going to send them a letter or an email? And how you share the information may be different based on your relationship with that person. So for example, you may sit down over coffee with a close family member to talk about your test results, but you may choose to write a letter to someone that you don't have that much contact with. The next thing that I think is really important is to be prepared. So before you even start to have this conversation, make sure that you have a clear understanding of your genetic test results, the implications to you and to the family member. That's super important before you even start to have the conversation so that you can explain things to people in simple terms without too much medical jargon and make sure you keep it straightforward. It's really helpful to have a copy of your genetic test results and to provide that to your relatives if you're comfortable doing so, because then they can take that information with them to their genetic counseling or genetic testing appointment, which can be incredibly essential in terms of making sure that they get the correct test at the right time and the test results are interpreted correctly. The only other suggestion I have is just to keep in mind that family members are going to react very differently to this information. And some people will be very matter of fact about it. Some people might get a little distracted by this whole thing. So just to be patient with people and keep the conversation open. Allow them to call you if you're willing to do that so that the conversation can develop over time because, you know, really, in the end, the goal is to make sure that everyone in the family is well informed and makes decisions based on their own health and their well-being. Dr. Allison Kurian: Thank you. I couldn't agree more. And we sometimes, as people may have heard, call this “cascade genetic testing.” So a patient is tested. Somebody who's already had cancer maybe is tested. But then we have the opportunity to have this cascade of beneficial genetic testing, where we can get to people before they have cancer and work on prevention and screening, which I'll talk about in a minute. And I will say that, in general, we here in the United States, and certainly other places as well, don't do as well as we would like with cascade testing despite all best efforts of everyone. And so just to emphasize that family notification is super important, genetic counselors are wonderful at helping people to do that. And I think also additional strategies and interventions are underway to try to help make that easier. So if I may, I'll talk just a little bit about kind of what we do when we find something. Is that okay to do? Kristen Shannon: That sounds great. Talk about people, you know, what they can do about their test results. Dr. Allison Kurian: Good. Yeah, so I always think that's important. I'm an oncologist by training. I'm not a geneticist. And again, it's only thanks to the brilliance of genetic counselors like Kristen that I have learned what I have for the last 2 decades working in the field. But so I tend to think in terms of what can we do to treat this person differently if they have cancer to prevent or reduce the risk of a future cancer. And so what I would say is increasingly over the last few years for a person with breast cancer, as well as some additional cancers, it started to matter what these results are in terms of how we treat the person, whether we might give different medications. And that's really exciting because for years in this field, we didn't have that, and now we do. And so the drugs that are increasingly important are called PARP, P-A-R-P, inhibitors. And sometimes, if a person has a BRCA1 or BRCA2 gene mutation, we might even offer those drugs to treat a breast cancer or, in other cases, ovarian, prostate, or pancreatic cancer. So I think the testing can matter like never before in terms of what we might do to take care of people's cancer. Sometimes we might also choose a different surgery. So sometimes a woman who has a diagnosis of breast cancer might choose to do a more extensive breast surgery, she might choose a double mastectomy to reduce her risk of getting a second breast cancer. That's never required. She certainly doesn't have to do so extensive a surgery if she doesn't choose, but it is an option that some people might choose. And there might also be other cancer risks to manage in somebody who had breast cancer. BRCA1 and BRCA2, for example, give a high risk of ovarian cancer. And so we might talk with someone about the possibility of removing ovaries to prevent an ovarian cancer, which often is recommended with BRCA1, BRCA2, and other such gene mutations. I will say that I think for somebody who hasn't had cancer yet, or hopefully ever, particularly as we think about breast cancer, we're often thinking about intensive screening. So starting often earlier than a person would if she didn't have high risk and generally adding magnetic resonance imaging, MRI, to screening with mammogram alone. And that really is, I think, the cornerstone for women at high risk is adding that breast MRI screening. For pretty much all of the genes I mentioned, that would be clinically indicated and covered by insurance and important to do. MRI has no radiation, very effective at finding breast cancer early. So I think to summarize, it's really all about understanding risk based on a particular gene mutation, understanding if a different kind of treatment is needed for the cancer that a person has, understanding if any sort of preventive measure is needed for future cancer risk, and making sure that the screening we have for breast and for other cancers is appropriate to the level of risk. Anything to add there, Kristen? Kristen Shannon: No. No, I think that that's great. Dr. Allison Kurian: Absolutely. Yeah, so I think it's wonderful to have this opportunity to speak about the importance of genetic testing, which is I think more important than it ever has been at this time for the care of patients with breast cancer and their families. And so as we move into breast cancer awareness month, it's great to be able to talk about this. Thanks so much. Kristen Shannon: Thank you so much. I agree. And if you have any questions, I would suggest you reach out to your doctor or look up on the ASCO website for a referral to a genetic counselor. ASCO: Thank you, Dr. Kurian and Ms. Shannon. Learn more about hereditary breast cancer and genetic testing at www.cancer.net/hboc. Cancer.Net Podcasts feature trusted, timely, and compassionate information for people with cancer, survivors, and their families and loved ones. Subscribe wherever you listen to podcasts for expert information and tips on coping with cancer, recaps of the latest research advances, and thoughtful discussions on cancer care. And check out other ASCO Podcasts to hear the latest interviews and insights from thought leaders, innovators, experts, and pioneers in oncology. Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds lifesaving research for every type of cancer, helping people with cancer everywhere. To help fund Cancer.Net and programs like it, donate at CONQUER.ORG/Donate.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.25.538200v1?rss=1 Authors: Peng, Y., Zhang, Y., Fang, R., Jiang, H., Lan, G., Liu, Y., Nie, Z., Zhang, S.-D., Ma, Y., Yang, P., Wang, F., Ge, H.-H., Zhang, W.-D., Luo, C., Li, A., He, W. Abstract: Centromere protein A (CENP-A) is a centromere-specific protein that determines kinetochore positioning and the accuracy of chromosome segregation. Despite its recognized importance in maintaining mitotic fidelity, the molecular details of CENP-A regulation in mitosis are still obscure. We performed a structure-activity relationship (SAR) study of the cell cycle-arresting indole terpenoid mimic JP18 and identified two more potent analogues, (+)-6-Br-JP18 and (+)-6-Cl-JP18. Tubulin was identified as a potential protein target of these two halogenated analogues by using the drug affinity responsive target stability (DARTS) based method. X-ray crystallographic analysis determined that (+)-6-Br-JP18 and (+)-6-Cl-JP18 bind to the colchicine-binding site of beta-tubulin. We further found that treatment of cancer cells with microtubule-targeting agents (MTAs), including these two compounds, upregulated CENP-A by destabilizing Cdh1, an E3 ubiquitin ligase component. The mechanistic study revealed that Cdh1 mediates proteolysis of CENP-A in mitosis, specifying the role of Cdh1 in maintaining mitotic fidelity. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

A new research paper was published in Oncotarget's Volume 14 on March 11, 2023, entitled, “Genomic landscape of metastatic breast cancer (MBC) patients with methylthioadenosine phosphorylase (MTAP) loss.” Homozygous deletion of methylthioadenosine phosphorylase (MTAP) upregulates de novo synthesis of purine (DNSP) and increases the proliferation of neoplastic cells. This increases the sensitivity of breast cancer cells to DNSP inhibitors such as methotrexate, L-alanosine and pemetrexed. In their recent study, Maroun Bou Zerdan, Prashanth Ashok Kumar, Elio Haroun, Nimisha Srivastava, Jeffrey Ross, and Abirami Sivapiragasam from SUNY Upstate Medical University and Foundation Medicine, Inc. analyzed 7,301 metastatic breast cancer (MBC) patients that underwent hybrid-capture based comprehensive genomic profiling (CGP). “We provide one of the first large analyses of the spectrum of GA [genomic alterations] occurring in MTAP deleted MBC with the hope that this would enable identifying potential therapeutic agents in the future.” Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Tumor cell PD-L1 expression was determined by IHC (Dako 22C3). 208 (2.84%) of MBC featured MTAP loss. MTAP loss patients were younger (p = 0.002) and were more frequently ER− (30% vs. 50%; p < 0.0001), triple negative (TNBC) (47% vs. 27%; p < 0.0001) and less frequently HER2+ (2% vs. 8%; p = 0.0001) than MTAP intact MBC. Lobular histology and CDH1 mutations were more frequent in MTAP intact (14%) than MTAP loss MBC (p < 0.0001). CDKN2A (100%) and CDKN2B (97%) loss (9p21 co-deletion) were significantly associated with MTAP loss (p < 0.0001). Likely associated with the increased TNBC cases, BRCA1 mutation was also more frequent in MTAP loss MBC (10% vs. 4%; p < 0.0001). As for immune checkpoint inhibitors biomarkers, higher TMB >20 mut/Mb levels in the MTAP intact MBC (p < 0.0001) and higher PD-L1 low expression (1–49% TPS) in the MTAP loss MTAP (p = 0.002) were observed. “MTAP loss in MBC has distinct clinical features with genomic alterations (GA) affecting both targeted and immunotherapies. Further efforts are necessary to identify alternative means of targeting PRMT5 and MTA2 in MTAP-ve cancers to benefit from the high-MTA environment of MTAP-deficient cancers.” Read the full research paper: DOI: https://doi.org/10.18632/oncotarget.28376 Correspondence to: Abirami Sivapiragasam - sivapira@upstate.edu Keywords: breast cancer, metastatic, MTAP loss About Oncotarget Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

Courtney Zentz is Founder of the nation's leading pediatric sleep consulting agency, Tiny Transitions. A organization born from her own struggles as a new parent. As she stood to build this company and enjoy new motherhood, she was diagnosed with the CDH1 gene. A mutation of the CDH1 gene meant she was at risk for developing an aggressive form of stomach and breast cancer. Courtney had to make a decision as to what to do with this knowledge, and how it would impact her life. Courtney's story is one of hope, interceding on the negative news we often hear on repeat. Courtney shares a raw look behind the scenes of new motherhood and the journey after diagnosis with CDH1. Bringing us up to today, in tune with her “authentic self” and feeling truly connected to her joy. If you are holding something bigger than you right now and you are not sure what the future looks like, this episode is for you. - - - SHOW NOTES Library of free sleep coaching and education: https://tinytransitions.com/work_with_courtney/opt-in-courtney-zentz/ Free sleep evaluation - which can be scheduled here: https://TinyTransitions.as.me/schedule-a-call More about CDH1: https://www.pennmedicine.org/cancer/types-of-cancer/stomach-cancer/stomach-cancer-risks-prevention/cdh1-mutation-and-stomach-cancer-risk CONNECT WITH KRISTINA Share Your Story or Ask Your Questions: ⁠⁠⁠Kristina@andthenbewell.com⁠⁠⁠⁠ Follow Along: ⁠⁠⁠Podcast IG⁠⁠⁠ ⁠⁠⁠⁠⁠⁠⁠ // ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠LinkedIn⁠⁠ ⁠ Don't forget to subscribe, rate and review after your favorite episodes. --- Support this podcast: https://podcasters.spotify.com/pod/show/andthenbewell/support

Vadim Gushchin, MD, Brian Badgwell, MD, and Jeremy Davis, MD discuss the role and timing of preoperative treatments before cytoreduction and HIPEC for gastric cancer. The panelists offer useful tips on surgical management of gastric cancer patients with peritoneal carcinomatoses, such as how to decide on the extent of the surgery, whether patients with CDH1 mutation should be treated differently, and others.

FDA连续批准2个治疗胃肠道间质瘤的靶向药 Nature Review 肠易激综合征的中饮食疗法的循证医学证据和机制的见解Science子刊 生活方式和遗传因素使亚洲人易患胃癌阿伐普替尼（Avapritinib）胃肠道间质瘤（GIST）是胃肠道最常见的间叶细胞肿瘤，目前普遍认为是是由编码酪氨酸激酶受体蛋白基因（KIT）突变、或血小板源性生长因子受体 α（PDGFRα）基因激活突变所诱发。其中以KIT突变最常见，占80%；PDGFRα突变占10%，PDGFRα外显子18 D842V是最常见突变，与伊马替尼耐药相关；还有10%的患者缺少KIT或PDGFRα突变，称为野生型胃肠道间质瘤。阿伐普替尼（Avapritinib）是一种高效、选择性、口服生活性的KIT和PDGFRα抑制剂。2020年1月9日，FDA批准Avapritinib用于治疗经过基因检测确认的PDGFRα18外显子突变的不可切除（无法通过手术切除）或转移性（癌细胞扩散至身体其他部位）胃肠道间质瘤患者。《NAVIGATOR研究：阿伐普替尼治疗PDGFRα D842V基因突变的、晚期胃肠道间质瘤的研究》Lancet Oncology，2020年7月 (1)NAVIGATOR研究是一项两部分、开放标签、剂量递增和剂量扩大的1阶段研究。这篇文章对PDGFRA D842V突变的患者进行单独分析，并报道了研究结果。研究纳入无法手术切除的、胃肠道间质瘤患者，其中56人携带PDGFRα D842V突变，其中20位患者进入剂量递增组（即从30mg qd逐渐加量至最大耐受剂量），36位患者进入剂量扩大组（即使用最大耐受剂量）。最大耐受剂量为400mg qd，推荐剂量为300mg qd。中位随访15·9个月，在PDGFRα D842V突变的56名患者中，9%完全缓解，79%部分缓解。治疗相关严重不良反应最常见的是贫血。在30-400mg qd的剂量下，没有观察到药物毒性；600mg qd时，两名患者出现剂量相关的不良反应。结论：阿伐普替尼在晚期PDGFRα D842V突变的胃肠道间质肿瘤患者中具有初步的抗肿瘤活性。瑞普替尼（ripretinib） 瑞普替尼（ripretinib）是一种对广泛的KIT和PDGFRA基因突变激酶抑制剂。2020年5月，FDA批准瑞普替尼（ripretinib）用于晚期胃肠道间质瘤的四线治疗。《INVICTUS研究：瑞普替尼治疗晚期胃肠间质肿瘤的3期试验》Lancet Oncology，2020年7月 (2)这项双盲、随机、安慰剂对照的第三期研究中，纳入晚期、进展性胃肠间质肿瘤患者129人，既往均使用过伊马替尼、舒尼替尼和瑞格拉非尼在内的治疗。患者随机分入瑞普替尼 150mg qd或安慰剂组，随机分配到安慰剂组的患者在疾病进展时允许转到瑞普替尼组。双盲期，瑞普替尼组和安慰剂组的中位无进展生存期分别为6.3个月和1.0个月（风险比0.15，p < 0.0001）。最常见的严重不良反应包括脂肪酶升高、高血压、疲劳和低磷血症，两组发生率相似。结论：瑞普替尼显著提高晚期胃肠道间质瘤患者的无进展生存期。乙型肝炎急性和慢性乙型肝炎感染均刻有不同的临床表现。急性期，临床表现可从亚临床、或无黄疸型肝炎至黄疸型肝炎，有时还会出现爆发性肝炎（

FDA连续批准2个治疗胃肠道间质瘤的靶向药 Nature Review 肠易激综合征的中饮食疗法的循证医学证据和机制的见解Science子刊 生活方式和遗传因素使亚洲人易患胃癌阿伐普替尼（Avapritinib）胃肠道间质瘤（GIST）是胃肠道最常见的间叶细胞肿瘤，目前普遍认为是是由编码酪氨酸激酶受体蛋白基因（KIT）突变、或血小板源性生长因子受体 α（PDGFRα）基因激活突变所诱发。其中以KIT突变最常见，占80%；PDGFRα突变占10%，PDGFRα外显子18 D842V是最常见突变，与伊马替尼耐药相关；还有10%的患者缺少KIT或PDGFRα突变，称为野生型胃肠道间质瘤。阿伐普替尼（Avapritinib）是一种高效、选择性、口服生活性的KIT和PDGFRα抑制剂。2020年1月9日，FDA批准Avapritinib用于治疗经过基因检测确认的PDGFRα18外显子突变的不可切除（无法通过手术切除）或转移性（癌细胞扩散至身体其他部位）胃肠道间质瘤患者。《NAVIGATOR研究：阿伐普替尼治疗PDGFRα D842V基因突变的、晚期胃肠道间质瘤的研究》Lancet Oncology，2020年7月 (1)NAVIGATOR研究是一项两部分、开放标签、剂量递增和剂量扩大的1阶段研究。这篇文章对PDGFRA D842V突变的患者进行单独分析，并报道了研究结果。研究纳入无法手术切除的、胃肠道间质瘤患者，其中56人携带PDGFRα D842V突变，其中20位患者进入剂量递增组（即从30mg qd逐渐加量至最大耐受剂量），36位患者进入剂量扩大组（即使用最大耐受剂量）。最大耐受剂量为400mg qd，推荐剂量为300mg qd。中位随访15·9个月，在PDGFRα D842V突变的56名患者中，9%完全缓解，79%部分缓解。治疗相关严重不良反应最常见的是贫血。在30-400mg qd的剂量下，没有观察到药物毒性；600mg qd时，两名患者出现剂量相关的不良反应。结论：阿伐普替尼在晚期PDGFRα D842V突变的胃肠道间质肿瘤患者中具有初步的抗肿瘤活性。瑞普替尼（ripretinib） 瑞普替尼（ripretinib）是一种对广泛的KIT和PDGFRA基因突变激酶抑制剂。2020年5月，FDA批准瑞普替尼（ripretinib）用于晚期胃肠道间质瘤的四线治疗。《INVICTUS研究：瑞普替尼治疗晚期胃肠间质肿瘤的3期试验》Lancet Oncology，2020年7月 (2)这项双盲、随机、安慰剂对照的第三期研究中，纳入晚期、进展性胃肠间质肿瘤患者129人，既往均使用过伊马替尼、舒尼替尼和瑞格拉非尼在内的治疗。患者随机分入瑞普替尼 150mg qd或安慰剂组，随机分配到安慰剂组的患者在疾病进展时允许转到瑞普替尼组。双盲期，瑞普替尼组和安慰剂组的中位无进展生存期分别为6.3个月和1.0个月（风险比0.15，p < 0.0001）。最常见的严重不良反应包括脂肪酶升高、高血压、疲劳和低磷血症，两组发生率相似。结论：瑞普替尼显著提高晚期胃肠道间质瘤患者的无进展生存期。乙型肝炎急性和慢性乙型肝炎感染均刻有不同的临床表现。急性期，临床表现可从亚临床、或无黄疸型肝炎至黄疸型肝炎，有时还会出现爆发性肝炎（

Stan Walker has revealed he was told he had to be "less Māori" to be successful in Australia.The singer and actor, who first made a name for himself when he won Australian Idol in 2009, has climbed the charts on both sides of the Tasman and won eight New Zealand Music Awards since.But Walker, whose iwi are Tūhoe and Ngāti Tuwharetoa, said many different people in the industry in Australia - "old heads who come from the old world" - told him he had to change to be on a mainstream platform."The more Māori I was, the less appealing I was to record sales, to be sold, basically," he told Newstalk ZB's Jack Tame."I literally was told, 'I think you're being too brown' and 'you're not like them' - I am every part of who 'them' is."Walker said he "got tired" of being someone he wasn't and realised something had to change."It all just got me to a place of, what the hell am I doing? This is not me. I got here because I'm me, not because of what they want."He said when he came back to New Zealand to be a judge on The X Factor in 2013, that he realised he needed to do for himself what he was encouraging other young artists to do."I had to come back and find myself again, coming home and spending time with my nannies."Now he's fully embraced who he is, with his new single Bigger/Tua being released in both English and te reo Māori.Walker said the song was a tribute to his tūrangawaewae, with the music video featuring scenes from his marae.Walker said the song was written "for such a time as this"."Considering where the world is at in 2020, for me it's really solidified what my purpose is and who I am and where I'm going."Walker also spoke about his experience with lockdown, saying it was "one of the most incredible things" to ever happen to him."I got to learn about myself, there was a lot of mending of relationships in my life."I was forced to be still ... it was the most still I've ever been since I had cancer."Walker had his stomach removed in 2017 after he was diagnosed with cancer. He had a rare mutation of the CDH1 gene that runs in his family, and they had already lost 25 family members to the disease.He took several years out from touring and releasing music but this year he has released Bigger/Tua and a memoir is due out on October 8 titled Impossible: My Story, with HarperCollins New Zealand.Asked how embracing his cultural identity might affect his commercial success, he said "What sells better than the truth?""I'm unapologetically Māori. When people ask 'Are you a Kiwi, are you an Aussie?' I'm Māori, I live in both countries but I'm Māori."

This podcast summarizes and provides commentary on the recent article by Yadav et al. in which the authors demonstrate that expansion of the current NCCN guidelines for genetic testing in breast cancer patients to include all women diagnosed at or below the age of 65 markedly improves the sensitivity for detecting pathogenic germline variants without requiring the testing of all breast cancer patients.   TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article “Evaluation of Germline Genetic Testing Criteria in a Hospital-Based Series of Women with Breast Cancer” by Yadav et al. My name is Erin Cobain, and I am a Clinical Lecturer at the University of Michigan Rogel Cancer Center in Ann Arbor, Michigan United States. My oncologic specialty is breast cancer. In this study, the authors sought to determine the sensitivity and specificity of current genetic testing criteria for the detection of pathogenic germline variants in women with breast cancer. Current national comprehensive cancer network (NCCN) guideline criteria, updated in January 2020, recommend that genetic testing be offered to all women diagnosed with breast cancer at age 45 or younger, those diagnosed with triple negative breast cancer at age 60 or younger as well as those with family history of breast, ovarian, prostate or pancreatic cancer that meet specific criteria. In addition, any patient with Ashkenazi Jewish ancestry is recommended to undergo testing. This most recent update to the guidelines also incorporates a recommendation to offer testing to individuals who have a greater than 5% risk of having a BRCA1 or BRCA2 mutation by prior probability models such as Tyrer-Cuzick or BRCAPro who would not otherwise meet criteria.  Prior to the publication of the present study by Yadav and colleagues, several recent articles including those by Beitsch et al. and Yang et al. indicate that many patients with pathogenic or likely pathogenic germline variants in genes associated with hereditary breast and ovarian cancer syndromes are missed by current testing criteria. The Beitsch et al. study analyzed results from a prospective registry whereby patients with previously or newly diagnosed breast cancer were consented and underwent genetic testing with an 80-gene panel test. Approximately 1,000 patients were enrolled and approximately half met NCCN guideline criteria for genetic testing. Among the patients who met NCCN guideline criteria, 9.4% had a pathogenic or likely pathogenic variant identified. For those patients not meeting NCCN guideline criteria for testing, 7.9% had a pathogenic or likely pathogenic variant. This led the authors to conclude that nearly half of breast cancer patients with pathogenic germline variants would be missed by NCCN criteria. Similarly, Yang and colleagues examined a cohort of patients with personal or family history of breast or gynecologic cancer from a Medicare database undergoing genetic testing. Data from over 4,000 patients tested indicated that the rate of identifying a likely pathogenic or pathogenic germline variant was nearly identical in the cohorts that met NCCN guideline criteria for testing versus those that did not, with the rate of pathogenic germline variants being approximately 10% in both groups. Indeed, the results from these studies lead the American Society of Breast Surgeons to issue a recommendation in October 2019 that all patients with personal history of breast cancer undergo genetic testing. While this recommendation would undoubtedly identify more patients with genetic susceptibility to breast cancer and other malignancies, the implications of this recommendation must be considered. Large scale testing would more readily identify patients with moderate penetrance genes that are without established cancer risk reduction guidelines. More testing also leads to increased identification of variants of uncertain significance, presenting challenges both for patients and their providers attempting to best counsel individuals with an ambiguous result. Finally, inequities in access to testing and genetic counseling resources as well as increased healthcare costs that result from broad testing are of major concern. If cost of testing is not covered by insurance, paying out of pocket may not be feasible for many patients.  In the present study, Yadav and colleagues attempted to address some of these apprehensions regarding the adoption of widespread genetic testing in breast cancer patients. The investigators enrolled patients with personal history of breast cancer over a 16 year period of time into a registry and evaluated for pathogenic germline variants in 9 cancer predisposition genes, including ATM, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, and TP53. These genes were selected because there are clear management recommendations in the NCCN guidelines when they are identified.  The authors found that among almost 4,000 women tested, those meeting current NCCN guideline criteria for testing (comprising 48% of the cohort) were more likely to harbor a pathogenic germline variant than those women who did not meet criteria. The rate of detection of pathogenic germline variants was 9% and 3.5% in these groups respectively. Despite the updated NCCN guideline criteria identifying patients with pathogenic germline variants more readily, there are undoubtedly still patients missed by these criteria. The authors conducted subsequent analysis to include all women diagnosed with breast cancer at age 65 or younger, which achieved 90% specificity for the 9 cancer predisposition genes selected and greater than 98% specificity for identification of pathogenic germline variants in BRCA1 and BRCA2. Given this, the authors concluded that expanding the NCCN genetic testing criteria to include all women diagnosed with breast cancer at or before the age of 65 will markedly improve the sensitivity of genetic testing and avoid the need to evaluate all patients with personal history of breast cancer. The major limitations of this study were that cost-effectiveness of this approach was not analyzed, and the majority of the patients included in the registry were White, limiting the applicability of these findings to a diverse patient population. Despite these limitations, this study offers a promising and considered approach to genetic testing in patients with personal history of breast cancer. While validation of this approach in additional study cohorts would be of great value, this data strongly suggests that testing all patients at or below age 65 at the time of breast cancer diagnosis achieves a balance between the two current testing paradigms, identifying the vast majority of patients at risk, and avoiding unnecessary testing of many. This concludes this JCO Podcast. Thank you for listening.

When Cherielee was 26 years old, she was found to carry a mutation in the CDH1 gene. Her genetic diagnosis led her down a path that included a prophylactic gastrectomy at the age of 30, followed by multiple complications. Today, Cherielee is 31 years old, still recovering but very glad of her decision to undergo prophylactic surgery and grateful for her aunt's cancer diagnosis and testing that allowed her to take steps to prevent cancer. Cherie is passionate about the need for doctors to focus on their patients’ cancer family history and either offer hereditary cancer testing or refer their patients on to a genetic counselor. She also recently started an Instagram account focused on Stomach Cancer Awareness: @previvor_perspective Story Reference Points: Cherie’s aunt is found to carry a CDH1 mutation @ 1:56 Cherie’s mother gets involved with No Stomach for Cancer and has genetic testing done through a genetic counselor @ 7:17 Medical management for someone with a mutation in CDH1 @ 10:30 Cherie and her younger brother and sister consider testing @ 15:26 Cherie receives her positive test results @ 17:57 From screenings to prophylactic gastrectomy @ 19:59 Multiple complications and a long recovery @ 24:04 Adjusting to life without a stomach @ 29:40 Breast screenings and a decision about prophylactic mastectomy @ 34:15 Cherielee’s story inspires her fiancé’s career @ 35:52 Cascade testing saves other relatives’ lives @ 39:40 Looking ahead to family planning @ 40:54 Inspiration to start the @previvor_perspective instagram account @ 43:32 Why are doctors missing patients who should be offered testing? @ 47:07 Links and Resources Cherie’s Instagram focused on Stomach Cancer Awareness: @previvor_perspective No Stomach for Cancer Facing Our Risk of Cancer Empowered (FORCE)/a> Cherie on Linkedin Cherie on Facebook Check out other Patient Stories podcast episodes. Read other Patient Stories on the Grey Genetics Patient Stories Page Do you want to support Patient Stories? You can now make a donation online! Want to support Patient Stories in a non-monetary way? Leave us a review on iTunes, or share your favorite episodes on Social Media. Patient Stories on Twitter: @GreyGeneticsPod Patient Stories on Instagram: @patientstoriespodcast Are you looking for genetic counseling? Patient Stories is sponsored by Grey Genetics, an independent telehealth genetic counseling and consulting company. Book an appointment with a genetic counselor specialized in hereditary cancer or in or another area of concern. Choose from our growing Network of Genetic Counselors. All genetic counseling appointments take place over secure, HIPAA-compliant video-conferencing or by phone. Check out ou

This work employed a mouse model of liver specific depletion of the gene Cdh1 and its respective protein E cadherin to study the role of this protein in liver homeostasis and pathophysiology. The experiment was done with specific focus on the effects concerning hepatocellular carcinoma (HCC) development. Background: Cadherins are present in all higher organisms, and have been studied rigorously in the past. The cadherin family is huge, encompassing more than 400 (known) members. E cadherin is the name-giver of that family and is considered to be of great importance to a broad range of physiological and pathophysiological functions. Known functions include cell-cell adhesion and deregulation of E-cadherin (in almost all cases a down-regulation) is associated with increased aggressiveness in both human and animal tumors. Aside from that, E-cadherin is of great importance during embryogenesis. Worldwide, HCC is an important disease in humans, especially in certain countries (mostly developing countries). While females are only occasionally affected by HCC, it ranks among the top 3 tumor-related death causes in males. The difficulties in treating this tumor curatively make research of genes or proteins relevant to HCC important for human medicine improvement. The existence of a connection between Cdh1 or E Cadherin and HCC has been suggested, but more research is still required. Methods: Employing Cre/loxP technology, a mouse model of liver specific E cadherin depletion was created (L Cdh1del/del). The mice were compared to littermates with normal Ecadherin levels (L Control). Mice body and organ weight was documented at different ages, and liver tissue was analyzed using qRT-PCR (cDNA), Western blot, histochemistry and immunohistochemistry. To test effects of the reduced E-cadherin on tumor development, a cohort of male mice was injected with a chemical carcinogen (DEN) at two weeks of age to induce HCC, and mice were analyzed 4, 8 or 12 months later. Results: Aside from a slight retardation in weight gain, L Cdh1del/del did not suffer from severe health effects or spontaneous tumor development. Histology showed some alterations around the small bile ducts in the liver (in the periportal fields) and RNA analysis showed that mice underwent a phase of considerably altered RNA activity (429 significantly regulated genes at 3 weeks of age), but later only a few up/down-regulated genes remained (28 genes at 6 weeks of age). Aside from Cdh1, no genes considered cadherin family members were regulated. Western blot analysis, qRT-PCR and IHC confirmed that E cadherin was down regulated on RNA level and on protein level in this animal model. All mice injected with DEN developed tumors, but L Cdh1del/del were affected more heavily, with tumors reaching large diameters faster. If mice were kept longer than 8 months, L Cdh1del/del had to be euthanized significantly earlier than L Control. A spin-off of the model was the establishment of a permanent cell line, developed from a liver tumor of a L Cdh1del/del mouse. PCR requiring a functional primer binding site on exon 10 of Cdh1 could not produce DNA product, indicating that the cell line was a derivative of an E-cadherin negative liver cell. Conclusion: Liver specific E cadherin reduction had a surprisingly small effect in the present mouse model (compared to the effects of E cadherin loss in organs like the skin or intestine, as documented in the literature) if mice were not challenged with a chemical carcinogen. If mice were challenged with experimental HCC induction, lack of E cadherin had a strong effect on the tumor growth. These findings attest, by an experimental animal model, the importance of E cadherin for tumor development in the liver. This data reinforces previous observations concerning E cadherin effects on tumors in studies working with resected human tumors of the liver or with conditional organ specific mouse models studying carcinoma in other organs (like the mammary gland, for example). Therefore, this animal model could help improve the understanding of mechanisms regulating aggressiveness in human tumors.

One third of gastric cancers harbor genetic or epigenetic alterations in the CDH1 gene, and those with structural changes have a poorer prognosis; gastric tumor profiling for oncogenic amplifications and mutations may identify targets for personalized therapeutics.

E-cadherin is a major component of adherens junctions. Impaired expression of E-cadherin in the small intestine and colon has been linked to a disturbed intestinal homeostasis and barrier function. Down-regulation of E-cadherin is associated with the pathogenesis of infections with enteropathogenic bacteria and Crohn's disease. To genetically clarify the function of E-cadherin in intestinal homeostasis and maintenance of the epithelial defense line, the Cdh1 gene was conditionally inactivated in the mouse intestinal epithelium. Inactivation of the Cdh1 gene in the small intestine and colon resulted in bloody diarrhea associated with enhanced apoptosis and cell shedding, causing life-threatening disease within 6 days. Loss of E-cadherin led cells migrate faster along the crypt-villus axis and perturbed cellular differentiation. Maturation and positioning of goblet cells and Paneth cells, the main cell lineage of the intestinal innate immune system, was severely disturbed. The expression of anti-bacterial cryptidins was reduced and mice showed a deficiency in clearing enteropathogenic bacteria from the intestinal lumen. These results highlight the central function of E-cadherin in the maintenance of two components of the intestinal epithelial defense: E-cadherin is required for the proper function of the intestinal epithelial lining by providing mechanical integrity and is a prerequisite for the proper maturation of Paneth and goblet cells.