JCO PO author Dr. Asaf Maoz at Dana-Farber Cancer Institute shares insights into article, "Causes of Death Among Individuals with Lynch Syndrome in the Immunotherapy Era." Host Dr. Rafeh Naqash and Dr. Maoz discuss the causes of death in individuals with LS and the evolving role of immunotherapy.

TRANSCRIPT

Dr. Rafeh Naqash: Hello, and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCOPO articles. I'm your host, Dr. Rafeh Naqash, podcast editor for JCO Precision Oncology and Associate Professor Medicine, at the OU Health Stephenson Cancer Center.

Today, I'm super thrilled to be joined by Dr. Asaf Maoz, Medical Oncologist at Dana-Farber Cancer Institute, Brigham and Women's Hospital, and faculty at the Harvard Medical School, and also lead author on the JCO Precision Oncology article entitled "Causes of Death Among Individuals with Lynch Syndrome in the Immunotherapy Era." This publication will be a concurrent publication with an oral presentation at the annual CGA meeting.

At the time of this recording, our guest's disclosures will be linked in the transcript.

Asaf, I'm excited to welcome you on this podcast. Thank you for joining us today.

Dr. Asaf Maoz: Thank you so much for highlighting our paper.

Dr. Rafeh Naqash: Absolutely. And I was just talking to you that we met several years back when you were a trainee, and it looks like you've worked a lot in this field now, and it's very exciting to see that you consider JCOPO as a relevant home for some of your work. And the topic that you have published on is of significant interest to trainees from a precision medicine standpoint, to oncologists in general, covers a lot of aspects of immunotherapy. So, I'm really excited to talk to you about all of this.

Dr. Asaf Maoz: Me too, me too. And yeah, I think JCOPO has great content in the area of cancer genetics and has done a lot to disseminate the knowledge in that area.

Dr. Rafeh Naqash: Wonderful. So, let's get started and start off, given that we have hosts of different kinds of individuals who listen to this podcast, especially when driving from home to work or back, for the sake of making everything simple, can we start by asking you what is Lynch syndrome? How is it diagnosed? What are some of the main things to consider when you're trying to talk an individual where you suspect Lynch syndrome?

Dr. Asaf Maoz: Lynch syndrome is an inherited predisposition to cancer, and it is common. So, we used to think that, or there's a general notion in the medical community that it is a rare condition, but we actually know now from multiple studies, including studies that look at the general population and do genetic testing regardless of any clinical phenotype, that Lynch syndrome is found in about 1 in 300 people in the general population. If you think about it in the United States, that means that there are over a million people living with Lynch syndrome in the United States. Unfortunately, most individuals with Lynch syndrome don't know they have Lynch syndrome at the current time, and that's where a lot of the efforts in the community are being made to help detect more individuals who have Lynch syndrome.

Lynch syndrome is caused by pathogenic germline variants in mismatch repair genes, MLH1, MSH2, MSH6, or PMS2, or as a result of pathogenic variants in EPCAM that cause silencing of the MSH2 gene.

Dr. Rafeh Naqash: Excellent. Thank you for that explanation. Now, one of the other things I also realized, similar to BRCA germline mutations, where you require a second hit for individuals with Lynch syndrome to have mismatch repair deficient cancers, you also require a second hit to have that second hit result in an MSI-high cancer. Could you help us understand the difference of these two concepts where generally Lynch syndrome is thought of to be cancers that are mismatch repair deficient, but that's not necessarily true for all cases as we see in your paper. Can you tease this out for us a little bit more?

Dr. Asaf Maoz: Of course, of course. So, the germline defect is in one of the mismatch repair genes, and these genes are responsible for DNA mismatch repair, as their name implies. Now, in a normal cell, we think that one working copy is generally enough to maintain the mismatch repair machinery intact. What happens in tumors, as you alluded to, is that there is a second hit in the same mismatch repair gene that has the pathogenic germline variant, and that causes the mismatch repair machinery not to work anymore. And so what happens is that there is formation of mutations in the cancer cell that are not present in other cells in the body.

And we know that there are specific types of mutations that are associated with defects in mismatch repair mechanisms, and those are associated a lot of times with frameshift mutations. And we have termed them 'microsatellites'. So there are areas in the genome that have repeats, for example, you know, if you have AAAA or GAGA, and those areas are particularly susceptible to mutations when the mismatch repair machinery is not working. And so we can measure that with DNA microsatellite instability testing. But we can also get a sense of whether the mismatch repair machinery is functioning by looking at protein expression on the surface of cancer cells and by doing immunohistochemistry. More recently, we're also able to infer whether the mismatch repair machinery is working by doing next-generation sequencing and looking at many, many microsatellites and whether they have this DNA instability in the microsatellites.

Dr. Rafeh Naqash: Excellent explanation. As a segue to what you just mentioned, and this reminds me of some work that one of my good friends, collaborators, Amin Nassar, whom you also know, I believe, had done a year and a half back, was published in Cancer Cell as a brief report, I believe, where the concept was that when you look at these mismatch repair deficient cancers, there is a difference between NGS testing, IHC testing, and maybe to some extent, PCR tes