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Outcome of Patients With Resected Early-Stage Non-small Cell Lung Cancer and EGFR Mutations: Results From the IFCT Biomarkers France Study

Open AccessPublished:August 29, 2022DOI:https://doi.org/10.1016/j.cllc.2022.08.013

      Highlights

      • In France, epidermal growth factor receptor mutations are present in 12.9% of the resected stage I-II.
      • Epidermal growth factor receptor mutations have no impact on disease-free survival and overall survival.
      • Patients with resected stage I-II non-small cell lung cancer have a 5-year Disease-Free Survival of 65% and a 5-year overall survival of 75%.

      Abstract

      Introduction

      Molecular profile of resected stage I–II non-small cell lung cancer (NSCLC) would help refine prognosis and personalize induction or adjuvant strategies. We sought to report the molecular profile of resected stage I–II NSCLC and analyzed the impact of epidermal growth factor receptor (EGFR) mutations on outcomes in a Western population.

      Patients and Methods

      Surgical cases were identified from Biomarkers France study, a nationwide prospective study including NSCLC patients screened for EGFR, HER2, KRAS, BRAF, PIK3CA, ALK alterations from 2012 to 2013. Among surgical patients, clinical charts of the largest centers were reviewed in order to analyze the prognostic impact of EGFR mutations.

      Results

      In the BMF database (n = 17.636), surgical patients (n = 854) were characterized by a higher proportion of EGFR mutations than nonsurgical patients (12.9% vs. 10.2%, P = .025), while the other molecular alterations did not differ. The proportion of EGFR mutations was 27% in women undergoing surgery. In the study group (n = 293; EGFR wild type, n = 235; usual mutation, n = 50; rare mutation, n = 8), after a median follow-up of 67 months, 215 patients (74.4%) had not relapsed. No difference was found between EGFR-mutant and EGFR-wt tumors regarding recurrence site, disease-free survival, and overall survival. The 5-year disease-free survival and overall survival after surgical resection of stage I-II EGFR-mutated tumors were 65% and 75%, respectively.

      Conclusion

      In resected stage I to II NSCLC, EGFR mutations were found in 12.9% of cases, associated with a 5-year overall survival of 75%, with no impact on recurrence site, disease-free survival, and overall survival.

      Keywords

      Introduction

      The last decade has seen several advances in the management of advanced non-small cell lung cancer (NSCLC), due to the increased use of targeted therapies and immunotherapy, which has led to dramatic outcome improvement for some patients.
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      Immune checkpoint inhibitors in thoracic malignancies: review of the existing evidence by an IASLC expert panel and recommendations.
      In localized disease, surgery alone or with perioperative chemotherapy can cure more than half of patients.
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      • et al.
      The IASLC lung cancer staging project: analysis of resection margin status and proposals for residual tumor descriptors for non-small cell lung cancer.
      The contribution of targeted therapies as induction or adjuvant treatment has long remained exploratory.
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      • Mao WM
      • et al.
      Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): a randomised, open-label, phase 3 study.
      As a consequence, the molecular examination of early stage tumors was usually not recommended in Europe, but the field is now evolving rapidly.
      Recently, the ADAURA trial reported a significant benefit of the third-generation EGFR-TKI osimertinib on Disease-Free Survival (DFS) following complete surgical resection of stage IB–III EGFR-mutant NSCLC.
      • Wu YL
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      Osimertinib in resected EGFR-mutated non-small-cell lung cancer.
      In this trial, adjuvant EGFR-TKI was associated with an impressive improvement in DFS with a hazard ratio of 0.20, but the DFS of the control group was also disappointing for stage I-II disease, and mature overall survival (OS) data are not available yet. In this setting, additional data on the incidence and long term prognostic impact of EGFR mutation in unselected patients undergoing surgery for localized NSCLC are still needed.
      The French National Cancer Institute (INCa) funded a nationwide program for the routine analysis of EGFR, HER2, KRAS, BRAF, PIK3CA, and ALK alterations in advanced nonsquamous NSCLC patients. The Biomarkers France (BMF) study sought to assess the characteristics, molecular profiles, and clinical outcomes of patients screened by this program, leading to the prospective collection of clinical and molecular data of 17,664 patients in 1 year.
      • Barlesi F
      • Mazieres J
      • Merlio JP
      • et al.
      Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT).
      Although this study intended to include only patients with advanced NSCLC, some patients had localized NSCLC. We conducted a retrospective study to analyze the prognostic impact of EGFR mutations in patients with resected localized NSCLC included in the BMF study.

      Patients and Methods

      BMF Study

      The design of the BMF study has already been reported.
      • Barlesi F
      • Mazieres J
      • Merlio JP
      • et al.
      Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT).
      Briefly, this study prospectively included advanced NSCLC patients who were routinely screened for EGFR, HER2 (ERBB2), KRAS, BRAF, PIK3CA, and ALK alterations, by 28 certified regional genetics centers in France. Patients were consecutively assessed over a 1-year period from April 2012 to April 2013. Although the study focused on patients with advanced (stage III-IV) and relapsed disease, it also included patients with localized (stage I-II) disease. This latter group is the subject of the current manuscript. The TNM classification reported in the BMF study and in this analysis is the 7th Edition published in 2007.
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      The IASLC lung cancer staging project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours.

      Ethics

      The BMF study was approved by a national ethics committee for observational studies (Comité d'Evaluation des Protocoles de Recherche Observationnelle [CEPRO]) on September 28, 2011, by the French Advisory Committee on Information Processing in Material Research in the Field of Health (Comité Consultatif sur le Traitement de l'Information en Matière de Recherche dans le Domaine de la Santé [CCTIRS]) on September 22, 2011, and by the National Commission of Informatics and Liberty (Commission Nationale Informatique et Libertés [CNIL]) on December 18, 2011, according to French laws.

      Study Design

      We conducted a retrospective study of the prospective BMF database. Clinical, biological, and outcome data were provided by clinicians that had included the patients. DFS and overall survival (OS) were assessed by each clinician. To analyze the prognostic impact of EGFR mutations within surgical patients, we reviewed the clinical charts and outcomes of centers with at least one case of EGFR-mutant early stages NSCLC, in order to favor patients with usual EGFR mutations (ie, del19 and L858R). Thus, the study group was composed of patients whose data have been verified and completed on site. Two subgroups were then formed based on EGFR status: patients with usual EGFR mutations and patients with wild-type (wt) EGFR. Analysis was performed on data that had been exported on September 9, 2019.

      Molecular Analyses

      The molecular analyses of EGFR (exons 18-21), HER2 (exon 20), KRAS (exon 2), BRAF (exon 15), and PIK3CA (exons 9 and 20) mutations, as well as of ALK rearrangements, were performed on a routine basis at 28 certified molecular genetics centers as previously reported.
      • Barlesi F
      • Mazieres J
      • Merlio JP
      • et al.
      Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT).
      ,
      • Beau-Faller M
      • Degeorges A
      • Rolland E
      • et al.
      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).
      • Blons H
      • Rouleau E
      • Charrier N
      • et al.
      Performance and cost efficiency of KRAS mutation testing for metastatic colorectal cancer in routine diagnosis: the MOKAECM study, a nationwide experience.
      • Beau-Faller M
      • Blons H
      • Domerg C
      • et al.
      A multicenter blinded study evaluating EGFR and KRAS mutation testing methods in the clinical non-small cell lung cancer setting–IFCT/ERMETIC2 Project Part 1: comparison of testing methods in 20 French molecular genetic National Cancer Institute platforms.

      Objectives

      The primary objective of this study was to study the prognostic impact of EGFR mutations in localized NSCLC patients, with a special focus on the impact of EGFR mutations on OS, DFS, type of recurrence, and second cancer. Secondary objective was to report the molecular profile of localized NSCLC patients undergoing surgical resection with a curative intent included in a nationwide database.

      Statistical Analysis

      Descriptive statistics were used, including the median and range or quartiles for continuous variables or frequencies and percentages for categorical variables. The median follow-up duration was defined as the time from the date of the molecular analysis assessment to the closing date of the analysis. DFS was defined as the time from the date of molecular analysis assessment to the date of the first recurrence or death from any cause. OS was defined as the time from the date of the molecular analysis assessment to the date of death or final follow-up. Survival curves were estimated using the Kaplan-Meier method and compared using the 2-sided log-rank test. The characteristics (with or without mutation) of each biomarker were compared using the χ2 test for qualitative variables or the nonparametric test for quantitative variables. Univariate Cox models were applied to select the most-promising prognostic variables (threshold P = .20). A multivariate Cox model was then applied to adjust for potential confounders (clinical or molecular characteristics associated with DFS or OS). Adjusted hazard ratios (HRs) with 95% confidence intervals (95% CIs) were also calculated. We then matched patients from EGFR-mutant and EGFR-wt groups according to sex, tobacco use, and stage, and compared the characteristics and prognosis of the matched groups. All statistical tests were 2-sided, and a P-value below .05 was considered statistically significant. All analyses were performed using SAS software (version 9.3, SAS Institute).

      Results

      BMF Database

      At the last monitoring data-lock in March 2018, the BMF database gathered 17,636 patients with NSCLC and available molecular profile. The study flowchart is shown in Figure 1, and patients characteristics are summarized in Supplemental Table 1. As compared to nonsurgical patients, surgical patients were characterized by a more frequent past-medical history of cancer (30% vs. 20.4%, respectively, P < .001) and more frequent EGFR mutations (12.9% vs. 10.2%, respectively, P = .025). EGFR mutation rates were also higher in women than in men, and in women undergoing surgery than in all women (27% vs. 20%, P < .01).

      Study Group

      After on-site visits, 293 surgical patients were included in the study group. Their characteristics are described in Supplemental Table 2. Compared with unselected surgical patients, patients included in the study group were more frequently recruited in university hospitals (62.8% vs. 35.8%, respectively, P < .001) and more frequently women (44.9% vs. 35%, respectively, P = .005).

      EGFR Mutation

      The study group included 235 patients with EGFR-wt tumors (80.3%), 50 patients with usual EGFR mutations (17%) and 8 patients with rare EGFR mutations (2.7%). The clinical and histological characteristics of patients with EGFR-mutant and EGFR-wt tumors are described in Table 1. Interestingly, EGFR mutations were more frequent in stage I than in stage II disease (21.9% vs. 7%, respectively, P = .003), leading to a tumor stage imbalance between groups with a majority of T1 tumors (n = 28, 57.1%) in patients with EGFR mutations and a majority of T2-T3 tumors (n = 139, 60.9%) in patients without EGFR mutations (P = .006).
      Table 1Characteristics of Patients With EGFR-Mutant and EGFR-Wild Type Tumors (n = 285 after Exclusion of 8 Patients With Rare EGFR Mutations)
      EGFR-Mutant (N = 50)EGFR-Wild Type (N = 235)P-Value
      SexN50234<.001
      MaleN (%)10 (20.0)149 (63.7)
      FemaleN (%)40 (80.0)85 (36.3)
      Age (years)N50235.16
      Mean ± SD66.04 ± 9.5663.87 ± 9.85
      Median67.8764.29
      Range[48.7-83.4][38.2-91.5]
      Asian originN38171.61
      YesN (%)2 (5.3)5 (2.9)
      NoN (%)36 (94.7)166 (97.1)
      SmokingN47229<.001
      SmokerN (%)2 (4.3)111 (48.5)
      Former smokerN (%)17 (36.2)98 (42.8)
      Non-smokerN (%)28 (59.6)20 (8.7)
      Personal history of cancerN47226.79
      YesN (%)12 (25.5)62 (27.4)
      NoN (%)35 (74.5)164 (72.6)
      Type of surgeryN49235.52
      Wedge resectionN (%)3 (6.1)30 (12.8)
      LobectomyN (%)45 (91.8)197 (83.8)
      PneumonectomyN (%)03 (1.3)
      OtherN (%)1 (2.0)5 (2.1)
      TNM - TumorN49228.006
      T1aN (%)15 (30.6)60 (26.3)
      T1bN (%)13 (26.5)29 (12.7)
      T2aN (%)18 (36.7)80 (35.1)
      T2bN (%)2 (4.1)19 (8.3)
      T3N (%)1 (2.0)40 (17.5)
      TNM - NodeN49231.16
      0N (%)45 (90.0)206 (88.0)
      1N (%)3 (6.0)25 (10.7)
      2N (%)1 (2.0)0
      StageN48228.003
      IN (%)42 (87.5)149 (65.4)
      IIN (%)6 (12.5)79 (34.6)
      Perioperative treatmentsN50232.57
      NoN (%)38 (76.0)168 (72.1)
      YesN (%)12 (24.0)65 (27.9)
      Induction treatmentN50232.69
      NoN (%)49 (98.0)223 (95.7)
      YesN (%)1 (2.0)10 (4.3)
      Adjuvant treatmentN50232.61
      NoN (%)39 (78.0)173 (74.6)
      YesN (%)11 (22.0)59 (25.4)
      Abbreviations: PS = performance status; SD = standard deviation.

      Relapse

      The median follow-up of the study group was 67 months (63.6-69.7). At the time of analysis, 215 patients (74.4%) had not relapsed, 67 (23.5%) had relapsed, and 3 (1%) were lost to follow-up. No difference was found between patients with EGFR-mutant and EGFR-wt tumors regarding the recurrence rate, site of recurrence, and occurrence of metachronous cancer, as shown in Table 2. Among the 58 patients with EGFR mutant tumor, 13 patients received adjuvant treatment based on chemotherapy while no patient received adjuvant TKI. Among the 16 patients with EGFR mutant tumors who experienced tumor relapse, 8 patients were treated with TKI and 2 patients were treated with chemotherapy.
      Table 2Outcome of Patients With EGFR-Mutant and EGFR-Wild Type Tumors (Study Group, n = 285 After Exclusion of 8 Patients With Rare EGFR Mutations)
      EGFR-Mutant (N = 50)EGFR-Wild Type (N = 235)Total (N = 285)P-Value
      Disease recurrenceN50229282.96
      NoN (%)38 (76.0)177 (76.3)215 (75.4)
      YesN (%)12 (24.0)55 (23.7)67 (23.5)
      Local recurrenceN1255671.0
      NoN (%)4 (33.3)18 (32.7)22 (7.7)
      YesN (%)8 (66.7)37 (67.3)45 (15.8)
      Brain metastasisN828361.00
      NoN (%)4 (50.0)16 (57.1)20 (7.0)
      YesN (%)4 (50.0)12 (42.9)16 (5.6)
      Extra cerebral metastasisN50235285
      NoN (%)45 (90.0)218 (92.8)263 (92.3).56
      YesN (%)5 (10.0)17 (7.2)22 (7.7)
      Metachronous NSCLCN50232283.21
      NoN (%)49 (98.0)216 (92.7)265 (93.0)
      YesN (%)1 (2.0)17 (7.3)18 (6.3)
      Abbreviations: NSCLC, non-small cell lung cancer.

      Survival

      DFS and OS are reported in Figure 2. In the study group, the 5-year DFS and OS were 65% and 75%, respectively. No significant difference was found in OS and DFS between EGFR-mutant and EGFR-wt patients. The prognostic factors associated with OS and DFS in the 2 groups are reported in Figure 3. In multivariate analyses including disease stage as a covariate, EGFR mutation was not associated with OS (HR 1.13, 95% CI 0.51-2.50, P = 0.76) or with DFS (HR 1.41, 95% CI 0.78–2.53, P = .25).
      Figure 2
      Figure 2Kaplan-Meier Curves of the 293 Patients included in the study group according to EGFR mutation after a follow-up of 67.0 months (IQR: 63.6-69.7): (A) overall survival (study group, n = 293); (B) Overall Survival According to EGFR Status after exclusion of 8 patients with rare EGFR mutations (n = 285); (C) disease-free survival (study group, n = 293); (D) disease-free survival according to EGFR status after exclusion of 8 patients with rare EGFR mutations (n = 285).
      Figure 3
      Figure 3Prognostic Factors included in the Multivariate Analysis of AssociatedwithSurvival (A) overall survival (study group, n = 293); (B) disease-free survival (study group, n = 293).

      Matching

      We then matched 39 patients with EGFR-mutant tumors with 39 patients with EGFR-wild type tumors with the same sex, tobacco history, and disease stage. The characteristics and prognosis of the matched groups are shown in Table 3. The survival curves of the matched groups are presented in Figure 4.There was no significant difference between groups regarding their characteristics, treatment, frequency of recurrence, and overall survival.
      Table 3Characteristics and Outcomes of Patients With EGFR-Mutant and EGFR-Wild Type Tumors (Matched Groups According to Sex, Tobacco Use, and Stage, n = 78).
      EGFR-Mutant (N = 39)EGFR-Wild Type (N = 39)P-Value
      SexN3939
      MaleN (%)9 (23.1)9 (23.1)1.00
      FemaleN (%)30 (76.9)30 (76.9)
      Age (y)N3939
      Mean ± SD64.54 ± 8.8566.17 ± 10.70.51
      Median66.3166.70
      Range[51.3-78.9][48.8-84.0]
      Asian originN3329
      YesN (%)1 (3.0)01.00
      NoN (%)32 (97.0)29 (100.0)
      SmokingN3939
      Smoker

      + former smoker
      N (%)21 (53.8)21 (53.8)1.00
      Non smokerN (%)18 (46.2)18 (46.2)
      PSN3234
      0N (%)14 (43.8)19 (55.9).68
      1N (%)16 (50.0)13 (38.2)
      2N (%)2 (6.3)2 (5.9)
      Personal history of cancerN3939
      YesN (%)6 (15.4)13 (33.3).06
      NoN (%)33 (84.6)26 (66.7)
      Type of surgeryN3839
      WedgeN (%)1 (2.6)7 (17.9).06
      LobectomyN (%)36 (94.7)31 (79.5)
      PneumonectomyN (%)00
      OtherN (%)1 (2.6)1 (2.6)
      StageN3939
      IN (%)30 (76.9)30 (76.9)1.0
      IIN (%)9 (23.1)9 (23.1)
      Adjuvant treatmentN3939
      NoN (%)26 (66.7)32 (82.1).12
      YesN (%)13 (33.3)7 (17.9)
      Induction treatmentN3939
      NoN (%)39 (100.0)39 (100.0)-
      YesN (%)00
      RecurrenceN3939
      NoN (%)26 (66.7)33 (84.6).06
      YesN (%)13 (33.3)6 (15.4)
      Figure 4
      Figure 4Kaplan-Meier Curves of the 78 Patients Included in the Matched groups (A) Overall survival (matched groups, n = 39 per group, P = .76); (B) disease-free survival (matched groups, n = 39 per group, P = .30).

      Discussion

      By studying the molecular profile and prognostic impact of EGFR mutations in patients with resected stage I-II NSCLC included in the BMF study, we found that the proportion of KRAS, ALK, PIK3CA, BRAF, and HER2 alterations did not significantly differ between surgical and nonsurgical patients. The proportion of EGFR mutations was higher in surgical than in non-surgical patients, ranging from 4% of men to 27% of women undergoing surgery, with no significant impact on DFS and OS. After surgical resection of stage I to II EGFR-mutated tumors, the 5-year DFS and OS were 65% and 75%, respectively.
      The frequency of EGFR mutations has been widely studied in advanced NSCLC. Post hoc analyses of the historical TRIBUTE and INTACT trials found EGFR mutations to be present in 12%
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      Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: molecular analysis of the IDEAL/INTACT gefitinib trials.
      to 13%
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      Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib.
      of cases. Consecutive studies have proven that the presence of EGFR mutations correlates with adenocarcinoma histology, female sex, Asian ethnicity, and non-smoking status.
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      EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib.
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      In the United States, the Lung Cancer Mutation Consortium (LCMC) was formed to analyze 10 oncogenic driver mutations in lung adenocarcinoma patients. Among the 1007 cases with mutation analysis performed, EGFR mutations were detected in 22%.
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      Conversely, reports on the frequency of EGFR mutations in patients with localized NSCLC are scarce. In Japan, Suda et al. recently analyzed 5780 surgically resected lung cancer, detecting EGFR mutations in 41% of them.
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      Clinical impacts of EGFR mutation status: analysis of 5,780 surgically resected lung cancer cases.
      In France, the BMF study included 18,679 molecular analyses of 17,664 NSCLC patients, with EGFR mutations detected in 10.2%.
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      • Mazieres J
      • Merlio JP
      • et al.
      Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT).
      We found a significantly higher frequency of EGFR mutations in the subgroup of patients resected for stage I to II NSCLC. Although this may be the result of selection bias, it still constitutes an interesting milestone for the future management of localized NSCLC in a Western population.
      EGFR mutation may generate a different natural history and therefore a different prognosis than that observed for wild-type tumors. In localized NSCLC, Suda et al. found that survival was significantly longer in EGFR-mutant than in EGFR-wt patients.
      • Suda K
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      Clinical impacts of EGFR mutation status: analysis of 5,780 surgically resected lung cancer cases.
      Conversely, our study suggests that EGFR mutations have no significant prognostic impact in localized resected NSCLC in a Western population. In advanced NSCLC, EGFR mutations have been reported to be associated with improved prognosis, compared to wt tumors.
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      Performance and cost efficiency of KRAS mutation testing for metastatic colorectal cancer in routine diagnosis: the MOKAECM study, a nationwide experience.
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      Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib.
      ,
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      Weighing tumor biology in treatment decisions for patients with non-small cell lung cancer.
      Since these studies, EGFR mutations have been found to be associated with improved response to EGFR-TKI,
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      and the presence of an EGFR mutation has been associated with longer survival, due to successive improvements in the efficacy of EGFR-TKI.
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      Taken together, these data suggest that, in addition to a possible favorable natural history that has not been confirmed in our study, the subset of NSCLC harboring EGFR mutations mostly benefit from the efficacy of TKIs.
      The development of adjuvant targeted therapy is thus highly desirable to optimize the outcome of resected localized EGFR-mutant NSCLC and reduce the toxicity of adjuvant treatments. The TASTE study demonstrated the feasibility of a biology-driven trial in the adjuvant setting, as 80% of patients with complete biomarker status were able to start adjuvant treatment within 2 months of surgery.
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      Further trials studying the impact of adjuvant TKI in EGFR-mutant NSCLC patients have been limited by the use of unreliable biomarkers,
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      Adjuvant Erlotinib versus placebo in patients with stage IB-IIIA non-small-cell lung cancer (RADIANT): A randomized, double-blind, phase III Trial.
      a limited number of patients,
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      SELECT: A phase II trial of adjuvant erlotinib in patients with resected epidermal growth factor receptor-mutant non-small-cell lung cancer.
      a focus on higher stages
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      or on an Asian population,
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      Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): a randomised, open-label, phase 3 study.
      and the absence of data on OS.
      • Zhong WZ
      • Wang Q
      • Mao WM
      • et al.
      Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): a randomised, open-label, phase 3 study.
      ,
      • Kelly K
      • Altorki NK
      • Eberhardt WE
      • et al.
      Adjuvant Erlotinib versus placebo in patients with stage IB-IIIA non-small-cell lung cancer (RADIANT): A randomized, double-blind, phase III Trial.
      ,
      • Pennell NA
      • Neal JW
      • Chaft JE
      • et al.
      SELECT: A phase II trial of adjuvant erlotinib in patients with resected epidermal growth factor receptor-mutant non-small-cell lung cancer.
      The results of available phase 3 trials studying the impact of adjuvant TKI in EGFR-mutant NSCLC patients are summarized in Table 4.
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      Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): a randomised, open-label, phase 3 study.
      ,
      • Wu YL
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      • He J
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      Osimertinib in resected EGFR-mutated non-small-cell lung cancer.
      ,
      • Zhong WZ
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      Gefitinib Versus Vinorelbine plus cisplatin as adjuvant treatment for Stage II-IIIA (N1-N2) EGFR-mutant NSCLC: final overall survival analysis of CTONG1104 phase III trial.
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      • et al.
      West Japan oncology group. randomized phase III study of gefitinib versus cisplatin plus vinorelbine for patients with resected stage II-IIIA non-small-cell lung cancer with EGFR mutation (IMPACT).
      Among them, the ADJUVANT CTONG trial of gefitinib in EGFR-mutated early stage NSCLC failed to demonstrate an OS benefit despite profound improvements in DFS.
      • Zhong WZ
      • Wang Q
      • Mao WM
      • et al.
      Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): a randomised, open-label, phase 3 study.
      ,
      • Zhong WZ
      • Wang Q
      • Mao WM
      • et al.
      Gefitinib Versus Vinorelbine plus cisplatin as adjuvant treatment for Stage II-IIIA (N1-N2) EGFR-mutant NSCLC: final overall survival analysis of CTONG1104 phase III trial.
      Table 4Results of Phase 3 Randomized Clinical Trials Studying the Impact of Adjuvant TKI in Patients With Stage I to III Resectable EGFRm NSCLC
      TrialCountryStageNTKIDesignDFS (95%CI)POSPRef
      ADJUVANT CTONG 1104ChinaII-IIIA222GG vs. ACT0,60 (0,42-0,87),00540,92 (0,62-1,36),673, 22
      EVIDENCEChinaII-IIIA322II vs ACT0,37 (0,24-0,55),0001Immature-23
      IMPACTJapanII-IIIA232GG vs. ACT0,92 (0,67-1,28),631,03 (0,65-1.65),8924
      ADAURAInternationalIB-II-IIIA682OO+ACT vs ACT0,20 (0,14-0,30)<,001Immature-4
      Abbreviations: TKI = tyrosine kinase inhibitor; DFS = disease free survival; OS = overall survival; G, gefitinib; I, icotinib; O, osimertinib; ACT = Adjuvant Chemotherapy.
      Wu et al. recently reported the results of the ADAURA trial randomizing 682 patients with EGFR-mutant stage IB to IIIA NSCLC to receive osimertinib or a placebo for 3 years after tumor resection and adjuvant chemotherapy, as indicated.
      • Wu YL
      • Tsuboi M
      • He J
      • et al.
      Osimertinib in resected EGFR-mutated non-small-cell lung cancer.
      The trial was unblinded early due to efficacy, as an unplanned interim analysis showed a statistically significant improvement in DFS (HR = 0.20; 99.12% CI, 0.14-0.30; P < .001). Interestingly, even if the direct comparison of prognosis is not possible between different studies, the DFS after surgical resection of EGFR-mutated tumors reported in our study appears higher than the DFS of the control arm of the ADAURA trial. This difference might be due to the presence of stage III disease in the ADAURA trial. However, even in stages Ib and II, the prognosis of the control arm of the ADAURA trial is indeed disappointing, urging the need to clarify the quality of preoperative staging and surgical resection in this study. Brain imaging was mandatory but PET-CT was not, and the completeness of lymph node dissection has not been reported so far.
      • West HJ
      • Gyawali B.
      Why not adore ADAURA?-The trial we need vs the trial we got.
      Whether the improvement in DFS reported in the ADAURA trial will correlate with an improvement in OS will be scrutinized in the near future.
      Since the BMF study was designed to collect data on a common cancer population from daily practice, it was limited by the shortness of the case-report form, the amount of missing data, the use of the 7th TNM, and the limited number of molecular alterations screened. These limitations might have been counterbalanced by the large number of patients included in the BMF study, and by the specific design of the study reported here, including on-site visits and a focus on EGFR mutations.
      In conclusion, using a large national registry to study the molecular alteration and outcome of resected early stages NSCLC, we found that 12.9% of operated patients harbored EGFR-mutant tumors, which had no significant impact on DFS and OS.

      Clinical Practice Points

      - The molecular profile of non-small cell lung cancer has been reported in Asian populations and in the United States, but it has not been analyzed in large scale studies in Western Europe.
      - The prognostic impact of EGFR mutations is still discussed.
      - We sought to determine the frequency and the prognostic impact of EGFR mutations in patients with resected non-small cell lung cancer included in the nationwide Biomarker France study.
      - EGFR mutations were found in 12.9% of resected stage I-II NSCLC
      - EGFR mutations were associated with 5-year DFS of 65% and 5-year OS of 75%.
      - No difference was found between EGFR-mutant and EGFR-wt tumors regarding recurrence site, disease-free survival, and overall survival.
      - The molecular profile of resected NSCLC should be determined as adjuvant targeted therapies could be beneficial in those patients.

      Acknowledgments

      This work was supported by the IFCT. The funding sources had no role in the design, data collection, analysis, or interpretation of the study, or in the preparation of this manuscript
      Author contribution statement: Dr Mordant had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Each author satisfies the criteria for authorship.
      Concept and design: Mordant, Brosseau, Milleron, Barlesi, Westeel
      Acquisition, analysis, or interpretation of data: All
      Drafting of the manuscript: Mordant, Brosseau, Milleron
      Critical revision of the manuscript of important intellectual content: All
      Statistical analysis: Missy, Langlais
      Obtained funding: Barlesi
      Administrative, technical, or material support: Missy, Langlais
      Supervision: Barlesi, Westeel

      Disclosure

      Dr Mordant, Dr Brosseau, Dr Milleron, Dr Santelmo, Dr Fraboulet, Mrs Langlais, Dr Gossot, Dr Thomas, Dr Pujol, Dr Madelaine, Dr Lamy, Dr Missy, Dr Blons report no conflict of interest.
      Dr Besse reports grants from Abbvie, Amgen, AstraZeneca, BeiGene, Blueprint Medicines, BMS, Boehringer Ingelheim, Celgene, Cristal Therapeutics, Daiichi-Sankyo, Eli Lilly, GSK, Ignyta, IPSEN, Inivata, Janssen, Merck KGaA, MSD, Nektar, Onxeo, OSE Immunotherapeutics, Pfizer, Pharma Mar, Roche-Genentech, Sanofi, Servier, Spectrum Pharmaceuticals, Takeda, Tiziana Pharma, Tolero Pharmaceuticals, during the conduct of the study.
      Dr Ricordel reports grants from Novartis, outside the submitted work.
      Dr Audigier-Valette reports personal fees and non-financial support from Roche, BMS, MSD, AstraZeneca, Abbvie, Pfizer, Takeda outside the submitted work.
      Dr Barlesi reports personal fees from Astra-Zeneca, Bayer, Bristol-Myers Squibb, Boehringer-Ingelheim, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Novartis, Merck, MSD, Pierre Fabre, Pfizer and Takeda, outside the submitted work.
      Dr Westeel reports honoraria from Roche, AstraZeneca, BMS and MSD and non-financial support from Roche and Pfizer.

      Appendix. Supplementary materials

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