JCO PO author Dr. Sanjeevani Arora shares insights into her JCO PO article, “Exploring Stakeholders’ Perspectives on Implementing Universal Germline Testing for Colorectal Cancer: Findings from a Clinical Practice Survey” Host Dr. Rafeh Naqash and Dr. Arora discuss germline genetic testing for all colorectal cancer (CRC) patients and advantages and barriers of implementing universal germline testing (UGT). 

TRANSCRIPT

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, social media editor for JCO Precision Oncology and assistant professor at the OU Health Stephenson Cancer Center at the University of Oklahoma. Today we're excited to be joined by Dr. Sanjeevani Arora, assistant professor at Fox Chase Cancer Center, and author of the JCO Precision Oncology article, Exploring Stakeholders' Perspectives on Implementing Universal Germline Testing for Colorectal Cancer: Findings From a Clinical Practice Survey.

At the time of this recording, our guest’s disclosures will be linked in the transcript. Dr. Arora, welcome to our podcast and thank you for joining me today.

Sanjeevani Arora: Hi, thank you so much for having me. It's a pleasure to be here.

Rafeh Naqash: As it happens, you were in Vegas for your meeting, which is relevant to this publication since this was, I believe, presented at the meeting as well. Is that correct? Sanjeevani Arora: Yes. Rafeh Naqash: Great. So, Dr. Arora, for background purposes, could you tell us what is the main theme of this project and what was the reasoning for doing this project in this important space of germline testing for colorectal cancer?

Sanjeevani Arora: So, we were interested in understanding what the stakeholder's perspectives would be for support as well as implementation of universal germline testing in all colorectal cancer patients. We know that colorectal cancer is one of the leading types of cancers in the United States as well as in the world.  And from what we understand is that the prevalence of mutations that would increase risk of colorectal cancer, that can vary in an unselected population, so somewhere about 15%. The criteria, however, to identify who might be harboring a variant that would predispose to colorectal cancer, there are various methods to do that. However, I think an important point to consider here is that many patients who harbor such variants do not meet established criteria for genetic testing. The problem with that is that that is a missed opportunity to not only manage a patient who may carry such variations, so that can impact their clinical management as well as in their family as well. So, missed opportunity for risk reduction and early detection with enhanced surveillance. So, really if you think about this is based on these, the NCCN itself has now recommended universal germline testing for individuals who are diagnosed with colorectal cancer who are younger than 50 years of age. And in June 2022, they also suggested to consider testing for those who are older than 50 years of age. But in spite of this, there is lack of data from stakeholders and lack of data on advantage of and barriers to implementing universal germline testing at different clinical practices. So, this was really the main reason why for us to go ahead and do this study so that we can understand what the challenges are related to universal germline testing and especially coming from the stakeholders and also to try to understand what the overall broad support is from the stakeholders.

Rafeh Naqash: Thank you so much for that explanation. I personally work in the early phase clinical trial space. So, for me, genomics makes a huge difference for people with cancer and not just from a testing standpoint, but also from a target standpoint drug discovery standpoint. And I think as I've gradually progressed in my career, I have felt that catching individuals with germline predispositions can make a huge difference for their families, especially. Prevention is better than cure in most respects. So, this is a very relevant and a very timely topic. And outside of this study, from a logistics perspective, could you tell us, since our listeners are not just academic clinicians or geneticists, but perhaps a bunch of them are probably community oncologists also and hopefully other disciplines that are not in the academic setting, how does it work for you in your current setup at Fox Chase of how people get this germline testing, people with colorectal cancer?

Sanjeevani Arora: The main challenge here is trying to, at least in terms of the perspectives of genetic counselors, is that currently they see all patients and eventually if there is implementation of universal setting in the way, they will perhaps only end up seeing those who truly are at high risk. So, that would really be a huge change in their own practice as well, like who they're seeing in the clinic.

In terms of how this could be implemented, obviously there are multiple challenges here. So, for example, it would go on from not only just the who would order and who would consent, but also then who would be disclosing the results because there would be a big demand for this.

So, the idea would be trying to really streamline if non-genetics providers could get the training to be involved in this. So, this system can be streamlined, I should say, that genetic providers would be more involved in the phase where they are truly required. So, perhaps that would be in the result disclosures or on a case-by-case basis.

Rafeh Naqash: I think you bring an important point as far as testing and who is responsible for discussing the implications of the results. And I know you touched into that aspect in your survey. Could you elaborate a little more on the results section side of what you found that had clinical relevance or meaningfulness from your survey standpoint?

Sanjeevani Arora: So, when we surveyed our respondents on support for the kind of providers who could be involved in ordering and consent for universal germline testing, the majority obviously supported genetics providers. So, here genetics providers were genetic counselors, medical genetics geneticists and genetic nurses.

However, there was also broad support for medical oncologists, gastroenterologists, and surgeons. There was even a minor part of our respondents also supported other providers as well. So, it's good to see that while there is broad support for genetics providers, there is room for other providers to be involved in this aspect of universal germline testing in a program.

We also looked at the opinions and how and when genetics education should be provided in such a program for universal germline testing. The majority of our respondents, said that pre-test genetic education is necessary. So, they all felt that this is an important aspect of a universal germline testing program.

However, there were nuances on what materials could be provided as well as who could potentially be involved in this. So, based on what the respondents said in their survey, it looks like this could be a good place for non-provider staff to be involved in this.

However, when we also asked them what the non-genetics providers in the knowledge that they have potentially when we directly ask them this, do they have the knowledge to consent for genetic testing? Going back to the consent point, again, the majority did not agree with this. However, there was a percent that also felt that they do have this knowledge, but when we asked them that if they have the knowledge to disclose results, there was a strong disagreement there.

So, there definitely is room for non-genetics providers to get the right training or to be involved in this aspect if needed. But it looks like at least for the consent, there is more support.

Rafeh Naqash: So, the more one thinks about this topic from a broader perspective, not just colorectal cancer but other tumor types. What comes to my mind as you have elaborated in your discussion and in your survey, is the education part of it that you just mentioned about.

If you were to think out of the box, do you think that the NIH has a potential role in creating mechanisms to help facilitate some of that? Since I think the bigger question comes back to funding at the end of the day. Institutions need to invest time, energy, resources in trying to educate and expand on this aspect of genetic testing, which I think is immensely important for individuals with strong family history of cancer, or even find out that they don't have high risk features, but they end up having some germline variants that are potentially actionable for them or their family.

So, have you as part of your association, the CGA, been able to think on some of those lines to get a stakeholder like the NIH to help facilitate fund some of these educational initiatives at institutions? Perhaps maybe to start with NCI-Designated institutions and then expand in the community.

Sanjeevani Arora: I think NIH would have a big role in this or NIH as well as other funding agencies because I think this effort for a universal germline testing program in academic centers and then eventually going on to community-based centers or maybe both at the same time, this will require a collaborative effort between genetics and non-genetics providers that we identify is going to be really very important going forward.

So, there is not only a big role for the institutions and the community itself, but also for the NIH as you mentioned, where this would be really necessary to really help us identify who is a high-risk individual and when the pre-test education and other post-test is required.

Rafeh Naqash: I think because in the bigger picture it does play out into the amount of funding that a government agency like the NIH spends in individuals with advanced cancer, which they could potentially prevent if some of these programs are well implemented early on and help with reducing morbidity and mortality when these events do happen later on.

But I guess these are discussions beyond the scope of this project in this podcast, but I was just thinking from an out of the box perspective, could that be an opportunity that your group can perhaps work with the NIH on? So, going back to the project, the publication, tell us a little bit more about the genes that were tested. You talk about the single gene versus the multi-gene panel. Could you elaborate a little more on that and what are the advantages of one or the other?

Sanjeevani Arora: We did survey our respondents on what they thought would be the best way to move forward in a universal germline testing program. And you can see that the majority really supported a standardized multi cancer gene panel. And I thought that was really interesting because if you look at the data here is that while 46% support that, there's also a smaller majority, about 26% that only support colorectal and some common cancer genes.

So, in terms of the large multi cancer gene panels, so this would be not only just the colorectal cancer genes, so these would be high risk, moderate risk or limited evidence, colorectal cancer genes, plus it would be all other genes that we test currently for hereditary cancer types. So, this would be a lot of data that would come about in a universal germline testing program.

And then I think the idea would be how would this be managed? Because many of the genes currently, we don't understand if they would increase colorectal cancer is, so how would be manage the risk for perhaps other cancer types if there is a positive result? I think that's something to think about.

The other would be how would the variance of uncertain significance would they be reported and how would that work about? So, those two would be really important as well to think about going forward in such a program.

Rafeh Naqash:

Now from a cancer standpoint, my experience with germline testing has been when I see individuals for clinical trials especially, and I do broad next generation sequencing the tumor tissue or on blood and identify something that has a very high variant allele frequency that triggers a question in my mind whether this is germline.

Unfortunately, these days we don't do a great job in taking history from the individual where you ask them about family history extensively. Some clinicians are better in this perspective than others, but I think there's a gap there.

And then you go back to the patient, you ask them whether they have a history, had a recent individual recently that had uveal melanoma, and then I identified a very high variant allele frequency in a gene called BAP1, which you might be aware of. And then went back to the patient asked them and they said, well yes, they have family history of mesothelioma, family history of this cancer that cancer, and that triggered germline testing, which was positive.

So, from your perspective, since a bunch of these individuals would have first-line contact, I would imagine with oncologists, mostly medical oncologists rather than surgeons, what should one look out for? Let's say a program does not have universal germline testing implemented yet.

If me or my colleagues sees an individual with colorectal cancer, what would be the three or four red flags that we should consider to focus on germline testing in those individuals? Let's say we're in the community and I'm someone who's not necessarily on the genomic side, I'm a clinician treating colorectal cancer. What would some of those things be that should prompt me to consider germline testing in that individual with colorectal cancer? From your perspective.

Sanjeevani Arora: Once the universal germline testing program is implemented, and you wouldn't necessarily need those questions actually, but without such a program, obviously family history is a major red flag that is very important to consider.

And another would be, for example, in terms of tumor set testing for Lynch, if there is any mutations in Lynch genes or MSI High that could at least trigger test if that came from the germline.

Rafeh Naqash: I think those are important points. And in the clinical setting it does often happen that you see so many individuals and sometimes some of this thought process can get lost in translation.

But I think it's important to emphasize, like you pointed out, asking for family history if the universal program for testing of these individual’s not implemented, then inquiring on family history and these days we see a lot of young onset colorectal cancers. Interestingly enough, my colleagues talk about it all the time and I think those aspects of it should ideally prompt people to go for germline testing.

Now, from an implementation standpoint, you also looked at that in your respondents which individuals would be the ideal candidates for this testing. Could you elaborate on that?

Sanjeevani Arora: Which individuals would the ideal candidates, I mean, I think the idea here was what is the support overall for testing everybody? So, the idea is to move away from having certain criteria.

Now it would be the NCCN recommends testing any colorectal cancer patient who is younger than 50 years for a germline multi-gene panel testing. And then the consideration is for those who are older than 50, I hope the NCCN will eventually decide to recommend it for all. But this way there would be no need for any criteria as such, but just test all patients.

Rafeh Naqash: I absolutely agree with you, and I think organizations such as NCCN, NCGA should ideally partner on creating some of this framework so that everybody's on the same page. Because I think that does play into the fact that how payers consider reimbursement for some of this testing. Did you encounter that in your respondents as one of the reasons why it could be challenging to implement universal germline testing, from a payer standpoint, insurance standpoint?

Sanjeevani Arora: One of the things that we did factor into the survey as one of the barriers that ... so, we had about 11 questions for what the clinical practice barriers would be in a universal germline testing program. And this was one of the questions that the respondents did majorly agree on that the insurance may not cover the cost of testing for all patients. So, I think obviously the things do have to modify in terms of coverage guidelines to include all patients.

Rafeh Naqash: Right. Because that again plays into logistics of ordering this for individuals and those individuals not having to see several thousand dollars bills resulting in financial toxicity. So, Ithink having these discussions, in your collaborative group is leading, I think extremely important from that perspective.

What would be the next step for this? You did the survey, you understood what are the pros, the cons, the limitations, the benefits, what is the next step that your group is planning to take to implement some of this, create the second stage for some of this work, if there is something that you would like to highlight.

Sanjeevani Arora: In terms of just in general speaking about this, I think as we finished this survey and we got it through publishing this, some of the things that we thought about and not necessarily that we may be doing this as a group or it might be just individuals, but just to talk about what we think could be the next steps here is obviously, this survey, the stakeholders here were those who are experts in hereditary GI cancers.

The idea would be to also see what the thoughts are for those who are not, because they would be big stakeholders in this as well. So, it would be good to understand what they also perceive as the barriers associated with this and how we could get this implemented and also see what their support is. So, I think that's one thing.

The other thing that's I think really important to point out here is that we don't have patient perspectives on a universal germline testing program. And what do they think about this? What do they perceive could be potential barriers even for them? I think that would be very important so that there is really a real uptake in the real world. I think that's very important to do, that the patient focus is very important.

Now, I'm not sure if we would be doing this, I would love to do this, but I think it's really important to really consider that going forward.

Another thought that I had that was based on a question that I got asked when I presented this at the CGA-IGC meeting in Vegas just last week was that how one of the things that was pointed out were that the majority of our respondents were, and I've already kind of touched on this too, were genetics providers.

So, perhaps the results could be for some of the perceived barriers for how non-genetics providers could be involved, could be skewed because the survey majorly had results from genetics providers. So, I think again, just pointing out that there is a real need for collaborative efforts between genetics and non-genetics providers to understand where are the areas that they could need help so that this could be realized.

Rafeh Naqash: Absolutely. I think as you pointed out there are definitely limitations associated, but I think your work and this publication lays some very important groundwork to initiate the discussion, at least. It's understood that community providers take care of at least 60% of individuals. There's maybe more with cancer.

So, having stakeholders from different aspects is important, but can be challenging also since your group is just starting this work. So, I think the patient perspective, the community perspective is definitely important and hopefully that'd be something that you and your group can further work on and hopefully in the years to come, maybe publish it again in JCOPO as you did this time.

Sanjeevani Arora: Yeah, that would be the hope to really get even broader perspectives. Yeah.

Rafeh Naqash: So, Dr. Arora, a couple of quick questions on you as a researcher now since you've touched upon your work. Could you tell us a little bit about your background, your professional background, your interest in genetics and your current role at your institution?

Sanjeevani Arora: So, my background, I have a PhD in biochemistry and cancer biology, as a postdoc I really expanded into molecular genetics. That's what really led for me to work in this area. So, currently I have a research lab at Fox Chase Cancer Center, and I'm in the Cancer Prevention and Control program. And a major part of my research program is looking at the genetics of colorectal cancer. And I'm very interested in understanding what could be the other genetic risk factors that is really leading to this alarming rise in incidents, especially in the young population.

So, that's one of the aspects of my work that I'm interested in. But another aspect of my work that I'm working on is looking at are there genetic factors in the germline that could potentially impact how individuals respond to their treatment? And so, yeah, I do have a big stake in knowing more about overall genetics of colorectal cancer.

Rafeh Naqash: Excellent. Well, thank you so much. It was great talking to you about this topic and hopefully our listeners find this interesting as well.

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