Why Is the UK so Much Better at Molecular Profiling?

Molecular testing is an invaluable resource in lung cancer, but recent evidence suggests that many US practitioners are not taking advantage of it. Real-world data on patients with stage IIIB or IV non–small cell lung cancer (NSCLC) found that only 54% were tested for epidermal growth factor receptor (EGFR) and 22% for anaplastic lymphoma kinase (ALK), ROS-1, and BRAF. Even when testing is performed, it may not be adequately informing treatment decisions. A 2019 study in JAMA reported that only two thirds of patients with an EGFR mutation or ALK rearrangement ever received an appropriate inhibitor over the course of their illness.

By comparison, the United Kingdom appears to have much to be proud of when it comes to molecular testing. Recently reported data from the UK's National Lung Cancer Audit revealed that 83% of patients with advanced adenocarcinoma underwent testing for EGFR, ALK, ROS-1, and programmed death ligand 1 (PD-L1). However, the audit's findings on the rates of patients receiving appropriate targeted treatments and median survival showed that the United Kingdom also has room to improve.

To find out what accounts for the differences in the UK and US approaches, Medscape contributor Dr Jack West spoke with Dr Sanjay Popat, professor of thoracic oncology at The Institute of Cancer Research and consultant in medical oncology at the Royal Marsden Hospital in London, United Kingdom.

H. Jack West, MD: Let's discuss what is working and what is ailing in both of our systems, as that is an important step toward fixing them.

Sanjay Popat, MD: In the United Kingdom, some things are slightly better, some are similar to problems in the United States, and some are slightly worse.

What we do very well is the penetration that testing has in the population. That was clear in the 83% testing rate for the National Health Service (NHS)-funded biomarkers. Those data were for every patient who walked through the doors of a number of centers in 2017.

But when you look a little bit deeper, you see the problems. Of those identified to be EGFR mutant positive, only 75% received an EGFR tyrosine kinase inhibitor (TKI) upfront. Even worse, only 58% of ALK-positive patients received an ALK inhibitor. I find this quite sad because these are the most effective drugs that we have.

There have to be reasons why these genotypes are not translating to a TKI prescription. Do oncologists actually pick up the result and figure out next steps based on this limited number of biomarkers? By and large, I think they do, because to prescribe immunotherapy in the United Kingdom, you have to attest on a form that the patient is wild-type for EGFR and ALK.

One possible cause may be turnaround times, which we have issues with. Or it may be more complex.

West: Turnaround time is certainly a major challenge in the United States, where it routinely takes 3 weeks or longer to get tissue-based testing done. A lot of patients want to get treated very quickly.

If molecular testing is going to take 3 to 4 weeks or longer, even oncologists who have a preference for it may feel that they're probably not going to be that wrong giving chemotherapy and immunotherapy. Or let's say you get PD-L1 results back very quickly and then have to wait for molecular testing; it's very tempting to act on a high PD-L1 level and perhaps just start single-agent pembrolizumab.

Then there is the sense of competition in the United States. Patients not inclined to wait may leave your practice for an oncologist down the road who will start treating them quickly. Many of my colleagues have expressed concerns about having to assure patients that it's better to wait for test results than to start a treatment now, just for the sake of getting something going.

Popat: We don't have the same commercial pressures of urgently needing to start some form of systemic therapy, even though it may not be clinically indicated. Patients don't have that expectation of going to another practice, who may not have availability even if they did.

There are some cultural differences as well. The NHS system simply doesn't allow you to prescribe pembrolizumab unless you've actually confirmed that the patient is wild-type for EGFR and ALK. It's the same thing for chemotherapy plus immunotherapy. You can prescribe it, but you have to attest that the patient is wild-type.

The other thing to consider is that in many centers, if you decide you want to give some sort of systemic therapy, patients may wait 2 weeks (if not longer) for the first cycle. That allows a bit of buffer time for the molecular results to come through.

Biopsy on Both Sides of the Atlantic

West: About 1 in 10 patients in the National Lung Cancer Audit report had insufficient tissue. In the United States, these patients may start on chemotherapy plus immunotherapy in the meantime. It doesn't sound like that's a real possibility in the United Kingdom, as you're essentially required to do whatever needs to be done to obtain the molecular data. How does that impact re-testing?

Popat: Re-testing rates in the UK audit were about 10% due to the initial specimen being inadequate. That is likely a gross underestimate, though. I suspect that a lot of people are starting chemo, with or without immunotherapy, in situations where we don't have sufficient specimens to robustly understand their true genotype. Those patients will probably get re-biopsied at some stage in the future, which is additionally challenging to do once they start receiving chemotherapy.

We really want to be moving toward liquid biopsy. I would love to be in a position where we have circulating tumor DNA next-generation sequencing (ctDNA NGS) upfront. Unfortunately, the United Kingdom is lagging behind in this, given the massive costs associated with ctDNA NGS. Some commercial providers have entered into schemes with individual institutions to allow this approach for biomarker selection of patients for trial enrollment, but it is certainly nowhere near standard.

West: Liquid biopsy is available in the United States, but it's inconsistently used and reimbursed.

Another issue we sometimes face here is that a genetic test report may get uploaded into a random media tab of a challenging and expansive electronic medical record, never to be seen by human eyes. How likely is that to happen in the UK system?

Popat: By and large, our system works very well in this regard. The hard stop exists of basically not prescribing chemotherapy plus immunotherapy or immunotherapy alone unless you know what you're looking at. That really does force those results to be seen and verified.

Most pathology and molecular diagnostic tests occur within established networks with oncologists, so those results do get fed back either to the oncologist or the clinical nurse specialist. The nurse specialist is absolutely instrumental in instigating the molecular testing, making sure the results have reached the laboratory and come back, and flagging any of the positive results to the oncologist. This means there is far less likelihood of a result just drifting off to a random page in the electronic medical record.

Room for Improvement in Both Systems

West: The success reported in the National Lung Cancer Audit was accompanied by fairly sobering results. The median survival for the broader population was just 7 months, and was only 1 year for those with an EGFR mutation. That's far less than I would have hoped to see for an enriched population with a targeted therapy. What do you think contributes to that?

Popat: I totally agree and, frankly, find it really embarrassing. I think you have to remember, however, that this is an overall population. This isn't just fit patients you would normally consider enrolling in trials, but also those who get diagnosed as an emergency, who are sick, or who are unwell. You're seeing the entire population, not just a crème de la crème subset.

Having said that, the outcome data are far worse than we would have expected. I think that can be partly explained by many things.

For example, we are still giving first-generation inhibitors in the EGFR setting and having to hunt for T790M testing prior to giving osimertinib. T790M testing is problematic. I am not convinced that we often really follow up a negative T790M test with an appropriate biopsy, as a patient slowly progresses.

I also worry that the patients themselves aren't interested in going through additional biopsies. There is always a dread of having chemotherapy, even though we know it is a highly effective salvage treatment for the T790M-negative population. I'd like to know more about the patient perspective here.

There is a lot of work to be done around optimally managing oncogene-addicted disease. We do not do oncogene oligoprogression very well here, as stereotactic body radiotherapy is not routinely funded. Those patients are having to go into trials. The stereotactic radiosurgery provision for patients with central nervous system (CNS) progression is highly variable. CNS monitoring of patients with oncogene-addicted diseases is patchy at best.

This all contributes to suboptimal outcomes. We really need to recognize that patients can do very well if treated aggressively, and getting on TKIs is the absolute critical part of this. And, obviously, recognizing that this is an oncogene-addicted patient in the first place is the key.

West: The take-home message for me is that there's obviously been great new advances in treatments and our understanding of how cancers adapt to them. It's going to take a lot of effort to implement that science and educate the broader community to realize this promise. Even with some of the successes that the United Kingdom has reported, none of us has yet cracked the code to a great working system.

H. Jack West, MD, associate clinical professor and executive director of employer services at City of Hope Comprehensive Cancer Center in Duarte, California, regularly comments on lung cancer for Medscape. West serves as web editor for JAMA Oncology, edits and writes several sections on lung cancer for UpToDate, and leads a wide range of continuing education programs and other educational programs, including hosting the audio podcast West Wind.

Sanjay Popat, PhD, FRCP, is a professor of thoracic oncology at The Institute of Cancer Research and a consultant in medical oncology at the Royal Marsden Hospital in London, United Kingdom. His research interests include identifying DNA variants that influence thoracic tumor development, identifying biomarkers predictive of therapeutic effect, and developing novel strategies for the treatment of thoracic tumors through clinical trials.

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