Biomarker Test Access for Precision Oncology Varies Widely in Europe, ESMO Survey Finds

PARIS – A survey of 53 European countries has captured the variable access cancer patients have to molecular tests that are increasingly necessary for personalizing therapy.

At the European Society for Medical Oncology Congress this weekend, Arnaud Bayle, a medical oncologist at the Gustave Roussy Cancer Center in France, shared topline findings from the survey designed by members of ESMO’s Global Policy Committee using an electronic survey tool and the contents of ESMO’s next-generation sequencing recommendations published in 2020. ESMO disseminated the survey to 201 field reporters — oncologists, biologists, and pathologists — from 48 countries to gather their perspectives on test access in the countries where they work.

The survey queried field reporters on a range of single-gene and multi-gene biomarker testing technologies. These included single-gene techniques like immunohistochemistry, fluorescence and chromogenic in situ hybridization, microsatellite instability testing, and polymerase chain reaction tests, as well as multi-gene techniques including small and large next-generation sequencing panels, targeted and full RNA sequencing, whole-exome sequencing, and whole-genome sequencing.

As far as NGS goes, the researchers defined a “small’ NGS panel as one with fewer than 50 genes and a “large” NGS panel as one with more than 50 genes. They also considered testing for tumor mutational burden as well as liquid biopsy -based testing approaches and other genomic assays.

For each of these techniques, respondents had to rank test access in their respective countries as “always available” or used routinely, “usually available,” “occasionally available,” “used in research or clinical trials only,” and “never available. ” The responses varied according to test type. For example, nearly all countries reported IHC was “always available,” while most countries reported WGS was “never available” or for “research only.”

“If we distinguish two groups, you can see the difference” between single-gene test availability versus multi-gene approaches, Bayle said. Most single-gene tests were always available across European countries, whereas multi-gene approaches tended to be seldom available, or accessible only in research settings, with a clear trend toward better access in higher-income countries.

For relatively simple tests such as IHC, most countries relied on the public sector for access, the survey showed, whereas for more complex testing technologies like NGS and liquid biopsy, most or about half of the access came from the private sector.

“There are very big differences between countries, because countries are organized very differently depending on their health systems,” Bayle said, adding that these differences can also be seen on the regional level within certain countries.

Even though the US healthcare system is structured quite differently to that of European countries, access to more complex cancer biomarker tests tends to be better at academic medical centers and large, well-resourced health systems. And while an annual survey conducted by Precision Oncology News shows these early adopter institutions are investing to integrate biomarker testing, the survey has found other barriers like reimbursement, limited access to clinical trials, and even the rapid changes to the standard of care hinders many cancer patients from receiving personalized care based on biomarker testing.

In the European survey, researchers also dug into how limited access to testing is impacting the practice of precision oncology broadly. They considered test access according to actionable biomarkers using the ESMO Scale for Clinical Actionability of molecular Targets, which assigns each molecular alteration to a numerical tier — tiers I, II, III, IV, V, and X — based on the clinical evidence backing its use guiding personalized cancer therapy. The actionability scale ranges from tier I alterations that have matched drugs known to improve patients’ outcomes in clinical trials, to tier X alterations that have no evidence supporting matched treatment.

Bayle presented survey results showing variable access to the ESCAT tier I biomarkers in lung, breast, colon, and prostate tumors. In lung cancer, testing for EGFR mutations, ALK alterations, and PD-L1 expression was almost always available across countries. Tests for other tier I biomarkers such as ROS1 and BRAF alterations were occasionally or usually available, and RET, NTRK, and MET biomarker tests were, for the most part, “occasionally” available.

Among tier I breast cancer biomarker tests, hormone receptor status and HER2/ERBB2 were the most accessible, tests for BRCA1/2 alterations fell somewhere in the middle, while tests for PIK3CA and NTRK alterations, and MSI status were much less available. For colon cancer, tests for MSI-high status, KRAS alterations, NRAS alterations, and BRAF V600E mutations were usually available while NTRK was only occasionally or rarely available, and in prostate cancer, two ESCAT tier I biomarker tests, BRCA1/2 and MSI status, were both occasionally available.

“Overall, the validated biomarkers that can be tested using relatively simple gene techniques not requiring extensive panels are … widely tested across countries,” Bayle said. But for the more advanced biomarkers, even those with the highest tier I ESCAT ranking, “The [alterations] are rarely tested for outside of clinical trials or research, even in EU countries and despite available drugs” targeting them.

Bayle offered the example of NTRK fusions, RET fusions, and tumor-mutational burden status in lung cancer. All of these biomarkers have matched treatment with regulatory approvals, but they’re still largely ranked as “only available in trials or research.”

Moreover, the ESMO survey revealed that oncologists across Europe may not be weighing clinical actionability when deciding which biomarkers to test their patients for. Sixty-five percent reported they did not use a genomic alteration scale; 27 percent said they did; and eight percent were unsure.

“We all agree it is very useful to rank molecular targets based on evidence, and one of the key messages [of this survey] could be that we need training to improve the knowledge among oncologists to make those tools more available,” Bayle said.

The establishment of a dedicated health authority in charge of biomolecular testing and a reference list for price and reimbursement can be indicators that a country is at least considering the value of biomarker testing in cancer care. However, the ESMO survey showed that more than one-quarter of countries did not have a health authority overseeing biomarker testing, and more than half did not have a reference list for price and reimbursement.

In fact, the survey showed great variability in pricing and out-of-pocket costs for biomarker tests across Europe. While the cost of simpler, single-gene tests were more stable, the costs for complex multi-gene tests were more dynamic, with costs reaching up to €3,000. Similarly, patients’ out-of-pocket costs for simpler tests like IHC tended to be low but increased more when trying to access experimental evaluations using WGS.

Almost 60 percent responded that financial reimbursement was frequently or very frequently a barrier to multi-gene tests, while only 24 percent said the same about single-gene tests. Bayle further highlighted that top barriers cited by respondents included difficulties in securing reimbursement for matched drugs, the accessibility of off-label matched drugs, and availability of clinical trials. Thirty percent of respondents noted that the absence of a proof of usefulness was a frequent or very frequent obstacle to prescribing biomarker tests.

Another indicator of a country’s prioritization of precision medicine broadly is if they have a national program like the 1,000 Genomes Project in the UK or France’s Genomic Medicine Plan 2025, but fewer than one-third of the respondents to ESMO’s survey said their countries had such a program, and only about half said they had access to molecular tumor boards.

What one can ultimately surmise from the test access disparities uncovered in ESMO’s survey is that cancer patients in Europe also have limited access to precision oncology advances. “Multiple gene testing is essential to enable broad access to personalized medicine,” Bayle said. “If you want access to agnostic-tumor treatment based on MSI status, TMB for immunotherapy, or NTRK fusions, you have to rely on robust testing capabilities.”

Indeed, precision oncology drugs are increasingly netting tissue-agnostic approval for biomarker-defined cancers in European countries, though slightly less frequently than in the US. For example, the Europeans Medicines Agency has approved NTRK-targeted drugs like Genentech’s Rozlytrek (entrectinib) and Bayer’s Vitrakvi (larotrectinib) for tissue-agnostic indications. But the EMA doesn’t approve companion diagnostics alongside drugs like the FDA does, which from a regulatory standpoint, disengages the process of molecular test access from the therapy.

Bayle compared the mismatch between targeted drugs and biomarker test access in Europe to how electric cars are outpacing the availability of chargers. “Electric cars, but no chargers … targeted therapies, but no molecular testing. … It’s the same question,” he said, suggesting that implementing an effective strategy for accessing these “chargers” — in this case, biomarker tests — will require cooperation between all stakeholders in Europe including industry, governments, third-party payors, oncologists, and patients.

During a separate presentation at ESMO, Denis Horgan, the director of the European Alliance for Personalized Medicine, agreed that it’s the availability of the tests and not necessarily the targeted drugs that’s holding up precision oncology. “I don’t believe drug access is the bottleneck of precision medicine,” Horgan said, noting that such discussions often unnecessarily veer to drug cost and access and overlook issues with test access. “It’s really the issue of molecular diagnostics. It’s broader than therapeutics.”

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