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Access and quality of biomarker testing for precision oncology in Europe

Open AccessPublished:October 01, 2022DOI:https://doi.org/10.1016/j.ejca.2022.09.005

      Highlights

      • The access to single biomarker tests is inadequate in many European countries.
      • In Europe, <10% of specimens requiring molecular testing are analysed with next generation sequencing.
      • Low participation in external quality assessment raises concerns about test quality.
      • Limited access to biomarker testing can preclude the access to precision medicines.

      Abstract

      Background

      Predictive biomarkers are essential for selecting the best therapeutic strategy in patients with cancer. The International Quality Network for Pathology, the European Cancer Patient Coalition and the European Federation of Pharmaceuticals Industries and Associations evaluated the access to and quality of biomarker testing across Europe.

      Methods

      Data sources included surveys of 141 laboratory managers and 1.665 patients, and 58 in-depth interviews with laboratory managers, physicians and payers. Four access metrics (laboratory access, test availability, test reimbursement, test order rate) and three quality metrics (quality scheme participation, laboratory accreditation, test turnaround time) were applied to rank the results.

      Results

      The access to precision medicines is higher in countries with public national reimbursement processes in place. Lack of diagnostic laboratory infrastructure, inefficient organization and/or insufficient public reimbursement narrow the access to single biomarker tests in many European countries. In countries with limited public reimbursement, pharma and patients’ out of pocket were the primary funding sources for testing. Uptake of multi-biomarker next generation sequencing (NGS) is highly varied, ranging from 0% to >50%. Financial constraints, a lack of NGS testing capabilities and the failure to include NGS testing in the guidelines represent the main barriers to NGS implementation. The quality of biomarker testing is highest in Western and Northern Europe, with more than 90% of laboratories participating in quality assurance schemes.

      Conclusions

      Our data clearly indicate the need for a call to action to ensure the clinical implementation of precision medicine in Europe.

      Graphical abstract

      Keywords

      1. Introduction

      Knowledge of cancer has improved vastly in the last two decades. The huge variability between cancer types and between patients with the same cancer type highlight the need for–and the promise of–tailoring cancer care to individual patient characteristics [
      • Garraway L.A.
      Genomics-driven oncology: framework for an emerging paradigm.
      ]. Fuelled by this knowledge, cancer treatment is increasingly shifting towards precision medicine that systematically utilises patient data to inform personalised treatment decisions [
      • Yates L.R.
      • Seoane J.
      • Le Tourneau C.
      • Siu L.L.
      • Marais R.
      • Michiels S.
      • et al.
      The European society for medical oncology (ESMO) precision medicine glossary.
      ].
      Significant progress has been made in the identification of biomarkers and matched therapies in oncology, with around 55% of all oncology clinical trials in 2018 involving the use of biomarkers, compared with around 15% in 2000 (https://clinicaltrials.gov/). It has been estimated that >25% of patients with cancer may receive a treatment based on biomarker testing [
      • Haslam A.
      • Kim M.S.
      • Prasad V.
      Updated estimates of eligibility for and response to genome-targeted oncology drugs among US cancer patients, 2006-2020.
      ,
      • Normanno N.
      • Apostolides K.
      • de Lorenzo F.
      • Beer P.A.
      • Henderson R.
      • Sullivan R.
      • et al.
      Cancer Biomarkers in the era of precision oncology: addressing the needs of patients and health systems.
      ]. In this regard, ever increasing knowledge of biomarkers is driving the use of broader tests of hundreds of genetic variants allowing for precise treatment decisions and monitoring [
      • Colomer R.
      • Mondejar R.
      • Romero-Laorden N.
      • Alfranca A.
      • Sanchez-Madrid F.
      • Quintela-Fandino M.
      When should we order a next generation sequencing test in a patient with cancer?.
      ,
      • Hyman D.M.
      • Taylor B.S.
      • Baselga J.
      Implementing genome-driven oncology.
      ,
      • Lamarca A.
      • Morfouace M.
      • Tejpar S.
      • Oliveira J.
      • Capela A.
      • Penel N.
      • et al.
      Molecular profiling and precision medicine in rare gastrointestinal cancers within EURACAN in the SPECTA Arcagen study (EORTC-1843): too few patients with matched treatment in Europe.
      ,
      • Chakravarty D.
      • Johnson A.
      • Sklar J.
      • Lindeman N.I.
      • Moore K.
      • Ganesan S.
      • et al.
      Somatic genomic testing in patients with metastatic or advanced cancer: ASCO provisional clinical opinion.
      ,
      • Pleasance E.
      • Bohm A.
      • Williamson L.M.
      • Nelson J.M.T.
      • Shen Y.
      • Bonakdar M.
      • et al.
      Whole-genome and transcriptome analysis enhances precision cancer treatment options.
      ]. In the future, the use of comprehensive biomarker testing is expected to support a shift away from traditional ‘organ-of-origin’ focused treatment paradigms towards the increased use of tumour-agnostic treatments based on patients’ molecular features [
      • Pestana R.C.
      • Sen S.
      • Hobbs B.P.
      • Hong D.S.
      Histology-agnostic drug development - considering issues beyond the tissue.
      ].
      The effective use of biomarker testing and applying high quality testing standards play a fundamental role in fulfilling the potential of precision medicine to transform patient outcomes [
      • Mateo J.
      • Steuten L.
      • Aftimos P.
      • Andre F.
      • Davies M.
      • Garralda E.
      • et al.
      Delivering precision oncology to patients with cancer.
      ]. A number of processes before and following clinical laboratory testing can affect the accuracy and reliability of test results and patient safety. This is even more critical for advanced diagnostic technologies, such as next generation sequencing (NGS) or digital pathology. External Quality Assurance (EQA) programs are the key to keep testing standards high and ensure that patients can benefit from precision medicine [
      • van Krieken J.H.
      • Normanno N.
      • Blackhall F.
      • Boone E.
      • Botti G.
      • Carneiro F.
      • et al.
      Guideline on the requirements of external quality assessment programs in molecular pathology.
      ,
      • Cree I.A.
      • Deans Z.
      • Ligtenberg M.J.
      • Normanno N.
      • Edsjo A.
      • Rouleau E.
      • et al.
      Guidance for laboratories performing molecular pathology for cancer patients.
      ,
      • Deans Z.C.
      • Costa J.L.
      • Cree I.
      • Dequeker E.
      • Edsjo A.
      • Henderson S.
      • et al.
      Integration of next-generation sequencing in clinical diagnostic molecular pathology laboratories for analysis of solid tumours; an expert opinion on behalf of IQN Path ASBL.
      ,
      • Deans Z.C.
      • Williams H.
      • Dequeker E.M.C.
      • Keppens C.
      • Normanno N.
      • Schuuring E.
      • et al.
      Review of the implementation of plasma ctDNA testing on behalf of IQN Path ASBL: a perspective from an EQA providers' survey.
      ,
      • Dufraing K.
      • Fenizia F.
      • Torlakovic E.
      • Wolstenholme N.
      • Deans Z.C.
      • Rouleau E.
      • et al.
      Biomarker testing in oncology - requirements for organizing external quality assessment programs to improve the performance of laboratory testing: revision of an expert opinion paper on behalf of IQNPath ABSL.
      ,
      • Van Casteren K.
      • Keppens C.
      • Schuuring E.
      • Deans Z.C.
      • Normanno N.
      • Patton S.J.
      • et al.
      External quality assessment schemes for biomarker testing in oncology: comparison of performance between formalin-fixed, paraffin-embedded-tissue and cell-free tumor DNA in plasma.
      ].
      The implementation of efficient biomarker testing with novel technologies is one of the key points (Flagship 6) identified in the Europe's Beating Cancer Plan (https://ec.europa.eu›files›eu_cancer-plan_en_0). The International Quality Network for Pathology (IQN Path), the European Cancer Patient Coalition (ECPC) and the European Federation of Pharmaceutical Industries and Associations (EFPIA), together with a consortium of industry and academic partners, have conducted research across the 27 European countries (EU27) and the United Kingdom (UK) in order to analyse the current biomarker testing practices in solid tumours and identify country-specific shortcomings.

      2. Materials and methods

      The research included a literature review on the current status of precision medicine treatment and testing in oncology, as well as interviews with key stakeholders, and two online surveys, one targeting laboratory managers and the other patients with cancer and patient advocates. The governance of the project and the survey questions are described in the supplementary material.

      2.1 Laboratory survey

      The laboratory manager survey, which opened in June 2020 and closed in August 2020, was aimed at providing a view of the testing landscape across biomarker test technologies in the EU27 plus UK. Invitations to participate in the survey were sent by scientific societies and EQA providers to their members. Survey responses were submitted by 141 laboratory managers from all countries, with the exception of Bulgaria and Luxembourg (Supplementary Table 1).
      Respondents were active in public and private laboratories, including large hospital laboratories/academic centres (more than 400 beds or academic centres, c.70% of respondents), small/medium hospital laboratories (not affiliated with a medical school and with fewer than 400 beds, c.15% of respondents), reference laboratories (laboratories that receive specimens from other centres) and dedicated NGS testing centres (c.15% of respondents).
      The questions covered a selection of key biomarkers (Table 1), corresponding with 37 ‘linked’ precision medicines approved by the European Medicine Agency (EMA) at the time of the survey (Supplementary Table 2). The investigated biomarkers and matched therapies are currently indicated in several types of cancer, including cancers of the lung, breast, colon, stomach and ovary and melanoma. Multi-biomarker tests refer to the use of NGS panels, ranging from targeted 50 gene panels up to whole genome/exome sequencing.
      Table 1Biomarker tests covered by the research. Tier 1 tests were covered in all countries, while Tier 2 tests were covered only in ‘focus’ countries.
      Tier 1 biomarker testsTier 2 biomarker tests
      Single biomarker tests: immunohistochemistry (IHC)/Fluorescence in situ hybridisation (FISH)PD-L1HER2
      ALK
      MMR/MSI
      Molecular (MDx): includes Polymerase Chain Reaction (PCR) and single biomarker next generation sequencing (NGS)BRCABRAF
      EGFRROS1
      NTRK
      Multi-biomarker test technologies: complex genomic signaturesNGS hotspot (up to 50 genes)/targeted panelN/A
      NGS comprehensive panel (more than 50 genes)N/A
      OtherN/ALiquid biopsy (ctDNA/plasma)
      The EU27 plus UK were divided into two groups, 10 ‘focus’ countries and 18 ‘additional’ countries, in order to concentrate the available resources on a group of countries representative of the different European health systems. In the 10 focus countries (Germany, Spain, France, Italy, UK, Belgium, Netherlands, Sweden, Poland and Greece), both tier 1 and tier 2 biomarkers were covered as part of the analysis, while in the additional countries only the tier 1 biomarkers were investigated (Table 1). For tier 1, innovative biomarkers (NGS hotspot and comprehensive), more recently introduced immunohistochemical biomarkers (PD-L1) and already standardised molecular markers Epidermal Growth Factor Receptor (EGFR) or more recent and complex markers (BRCA, NTRK) were selected by the Executive Committee in order to get a picture of the laboratories’ ability to respond to new requests (see also supplementary material). Tier 2 biomarkers include some markers introduced long ago in molecular diagnostics (HER2, ALK, ROS1, MMR/MSI and BRAF) and liquid biopsy as an innovative biomarker.

      2.2 Patient survey

      The patient survey (from February 2020 to September 2020) was conducted by European Cancer Patient Coalition among patients with cancer and patient advocates through national patients’ organizations belonging to its network, to characterise the patient experience along the cancer diagnostic journey. The survey included questions on the following: (i) the level and quality of patient education on biomarker testing; (ii) the degree of patient satisfaction around the testing process; (iii) the availability of public reimbursement to cover the cost of biomarker testing; (iv) the availability different biomarker test technologies and test turnaround time (TAT). Overall, 1587 survey responses from 16 European countries were submitted (Supplementary Table 3).

      2.3 In-depth interviews

      Survey results were supplemented by in-depth interviews with 21 laboratory managers, 27 oncologists and 10 payers/commercial experts, to develop a more detailed understanding of country performance against access and quality metrics, identify potential barriers to biomarker testing as well as discuss initiatives to achieve the vision of rapid and widespread access to biomarker testing.

      2.4 Data analysis

      Biomarker tests were assessed according to key access and quality metrics (Supplementary Table 4) in order to evaluate the current provision of precision medicine and biomarker testing as well as the key barriers to widespread adoption of biomarker testing.

      3. Results

      3.1 Access to precision medicines

      The access to precision medicines in EU27 and UK was ranked based on the number of medicines reimbursed out of the available medicines (Table 2). With the exception of Germany in which drug approval and inclusion into national formulary is directly linked to EMA, in most countries the approval and commercial launch of new medicines has some delays following EMA decision. Some countries were downgraded due to reported variations in reimbursement by region/hospital, medicines shortage, availability only through special funds or on a case-by-case basis. Medicines access is higher in countries with public national reimbursement processes in place. However, some limits in the availability of precision medicines were identified in the majority of European countries.
      Table 2Access to precision medicines.
      Rank
      Ranking based on the number of medicines available (approved at national level and commercially launched) and % of medicine publicly reimbursed.
      CountryN. medicines reimbursedN. medicines available% reimbursed
      1Germany353795%
      2Netherlands35
      Downgraded as some variation in reimbursement by region/hospital reported.
      3695%
      3UK29+5
      5 medicines available only through the cancer drug fund (CDF).
      3695%
      4Spain31
      Downgraded as some variation in reimbursement by region/hospital reported.
      3395%
      5Italy30
      Downgraded as some variation in reimbursement by region/hospital reported.
      3390%
      6Denmark2929100%
      7Belgium282995%
      8Croatia2828100%
      9Sweden273575%
      10France273480%
      11Bulgaria26
      Downgraded as actual availability of these medicines may be unstable, with several reports of regular medicine shortages.
      2990%
      12Austria25
      Some medicines may only be reimbursed on a case-by-case basis following physician request (e.g., larotrectinib).
      3375%
      13Finland243470%
      14Ireland243375%
      15Poland232785%
      16Romania222780%
      17Slovenia203360%
      18Hungary202580%
      19Greece192675%
      20Czech Republic192575%
      21Slovakia183160%
      22Portugal182670%
      23Luxembourg172665%
      24Estonia172375%
      25Lithuania152465%
      26Latvia102440%
      27Cyprus72725%
      28Malta77100%
      a Ranking based on the number of medicines available (approved at national level and commercially launched) and % of medicine publicly reimbursed.
      b Downgraded as some variation in reimbursement by region/hospital reported.
      c 5 medicines available only through the cancer drug fund (CDF).
      d Downgraded as actual availability of these medicines may be unstable, with several reports of regular medicine shortages.
      e Some medicines may only be reimbursed on a case-by-case basis following physician request (e.g., larotrectinib).

      3.2 Single biomarker test access

      The composite score to measure single biomarker test access was based on the average proportion of laboratories offering each single biomarker test in-house or through referral, the average proportion of tests covered by public reimbursement and the single biomarker test order rate (Supplementary Table 5). Limits to the access to single biomarker tests were identified in many European countries (Fig. 1A). In the countries with the lowest performance (i.e. Slovakia, Romania, Bulgaria), diagnostic laboratory infrastructure remains underdeveloped or not efficiently organised, providing insufficient coverage. Single biomarker test access is also impeded in Southern and Eastern Europe due to lower levels of public reimbursement for testing and variability in order rates. In countries with limited public reimbursement, pharma and patients’ out of pocket were the primary funding sources for testing. Timing to adoption of new tests was >1 year in 15/28 countries (Supplementary Table 5).
      Fig. 1
      Fig. 1The current status on quality and access to biomarker testing in Europe: (A) Single biomarker test access; (B) multi-biomarker test access; (C) biomarker test quality.

      3.3 Multi-biomarker test access

      The multi-biomarker test access score is a function of the availability of NGS testing, the capability to perform NGS testing with hotspot, small panels (<50 genes) or comprehensive panels (>50 genes), the time from introduction and the level of uptake. In addition, the average proportion of tests covered by public reimbursement and the proportion of non-small-cell lung cancer (NSCLC) biopsies tested with NGS were considered (Supplementary Table 6).
      The uptake of NGS is highly varied, ranging from 0% in Slovakia to more than 50% in Denmark and the Netherlands (Fig. 1B). Low uptake can be driven by a variety of factors (Supplementary Table 6). In Eastern European countries (e.g. Slovakia, Slovenia, Bulgaria and Romania), fewer than 75% of laboratories have access to NGS technologies either internally or via referral. In Southern Europe (e.g. Spain and Greece), the use of NGS panels is limited by the availability of funding. In these countries, more than 25% of the cost of NGS testing must be covered either by the patient or by pharmaceutical sponsors. In Northern and Western European countries, the availability of NGS is generally high, with all surveyed laboratories in the UK, France, Germany, Belgium and the Nordics reporting that they have at least 1 of 3 technologies (i.e. NGS hotspot, NGS panel and NGS comprehensive panel) available in house or via referral; however, funding is often limited to certain sample types. Order rates for multi-biomarker testing for NSCLC are high (NGS testing performed in >75% of total metastatic NSCLC biopsies) in Denmark, Belgium, Cyprus, France, Sweden and Portugal. In countries with low to medium NGS order rates, key barriers include financial constraints, a lack of NGS testing capabilities and the failure to include NGS testing in the guidelines.

      3.4 Biomarker test quality

      The quality of biomarker testing, measured in terms of the proportion of laboratories participating in at least one EQA scheme and the extent of ISO accreditation, is highest in Western and Northern Europe, with more than 90% of laboratories participating in EQA schemes (Fig. 1C). For example, in Belgium, all molecular diagnostic laboratories must be ISO accredited for around 80% of all molecular testing procedures performed in-house and EQA participation is essential for ISO15189 accreditation [
      • Mosele F.
      • Remon J.
      • Mateo J.
      • Westphalen C.B.
      • Barlesi F.
      • Lolkema M.P.
      • et al.
      Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: a report from the ESMO Precision Medicine Working Group.
      ].
      In Southern and Eastern Europe, fewer laboratories report quality scheme participation (e.g. c.56% in Greece and c.78% in Italy), mainly due to a lack of dedicated funds to support participation. In some Eastern European countries, however, other factors can also play a role: for example, in Slovakia, neither EQA participation nor ISO accreditation are required for public funding or clinical trial participation.
      Across Europe, TAT for single biomarker testing are generally good (mean 12.6 days; median 12 days; range 4–21 days), with only 7 countries reporting TAT >14 days (e.g. Bulgaria, Cyprus, Latvia, Poland, Romania, Slovakia and Sweden). However, longer TAT associated with multi-biomarker testing are more common, with mean TAT 17.2 days, median 15 days and range 4–40 days. In particular, 12 countries reported TAT in delivery of results >14 days (Supplementary Table 7).

      3.5 Patient survey findings

      Approximately 30% of the 1587 patient survey respondents reported that they had undergone biomarker testing. Testing rates were the highest for patients treated in large public hospitals, with more variable testing occurring in smaller public hospitals and in private hospitals (Supplementary Table 8).
      Patients rated their satisfaction with the information received as medium in most countries except for the UK, Spain, the Netherlands and Belgium (high satisfaction) (Table 3). On average, one third of patients who underwent biomarker testing did not receive explanations by physicians during the testing process (Supplementary Table 9). However, these findings need to be interpreted with caution due to the low number of patients who responded to the survey in some countries. TAT for different stages of the biomarker testing process, from biopsy appointments to the discussion of biomarker test results with the physician, were reported to be similar across countries, with wait times overall longest between the time of the biopsy and the receipt of the test results (Supplementary Table 10).
      Table 3Patient survey results: patient satisfaction with information provided by physicians
      Respondents were asked to score their satisfaction on a scale from 1 to 7, where 1 = not satisfied at all and 7 = very satisfied 1: Has your doctor informed you sufficiently about your cancer and the planned treatment before prescribing your treatment? 2: How satisfied were you with the information you received about the testing procedure overall? 3: Were you satisfied with the breadth and depth of information given to you by your doctor about the test results and how they would/might impact your treatment?
      .
      Country# of responsesPatient satisfaction with
      Information on cancer and treatment planInformation on testing procedureInformation on test results and implications for treatment
      Belgium164.65.46.4
      Bulgaria185.04.05.2
      Croatia505.25.35.7
      Czech Republic274.64.36.0
      Denmark266.54.55.2
      France164.34.35.4
      Germany905.45.55.3
      Greece1635.45.35.4
      Ireland195.85.85.2
      Italy2085.25.45.7
      Lithuania5165.35.35.4
      Netherlands1745.55.46.2
      Poland214.74.34.8
      Romania234.74.64.8
      Spain1615.95.85.7
      UK596.16.36.2
      Average15875.45.45.6
      a Respondents were asked to score their satisfaction on a scale from 1 to 7, where 1 = not satisfied at all and 7 = very satisfied 1: Has your doctor informed you sufficiently about your cancer and the planned treatment before prescribing your treatment? 2: How satisfied were you with the information you received about the testing procedure overall? 3: Were you satisfied with the breadth and depth of information given to you by your doctor about the test results and how they would/might impact your treatment?

      4. Discussion

      The increasing availability of biomarkers and matched drugs is radically changing the diagnostic and therapeutic approach to cancer. The approval of new complex biomarkers, the need to identify rare genomic alterations and the introduction of the ‘tumour agnostic’ biomarkers is making the use of NGS technologies increasingly indispensable for tumour genomic profiling [
      • Mosele F.
      • Remon J.
      • Mateo J.
      • Westphalen C.B.
      • Barlesi F.
      • Lolkema M.P.
      • et al.
      Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: a report from the ESMO Precision Medicine Working Group.
      ,
      • Chakravarty D.
      • Solit D.B.
      Clinical cancer genomic profiling.
      ]. The possibility for patients to access innovative therapies is directly linked to the availability of high quality biomarker tests [
      • Mateo J.
      • Steuten L.
      • Aftimos P.
      • Andre F.
      • Davies M.
      • Garralda E.
      • et al.
      Delivering precision oncology to patients with cancer.
      ].
      Our research has uncovered an inconsistent picture of the access, information and quality of biomarker testing in Europe. In many European countries, there are restrictions on the availability and reimbursement of precision medicines and biomarkers tests. Surprisingly, access to tests for single biomarkers with technologies long introduced in clinical practice is also limited in several countries. In agreement with previous reports [
      • Ryska A.
      • Berzinec P.
      • Brcic L.
      • Cufer T.
      • Dziadziuszko R.
      • Gottfried M.
      • et al.
      NSCLC molecular testing in Central and Eastern European countries.
      ], we found that the lack of adequate infrastructure in some Central and Eastern European countries and more generally the presence of inadequate budgets with regional differences in reimbursement policies, make access to tests difficult for many patients. In some countries, patients must cover all or part of the cost of biomarker tests, which might contribute to the “‘financial toxicity” associated with cancer [
      • Perrone F.
      • Jommi C.
      • Di Maio M.
      • Gimigliano A.
      • Gridelli C.
      • Pignata S.
      • et al.
      The association of financial difficulties with clinical outcomes in cancer patients: secondary analysis of 16 academic prospective clinical trials conducted in Italy.
      ].
      In several countries, there is no link between precision medicine and matched biomarker test approval. As consequence, the price authorization and reimbursement of biomarker test delay considerably compared with the approval of the medicines. This misalignment in procedures contributes to delaying the introduction of new tests in clinical practice and represents a ‘de facto’ limitation to access to new drugs. This problem has been addressed and resolved in some countries. In Belgium, the so-called Platform CDx includes competences of the Commission for Reimbursement of Medicines and the Technical Medical Council, which provides advice on the practices and the tests to be reimbursed by the healthcare system [
      • Van Valckenborgh E.
      • Hebrant A.
      • Antoniou A.
      • Van Hoof W.
      • Van Bussel J.
      • Pauwels P.
      • et al.
      Roadbook for the implementation of next-generation sequencing in clinical practice in oncology and hemato-oncology in Belgium.
      ].
      In Europe, less than 10% of specimens requiring the molecular testing are currently analysed with NGS, with many countries reporting less than 2% of tumours tested. International guidelines recommend the use of NGS for biomarker testing in NSCLC [
      • Mosele F.
      • Remon J.
      • Mateo J.
      • Westphalen C.B.
      • Barlesi F.
      • Lolkema M.P.
      • et al.
      Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: a report from the ESMO Precision Medicine Working Group.
      ]. We found that the fraction of NSCLC cases for which an NGS test is being performed today at diagnosis is less than 50% for many European countries. These data are similar to those reported for community hospitals in the United States [
      • Robert N.J.
      • Nwokeji E.D.
      • Espirito J.L.
      • Chen L.
      • Karhade M.
      • Evangelist M.C.
      • et al.
      Biomarker tissue journey among patients (pts) with untreated metastatic non-small cell lung cancer (mNSCLC) in the U.S. Oncology Network community practices.
      ], underlining how the problem of NSCLC sub-genotyping is unfortunately relevant across various healthcare systems. Indeed, a global survey on molecular profiling in lung cancer confirmed that less than 50% of patients receive biomarker testing [
      • Smeltzer M.P.
      • Wynes M.W.
      • Lantuejoul S.
      • Soo R.
      • Ramalingam S.S.
      • Varella-Garcia M.
      • et al.
      The international association for the study of lung cancer global survey on molecular testing in lung cancer.
      ]. In agreement with our findings, several barriers to biomarker testing were identified including cost, quality of samples, access, awareness and timing.
      The quality of biomarker testing is essential to ensure appropriate treatment for patients with cancer. We found that participation in EQA schemes is not mandatory for most European countries and few laboratories have received ISO accreditation. Several studies have shown that the quality of the new tests introduced in clinical practice is often limited and only the participation in EQA schemes can detect methodological errors that can have serious consequences on patients’ outcome [
      • van Krieken J.H.
      • Siebers A.G.
      • Normanno N.
      Quality Assurance for Molecular Pathology g. European consensus conference for external quality assessment in molecular pathology.
      ].
      Patients are increasingly informed and take an active part in the decision on the therapeutic strategy. An area of opportunity was identified given that one third of the patients surveyed did not receive enough information on biomarkers and biomarker tests indicated for their cancer. These data underline the need for continuous education of all stakeholders to ensure that patients are properly informed about all available therapeutic options and their implications [
      • Lawler M.
      • Le Chevalier T.
      • Banks I.
      • Conte P.
      • De Lorenzo F.
      • Meunier F.
      • et al.
      A bill of rights for patients with cancer in Europe.
      ].
      Our data indicate the need for a call to action to ensure the clinical implementation of precision medicine in Europe. In fact, the expected increase in approved agnostic therapies will lead to an increase of the number of patients to be analysed for biomarkers and, probably, of the cases candidates for NGS tests, whose capacity is currently highly limited. In this respect, our group identified a few general recommendations to improve this system. A process should be developed for the parallel regulatory and reimbursement approval of the precision medicine and the associated biomarker test. Investments in testing infrastructure and training of test personnel are definitely required. An adequate budget must be identified to be allocated to biomarkers, to meet all needs. A stringent system for verifying the quality of the tests must be implemented to guarantee patient safety. These initiatives are urgent to remove the barriers to biomarker test access and therefore guarantee equal access to the new therapeutic possibilities for all European patients, as highlighted in the European Code of Cancer Practice (https://www.europeancancer.org/2-standard/66-european-code-of-cancer-practice) and in the Europe's Beating Cancer Plan. Furthermore, they are essential to ensure the development in Europe of precision medicine, which in the future will rely more and more on the integration of routine clinical genomic analysis with clinical data [
      • Denny J.C.
      • Collins F.S.
      Precision medicine in 2030-seven ways to transform healthcare.
      ]. Many European countries risk being excluded from this progress if the issues identified by our survey are not addressed and resolved.

      Author contributions

      Study design: N. Normanno, K. Apostolidis, A. Wolf, Definition and distribution of questionnaires, data collection and analysis: N. Normanno, K. Apostolidis, A. Wolf, R. Al Dieri, Z. Deans, J. Fairley, J. Maas, A. Martinez, H. Moch, S. Nielsen, T. Pilz, E. Rouleau, S. Patton, V. Williams, Drafting of the manuscript: N. Normanno, Approval of the manuscript: N. Normanno, K. Apostolidis, A. Wolf, R. Al Dieri, Z. Deans, J. Fairley, J. Maas, A. Martinez, H. Moch, S. Nielsen, T. Pilz, E. Rouleau, S. Patton, V. Williams.

      Role of the funding source

      The project was coordinated by the IQN Path President N.N., principal investigator of the project, and by the representatives of the academic members of IQN Path and ECPC (see also supplementary material). The project was funded by grants from MSD , Roche Pharmaceuticals, Novartis , AstraZeneca , GSK and at lesser extent Guardant Health, BMS, Merck KGaA , Lilly and Bayer , and institutional funds from IQN Path. Funding was mainly used to cover the expenses of L.E.K. consulting for the assistance in the collection of data and the analyses of the results.

      Conflict of interest statement

      The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: N. Normanno declares: speaker's fee and/or advisory boards from MSD, Bayer, Biocartis, Illumina, Incyte, Roche, BMS, MERCK, Thermofisher, Astrazeneca, Eli Lilly; financial support to research projects (institutional grants) from MERCK, Thermofisher, QIAGEN, Roche, Astrazeneca, Biocartis, Illumina; non-financial interests President of the International Quality Network for Pathology (IQN Path) and President of the Italian Cancer Society (SIC).
      K. Apostolidis declares no conflicts of interest.
      A. Wolf declares employment in EFPIA.
      R. Al Dieri declares no conflicts of interest.
      Z. Deans declares paid employment as Deputy Director, Genomics Unit, NHS England and NHS Improvement; consultancies from AstraZeneca, MSD; educational grants from AstraZeneca, MSD, Qiagen, Eli Lilly.
      J. Fairley declares Advisory Board for Eli Lilly and paid lectures for AstraZeneca.
      J. Maas declares no conflicts of interest.
      A. Martinez declares no conflicts of interest.
      H. Moch declares research funding to own institution from Roche.
      S. Nielsen declares no conflicts of interest.
      T. Pilz declares no conflicts of interest.
      E. Rouleau declares fees for presentations, board, travel from Roche, BMS, AstraZeneca, Clovis, GSK.
      S. Patton declares no conflicts of interest.
      V. Williams declares no conflicts of interest.

      Acknowledgements

      The authors thank Chatrina Melcher, former Executive Director of IQN Path, for coordinating the project. The authors also thank L.E.K. Consulting, namely Leah Ralph and Verena Ahnert, for support in collecting and analysing the data and in the writing of this article.

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

      References

        • Garraway L.A.
        Genomics-driven oncology: framework for an emerging paradigm.
        J Clin Oncol. 2013; 31: 1806-1814
        • Yates L.R.
        • Seoane J.
        • Le Tourneau C.
        • Siu L.L.
        • Marais R.
        • Michiels S.
        • et al.
        The European society for medical oncology (ESMO) precision medicine glossary.
        Ann Oncol. 2018; 29: 30-35
        • Haslam A.
        • Kim M.S.
        • Prasad V.
        Updated estimates of eligibility for and response to genome-targeted oncology drugs among US cancer patients, 2006-2020.
        Ann Oncol. 2021; 32: 926-932
        • Normanno N.
        • Apostolides K.
        • de Lorenzo F.
        • Beer P.A.
        • Henderson R.
        • Sullivan R.
        • et al.
        Cancer Biomarkers in the era of precision oncology: addressing the needs of patients and health systems.
        Semin Cancer Biol. 2021; 84: 293-301
        • Colomer R.
        • Mondejar R.
        • Romero-Laorden N.
        • Alfranca A.
        • Sanchez-Madrid F.
        • Quintela-Fandino M.
        When should we order a next generation sequencing test in a patient with cancer?.
        EClinicalMedicine. 2020; 25100487
        • Hyman D.M.
        • Taylor B.S.
        • Baselga J.
        Implementing genome-driven oncology.
        Cell. 2017; 168: 584-599
        • Lamarca A.
        • Morfouace M.
        • Tejpar S.
        • Oliveira J.
        • Capela A.
        • Penel N.
        • et al.
        Molecular profiling and precision medicine in rare gastrointestinal cancers within EURACAN in the SPECTA Arcagen study (EORTC-1843): too few patients with matched treatment in Europe.
        Ann Oncol. 2022; S0923-7534(22): 01857-01859
        • Chakravarty D.
        • Johnson A.
        • Sklar J.
        • Lindeman N.I.
        • Moore K.
        • Ganesan S.
        • et al.
        Somatic genomic testing in patients with metastatic or advanced cancer: ASCO provisional clinical opinion.
        J Clin Oncol. 2022; 40: 1231-1258
        • Pleasance E.
        • Bohm A.
        • Williamson L.M.
        • Nelson J.M.T.
        • Shen Y.
        • Bonakdar M.
        • et al.
        Whole-genome and transcriptome analysis enhances precision cancer treatment options.
        Ann Oncol. 2022; 33: 939-949
        • Pestana R.C.
        • Sen S.
        • Hobbs B.P.
        • Hong D.S.
        Histology-agnostic drug development - considering issues beyond the tissue.
        Nat Rev Clin Oncol. 2020; 17: 555-568
        • Mateo J.
        • Steuten L.
        • Aftimos P.
        • Andre F.
        • Davies M.
        • Garralda E.
        • et al.
        Delivering precision oncology to patients with cancer.
        Nat Med. 2022; 28: 658-665
        • van Krieken J.H.
        • Normanno N.
        • Blackhall F.
        • Boone E.
        • Botti G.
        • Carneiro F.
        • et al.
        Guideline on the requirements of external quality assessment programs in molecular pathology.
        Virchows Arch. 2013; 462: 27-37
        • Cree I.A.
        • Deans Z.
        • Ligtenberg M.J.
        • Normanno N.
        • Edsjo A.
        • Rouleau E.
        • et al.
        Guidance for laboratories performing molecular pathology for cancer patients.
        J Clin Pathol. 2014; 67: 923-931
        • Deans Z.C.
        • Costa J.L.
        • Cree I.
        • Dequeker E.
        • Edsjo A.
        • Henderson S.
        • et al.
        Integration of next-generation sequencing in clinical diagnostic molecular pathology laboratories for analysis of solid tumours; an expert opinion on behalf of IQN Path ASBL.
        Virchows Arch. 2017; 470: 5-20
        • Deans Z.C.
        • Williams H.
        • Dequeker E.M.C.
        • Keppens C.
        • Normanno N.
        • Schuuring E.
        • et al.
        Review of the implementation of plasma ctDNA testing on behalf of IQN Path ASBL: a perspective from an EQA providers' survey.
        Virchows Arch. 2017; 471: 809-813
        • Dufraing K.
        • Fenizia F.
        • Torlakovic E.
        • Wolstenholme N.
        • Deans Z.C.
        • Rouleau E.
        • et al.
        Biomarker testing in oncology - requirements for organizing external quality assessment programs to improve the performance of laboratory testing: revision of an expert opinion paper on behalf of IQNPath ABSL.
        Virchows Arch. 2021; 478: 553-565
        • Van Casteren K.
        • Keppens C.
        • Schuuring E.
        • Deans Z.C.
        • Normanno N.
        • Patton S.J.
        • et al.
        External quality assessment schemes for biomarker testing in oncology: comparison of performance between formalin-fixed, paraffin-embedded-tissue and cell-free tumor DNA in plasma.
        J Mol Diagn. 2020; 22: 736-747
        • Mosele F.
        • Remon J.
        • Mateo J.
        • Westphalen C.B.
        • Barlesi F.
        • Lolkema M.P.
        • et al.
        Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: a report from the ESMO Precision Medicine Working Group.
        Ann Oncol. 2020; 31: 1491-1505
        • Chakravarty D.
        • Solit D.B.
        Clinical cancer genomic profiling.
        Nat Rev Genet. 2021; 22: 483-501
        • Ryska A.
        • Berzinec P.
        • Brcic L.
        • Cufer T.
        • Dziadziuszko R.
        • Gottfried M.
        • et al.
        NSCLC molecular testing in Central and Eastern European countries.
        BMC Cancer. 2018; 18: 269
        • Perrone F.
        • Jommi C.
        • Di Maio M.
        • Gimigliano A.
        • Gridelli C.
        • Pignata S.
        • et al.
        The association of financial difficulties with clinical outcomes in cancer patients: secondary analysis of 16 academic prospective clinical trials conducted in Italy.
        Ann Oncol. 2016; 27: 2224-2229
        • Van Valckenborgh E.
        • Hebrant A.
        • Antoniou A.
        • Van Hoof W.
        • Van Bussel J.
        • Pauwels P.
        • et al.
        Roadbook for the implementation of next-generation sequencing in clinical practice in oncology and hemato-oncology in Belgium.
        Arch Publ Health. 2018; 76: 49
        • Robert N.J.
        • Nwokeji E.D.
        • Espirito J.L.
        • Chen L.
        • Karhade M.
        • Evangelist M.C.
        • et al.
        Biomarker tissue journey among patients (pts) with untreated metastatic non-small cell lung cancer (mNSCLC) in the U.S. Oncology Network community practices.
        J Clin Oncol. 2021; 39: 9004
        • Smeltzer M.P.
        • Wynes M.W.
        • Lantuejoul S.
        • Soo R.
        • Ramalingam S.S.
        • Varella-Garcia M.
        • et al.
        The international association for the study of lung cancer global survey on molecular testing in lung cancer.
        J Thorac Oncol. 2020; 15: 1434-1448
        • van Krieken J.H.
        • Siebers A.G.
        • Normanno N.
        Quality Assurance for Molecular Pathology g. European consensus conference for external quality assessment in molecular pathology.
        Ann Oncol. 2013; 24: 1958-1963
        • Lawler M.
        • Le Chevalier T.
        • Banks I.
        • Conte P.
        • De Lorenzo F.
        • Meunier F.
        • et al.
        A bill of rights for patients with cancer in Europe.
        Lancet Oncol. 2014; 15: 258-260
        • Denny J.C.
        • Collins F.S.
        Precision medicine in 2030-seven ways to transform healthcare.
        Cell. 2021; 184: 1415-1419