JCO PO authors Dr. Edward Esplin and Professor Heather Hampel share insights into their JCO PO commentary, “Universal Germline Genetic Testing for Hereditary Cancer Syndromes in Patients With Solid Tumor Cancer” and discuss practical implications of testing for patients, geneticists, and clinicians. Host Dr. Rafeh Naqash, Dr. Esplin, and Professor Hampel discuss standard of care guidelines, insurance coverage, and benefits of testing. Click here to read the article!

TRANSCRIPT

Dr. Abdul Rafeh Naqash: Welcome to ASCO's JCO Precision Oncology Conversations, where we bring you the highlights and overview of Precision Oncology. Episodes will feature engaging conversations with authors of clinically relevant and highly significant JCO PO articles. These articles can be accessed at ascopubs.org/journal/po.

Hello and welcome. My name is Dr. Abdul Rafeh Naqash. I'm a medical oncologist and assistant professor at the OU Health Stephenson Cancer Center. I'm also the social media editor for JCO Precision Oncology, and you're listening to JCO Precision Oncology Conversations podcast.

Today I am thrilled to be talking with Dr. Edward Esplin and Professor Heather Hampel about their recent paper, ‘Universal Germline Genetic Testing for Hereditary Cancer Syndromes in Patients with Solid Tumor Cancers’. Heather Hampel is the associate director in the Division of Clinical Cancer Genomics and is a professor in the Department of Medical Oncology and Therapeutics Research at the City of Hope National Medical Center. Dr. Edward Esplin is a clinical geneticist and also the Head of Clinical Trials at Invitae in San Francisco, California.

For the purpose of this podcast, we'll be referring to each other using our first names. So welcome both Heather and Ed. Thank you for joining us today.

Dr. Edward Esplin: Thank you, Rafeh.

Professor Heather Hampel: Thanks for having us.

Dr. Abdul Rafeh Naqash: Well, first of all, I'd like to start by discussing some of the context behind this very interesting commentary. For the sake of our listeners, this is one of our first commentaries that we're doing a podcast on because this is very clinically relevant, especially for patients with cancer and without cancer, as I was reading through this commentary. So could you tell us, Ed, what prompted you to start this commentary, and what was the context of and the importance behind why something like this would make a difference in the clinical care of patients with cancer?

Dr. Edward Esplin: Yes, I'd be glad to. I think that we have seen over the past couple of years an ever-growing application and opportunity for application of precision therapies in patients with cancer of various kinds. And there has been with that a growing amount of evidence connecting germline genetic variants of a pathogenic nature with various types of cancer, breast cancer being one of the ones that is the most prominent. And as we've seen this evidence accrue in cancer types such as breast, which has probably got the longest history of a connection to germline genetics, but also accruing in other cancer types such as pancreatic cancer, prostate cancer, ovarian cancer, colorectal cancer, it became clearer and clearer that there is evidence to support a broader application of germline genetic testing than is currently the standard of practice. In part driven by the desire for access to these precision therapies that are driven in part by patients' germline genetic makeup and for the opportunity that germline genetic testing results have for affording patients potential access to clinical treatment trials - so the cutting edge of what is driving some of these treatment opportunities - and reviewing the amazing amount of work that has been done by a number of people across the country and across the world to support these opportunities and support this becoming more and more the standard of care really motivated us to do this project together, and we've been fortunate to have been involved in a number of the studies that we review in this commentary.

Dr. Abdul Rafeh Naqash: Thank you so much for that explanation, Ed. So, Heather, you, and both Ed, have obviously led and been part of a lot of work in this space and have developed guidelines in this space. For the sake of our listeners, whether they are clinicians or patient advocates, what are the current guidelines behind germline testing for patients with cancer and patients without cancer?

Professor Heather Hampel: That's a really good question, and that's a lot of what's driving it for me, just from a clinical perspective.

So currently, we mainly use the NCCN guidelines in the US for deciding when a patient is appropriate for germline genetic testing. And they only recommend or suggest considering germline genetic testing for all cases of three particular cancers: all cases of ovarian, pancreatic, and, most recently, this summer, all cases of colorectal cancer, they've said you could consider offering germline testing to. The other one that has a recommendation is prostate cancer, but that's restricted to patients with metastatic or advanced prostate cancer, so it's not all prostate cancers. When you look at the guidelines, you ask yourself, how did they decide that? Was it based on the prevalence of finding a germline mutation? Because if it was, there are several other cancers where germline mutations are just as prevalent, but that recommendation has not been made.

And what is happening really on the front lines is that some patients are not having access to genetic testing because we have very complex criteria requiring ages of diagnosis, certain tumor markers, particular family history constellations that make the criteria difficult to use for frontline primary care physicians and patients deciding who needs referred, and do I need to see cancer genetics? And how much more straightforward would it be if we just said everybody with cancer needs gene testing? At this point, we pulled the data together for this commentary. We feel like the odds of testing positive are high enough in every single solid tumor to support a change in the recommendations like that.

Dr. Abdul Rafeh Naqash: Thank you. And from the data that you highlight in this commentary, apart from the tumors that you mentioned, Heather, that have recommendations for germline testing, what other tumors would you try to incorporate this in subsequently as a first, second, third approach, maybe if you can't get to all tumors at the same time?

Dr. Edward Esplin: I would say that one of the ones that we would highlight, I think, also, is breast cancer, right? That's one that there's a clear link. And as Heather appropriately noted, while a universal guideline per se has not been established by the NCCN for breast cancer, about three years ago now, based on a publication in Journal of Clinical Oncology, there was the observation that the guidelines that existed at that time did not find a significantly increased number of pathogenic germline findings in patients who met the criteria as they existed at that time compared to those patients who did not meet the criteria. And based in part upon that data, the American Society of Breast Surgeons came out with guidelines that recommended, indeed, the time is now for universal germline genetic testing for all patients who have been diagnosed with breast cancer. So I think that one's another one that there's a great deal of opportunity for that to be implemented, consistent with what Heather has already noted.

And I think there is also data that's been presented at ASCO here very recently, suggesting that similar evidence supports testing not just for metastatic prostate cancer but possibly for a broader collection of prostate cancer patients as well, perhaps all of them with a similar finding where in a prospective observational cohort of unselected patients with prostate cancer. Again, when you applied the current guidelines for testing, there was no statistically significant difference in the number of actionable pathogenic germline findings in patients who met the current criteria compared to those who do not. Which unfortunately suggests that all those patients who are being excluded when we adhere to these guidelines are not able to access the genetic information that could be crucial to their treatment. And it's just because they're not being considered, even though there is a significant fraction of those individuals who do have germline genetic information that could impact their care and possibly the preventive care of their at-risk family members as well.

Professor Heather Hampel: And, Ed, let me add a study I did with you and your team on endometrial cancer. So the truth is, Rafeh, we don't want to pick. We want all solid tumor patients to get germline genetic testing through a multigene panel. But I think if we did have to pick, I would also add endometrial. We did a study of nearly 1000 unselected endometrial cancer patients in the state of Ohio and found just over 10% had a pathogenic variant in a cancer susceptibility gene. And you really could not predict, based on personal or family history factors, who was going to test positive.

Dr. Abdul Rafeh Naqash: And that was definitely something interesting that I caught in this commentary as I was going through it. One of the sentences that was definitely interesting for me was where you mentioned that these guidelines should include risk factors beyond family history and just testing for genes beyond BRCA1 and BRCA2, which are commonly identified entities associated with germline testing, that prompt germline testing.

But one of the other things is the financial aspect of it, which you have highlighted in your commentary. So, I wanted to briefly touch on that and understand what are the policies. It seems like different coverage policies cover different aspects of germline testing, so that's number one. Could you comment on that? And number two, a few years back, there has been an effort you might have heard of related to TMB or Tumor Mutational Burden Harmonization. Could there be some sort of harmonization to identify what are the most important testing genes that are or should be covered by some of these insurance policies? And could you highlight some of the aspects around that?

Dr. Edward Esplin: That's an excellent point. And what we have found has been the course this usually proceeds through is when the guidelines have established what the criteria should be for testing, then, over a certain period of time, naturally, the various insurance payers will then incorporate this into their medical policies. And, for better or for worse, this takes time. I think, in the opinion of most, the time that it takes is unfortunately prolonged for reasons that I don't personally understand.

But noting a bright spot, I'll highlight that UnitedHealthcare has actually taken the step of instituting a very patient-first medical policy. They did this back in 2020, where they recommend and consider medically necessary standard of care germline genetic testing for any patient who has a diagnosis of any cancer that is associated with Lynch syndrome. So meaning that any patient covered by their policy who has a personal diagnosis of colon cancer, endometrial cancer, the long list of cancers associated with Lynch syndrome, qualifies for germline genetic testing. And that's covered as part of the standard of care, which is a great move in the right direction for this, the largest private commercial insurance provider in the United States.

Now, do we need to see more of that? We absolutely do, because, as Heather’s already noted, there is an access issue, and there is a disparity issue for those individuals that don't meet the criteria of their own insurance policies, medical policy, they don't have access. And that requires them, if they choose, to get germline genetic testing, to pay an out-of-pocket cost of $250 or more, depending. And that may be something that is simply not accessible to individuals. And so there's a tremendous amount of effort that needs to be done to incorporate the guidelines as they currently exist into medical policy.

And I think, to your point as well, the discrepancies between various medical policies is certainly a challenge, and I don't have a good answer for how to address that. But it is frustrating, to say the least, that any clinician has to guess what their own particular patient that's sitting in front of them right now has in terms of medical policy coverage for germline genetic testing. And then that should in any way cause them to have to second guess ‘How am I going to get the standard of care to this patient?’ One of the other challenges that that potentially raises is, as we noted in our commentary as well, unfortunately, even for those cancer types where there is an established recommendation for universal germline testing, there is nowhere near the implementation of that that there ought to be.

For ovarian cancer, I think it's in the neighborhood of 30% of patients with ovarian cancer are getting this testing. For breast cancer, I think it's 25%. I can't remember if this was cited in this paper or not, but in a recent publication that we did with collaborators from Optum Health, we found that 5% or less of colorectal cancer patients who fell under this very progressive UnitedHealthcare policy were getting testing where everyone qualified for it under the medical policy. And so it really raises concerns about these missed opportunities in the setting of not effectively implementing germline genetic testing even when it is already recommended as the standard of care for the guidelines as they currently exist and not to be available to many more patients with various cancer types, as we've already noted.

Dr. Abdul Rafeh Naqash: Thanks for highlighting some of those very extremely important points. And, to your point, it's not implemented as much as it should.

Heather, have you, or others in this field, tried to understand what are those exact barriers that maybe me, as a clinician who sees at least patients with cancer, should know, or any other community-based oncology practice physician, should know that these are patients where testing is important and will have clinical implications. But what would be the barriers that potentially do not result in as much of a higher implementation of this testing than one would expect?

Professor Heather Hampel: Well, you may be surprised to hear this coming from a genetic counselor, but I've become convinced over the years that requiring pretest genetic counseling is one of the biggest barriers that actually keeps patients from getting genetic testing when it's appropriate. And not that we're trying to be, but just that we have long wait times. Patients may have a lot of appointments because of a new cancer diagnosis, and they’re overwhelmed. It just adds one more thing that's a little difficult.

And so, I really am interested in flipping the paradigm, and this is what we're doing at City of Hope now, currently, which is offering a precision medicine or a mainstreaming approach, where every single patient at the institution is offered germline genetic testing regardless of age, regardless of family history, regardless of tumor type. And then, believe it or not, this actually supports hiring more genetic counselors because you're dealing then with thousands of results that need to be hand-reviewed, and all positives, of course, get invited in for full post-test genetic counseling. And that saves that resource, that scarce resource of genetic counseling for the people who need it the most, the people who tested positive, whose family members need testing, who need to implement all the management that comes with testing positive.

I find those sessions much more rewarding because I can be much more helpful for the patient and the family, and our negative patients, or patients with variants of uncertain significance, get templated letters. We've got a team of genetic counseling assistants that are helping get those out because, of course, that's the majority of patients. But if they have questions or concerns or a strong family history, they can, of course, come in for post-test genetic counseling, too. But I think we're on the cusp of switching the paradigm of how cancer genetics is delivered, and that's really the only way to get it at scale to the large number of patients who actually need it.

Dr. Abdul Rafeh Naqash: Thank you. And, to that point, I wanted to say that, as cancer care becomes more and more multidisciplinary, it's right there in front of us that, I think, genetic counselors or clinical geneticists need to be part of these multidisciplinary teams, whether it's through molecular tumor boards or outside of molecular tumor boards. But I think that's where the gap is, at least from what I see on my end. And that's where communication gaps create issues. I recently had at least two patients in their 30s and 40s, one with a PALB2 and another with the CHEK2 alteration and initially identified on liquid biopsy, actually, and that prompted me to check for germline testing. And lo and behold, both were positive. And that resulted, as Ed, you mentioned, cascade testing and eligibility for trials, both ended up on different DNA damage-based trials. So, definitely a lot of clinical implications.

In your practice, when you were on the academic side, Ed, did you have instances where you definitely could see a lot of difference with respect to clinical management of a patient when such an event was identified when a pathogenic germline alteration was identified? And could you give us a few examples so that listeners maybe could try to understand better how some of these things can have significant clinical implications?

Dr. Edward Esplin: Well, I practiced when I was at Stanford in perhaps a little bit of a skewed environment, skewed to the better, where much of my interaction with patients with cancer and with molecular tumor board as well was in the setting of the Stanford Cancer Genetics Clinic. And so that's certainly highly enriched for well-informed individuals, very genetic-savvy medical oncologists. Obviously, the genetic counselors were the foundation there, and me, as a clinical geneticist, was actively involved in such a way that, yes, I think it made a lot of difference from the standpoint of patients with cancer, knowing what all of their options were. And in a number of cases also, the first thing, I think that at least from my standpoint, thinking about genetics a lot that many patients want to know is: why do I have this cancer? Did I do something to cause this? What's the underlying reason for this? And being able to either provide them reassurance that this was not something that was genetic, that this was not something that anyone in their family needed to be particularly concerned about, or that there was anything further that needed to be done about that. Versus the alternative, each of those answers was incredibly valuable to the patient and the patient's family for the reasons I think that you already alluded to.

If there is a genetic cause, then there are known actions that can be taken, whether it's an approved precision therapy or a clinical treatment trial. But then I think equally important, especially in those families where there was a known history of various cancers, and this is the first person who had any genetics done, then being able to share with that patient and with the patient's family that they're going through an excruciating disease course, but there is an opportunity for some of that to be mitigated, some of that risk to be mitigated in their family members; I think brought a certain amount of, I don't know if reassurance is the right word, but it was valuable and was greatly appreciated by those individuals.

One situation that I recall actually was a patient that– I can't remember what her age was, she was probably in her 40s or 50s, but she had developed a colorectal cancer. She had had appropriate germline genetic testing performed and had had a variant identified; I believe it was one of the Lynch syndrome genes, I’m not recalling exactly right now. But while she was undergoing her treatment, I mean, to her credit, she went right away to her family in particular, to, it happened to be her son who was one that got tested, and he was, I think, late teens, maybe early 20s, he had tested positive for the same thing. She made sure that he went in, he got his colonoscopy right away, and lo and behold, right, they find an advanced polyp in this 20-year-old kid that, had that not been done, that would have been identified in just a very tragic way. And yet, as a result of her taking charge and having the information that she needed to take charge for herself and for her family members, a cancer was literally prevented. And that individual's life was prolonged, if not saved, because of that action being taken on behalf of that individual who had the information they needed to do that.

Professor Heather Hampel: Yeah, I would just add I was talking to some of the docs at one of our network sites recently and talking about all of these benefits, which are 100% clear and really also hitting on the targeted therapy benefit quite a bit. And they reminded me of another benefit which we all often forget, and that is even surgical decision-making. So if we got this done early enough, there are certainly patients who have BRCA mutations who might elect to have bilateral mastectomies instead of a unilateral mastectomy or a lumpectomy and patients with Lynch syndrome who might elect to have a subtotal colectomy instead of a segmental resection. And again, this is where not only do we need to be offering this to everybody, but we need to be offering it early at the time of biopsy-proven cancer in some cases, where it could actually affect even their surgery.

Dr. Abdul Rafeh Naqash: Absolutely. And thanks, Ed, for highlighting some of those interesting and important examples.

Now, Heather, when we talk about 80%-85% of the places in the country, at least in the US, they may or may not likely have access to experts like yourself or elaborate, broad, experienced teams that you guys have been part of. So on the oncology side, in a clinic, we get a patient who gets next-generation sequencing done, a 500-600 gene panel where we may or may not have a geneticist, or the wait times are longer. What is your suggestion for individuals, both clinicians and for patients, in that setup? What are the things that one should think of to mitigate some of those delays in that setup where you may not get a geneticist to see that patient or a counselor to see that patient immediately? Looking at that sequencing panel, what couple of things would you think of should prompt a physician to refer a patient to a genetic counselor if it's on a need basis and not available for everybody?

Professor Heather Hampel: And you're talking about a tumor panel that's coming back.

Dr. Abdul Rafeh Naqash: Correct. I'm talking about NGS 600 gene panel because that's what gets done clinically every day, all day, when you're talking about patients with cancer. What are the few things that one should look out for?

Professor Heather Hampel: So there's some nice ESMO guidelines around this, and that's what we were using. Where I used to work, I would actually hand-review the tumor test that came in and kind of send an email to the docs when I said, "Hey, this may be germline. I think this patient needs a referral." Some of the labs are now calling those out themselves, which is nice. So if they're calling it out themselves, definitely pay attention to those boxes that say "Potential germline finding," and make sure you refer any patients with anything there. If you're using a lab that's not calling it out, certainly some of the rules—there's already guidelines - anyone with a BRCA1 or BRCA2 mutation found in their tumor should be referred, regardless of what kind of tumor they have. So that one's easy.

Some of the things I like to look at is what was the variant allele fraction. If it's around 50% or anything over 35%, you start thinking maybe that's germline, that's a nice red flag. Cautionary tales - every colon tumor has an APC mutation in it, so we don't want those referred to genetics. Most of them don't have familial adenomatous polyposis. So only send a patient with an APC mutation in their colon tumor if they– in the setting of polyposis. Same goes for TP53. You're going to find that in almost every tumor, and very few of them are going to have Li-Fraumeni Syndrome.

So in the ESMO guidelines, I believe in addition to having a TP53 and an APC around a VAF of over 35%, they want to see it in a young age tumor so that you have an indication that you might be dealing actually with Li-Fraumeni syndrome. The Lynch syndrome genes, I think the common genes, if you see a mutation in them, go ahead and refer. Consider the variant allele fraction and then beware of genes that are commonly mutated in all cancers because most of those won't be hereditary, and genetics can't handle seeing every single patient who has a TP53 mutation in their tumor. So we need to see an early age or some strong family history in those cases.

The other thing just to point out, because there are long waits and not everybody has a genetic counselor or geneticist on staff is COVID turned out to have a little silver lining for the genetics community, and that is cancer genetics transition very well to televideo medicine. And there are now multiple companies providing televideo medicine. And you can usually get your patient in within a day or two for a televideo genetic counseling appointment. And so, just be aware if you can't get them to an in-person clinic in a timely manner, there are many, many televideo companies now providing genetic counseling services remotely from the comfort of their own home within two days' notice, evening appointments, weekend appointments to make it convenient for the patient. I don't work for any of those companies, but I would say just that people should be aware that those options exist so that their patients don't have to have a long wait time.

Dr. Edward Esplin: Just one quick thought along those lines. And in the context of the commentary that we talked about, I think there is a good rationale that if the patient that we're talking about with respect to receiving the tumor profiling NGS they're having any of those solid tumor types that we're discussing, it does make a lot of sense now to order that Germline genetic test at the same time that they're getting that tumor test. And doing that via what I've heard described in the literature is a mainstream approach where the clinical oncologist can be the person who is initiating both the tumor test and that germline genetic test. Get both those things cooking at the same time, such that when you're getting those results back, and in many cases, you'll probably get the germline results back sooner, then you don't have to ask those questions. And the referral to genetics can take place at the same time as well, potentially, where those results can then be discussed in detail. And I say that in part because testing all these patients with these tumor types that we've described and taking a more universal approach can make a lot of difference, for example, in patients having the information they need to actually prevent or mitigate the risk for a second primary cancer.

We did a retrospective here a little while ago where we looked at patients who had received germline testing as a reflex to the tumor testing they’d received already. And appropriately so, I think, these savvy clinicians doing exactly what Heather described and referring them for germline testing. The unfortunate thing we found is in about 10% of the individuals that had a positive finding in their germline genetic test that was done as a downstream effect from their tumor profiling test, they had had this done on the second cancer that they had developed. And the genetic result that they received in their germline test was consistent with their first cancer that they had developed. In fact, if they had the germline testing done with the first cancer that they had developed, they would have the opportunity to have had that second cancer either downstaged by screening or completely avoided in its entirety with that information being at hand. And of course, it’s practically unconscionable that a patient who has successfully defeated cancer, beat it back into remission, would need to be at unknown increased risk of a second primary tumor simply for lack of getting germline genetic testing at the time when they were first diagnosed with cancer.

Professor Heather Hampel: And not to pile on, but I'm a big fan of paired tumor and germline testing as well. And I'll just mention a Memorial Sloan Kettering paper which showed that about 10% of the mutations found on germline testing had been missed on the tumor testing because they were large rearrangements or some other type of mutation that tumor testing is really not designed to detect. So you also can't feel reassured by a normal tumor test that there isn't a germline mutation because that's not the purpose of the test, and it doesn't find every type of mutation. And so I am also a big fan of paired testing when you can get it. I also think it gives you some potential for sorting out variants of uncertain significance because you can look for second hits, et cetera. So again, I think that's the future of cancer genetics.

Dr. Abdul Rafeh Naqash: Absolutely. And I learned a lot from all the stuff that you guys mentioned. And one of the things that you just mentioned that was on my mind was VUSs or Variants of Undetermined Significance. And briefly, I wanted to touch on VUSs. If I have a BRCA1, BRCA2 VUS, what should I do?

Dr. Edward Esplin: Nothing. Absolutely nothing.

Dr. Abdul Rafeh Naqash: Should I refer to genetics or just wait and watch?

Dr. Edward Esplin: Well, I'll speak with my Invitae hat on. The waiting and watching, like you describe, I think, is very relevant because Invitae and other labs are actively involved in interrogating these VUSs on a routine basis. We see thousands of patients every day, and we see these VUSs popping up, and we're combing the literature on an ongoing basis. We're depositing new variants into ClinVar all the time, and that is part of what we consider to be our responsibility to continuously review the evidence underlying these VUSs.

And in fact, in a paper published, I think it was in JCO Global Oncology here pretty recently, we noted that over the course of about, I think it was a five-year retrospective of patients who had undergone breast cancer testing, that we looked at how many of those individuals had a variant of uncertain significance, for example, in BRCA 1 and BRCA 2, and over that period of time how many of them got reclassified, and if so, what was the reclassification. There was some small fraction that over that time period got reclassified. I think I'm going to say it's in the order of like 10% or 20% and I'm saying that wrong. But more importantly, of all of the ones that got reclassified over that five-year period of time, 10% or less ended up being pathogenic or likely pathogenic. The vast majority of them ended up being benign or likely benign, which just underscores there's nothing that needs to be done for VUS when the evidence might ever accrue that would help to reclassify that. The vast majority of the time, it's going to end up downgrading it. That's not even the right term to use for a VUS. It's going to reclassify it as a benign or likely benign variant. And if it is something that should be actionable at some point in time, all of the reputable labs out there will notify clinicians of that change in status, and that is the time when action ought to be taken.

Professor Heather Hampel: Yeah, I think that's one of the biggest cons people will have against offering germline testing to every patient is the high variant of uncertain significance rate and a fear that those patients will be mismanaged as positives, particularly in settings where there aren't genetics professionals on staff. And so I think that's a really important point. I remember when Mary-Claire King was with her Lasker Award recommending germline genetic testing for all breast cancer, all women actually, unaffected, to try and prevent breast cancer. She had suggested that in that setting, they maybe should not report variants out at all because of the risk of them being mismanaged, and I think it's an interesting idea. Most of the academic centers like to have them; sometimes, they like to work on getting some of them reclassified. But I think it's something we need to consider if we start doing testing at this large of a scale or just being sure that everybody knows that a variant of uncertain significance should be treated like a negative until proven otherwise.

Dr. Edward Esplin: I'll pile on that just briefly to note that at ASHG American Society of Human Genetics just last year there was an entire session devoted to exactly that kind of topic, and it was broadly discussed, the potential opportunity to, for example, within a cancer gene multigene panel is that a panel where returning VUS is just not a useful thing to do, restricted to pathogenic, likely pathogenic. We do that on other panels already. We do that on panels for ostensibly healthy folks and other situations. So I think that is a very worthwhile approach to consider.

And at the same time, we've also seen in the literature, Heather brings up a concern that is broadly raised and repeatedly raised, we've seen evidence that clinicians are not acting inappropriately as much as they had done, perhaps in the past, that we're getting our house in order. Breast surgeons and other physicians are treating these things like the negative results that they, in reality, are, and so that in my opinion, the potential for increased VUS identification should not be an obstacle to folks getting clinically indicated testing because that's what's needed for them to have appropriate treatment and appropriate prevention.

Dr. Abdul Rafeh Naqash: Absolutely. Well, this has been very engaging and very interesting, and hopefully, our listeners will feel the same. Thank you, both Heather and Ed, for joining us today and especially choosing JCO PO as one of the destinations for your very interesting commentary.

Thank you for listening to JCO Precision Oncology Conversations. If you like today's episode, please leave a rating and review. You can find all our shows, including this one, at asco.org/podcasts and continue to stay updated by following JCO PO on Twitter with the handle @jcopo_asco. All JCO PO articles and series can be found at ascopubs.org/journal/po.

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Guest bios

Prof. Heather Hampel, MS, is an Associate Editor of JCO Precision Oncology. She is the associate director in the Division of Clinical Cancer Genomics and is a professor in the Department of Medical Oncology and Therapeutics Research at the City of Hope National Medical Center.

Dr. Edward D. Esplin, MD, PhD, FACMG, CGAF, FACP is board-certified in clinical genetics and internal medicine and completed his clinical fellowship training in medical genetics at Stanford University. He now works at Invitae.

Guest disclosures (See also: Universal Germline Genetic Testing for Hereditary Cancer Syndromes in Patients with Solid Tumor Cancers)

Heather Hampel

Stock and Other Ownership Interests: Genome Medical, GI OnDemand

Consulting or Advisory Role: InVitae, Genome Medical, Pomega, 23andMe, GI OnDemand, Natera

Edward D. Esplin

Employment: Invitae

Stock and Other Ownership Interests: Invitae

Consulting or Advisory Role: Taproot Health Inc

Universal Genetic Germline Testing in Solid Tumor Cancer Patients

JCO Precision Oncology Conversations