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Greg Guthrie: Hi, everyone. I'm Greg Guthrie, and I'm a member of the Cancer.Net content team, and I'll be your host for today's Cancer.Net podcast. Cancer.Net is the patient information website of ASCO, the American Society of Clinical Oncology. Today, we're going to be talking about the ASCO provisional clinical opinion, “Somatic Genomic Testing in Patients With Metastatic or Advanced Cancer.” Our guests today are the co-chairs of the team that wrote these recommendations. Dr. Funda Meric-Bernstam from the University of Texas MD Anderson Cancer Center in Houston, Texas. Thank you for joining us today, Dr. Meric-Bernstam.

Dr. Meric-Bernstam: Thank you for having us.

Greg Guthrie: And our second guest today is Dr. Mark Robson from Memorial Sloan Kettering Cancer Center in New York City. Dr. Robson, thank you for joining us today, too.

Dr. Robson: Thank you for having me.

Greg Guthrie: So before we begin, I should mention that Dr. Meric-Bernstam does not have any relationships to disclose related to this podcast. Dr. Robson has led clinical trials in PARP inhibitors but has not received any personal compensation for this research. Full disclosures for this podcast can be found on Cancer.Net. So, Dr. Robson, let's begin by discussing what a provisional clinical opinion is and why they are important.

Dr. Robson: So there are times when there are sea changes or incredibly important changes taking place in oncology practice. And sometimes these are clinical trial data, and sometimes they are more global. And this is a situation where it's one of those global challenges. And what ASCO does in situations like this is pull together a group of experts to provide guidance for the membership through a process of discussion and informal consensus rather than necessarily direct evaluation of clinical studies. And this is important because it allows the membership to benefit from these expert opinions.

Greg Guthrie: Now, Dr. Meric-Bernstam, this provisional clinical opinion discusses somatic genomic testing in metastatic or advanced cancer. What is somatic genetic testing, and how is it used in cancer treatment?

Dr. Meric-Bernstam: Oh, thank you. This is a really exciting time in the last decade. We have a lot more tools to understand cancer biology. And cancer is a genomically-driven phenomena, where there's alterations in the DNA, in the tumor, that confers the cancer cells a competitive growth and survival advantage. And only 10 years ago, we had the capability of doing this 1 gene at a time, to sequence a gene to see what is different, but now we have technologies where we can look at several hundred genes at a time. We are referring to these as multigene panels. And we're talking about genomic testing or somatic genomic testing. These are tests that look at several hundred genes, either looking at the tumor sequence alone or looking at the tumor sequence and comparing it to the normal sequence so we can see what has differed in the tumor that may give it a competitive advantage. We're doing this to be able to identify if there are genes that are altered that are therapeutically actionable. What we mean by that is, is there an alteration that we think confers the cancer cell an advantage for which we have a drug that either directly or indirectly we can use to help inhibit the cancer cell growth or preferably cause the cancer cell death?

Greg Guthrie: Great. And so how is somatic testing different from germline testing?

Dr. Robson: So somatic testing is testing the DNA or the nucleic acids, if you will, in the tumor itself, and germline testing is testing the DNA in normal tissue. And so the DNA in the normal tissue is what people are born with, and of course, most of the DNA in the tumor is the same as what people were born with. But there are specific changes that develop as the cancer arises, and it's those specific changes that are called somatic alterations.

Dr. Meric-Bernstam: This is actually a really interesting point though because some tests report out germline alterations as well because only the tumor is sequenced, while some tests report the tumor, only subtracting what was in the germline. Thus, unless the germline result is specifically reported, a patient that has a known germline alteration may be surprised to see that it's not in the tumor report. And on the flip side, a tumor-only test may find a germline alteration, and thus it's important that physicians and patients are aware of that. That needs to be further pursued with the genetic testing.

Greg Guthrie: Wow, just a wealth of information coming from this testing now. Sometimes I hear the term next-generation sequencing mentioned in regard to cancer. Does this provisional clinical opinion also touch on that?

Dr. Meric-Bernstam: Yes. When we are referring to genomic testing panels or multigene panels, we are talking about the next-generation sequencing technology that has the ability now to use a small amount of tumor to be able to report out the sequence of several hundred genes. We have, of course, broader panels also coming, such as whole exome sequencing, whole genomic sequencing. Although, majority of our provisional clinical opinion is talking about the use of these in several hundred gene panels.

Greg Guthrie: Amazing. Alright. Dr. Meric-Bernstam, so what should people with cancer and their loved ones know about this opinion?

Dr. Meric-Bernstam: This has been a really complicated time because the introduction of next-generation sequencing made genomic testing available, but to be fair, not widely available initially. Only more recently is it more broadly available, and there's been some confusion about which patients with which diseases should get or can get genomic testing or would benefit from genomic testing. So we wanted to frame this by first highlighting that if a patient has a metastatic or advanced cellular tumor type and there is a genomic biomarker that is linked to a therapy approved for a regulatory agency, or they have a tumor type where there's a drug that's approved but there's a known genomic resistance marker, these are scenarios where we feel patients should get genomic testing. Now, the more complicated area, a little more controversial, has been scenarios where the patient has a disease that is not one of those diseases that has a disease-specific approval for a drug. And in that scenario, we believe there's still value in genomic testing for several reasons.

There's been several new drug approvals for what we call tumor-agnostic drugs. That means if you have an alteration that gives you sensitivity to immunotherapy because you have what we call microsatellite instability, and some next-generation sequencing panels can report that out, then, regardless of your tumor type, you may be able to get offered immunotherapy. If you have multiple mutations in your tumor, something we call the increased tumor mutation burden, that is now linked to immunotherapy approval. So irrespective of tumor type, if a patient is eligible for immunotherapy, they benefit from getting genomic testing. And then on top of that, we now are seeing more and more that patients may have a genomic alteration that we think is a compelling target. But they may have it-- they may have it in a disease where that drug was not approved. And we're now starting to see that in many clinical trials. We're seeing activity by targeting those alterations. So there may be additional opportunities, especially for clinical trial enrollment, by identifying these potentially actionable alterations in other diseases.

So taking this together, we believe multigene testing will provide both additional approved indications and clinical trial indications. And in addition, fusion testing can identify TRK fusions, a fusion type that's found commonly in some uncommon cancers and uncommonly in some common cancers. But when it's found, it is a very compelling target. So again, because patients would be eligible for TRK inhibitors, irrespective of their tumor type, that's another scenario where next-generation sequencing may be beneficial for patients with advanced and metastatic disease, irrespective of tumor type.

Greg Guthrie: Wow, that's just an amazing overview right there. And one question that occurs to me is, is all of this genetic testing done from a biopsy sample? Or are there other ways a patient may experience this testing?

Dr. Meric-Bernstam: The traditional tumor-based testing is usually done either from a surgical sample or a biopsy sample. And again, it could be tumor-only testing or tumor plus a normal. Usually, normal would be something like blood as a comparator. However, there are times where a patient doesn't have a tumor accessible for a biopsy. In that scenario, there is now the opportunity to look at circulating free DNA to do panel testing on circulating free DNA for some of the more common actionable alterations. So there's a lot of momentum in using that approach, and this is what we often refer to as a liquid biopsy. And the liquid biopsy strategy is also very interesting because it's another way to pick up what changes of the tumor with treatment as well. So there's a lot of research going into using liquid biopsies when the patient also progresses on targeted therapy to see what has changed and how we need to change our therapy to address the tumor's evolution.

Greg Guthrie: Wow. Thanks for that, Dr. Meric-Bernstam. Dr. Robson, what are the emerging ways that genetic testing may be used to help people with cancer?

Dr. Robson: I think there are many, many ways. I was reflecting on this question, and I think it's important to kind of separate, as we did earlier, what we mean by genetic testing, again, because I think there's a lot of confusion. And there's certainly a lot of work going on in terms of testing of inherited DNA, so germline testing, to identify risks for cancer and potentially therapeutic targets. And that's not something that was discussed in this particular opinion, but it is an important way that genetics is being used to help people. On the side of the folks who already have cancer, the application of genetic technologies, as Dr. Meric-Bernstam said earlier, is identifying more and more targets. In other words, more and more alterations that are driving the cancers and for which we can test new drugs and hopefully achieve successes in a much more focused and less toxic way. And that work is going on at an exponential pace, and indeed, perhaps most of the new drugs that are entering the development pathway right now are indeed targeted therapies, not conventional broad-spectrum chemotherapies.

The genetic technologies are also being used as, again, Dr. Meric-Bernstam said, to look at DNA from the tumors that are circulating in the bloodstream. And one way is the liquid biopsy, which is for characterization. But another way that's coming online is just simply to look for the presence or absence of circulating DNA in people who are, for instance, post-op and don't have any evidence of disease to see whether or not they might, in fact, have some cancer that hasn't been detected by imaging. And then the hope is that we could then intervene earlier in that setting and perhaps prevent those circulating DNA from representing true metastasis, detectable metastasis. And again, a lot of work going on there. And there's a diagnostic and prognostic component to what's happening as well. There are, unfortunately, a number of people who present with metastatic cancer, and it's not obvious at all where that started. And work is being done now to use testing of the tumor DNA to help categorize the tumors, to direct the correct therapies, instead of just doing something generic and empiric. And there are many, many other ways that genetic technologies are being applied. It's really 1 of the 2 big frontiers in cancer therapy right now. The other one, of course, being immunotherapy. But it is an exciting time, and I think it's just going to continue to grow as the technologies become more and more innovative.

Greg Guthrie: That's really exciting. And thank you for sharing all of that perspective. I really wonder if helping with this somatic testing can help increase enrollment in clinical trials, too, to advance progress in other rare cancers?

Dr. Robson: I think it did, not necessarily just in rare cancers. I mean, people are—

Greg Guthrie: Agreed.

Dr. Robson: —certainly doing testing in common diseases and identifying these new targets. And you're exactly right. The only way we're going to be able to develop new therapies in that setting is through clinical trials. And so, for the appropriate people, genetic testing or testing of the tumor or somatic testing could very well identify clinical trial opportunities for them, and that's the way we're going to move forward.

Greg Guthrie: Outstanding. And again, I really love this distinction between somatic and germline testing and clarifying that for our listeners today. Dr. Meric-Bernstam and Dr. Robson, thanks so much for your time today and for sharing your expertise on these ASCO recommendations. It's been great having you and chatting with you today.

Dr. Robson: Thanks.

Dr. Meric-Bernstam: Thank you for having us.

Greg Guthrie: And for our listeners, if you'd like to learn more about genetics, genetic testing, and cancer, visit www.cancer.net/genetics. Thanks so much for joining us today, and be well.

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