David R. Gandara, MD

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: When you discuss next-generation sequencing and comprehensive genomic profiling platforms, ordinarily the first thing that comes to mind is a patient with advanced stage disease. Since 2021, and within the next few months, we have a number of studies emerging suggesting that particularly liquid biopsy—circulating tumor DNA [ctDNA], RNA, or epigenomic abnormalities—can help us either diagnose patients earlier as per screening or to help us identify which patients after surgery are at risk for recurrence. We call that MRD, or minimal residual disease. The examples I use here is we have an FDA [Food and Drug Administration] approval for an 

[epidermal growth factor receptor] tyrosine kinase inhibitor, osimertinib [Tagrisso], after surgery in patients with stage II and III non-small cell lung cancer who have undergone surgical resection and their cancer is found to have one of these 

 mutations. In the future, I’m quite confident that assessing liquid biopsy after surgery will help identify which patients are at greatest risk for recurrence, and which patients might benefit the most. For example, if the patient has the surgical procedure, they had an 

mutation in their cancer and may be shown in blood before surgery, now it’s a month after surgery, you repeat that liquid biopsy and it’s a negative, that patient may be cured. Not sure, but they may well be. On the other hand, if you find that same 

mutation in their blood 4 to 6 weeks after surgery, they’re almost guaranteed to relapse. This may help us, for example, differentiate who needs these adjunct therapies and who does not. The same will apply to the recent FDA approval for immunotherapy with atezolizumab [Tecentriq]. For instance, if the ctDNA a few weeks after surgery is still positive, it’s quite likely that those patients are the ones who will benefit the most from therapy. We need to show this, those 2 trials I just mentioned, have blood collected and eventually we will know this information. If it is as I expect it will be, this will be a huge step forward in resource utilization. Which patients need the therapy, which patients do not.

Videos

Closing out his discussion on CGP, David Gandara, MD, looks toward future opportunities for CGP in screening patients before or after surgery.

Expanding the Use of CGP in Screening and Surgery

 The field of molecular testing and cancer is moving so rapidly, that it’s hard for everyone to keep up. It’s hard for general oncologists seeing a variety of different cancer types to know what’s brand new in their cancer. It’s also hard for payers to know when they should approve something, when it should be still considered research, what is in transition. In transition in the past meant that you had a new drug, or you had a new test, and it was researched for 2 or 3 years, and then eventually it might reach standard of care. These days, the timeline has accelerated tremendously so that what was researched yesterday is the standard of care today, guidelines such as NCCN [National Comprehensive Cancer Network] can help with this but they can’t replace payers. For example, keeping up and knowing when they should approve something rather than issuing an initial disapproval or what has become overwhelmingly difficult for physicians and that is making a physician go through a peer-to-peer review for every little test. Sometimes that peer-to-peer review is not with someone who is a specialist in the field, so you’re explaining something and it’s beyond comprehension. The best way to make it optimal for our patients is communication and education. I have spoken at several meetings, for instance, managed care summits, next-generation summits, where the audience either consists of or largely is attended by the payers themselves, including CMS [Centers for Medicare and Medicaid Services]. Those interchanges have been positive. They have been informative for me as well as for the payers to know where they’re coming from. I have found that more in the United States that they understand. They understand why we need the testing. Now, the problem, of course, is that we have an entire worldwide population of cancer patients. In some other areas of the world it’s more difficult. Not only to do the testing, but it’s also more difficult if you find the abnormality and you don’t have the drugs, you haven’t done much for the patient. Nevertheless, our guidelines such as those from our own high IASLC, International Association for the Study of Lung Cancer, they apply worldwide and they help oncologists, medical societies, and other countries around the world bring this information to their governments and to the payers there so that they understand why it’s so important.

Considering the value of comprehensive genomic profiling, David Gandara, MD, highlights the importance of supporting access to testing. 

Supporting Access to Comprehensive Genomic Profiling 

 One thing I haven’t talked about is whether it’s preferable to do this testing of next-generation sequencing broad-based within your institution, and a homegrown test, or to send it to a commercial vendor. With a few exceptions, it’s better to use the commercial tests from a good, reliable company, with good sensitivity and specificity in their assay, because not only can you get the results and in a timely fashion, but all the annotation in the report is important and difficult to keep up.

I’ll give you an example. Let’s say a patient is found to have a ROS1 fusion in their cancer, and the good next-generation sequencing comprehensive genomic profiling reports tells you that we found this. It tells you what the allele frequency is and how much is there. It tells you if it’s functional or not. If it’s not, it tells you that it’s a variant of unknown significance. It’s not actionable, not treatable. It tells you what drugs the abnormality is sensitive to. It tells you what clinical trials are available for that patient against this target, and it gives all the references.

If you have a test like this, you need an army of people updating the report. New drugs come on board, new clinical trials open or close. Although you can do this in your own institution, it’s quite laborious. At UC [University of California], Davis, we have our own next-generation sequencing platform. We use it only for research, and the reason is because otherwise, you have to have this rapid turnaround time and you have to have all the annotation that a clinician needs. This differentiates the commercial next-generation sequencing from most institutional platforms.

A brief discussion on the value of commercially available comprehensive genomic profiling over homegrown testing.

Benefits of Commercially Available CGP Tests

 Our thinking about who should get next-generation sequencing done by a comprehensive genomic profiling platform has changed over the years. I’m referring to non–small cell lung cancer because this is the clearest example. Initially, we said, “Maybe this should be only in never-smokers, in adenocarcinoma, or this should just be in young patients in the United States who are Asian American because of a higher prevalence of 

-mutated disease. Our thinking has changed because if you find that abnormality, it’s like hitting a grand slam home run, using baseball terminology. Even if that patient has a prior smoking history, there’s still a significant chance you’ll find 1 of the oncogenes. It’s going to be much less—for example, for EGFR—but if you use next-generation sequencing, you test for all the abnormalities all at once.

A patient I recently saw who was Japanese American had a light smoking history. I suspected that he would have an 

 mutation and instead he had an ALK translocation. I wasn’t looking for ALK—I was expecting EGFR—but this was tremendously important for this patient. Now it would be everyone with advanced-stage non–small cell lung cancer. In guidelines a case is being made for those with squamous cell lung cancer as well, particularly younger patients and those with a lighter smoking history. The reason is that although they’re less common, you can still find these abnormalities in squamous cell lung cancer. It’s like night and day in terms of the options for them.

One study where I wrote the editorial—the LUX-Lung 8—21% of patients with pure squamous cell lung cancer had a HER [human epidermal growth factor receptor] family mutation. EGFR is HER1, but there’s also HER1, HER2, HER3, HER4. The benefit in this trial for a pan-HER inhibitor like afatinib was markedly better in patients who had 1 of these abnormalities with very long survival in some of them. Today it’s everyone.

David Gandara, MD, explains how the scope of comprehensive genomic profiling has shifted from a select few patients to the majority. 

Is There an Ideal Patient for Comprehensive Genomic Profiling? 

 The issue of cost-effectiveness is important when we talk about molecular testing. Everyone—not only oncologists and oncology organizations but also payers, including Medicare and private insurers in the United States—have all realized that it’s better for the patient and more cost-effective to do your broad testing up front. The example I give is that there are several ways you could do testing. In the old days, we did sequential testing. We tested for EGFR or KRAS. If that was negative, then we tested sequentially. Then there was so-called multiplexing or hot spot testing. We would test for a limited number of oncogenes.

Now we have next-generation sequencing and comprehensive genomic profiling. In the example of non–small cell lung cancer, which is a poster child, several studies have shown that it’s more cost-effective to test for all the genes up front simultaneously with next-generation sequencing than it is using sequentially or exclusion testing where, you exclude certain abnormalities before you go to next-generation sequencing. This has been shown to be the same in blood—that it’s more cost-effective in blood to do next-generation sequencing.

This was nicely shown in a presentation by Natasha Leighl from Toronto, Canada, and the Canadian system at our annual International Society for Liquid Biopsy Congress. She described what they have named the value study, which showed an analysis that you could save a lot of dollars by employing next-generation sequencing in blood up front. Insurers understand that they’re not paying individually for 500 genes. They’re paying for a result that is practice changing. The decision-making process for that patient will turn on its heel if 1 of the actionable oncogenes is found.

I’ve had many examples in my clinic. Within the last week, a patient was referred to me with fairly rapid disease, the patient had a remote history of smoking. I recommended instead of starting chemotherapy and immunotherapy to get next-generation sequencing in blood, because of the faster turnaround time. Within 1 week, an ALK translocation was found. The patient was started on appropriate therapy within 3 days of starting that therapy. The patient reported to me—we have a chart; that’s how you communicate—that his shortness of breath, his chest pain had almost completely gone away within 72 hours. This is like turning off a light switch. If you don’t find that target, this same patient has been proven in studies to do poorly with immunotherapy. Typically, we exclude patients with 

 mutation: the other nonsmoker-related oncogenes from initial treatment with immunotherapy. This is a practical example of why this is important, and insurers understand that. It used to be that we would get disapprovals left and right when we order next-generation sequencing. Where I practice in California, that essentially never happens anymore.

A review of how comprehensive genomic profiling can better inform treatment planning and alleviate health care economic burden.

The Economic Value of Comprehensive Genomic Profiling 

 The value of comprehensive genomic profiling can’t be overstated. Non–small cell lung cancer is a poster child for the use of broad-based testing, but this is coming on rapidly and strongly in several other tumor types. Let’s say you’re a practicing oncologist. You’re seeing a new patient with stage IV adenocarcinoma of the lung. Your choices are to treat empirically—with immunotherapy plus or minus chemotherapy, more the combination of chemotherapy and immunotherapy—or to wait until the results of the next-generation sequencing come back. Having a rapid turnaround time facilitates that. 

The mistake that’s made is the patient is started on immunotherapy and chemotherapy before the results of the molecular testing come back. When it does come back, it shows a highly favorable oncogene, such as an 

 mutation. The problem then is stopping the immunotherapy component and starting the patient on the TKI [tyrosine kinase inhibitor] because growing evidence suggests that the efficacy of the TKI is not only diminished by that prior exposure even briefly to checkpoint immunotherapy, but the adverse-effect profile of the TKI is also increased. For instance, interstitial pneumonitis. All the guidelines recommend waiting if possible. If it’s a true emergency, rapidly progressive disease, or falling performance status, an oncologist needs to start treatment emergently. This is less than 10% in advanced-stage non–small cell lung cancer. The recommendation is to start with chemotherapy alone, so you avoid that subsequent negative interaction if you have to switch to a TKI.

For a newly diagnosed patient with advanced-stage non–small cell lung cancer, once I explain to them that we have a variety of options for their treatment and some of these could be quite effective. If we find an abnormality in the cancer that’s specific to them, we’ll be able to individualize therapy, and this will be a much better outcome. There’s a better chance of them responding even in the long term. When I tell them that, I say that we could start empirical therapy, but I don’t recommend that. I recommend we do the testing and wait, and 100% of patients say, “I want something for me.” In other words, that’s why I came to you: I want precision medicine. They may say personalized medicine or individualized. Patients are very proactive about this. Before we had liquid biopsy and we said, “We’re going to send off your tissue.” We don’t know if it’s adequate or if we’re going to need a new biopsy. Even then, they were enthusiastic about it. But if I say, “I’m going to send you downstairs, and we’re going to draw a tube of blood today,” and I expect the results within 1 week, that’s incredible. Patients are the biggest advocate for this testing.

Expert perspective on clinical and personal improvements in cancer care made available by appropriate use of comprehensive genomic profiling. 