Three Rounds of External Quality Assessment in France to Evaluate the Performance of 28 Platforms for Multiparametric Molecular Testing in Metastatic Colorectal and Non-Small Cell Lung Cancer
2016; Elsevier BV; Volume: 18; Issue: 2 Linguagem: Inglês
10.1016/j.jmoldx.2015.09.004
ISSN1943-7811
AutoresElisabeth Dequeker, Cleo Keppens, C. Egelé, Sofie Delen, Aude Lamy, Antoinette Lemoine, Jean‐Christophe Sabourin, Catherine Andrieu, Marjolijn J. L. Ligtenberg, D. Fétique, Bastiaan B. J. Tops, Clotilde Descarpentries, Hélène Blons, Yves Denoux, Cécile Aubé, Frédérique Penault‐Llorca, Paul Hofman, Karen Leroy, Cedric Le Maréchal, Laurent Doucet, Valérie Duranton‐Tanneur, Florence Pédeutour, Isabelle Soubeyran, Jean‐François Côté, Jean‐François Emile, Jean-Michel Vignaud, Nathalie Monhoven, Véronique Haddad, Pierre Laurent‐Puig, J. Han van Krieken, Frédérique Nowak, Etienne Lonchamp, Jean‐Pierre Bellocq, Étienne Rouleau,
Tópico(s)Cancer Genomics and Diagnostics
ResumoPersonalized medicine has gained increasing importance in clinical oncology, and several clinically important biomarkers are implemented in routine practice. In an effort to guarantee high quality of molecular testing in France, three subsequent external quality assessment rounds were organized at the initiative of the National Cancer Institute between 2012 and 2014. The schemes included clinically relevant biomarkers for metastatic colorectal (KRAS, NRAS, BRAF, PIK3CA, microsatellite instability) and non-small cell lung cancer (EGFR, KRAS, BRAF, PIK3CA, ERBB2), and they represent the first multigene/multicancer studies throughout Europe. In total, 56 laboratories coordinated by 28 regional molecular centers participated in the schemes. Laboratories received formalin-fixed, paraffin-embedded samples and were asked to use routine methods for molecular testing to predict patient response to targeted therapies. They were encouraged to return results within 14 calendar days after sample receipt. Both genotyping and reporting were evaluated separately. During the three external quality assessment rounds, mean genotype scores were all above the preset standard of 90% for all biomarkers. Participants were mainly challenged in case of rare insertions or deletions. Assessment of the written reports showed substantial progress between the external quality assessment schemes on multiple criteria. Several essential elements such as the clinical interpretation of test results and the reason for testing still require improvement by continued external quality assessment education. Personalized medicine has gained increasing importance in clinical oncology, and several clinically important biomarkers are implemented in routine practice. In an effort to guarantee high quality of molecular testing in France, three subsequent external quality assessment rounds were organized at the initiative of the National Cancer Institute between 2012 and 2014. The schemes included clinically relevant biomarkers for metastatic colorectal (KRAS, NRAS, BRAF, PIK3CA, microsatellite instability) and non-small cell lung cancer (EGFR, KRAS, BRAF, PIK3CA, ERBB2), and they represent the first multigene/multicancer studies throughout Europe. In total, 56 laboratories coordinated by 28 regional molecular centers participated in the schemes. Laboratories received formalin-fixed, paraffin-embedded samples and were asked to use routine methods for molecular testing to predict patient response to targeted therapies. They were encouraged to return results within 14 calendar days after sample receipt. Both genotyping and reporting were evaluated separately. During the three external quality assessment rounds, mean genotype scores were all above the preset standard of 90% for all biomarkers. Participants were mainly challenged in case of rare insertions or deletions. Assessment of the written reports showed substantial progress between the external quality assessment schemes on multiple criteria. Several essential elements such as the clinical interpretation of test results and the reason for testing still require improvement by continued external quality assessment education. Personalized medicine has become a key component in clinical oncology. Various targeted therapies have become accessible for several cancer types, and an increasing number of clinically important biomarkers were implemented in routine practice. For instance, testing of RAS mutations in metastatic colorectal cancer (mCRC) has been recognized as essential for the prediction of patient response to anti–epidermal growth factor receptor (EGFR) monoclonal antibodies. Similarly, molecular testing of the EGFR gene could predict the treatment outcome of tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC), and BRAF mutations anticipate the response of selective BRAF inhibitors in metastatic malignant melanoma. Therefore, quality of molecular tests must be assured to avoid uninformative, false-positive, or false-negative results that could worsen patient prognosis or expose them to unnecessary adverse effects. To ensure high-quality testing in molecular pathology, external quality assessment (EQA) rounds are organized which reflect the routine diagnostic practice as close as possible. Moreover, participation in interlaboratory comparisons is a necessary part of the quality framework of diagnostic laboratories, required by the International Organization for Standardization.1International Organization for StandardizationISO 15189: 2012 Medical laboratories: particular requirements for quality and competence. ISO, Geneva2012Google Scholar At the European level, different EQA providers such as the European Society of Pathology,2Bellon E. Ligtenberg M.J. Tejpar S. Cox K. de Hertogh G. de Stricker K. Edsjo A. Gorgoulis V. Hofler G. Jung A. Kotsinas A. Laurent-Puig P. Lopez-Rios F. Hansen T.P. Rouleau E. Vandenberghe P. van Krieken J.J. Dequeker E. External quality assessment for KRAS testing is needed: setup of a European program and report of the first joined regional quality assessment rounds.Oncologist. 2011; 16: 467-478Crossref PubMed Scopus (80) Google Scholar the European Molecular Genetics Quality Network,3Patton S. Normanno N. Blackhall F. Murray S. Kerr K.M. Dietel M. Filipits M. Benlloch S. Popat S. Stahel R. Thunnissen E. Assessing standardization of molecular testing for non-small-cell lung cancer: results of a worldwide external quality assessment (EQA) scheme for EGFR mutation testing.Br J Cancer. 2014; 111: 413-420Crossref PubMed Scopus (37) Google Scholar and the United Kingdom National External Quality Assessment Service4Deans Z.C. Bilbe N. O'sullivan B. Lazarou L.P. de Castro D.G. Parry S. Dodson A. Taniere P. Clark C. Butler R. Improvement in the quality of molecular analysis of EGFR in non-small-cell lung cancer detected by three rounds of external quality assessment.J Clin Pathol. 2013; 66: 319-325Crossref PubMed Scopus (33) Google Scholar have established EQA rounds for testing biomarker mutations in mCRC and NSCLC. Because participation in European EQA schemes is optional, these schemes are not appropriate to evaluate national performances. Therefore, nationwide schemes for mCRC or NSCLC have been conducted in Italy,5Normanno N. Pinto C. Taddei G. Gambacorta M. Castiglione F. Barberis M. Clemente C. Marchetti A. Results of the First Italian External Quality Assurance Scheme for somatic EGFR mutation testing in non-small-cell lung cancer.J Thorac Oncol. 2013; 8: 773-778Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar Germany,6Jung A. Baretton G. Dietel M. Gabbert H. Kreipe H. Schlake W. Tannapfel A. von Knebel Döberitz M. Kirchner T. The German quality assurance system for the molecular-pathological detection of KRAS mutations in colorectal cancer.J Clin Oncol. 2009; 27 (abstr. 4018)PubMed Google Scholar and Spain (https://www.seap.es/informes-de-rondas, last accessed August 26, 2015). In France, the French National Cancer Institute (INCa) and the French Ministry of Health have invested 25 million euros since 2008 to set up a national network of 28 regional molecular genetics centers (coordinating 56 laboratories) to implement routine molecular testing on cancer tissue.7Nowak F. Soria J.C. Calvo F. Tumour molecular profiling for deciding therapy-the French initiative.Nat Rev Clin Oncol. 2012; 9: 479-486Crossref PubMed Scopus (76) Google Scholar The goal of this centralized organization is to provide equal access to personalized cancer diagnosis and treatment all over France. Indeed, two national studies in France have shown that, although test methods are likely to depend on the locally available equipment and technical expertise, most laboratories were able to correctly identify the mutational status of all samples with a good interlaboratory comparison.8Beau-Faller M. Degeorges A. Rolland E. Mounawar M. Antoine M. Poulot V. Mauguen A. Barbu V. Coulet F. Pretet J.L. Bieche I. Blons H. Boyer J.C. Buisine M.P. de Fraipont F. Lizard S. Olschwang S. Saulnier P. Prunier-Mirebeau D. Richard N. Danel C. Brambilla E. Chouaid C. Zalcman G. Hainaut P. Michiels S. Cadranel J. Cross-validation study for epidermal growth factor receptor and KRAS mutation detection in 74 blinded non-small cell lung carcinoma samples: a total of 5550 exons sequenced by 15 molecular French laboratories (evaluation of the EGFR mutation status for the administration of EGFR-TKIs in non-small cell lung carcinoma [ERMETIC] project–part 1).J Thorac Oncol. 2011; 6: 1006-1015Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar, 9Blons H. Rouleau E. Charrier N. Chatellier G. Cote J.F. Pages J.C. de Fraipont F. Boyer J.C. Merlio J.P. Morel A. Gorisse M.C. de Cremoux P. Leroy K. Milano G. Ouafik L. Merlin J.L. Le Corre D. Aucouturier P. Sabourin J.C. Nowak F. Frebourg T. Emile J.F. Durand-Zaleski I. Laurent-Puig P. MOKAECM Collaborative GroupPerformance and cost efficiency of KRAS mutation testing for metastatic colorectal cancer in routine diagnosis: the MOKAECM study, a nationwide experience.PLoS One. 2013; 8: e68945Crossref PubMed Scopus (21) Google Scholar The EQA initiative by INCa is unique because it includes many participants from one country and the possibility to follow them over a 3-year period. Moreover, the schemes combine testing of EGFR, RAS, and other markers for NSCLC and mCRC. These markers include BRAF, PIK3CA, and microsatellite instability (MSI) for mCRC and KRAS, PIK3CA, BRAF, ERBB2 for NSCLC. Both BRAF and PIK3CA are kinases for which mutations may lead to a negative outcome to targeted therapy and poor prognosis in mCRC or NSCLC.10Kirstein M. Lange A. Prenzler A. Manns M.P. Kubicka S. Vogel A. Targeted therapies in metastatic colorectal cancer: a systematic review and assessment of currently available data.Oncologist. 2014; 19: 1156-1168Crossref PubMed Scopus (82) Google Scholar MSI is a state of genetic hypermutability associated with the presence of mCRC,11Birgisson H. Edlund K. Wallin U. Påhlman L. Kultima H.G. Mayrhofer M. Micke P. Isaksson A. Botling J. Glimelius B. Sundström M. Microsatellite instability and mutations in BRAF and KRAS are significant predictors of disseminated disease in colon cancer.BMC Cancer. 2015; 15: 125Crossref PubMed Scopus (25) Google Scholar whereas the clinical impact of mutations in ERBB2 in NSCLC is not yet known.12Peters S. Zimmermann S. Targeted therapy in NSCLC driven by HER2 insertions.Transl Lung Cancer Res. 2014; 3: 84-88Google Scholar This article summarizes the results of three EQA rounds supported by INCa in 2012 to 2014 with the purpose to reveal and improve the current status of molecular testing in mCRC and NSCLC in France. Results of the BRAF mutation analysis for malignant metastatic melanoma have already been published for the 2012 EQA round.13Emile J.F. Tisserand J. Bergougnoux L. Nowak F. Faucher G. Surel S. Lamy A. Lecorre D. Helias-Rodzewicz Z. Hofman P. Sabourin J.C. Laurent-Puig P. BRAF EQA GroupImprovement of the quality of BRAF testing in melanomas with nationwide external quality assessment, for the BRAF EQA group.BMC Cancer. 2013; 13: 472Crossref PubMed Scopus (11) Google Scholar Contrary to other national EQA schemes, all French clinical laboratories are obliged to reach the International Organization for Standardization (ISO) accreditation standard ISO 15189 before 20161International Organization for StandardizationISO 15189: 2012 Medical laboratories: particular requirements for quality and competence. ISO, Geneva2012Google Scholar, 7Nowak F. Soria J.C. Calvo F. Tumour molecular profiling for deciding therapy-the French initiative.Nat Rev Clin Oncol. 2012; 9: 479-486Crossref PubMed Scopus (76) Google Scholar and to participate in the three EQA rounds of 2012 to 2014, allowing the study of the national intralaboratory and interlaboratory evolution. A total of 28 molecular platforms participated to the EQA rounds, covering 56 different laboratories. Each platform and its laboratories are certified by INCa. Depending on their local organization, laboratories could be specialized in molecular testing for either mCRC or NSCLC. In 2014, the organization of both the mCRC and NSCLC EQA rounds was joined into one scheme, leading to some of the laboratories to work together as one during the 2014 EQA scheme. The three EQA rounds were organized by the Gen&Tiss consortium, consisting of the French Association for Quality Assurance of Pathology (AFAQAP), the French Group of Oncology Cytogenomics, Institute Curie and the Biomedical Quality Assurance research unit of KULeuven (www.genetiss.org, last accessed August 26, 2015). A steering committee of 16 members from French molecular genetics platforms supervised the schemes. Each EQA round included two schemes, namely one for mCRC and one for NSCLC. The goal of the schemes was to evaluate both the preanalytical (histologic validation), analytical (mutation analysis), and postanalytical (quality and time frame of reporting) phases of the laboratory process. Although in 2012 mutation analysis included EGFR and KRAS testing, several additional markers were evaluated from 2013 and 2014 to enlarge the diagnostic possibility and to anticipate the development of multiparametric analyses. During all EQA rounds, participation in KRAS and EGFR testing was mandatory for the mCRC and NSCLC schemes, respectively. Since 2014, testing of NRAS was obliged for the mCRC scheme as well. Because the clinical relevance of the other markers has not yet been determined, participation in the additional markers was free of choice. Participants were asked to use their routine procedures and to submit results within 14 calendar days. Results were submitted via a web-based questionnaire that retrieved information, on which mutations were tested, the methods used, the percentage of neoplastic cells, the genotyping results, and laboratory characteristics. The questionnaire consisted of two parts: a genotype table to enter the results per sample and a general questionnaire for the technical information about the analysis. Since 2014, an additional questionnaire on next-generation sequencing (NGS) was included as well, to verify if and how many laboratories were implementing the technique in their laboratory with the prospect of future schemes. Finally, written reports, hematoxylin and eosin-stained sections to show the tissue area cellularity, and optional raw data needed to be uploaded as well. To ensure anonymity, a unique identifier and email address were issued to each participant by a legal officer. Communication with the scheme organizers was restricted to this number only, allowing evaluation of all laboratories, including the ones involved in the organization of the schemes (provision or validation of biological samples). The same identifier was used during the three subsequent schemes to monitor the participants' evolution. In 2012 and 2013, each participating laboratory received 10 formalin-fixed, paraffin-embedded (FFPE) samples for the NSCLC EQA scheme and 10 FFPE samples for the mCRC scheme. In 2014, five FFPE samples were distributed per scheme, leading to a total of 10 cases for laboratories that participated in both the NSCLC and mCRC schemes. Tissue was provided by laboratories of the regional centers and members of the steering committee. Samples were approved by the French Association for Quality Assurance of Pathology to ensure compliance with the selection criteria: minimum 30% of tumor cells after macrodissection and sample homogeneity across the block. If these criteria were met, slides with a thickness of 6 μm (2012) or 5 μm (2013 and 2014) were prepared, and biological validation was performed by Institute Curie on three slides at both sides of the block with high-resolution melting analysis and Sanger sequencing. A second validation was performed by an external reference laboratory at the Radboud University Medical Center (Nijmegen, the Netherlands) with Sanger Sequencing in 2012 and NGS with the use of a targeted amplification in 2013 and 2014 (Ion Torrent PGM System; ThermoFisherScientific, Waltham, MA). In 2014, one optional educational sample per scheme was sent to the participants to evaluate the performance of rare mutations and mutations with an allelic frequency <20%. These samples were cell lines provided by Horizon Diagnostics (Cambridge, UK) that contained a KRAS exon 12 mutation for the mCRC EQA round and an EGFR exon 20 mutation for the NSCLC EQA round. Assessment of both genotyping results and written reports was based on an international standard14van Krieken J.H. Normanno N. Blackhall F. Boone E. Botti G. Carneiro F. Celik I. Ciardiello F. Cree I.A. Deans Z.C. Edsjo A. Groenen P.J. Kamarainen O. Kreipe H.H. Ligtenberg M.J. Marchetti A. Murray S. Opdam F.J. Patterson S.D. Patton S. Pinto C. Rouleau E. Schuuring E. Sterck S. Taron M. Tejpar S. Timens W. Thunnissen E. van de Ven P.M. Siebers A.G. Dequeker E. Guideline on the requirements of external quality assessment programs in molecular pathology.Virchows Arch. 2013; 462: 27-37Crossref PubMed Scopus (62) Google Scholar and a French recommendation from INCa.15Antoine M, Beau-Faller M, Bellocq J-P, Cadranel J, Denis M, Emile J-F, Laurent-Puig P, Rouleau E: Good practice guidelines for somatic mutation detection in solid tumors for therapeutic indications. [French]. Boulogne-Billancourt, France, National Cancer Institute, 2010. Available at: http://www.e-cancer.fr/Expertises-et-publications/Catalogue-des-publications/Bonnes-pratiques-pour-la-recherche-a-visee-theranostique-de-mutations-somatiques-dans-les-tumeurs-solides.Google Scholar Laboratories were denoted as participants for a given marker when at least eight of 10 (four of five in 2014) samples were analyzed. For each correctly assigned sample, a score of two points was awarded. In case of a genotyping error, points were deducted depending on the type of error (Table 1). Successful participation was defined as ≥90% (18 out of 20) for a marker.Table 1Genotype Marking Criteria for the mCRC and NSCLC Schemes in 2012, 2013, and 2014Marking criteriaMarks 2012Marks 2013Marks 2014The sample was assigned correctly222The sample mutation was not screened/cascade testing222Mutation detected but not specified (exon 19)222A mutation was found that is not classified as an active mutation22Sample mutation was incorrect in the datasheet, but correctly found in reports22The status is correct, but there is an error in the nomenclature∗In 2012, two points were given in case of a nomenclature error for an exon 19 deletion; in 2013, one point was awarded if an error was made in the exon 19 deletion name.111.5The status is correct, but the genotype is not specifiedThe allele was incorrectly assigned or a benign variant was reported as a mutation000A supplementary mutation was found that is classified as an active mutation000Not contributive – technical error, no or not enough amplified product for a reliable result000.5No HGVS nomenclature used2−0.5 (once)−0.25 (once)Samples were switched111mCRC EQA: RAS wild-type without screening exon 4−0.25 (once)EQA, external quality assessment; HGVS, Human Genome Variation Society; mCRC, metastatic colorectal cancer; NSCLC, non-small cell lung cancer; RAS, rat sarcoma.∗ In 2012, two points were given in case of a nomenclature error for an exon 19 deletion; in 2013, one point was awarded if an error was made in the exon 19 deletion name. Open table in a new tab EQA, external quality assessment; HGVS, Human Genome Variation Society; mCRC, metastatic colorectal cancer; NSCLC, non-small cell lung cancer; RAS, rat sarcoma. For RAS and EGFR testing, participants were asked to submit three written reports of two mutated and one wild-type case, for which mock clinical information had been provided beforehand. Only in 2013, laboratories were expected to upload a written report of the additional markers (BRAF, PIK3CA, and MSI for mCRC and KRAS, BRAF, PIK3CA, ERBB2 for NSCLC), for one mutated and one wild-type case. All reports were evaluated by two independent assessors for the presence and correctness of 32, 34, and 30 marking criteria in the 2012, 2013, and 2014 EQA rounds, respectively. One point was assigned if an item was present or if it was present but unclearly defined, whereas no points were awarded if the item was incorrect or absent. A final score of all marking criteria was reported on 100%. Special attention was given to the correct use of the Human Genome Variation Society (HGVS) nomenclature (http://www.hgvs.org/mutnomen/recs.html, last accessed May 11, 2015), and points were deducted (Table 1) for both the genotype results and the written reports in case of reporting a non-HGVS mutation. Participants were encouraged to perform macrodissection to optimize the amount of neoplastic cells and to identify the presence of necrosis and/or mucus in the samples. Estimates needed to be entered along with the genotype results, meeting specific intervals or values ( 19 of 20 (Supplemental Table S1). Error rates were calculated taking into account false-positive and false-negative results and mutation errors, and they were at least twice as high for the NSCLC scheme compared with the mCRC scheme for all three EQA rounds. Namely, error rates for EGFR and KRAS, respectively, counted 0.9% and 0.4% in 2012 compared with 3.6% and 0.6% in 2013. In 2014, NRAS was included in the mCRC EQA scheme as a second obligatory marker besides KRAS, and 0.6% of samples were incorrectly assigned for KRAS and NRAS. For EGFR testing, a high error rate of 10.4% could be observed in 2014. These high error rates could be particularly observed for EGFR exon 18 and 19 mutations. For the additional markers besides EGFR and KRAS, 4.4% and 0.6% of the samples were incorrectly assigned during the NSCLC and mCRC EQA in 2013, in comparison with 0.1% and 0.8% in 2014. The error rate of 4.4% during the 2013 NSCLC scheme was mainly because of 42 false-negative results in identifying a KRAS insertion (KRAS c.29_31dup, p.Gly10dup) and deletion (KRAS c.34_35del, p.Gly12Phe). In 2012, 1.1% of the samples were denoted as being not-contributive during the NSCLC scheme. During all other EQA rounds, the percentage of not-contributive samples did not exceed 0.5% (Table 2). Nomenclature errors were made in 1.3% and 1.1% of the samples for the NSCLC scheme, and 0.3% and 0.5% in the mCRC scheme during the 2013 and 2014 EQA rounds, respectively. Nomenclature errors were especially prominent for EGFR exon 19 mutations and for ERBB2 duplications in the NSCLC EQA scheme (Table 2). In 2012, nomenclature was not assessed for the genotyping results, because they were submitted via a predefined drop-down menu.Table 2Error Rates for All Markers of the NSCLC and mCRC EQA Scheme in 2012, 2013, and 2014MarkerEQA round 2012EQA round 2013EQA round 2014No. of samples per participantNo. and type of errorsNo. of samples per participantNo. and type of errorsNo. of samples per participantNo. and type of errorsNSCLC EQA scheme EGFR45 laboratories, 450 samples45 laboratories, 449 samples46 laboratories, 230 samplesWT51 FP, 4 NC41 NC20Exon 18 mutation212 FN1∗Total of six samples because one sample contained both an exon 18 and exon 21 mutation.8 MEExon 19 mutation41 FN,21 ME, 7 NE113 FN, 1 ME, 3 NEExon 21 mutation11 FN, 1 ME, 1 NC23 FN2∗Total of six samples because one sample contained both an exon 18 and exon 21 mutation.2 FN KRAS39 laboratories, 389 samples43 laboratories, 209 samplesWT71 NC40Insertion/deletion242 FNMutation1010 ERBB232 laboratories, 332 samples41 laboratories, 201 samplesWT9040Duplication112 NE11 FN, 1 NC, 7 NE PIK3CA13 laboratories, 115 samples22 laboratories, 110 samplesWT9050Mutation12 FN BRAF18 laboratories, 158 samples39 laboratories, 187 samplesWT101 NC51 NCmCRC EQA scheme KRAS50 laboratories, 500 samples49 laboratories, 490 samples49 laboratories, 245 samplesWT304030Mutation72 ME, 1 NC62 FN, 1 ME, 1 NC, 3 NE21 FN, 4 NE NRAS49 laboratories, 244 samplesWT30Mutation22 FN, 1 NE BRAF42 laboratories, 383 samples45 laboratories, 218 samplesWT71 NC40Mutation (>20%)2011 FNMutation ( T, p.Thr790Met) with an allelic frequency of 15% to 20%. Only 2 of 41 participants made an error, including one false-negative result and one additional EGFR mutation (Supplemental Table S2). For the mCRC EQA scheme, the educational sample contained a KRAS mutation (c.35G>A, p.Gly12Asp) with an even lower allelic frequency of 5% to 6%. Of 39 participants, five errors were made of which four were false-negative results and one was a mutation error (c.38G>A instead of c.35G>A). Three written reports of two mutated and one wild-type case were assessed for the presence and correctness of 32, 34, and 30 marking criteria in the 2012, 2013, and 2014 EQA rounds, respectively. The overall reporting score has improved over time from 71.5% to 73.8% and 84.2% for EGFR and from 70.9% to 72.9% and 85.1% for KRAS in 2012, 2013, and 2014 respectively. An important item is the presence or correctness of the clinical interpretation of genotype results, for which an obvious increase is present across the three EQA rounds (Figure 1). Interpretations were evaluated on the basis of the current knowledge about the impact of the test result on treatment response. In 2012, the clinical interpretation of EGFR analysis is present in 47.5% of the written reports for cases that carry a mutation, compared with 4.6% for wi
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