cancers Article A Nationwide Study on the Impact of Routine Testing for EGFR Mutations in Advanced NSCLC Reveals Distinct Survival Patterns Based on EGFR Mutation Subclasses Bart Koopman 1 , Betzabel N. Cajiao Garcia 1 , Chantal C. H. J. Kuijpers 2 , Ronald A. M. Damhuis 3 , Anthonie J. van der Wekken 4 , Harry J. M. Groen 4 , Ed Schuuring 1 , Stefan M. Willems 1 and Léon C. van Kempen 1, *   Citation: Koopman, B.; Cajiao Garcia, B.N.; Kuijpers, C.C.H.J.; Damhuis, R.A.M.; van der Wekken, A.J.; Groen, H.J.M.; Schuuring, E.; Willems, S.M.; van Kempen, L.C. A Nationwide Study on the Impact of Routine Testing for EGFR Mutations in Advanced NSCLC Reveals Distinct Survival Patterns Based on EGFR Mutation Subclasses. Cancers 2021, 13, 3641. https://doi.org/10.3390/ cancers13143641 Academic Editor: Federico Cappuzzo Received: 9 July 2021 Accepted: 16 July 2021 Published: 20 July 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands; b.koopman@umcg.nl (B.K.); b.n.cajiao.garcia@umcg.nl (B.N.C.G.); e.schuuring@umcg.nl (E.S.); s.m.willems@umcg.nl (S.M.W.) 2 Foundation PALGA, De Bouw 123, 3991 SZ Houten, The Netherlands; Chantal.Epskamp-Kuijpers@palga.nl 3 Netherlands Comprehensive Cancer Organisation (IKNL), P.O. Box 19079, 3501 DB Utrecht, The Netherlands; R.Damhuis@iknl.nl 4 Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands; a.j.van.der.wekken@umcg.nl (A.J.v.d.W.); h.j.m.groen@umcg.nl (H.J.M.G.) * Correspondence: l.van.kempen@umcg.nl; Tel.: +31-(0)50-3615129 Simple Summary: The presence of an EGFR activating mutation in tumors of non-small-cell lung cancer patients enables effective targeted therapy towards EGFR. Studies that describe a nationwide uptake of EGFR testing, the impact of the switch from single-gene EGFR to multi-gene testing, and the clinical response towards EGFR inhibitors in first-line treatment are limited. From 2013 to 2017 the percentage of patients routinely tested for EGFR mutations increased from 73% to 81% in the Netherlands. A strong shift towards EGFR testing as part of a multi-gene next generation sequencing analysis was observed. However, this did not change the percentage of EGFR mutations that were reported for this patient population, which remained stable at 12%. When treated with EGFR inhibitors that were available in a routine clinical setting prior to 2018, clear differences were observed between the type of EGFR mutation and survival. Abstract: EGFR mutation analysis in non-small-cell lung cancer (NSCLC) patients is currently standard-of-care. We determined the uptake of EGFR testing, test results and survival of EGFR- mutant NSCLC patients in the Netherlands, with the overall objective to characterize the landscape of clinically actionable EGFR mutations and determine the role and clinical relevance of uncommon and composite EGFR mutations. Non-squamous NSCLC patients diagnosed in 2013, 2015 and 2017 were identified in the Netherlands Cancer Registry (NCR) and matched to the Dutch Pathology Registry (PALGA). Overall, 10,254 patients were included. Between 2013–2017, the uptake of EGFR testing gradually increased from 72.7% to 80.9% (p < 0.001). Multi-gene testing via next-generation sequencing (increased from 7.8% to 78.7% (p < 0.001), but did not affect the number of detected EGFR mutations (n = 925; 11.7%; 95% confidence interval (CI), 11.0–12.4) nor the distribution of variants. For patients treated with first-line EGFR inhibitors (n = 651), exon 19 deletions were associated with longer OS than L858R (HR 1.58; 95% CI, 1.30–1.92; p < 0.001) or uncommon, actionable variants (HR 2.13; 95% CI, 1.60–2.84; p < 0.001). Interestingly, OS for patients with L858R was similar to those with uncommon, actionable variants (HR 1.31; 95% CI, 0.98–1.75; p = 0.069). Our analysis indicates that grouping exon 19 deletions and L858R into one class of ‘common’ EGFR mutations in a clinical trial may mask the true activity of an EGFR inhibitor towards specific mutations. Keywords: EGFR; non-small cell lung cancer; molecular diagnostics; nationwide; real-world; survival Cancers 2021, 13, 3641. https://doi.org/10.3390/cancers13143641 https://www.mdpi.com/journal/cancers