Intro: Welcome to the CGA-IGC podcast series, brought to you by CGA's Education Committee and made possible through the generous support of our sponsor, Lynsight. Each episode aims to bring you an in-depth discussion related to emerging data, clinical challenges, and unique perspectives in the world of hereditary GI cancers.

Before we start, we'd like to remind you that the content of this podcast is not intended to replace professional medical advice, diagnosis, or treatment, and the content reflects expert opinion at the time of recording. Keep listening to find out more about this episode's host, guest and featured topic. Also, be sure to learn more about our sponsor at lynsightlabs.com. That's L-Y-N-S-I-G-H-T labs.com.

Josie Baker (Host): My name is Josie Baker and I am a genetic counselor at the Ohio State University, and I'll be your host today. During today's podcast, I'll be speaking with Maegan Roberts, a certified genetic counselor from the Ohio State University. Our focus will be on CDH1 and hereditary diffuse gastric cancer, specifically talking about the challenges genetic counselors and providers face when discussing risks and recommendations to patients.

Maegan, thank you so much for speaking with us today. Our listeners will be familiar with hereditary diffuse gastric cancer as being a highly penetrant predisposition syndrome, associated mainly with diffuse gastric cancer and lobular breast cancer. With recent data published on penetrance with CDH1 gene variants, we are facing challenges in discussing changes in cancer risks and management recommendations with patients and providers. Maegan, working at OSU, you specialize in working with hereditary GI cancer predisposition syndromes. Can you tell us a little bit about your experience with hereditary diffuse gastric cancer?

Maegan Roberts: Sure. My CDH1 expertise really started to develop around 2013 when I was in a laboratory-based position. In this role, I was involved in the development of CDH1 ACMG-based classification rules.

I was then also responsible for the classification of CDH1 variants identified on both multi-gene cancer panels as well as exome. In 2022, I made the move to Ohio State to become more involved in the clinical care of patients with hereditary diffuse gastric cancer. I am currently co-chair of the Gastric Cancer ClinGen Variant Curation Panel, a member of the International Gastric Cancer Linkage Consortium, and a member of the Blepharocheilodontic Syndrome Consortium, better known as BCDS.

Host: And going into a little bit more data and information around CDH1, can you give us an overview of how the newly published data on CDH1 penetrance and management recommendations contradict past historical data?

Maegan Roberts: The history surrounding the identification of CDH1 and subsequent penetrance estimates is such an important topic to cover. CDH1 was first discovered in 1998 with the first penetrance estimates being published in 2001. Initial lifetime gastric cancer risks were estimated to be 67-83% lifetime. Subsequent publications in 2007 and 2015 estimated the lifetime risk to be 40-70%.

The key to understanding these initial gastric cancer penetrance estimates is understanding that they were all subject to ascertainment bias based on study design. More recent publications after the introduction of multi-gene panels have not ascertained based on strong family history of gastric cancer, which has resulted in lower overall penetrance estimates.

Commercial laboratory-based data in 2019 reported a lifetime gastric cancer risk of 25 to 42%. While in 2024, penetrance was reported to be as low as 10% lifetime with no family history of gastric cancer. Multi-gene panels have forced us to accept, or maybe better said learn, that the identification of a germline CDH1 pathogenic variant is not a guarantee that the patient will develop diffuse gastric cancer. This in turn has led to medical management recommendations, which are more personalized based on the patient's medical and family history.

Host: To dive a little deeper into this, can you tell us the difference in IGCLC and NCCN'S approach to management recommendations?

Maegan Roberts: This is also such an important topic to cover. First, the International Gastric Cancer Linkage Consortium, best known as the IGCLC is an international consortium. The National Comprehensive Cancer Network, known as NCCN, is a US-based consortium. The IGCLC is a great organization, but there are some things about it that are important to understand as a US-based provider. IGCLC's membership has a very large number of European members. In Europe, most countries have universal healthcare systems. Genetic testing is tightly regulated, and strict phenotype-based criteria is used to make genetic testing decisions.

As a result, European cohorts often have a more severe clinical presentation compared to what we see here in the U.S. This trickles down to IGCLC and is seen with a more conservative approach in their genetic testing criteria and management recommendations. I find it very encouraging that, last year, NCCN moved CDH1 out of the gastric cancer guidelines and into the detection, prevention, and risk reduction guidelines. These updated management, and genetic testing guidelines are much more reflective of the population we are identifying here in the US.

I do think that updated IGCLC guidelines will be a bit more relaxed compared to previous versions, but NCCN guidelines will still be the better option for us to follow here in the US for our US-based patients. We need to remember NCCN guidelines are being written by clinicians, seeing patients based on experiences here in the US.

Host: And with these changes, many genetic counselors have expressed difficulty having these conversations with both patients and providers. How should genetic counselors approach the conversation about CDH1 with patients?

Maegan Roberts: I think honesty and confidence is really the key here. A large part of patient counseling for germline CDH1 pathogenic variance is simply educating yourself to create that confidence. It is also important to know how the gastroenterology and the GI surgical teams that you work with approach these topics with patients so that there can be one solidified message to the patient. Additionally, it is pertinent to prepare patients for the discussions that will occur when they meet with these providers surrounding endoscopic screening and surgical options.

Host: Are there any specific phrases or techniques that you use to help patients process this information?

Maegan Roberts: This is a great question. There's one specific topic that comes to mind, and that's pT1a signet ring cell carcinomas, okay? We often refer to these as T1a SCCs or, you know, a T1a signet ring cell carcinoma. But this is a term on the pathology report that can lead to a lot of confusion and anxiety. So, setting the stage ahead of time is so incredibly important. A T1a Signet ring cell carcinoma is technically considered a cancer, but is one that is contained to the lamina propria. They're fairly common finding when endoscopic screening is completed. In fact, the a priori chance of identifying at least one T1a signet ring cell carcinoma, and a total gastrectomy specimen has been shown to be around 90-95%. So the question isn't "Are they present?" but more "Will one be detected if screening endoscopy with random biopsies elected?" It has been shown that these T1a lesions can remain indolent and are not a guarantee to develop into an invasive gastric cancer.

As such, I do some really heavily counseling around the expected presence of T1a signet ring cell carcinomas, and often refer to them as a precursor lesion. I have also found that using a counseling tool to show a cross section of the stomach where the T1a signet ring cell carcinomas are located, help patients wrap their head around the information.

Host: Have you encountered situations where patients feel conflicted or resistant to updated medical advice? And how do you handle those discussions?

Maegan Roberts: My experience has been more the opposite with patients embracing the updated management recommendations. Now, we're identifying more patients without a strong family history of gastric cancer. They seem quite relieved to find out that NCCN provides options for both endoscopic surveillance and prophylactic gastrectomy. One specific family is coming to mind where the proband had a prophylactic gastrectomy 15 to 20 years ago due to the identification of a known familial CDH1 pathogenic variant. He's had a very difficult time after his prophylactic gastrectomy. He and his wife were quite relieved to hear that, more recently, there has been more support for consideration of endoscopic screening as his children now start to approach the ages to consider testing for the familial variant.

Host: And switching over to discussions with providers, how can genetic facilitate productive conversations between surgeons, gastroenterologists, or other specialists regarding evolving recommendations?

Maegan Roberts: My approach has been to keep the physicians and the genetic counselors that I work with up to date on CDH1 penetrance publications and changes to management guidelines. So, my advice is to share publications with your collaborating physicians and engage them in conversations.

As I highlight above, it's really important to know where your collaborating physicians stand on the management of patients with germline CDH1 pathogenic variance. You will want to make sure that one clear, concise message is being delivered to the patient so that they can make a well-informed decision.

Host: Do you have any advice or recommendations on what the best approach is when a provider may be skeptical of changing previously known guidelines and management recommendations for patients?

Maegan Roberts: This is quite a hard question to answer. Ultimately, I think my answer depends on how closely you work with that physician and how open they are to discussing the updated guidelines. I have to say I've been known to push the buttons of the physicians that I work with a bit with regards to getting them to think outside of the one-size-fits-all box that has existed for the last 20 years. In the end though, I always knew where they stood and tailored my counseling so that they would be prepared to meet with my collaborating physicians.

Host: What strategies can genetic counselors use to foster long-term collaboration with providers as genetic knowledge continues to evolve?

Maegan Roberts: My best advice would be to not be afraid to keep the conversation going or to suggest periodic review of newly published guidelines and papers as a team.

Host: To wrap up our conversation today, do you have any take-home messages or last thoughts you would like to share with our listeners?

Maegan Roberts: Sure. My best advice is to educate yourself and approach the topic with confidence. If you understand the hows and the whys of the NCCN CDH1 management guidelines, the significance, or should I rather say, the lack of significance of T1a signet ring cell carcinomas, you'll be better versed to counsel patients found to have germline CDH1 pathogenic variants.

Lastly, get to know the team that will be managing these patients with you. Understand where they stand on the topic, share new data as it becomes available, and keep the conversation going.

Host: At this time, we'll conclude this podcast once again. Thank you, Maegan, for joining us for an episode of the 2025 CGA-IGC podcast series. Stay tuned for our next episode to come. Thank you to all of our listeners.