Abstract
Background:
Few epidemiological data are available on surgically treated Caucasian patients with non-small-cell lung cancers (NSCLCs) harboring epidermal growth factor receptor (EGFR) mutations. The main objective of this study was to describe, in the real-world setting, these patients’ incidence, clinical, and tumoral characteristics.
Methods:
The participating centers included all consecutive localized non-squamous NSCLC patients undergoing surgery between January 2018 and December 2019 in France. EGFR status was determined retrospectively when not available before surgery.
Results:
The study includes 1391 no squamous NSCLC patients from 16 centers; EGFR status was determined before surgery in 692 (49.7%) of the cases and conducted as part of the study for 699 (50.3%); 171 (12.3%) were EGFR mutated; median age: 70 (range: 36–88) years; female: 59.6%; never smokers: 75.7%; non-squamous histology 97.7%, programmed death ligand-1 expression 0%/1–49%/⩾50 in 60.5%/25.7%/13.8%, respectively. Surgery was predominantly lobectomy (81%) or segmentectomy (14.9%), with systematic lymph node dissection in 95.9%. Resection completeness was R0 for 97%. Post-surgery staging was as follows: IA: 52%, IB: 16%, IIA: 4%, IIB: 10%, IIIA: 16%, and IIIB: 0.05%; EGFR mutation exon was Del19/exon 21 (L858R)/20/18 in 37.4%/36.8%/14%, and 6.4% of cases, respectively; 31 (18%) patients received adjuvant treatment (chemotherapy: 93%, EGFR tyrosine kinase inhibitor: 0%, radiotherapy: 20%). After a median follow-up of 31 (95% confidence interval: 29.6–33.1) months, 45 (26%) patients relapsed: 11/45 (24%) locally and 34 (76%) with metastatic progression. Median disease-free survival (DFS) and overall survival were not reached and 3-year DFS was 60%.
Conclusion:
This real-world analysis provides the incidence and outcomes of resected EGFR-mutated NSCLCs in a European patient cohort.
Keywords: EGFR mutation, lung cancer management, surgery
Introduction
In France, non-small-cell lung cancer (NSCLC) represents the most common lung tumor (80–85% of cases) of which approximately 20% are localized or 20% locally advanced at diagnosis. 1 The standard treatment for localized NSCLCs is surgery, including complete lymph node dissection.2,3 Adjuvant chemotherapy is recommended for tumors >4 cm in diameter and/or with lymph node involvement.2,3 Adjuvant chemotherapy has achieved only minor benefits with a limited 5-year overall survival (OS) gain of 5.4%. 4 Since the publication of the Lung Art study results, the place of postoperative radiotherapy seems marginal. 5
However, significant progress in knowledge about NSCLC oncogenesis has been made in recent years, particularly the discovery of a specific oncogene playing a role in the oncogenic addiction responsible for NSCLC development.6–10 Activating mutations in the epithelium growth factor receptor (EGFR) gene have been found in 10–15% of patients with metastatic NSCLCs in Europe, and 80–85% of them are activating mutations in exons 19 and 21 L858R (common mutations), sensitive to targeted EGFR-tyrosine kinase inhibitors (TKIs). 11
The benefit of adjuvant EGFR-TKI (first generation) therapy for localized EGFR-mutated NSCLCs was evaluated in several studies.11–14 These studies seemed to show an improvement in disease-free survival (DFS) for patients treated with adjuvant EGFR-TKI.
Recently, the ADAURA study tested the efficacy of adjuvant osimertinib treatment for 3 years versus placebo for patients with resected stage IB–IIIA, EGFR-mutated NSCLCs. 15 That study’s results showed a significantly longer DFS for osimertinib-treated stage II–IIIA patients [hazard ratio (HR): 0.17 (99.06% confidence interval (CI): 0.11–0.26); p < 0.001]. In stage II–IIIA disease, the 4-year DFS rate was 70% (osimertinib) and 29% (placebo). In the overall population, the 4-year DFS rate was 73% (osimertinib) and 38% (placebo). 15 A recent update of the study showed a significant improvement in OS for patients treated with adjuvant osimertinib versus placebo. 16 In the overall population (stage IB–IIIA), OS HR was 0.49 (95% CI: 0.34–0.70; p < 0.0001); the 5-year OS rate was 88% with osimertinib versus 78% with placebo, with a median follow-up for OS of 60.4 months (osimertinib) and 59.4 months (placebo). 16
Osimertinib adjuvant therapy for resected EGFR-mutated NSCLCs would appear to be a new standard for treatment but we still have a few data on the epidemiology of the EGFR mutation in these patients, especially Europeans. The primary objective of this study was to describe, in the real-world setting, the incidence, clinical characteristics, the mode of progression in patients with resected EGFR-mutated NSCLCs.
Methods
This retrospective multicenter study included all consecutive patients >18 years old, with resected non-squamous NSCLCs or non-smokers with squamous NSCLCs, stages I–IIIA (neoadjuvant or adjuvant chemotherapy was allowed) from 1 January 2018 until 31 December 2019. The main exclusion criteria were patients under guardianship or inability to retrieve collected data, and no available tissue for retrospective testing.
The following information was recorded: sociodemographic parameters, smoking status, medical history; NSCLC characteristics: histology, stage, mutation search before surgery or not; perioperative treatments. When EGFR status was not available, it was determined retrospectively, either locally or by a central laboratory. EGFR mutation was assessed by Cobas, Sanger sequencing, and/or next-generation sequencing. Ex19del, L858R, and other uncommon EGFR mutations were included. All patients were staged according to the American Joint Committee on Cancer eighth edition.
Patient follow-up was consistent with the participating center’s usual practices.
Sample size
In light of the descriptive design of the study, the number of patients was not calculated. It is estimated that 50,000 new lung cancers are diagnosed and 10,000 curative resections are performed annually in France; among them, 65% are patients with non-squamous histology. 17 Inclusion of 1300 patients over 2 years would suffice as a representative sample.
Statistical methods
Qualitative parameters are expressed as numbers (%) and (95% CIs) and quantitative parameters as mean ± standard deviation or median [interquartile range (IQR)]. Numbers of missing data are reported. The primary outcome was EGFR-mutated NSCLC incidence. Secondary outcomes included DFS, defined as the date from surgery until disease relapse or death (whichever occurred first); surviving patients without relapse were censored from the date of their last follow-up visit. OS was defined as the time from initial surgery (date) to date of death, with surviving patients censored at the date of their last follow-up visit. Statistical analyses were computed with SAS® software.
The study conformed to the principles of the Declaration of Helsinki and Good Clinical Practice Guidelines. The study received Ethics Committee approval (Comité de Protection des Personnes, Sud-Est) on 06/04/2021 (no. ID RCB: 2020-A03528-31). The Groupe Francais PneumoCancerologie (GFPC) has committed to the Commission Nationale Informatique et Libertés (CNIL) to respect the MR-003 reference methodology in the prospective module for research involving human subjects category 3 studies. A written informed consent was obtained from all patients.
The reporting of this study conforms to the STROBE guidelines statement (Supplemental Table S1). 18
Results
From 1 January 2018 to 31 December 2019, 1391 consecutive patients were included in 16 centers (Supplemental Table S1). Histological diagnoses were known before surgery for 49.7% of the patients. This study provided the EGFR status for 100% of them: that is, 171/1391 (12.3%) patients harbored an EGFR-activating mutation: 102/171 (59.6%) women, 126/171 (73.7%) no-smokers, with a median age of 70 (36–88) years. Almost all NSCLCs (97.7%) were non-squamous. Tumor-cell expression of programmed death ligand-1 (PD-L1) was negative for 60.5% of them. The molecular assay used for EGFR testing was Next Generation Sequencing (132/171: 77%, Sanger sequencing 7%, unknown 16%). Exon 19 deletion (37.4%) and exon 21 L858R (36.3%) EGFR mutations were the most common (Table 1). Uncommon mutations were as follows: exon 21 L861Q, n = 2, exon 20 insertion, n = 22, with T790M de novo alone, n = 3 and with exon 21 L858 R mutation, n = 1, exon 18, n = 9. Six patients had detectable co-mutations: three Kirsten rat-sarcoma viral oncogene, one human epidermal growth factor receptor-2, one anaplastic lymphoma kinase, and one proto-oncogene tyrosine-protein kinase-1 (ROS-1). Seven patients had complex EGFR mutations.
Table 1.
Clinical characteristics of all Caucasian patients with resected, EGFR-mutated NSCLCs.
| Characteristic | Total, N = 171 | Stage I (n = 117, %) | Stage II (n = 24, %) | Stage III (n = 28, %) |
|---|---|---|---|---|
| Male sex | 69 (40.4) | 50 (42.7) | 10 (41.7) | 9 (32.1) |
| Age, median [IQR] | 70 [36–88] | 73.6 [36–88] | 70.4 [51–81] | 67.3 [43–79] |
| Smoking status | ||||
| Former and current smokers | 45 (26.3) | 28 (23.9) | 9 (37.5) | 8 (28.6) |
| Non-smokers | 126 (73.7) | 89 (76.1) | 15 (62.5) | 20 (71.4) |
| Body mass index >30 | 8 | 6 | 1 | 1 |
| Symptoms | 49 (28.6) | 28 (23.9) | 7 (29.2) | 14 (50) |
| Respiratory | 48 (28.1) | 30 (25.6) | 6 (25) | 12 (42.9) |
| Thrombosis | 8 (4.7) | 5 (4.3) | 2 (8.3) | 1 (3.6) |
| Occupational exposure | 16 (9.4) | 12 (10.3) | 3 (12.5) | 1 (3.6) |
| Incidental diagnosis | 99 (57.9) | 74 (63.2) | 13 (54.2) | 12 (42.9) |
| Non-squamous histology | 167 (97.7) | 117 (100) | 23 (95.8) | 26 (92.9) |
| PD-L1 status (n = 109) | 109 | 63 | 20 | 26 |
| 0 | 66 (60.6) | 41 (65) | 10 (50) | 15 (57) |
| 1–49% | 28 (25.6) | 17 (27) | 5 (25) | 6 (23) |
| ⩾50% | 15(13.8) | 5 (8) | 5 (25) | 5 (19) |
| EGFR status (mutation/deletion) | ||||
| Exon 19 deletion | 64 (37.4) | 47 (40.2) | 10 (41.7) | 7 (25) |
| Exon 21 L858 R (including L861Qn = 2) | 63(36.8) | 44 (37.6) | 6 (25) | 13 (46.4) |
| Exon 20 insertion (including n = 4 T790M de novo) | 24 (14.0) | 15 (12.8) | 5 (20.8) | 4 (14.3) |
| Exon 18 | 11 (6.4) | 5 (4.3) | 2 (8.3) | 4 (14.3) |
| Other exons | 2 (1.2) | 2 (1.7) | 0/– | 0/– |
| Co-mutations | 7 a (4.1) | 6 b (5.1) | 1 c (4.2) | 0/– |
| Surgery (n = 168) | ||||
| Wedge | 6 (3.6) | 4 (3.4) | - 0/– | 2 (7.1) |
| Segmentectomy | 25 (14.9) | 25 (21.4) | - 0/– | - 0/– |
| Lobectomy | 136 (81) | 87 (74.4) | 24 (100) | 25 (89.3) |
| Pneumonectomy | 1 (0.6) | - 0/– | - 0/– | 1 (3.6) |
| Complete lymph node | 164 (97.6) | 116 (99.1) | 22 (91.7) | 26 (92.9) |
| Resection completeness RO | 162 (96.5) | 114 (97.4) | 21 (87.5) | 27 (96.4) |
Results are expressed as n (%) unless stated otherwise.
One patient’s stage is unknown and one patient is stage IV.
Exons 18–20: 3, exons 19–20: 2, exons 20–21: 1.
Exons 19–18: 1.
EGFR, epidermal growth factor receptor gene; NSCLC, non-small-cell lung cancer; PD-L1, programmed death protein-1 ligand.
Surgical techniques (n = 171) were video-assisted thoracoscopy (45%), robot-assisted thoracoscopy (12%), and thoracotomy (38%) (unknown 5%). Lobectomy (81%) was the predominant surgical procedure and 96% of patients underwent systematic lymph node dissection (Table 1). The completeness of the surgical resection was R0 for 97%. The most frequent, postoperatively determined stages were IA (89; 52%) and IB (28; 16%). Only 9 (5%) patients received neo-adjuvant treatment (chemotherapy for 7 and EGFR-TKI for 2) and 31 (18%) were prescribed adjuvant treatment (chemotherapy for 29 and radiotherapy for 6); none were given EGFR-TKI.
After a median follow-up of 31 [95% CI: 29.6–33.1] months, 45 (26%) patients relapsed: 12/45 (24%) locally and 33 (74%) with metastatic progression (Table 2). The most frequent metastatic sites were brain 24% (n = 11; patients stage: IIIa: n = 3, stage II: n = 4, stage I: n = 4), bone 24% (n = 11), and lung 22% (n = 10). Relapse patients stage I, stage II, and stage III relapse locally (n = 5, n = 5, and n = 2, respectively), relapse with metastatic progression (n = 7, n = 6, and n = 11, respectively), and both (n = 2, n = 2, and n = 5, respectively) (Supplemental Table S2).
Table 2.
Characteristics of patients with resected, early-stage, EGFR-mutated NSCLCs according to relapse status.
| Characteristic | Without relapse (n = 126, %) | With relapse (n = 45, %) |
|---|---|---|
| Male sex | 49 (38.9) | 20 (44.4) |
| Age, median [range] | 68.3 [40–85] | 69.5 [43–86] |
| Smoking status | ||
| Former and current smokers | 34 (27) | 11 (24.4) |
| Non-smokers | 92 (73.0) | 34 (75.6) |
| Body mass index >30 | 7 (5.6) | 1 (2.2) |
| Symptoms | 33 (26.2) | 16 (35.6) |
| Respiratory | 32 (25.4) | 16 (35.6) |
| Thrombosis | 6 (4.8) | 2 (4.4) |
| Occupational exposure | 11 (8.7) | 5 (11.1) |
| Incidental diagnosis | 78 (61.9) | 21 (46.7) |
| Non-squamous histology | 125 (99.2) | 42 (93.3) |
| PD-L1 status (n = 109) | 74 | 35 |
| 0 | 48 (64.9) | 18 (40) |
| 1–49% | 15 (20.3) | 13 (28.9) |
| ⩾50% | 11 (14.9) | 4 (8.9) |
| EGFR status | ||
| Exon 19 | 49 (38.9) | 15 (33.3) |
| Exon 21 | 46 (36.5) | 17 (37.8) |
| Exon 20 | 16 (12.7) | 8 (17.8) |
| Exon 18 | 6 (4.8) | 5 (11.1) |
| Other exons | 2 (1.6) | - 0/– |
| Co-mutations | 7 (5.6) | - 0/– |
| Wedge | 5 (4) | 1 (2.2) |
| Segmentectomy | 23 (18.3) | 2 (4.4) |
| Lobectomy | 97 (77) | 40 (88.9) |
| Pneumonectomy | 0 | 1 (2.2) |
| Complete lymph node | 122 (96.8) | 42 (93.3) |
| Resection completeness R0 | 124 (98.4) | 41 (91.1) |
| Chemotherapy peri-operative | 14 (11.1) | 15 (33.3) |
| Radiotherapy post-surgery | 5 (4) | 1 (2.2) |
| p Stage | ||
| I | 103 (81.7) | 14 (31.1) |
| II | 11 (8.7) | 13 (28.9) |
| III | 10 (8) | 18 (40) |
EGFR, epidermal growth factor receptor gene; NSCLC, non-small-cell lung cancer; PD-L1, programmed death protein-1 ligand.
Among the patients whose disease progressed, 18/45 (40%) had a new biopsy (tissues and liquid biopsies for 15, only liquid biopsies for 3). EGFR mutation findings were the same for 14/18 (77.8%) of them (an EGFR mutation was not found in one patient and the results are not available for three others). Almost all patients with exclusively local progressive disease (10/11, 91%) received local treatment. When used, systemic agents were most often EGFR-TKI (24/34, 71%), chemotherapy (4/34, 11.8%), and immune checkpoint inhibitor (4/34, 11.8%). Median DFS and OS were not reached (Table 3). The 3-year DFS and OS were 60% and 84.7%, respectively (Table 3).
Table 3.
DFS and OS according to NSCLC p stage.
| Parameter | Total | NSCLC p stage | IA–III (n = 169) | II–III (n = 52) | |||
|---|---|---|---|---|---|---|---|
| (n = 171) | I (n = 117) | IIA (n = 7) | IIB (n = 17) | IIIA (n = 28) | |||
| DFS median (95% CI) | 31.5 (29.6–33.1) | 31.6 (29.4–33.5) | 35.8 (21.4–43.1) | 31.7 (19.6–36.9) | 29.3 (25.5–31.8) | NR (20.4–34.5) | 25 (20.4–34.5) |
| DFS, % | |||||||
| 12 months | 85.1 | 91.4 | 85.7 | 56.5 | 74.1 | 85.5 | 70.1 |
| 24 months | 75.6 | 85.9 | 53.6 | 43.9 | 59.3 | 75.9 | 53.9 |
| 36 months | 60.0 | 74.4 | 53.6 | 31.4 | 25.8 | 60.2 | 32.2 |
| OS, % | |||||||
| 12 months | 94.6 | 94.0 | 100.0 | 87.5 | 100.0 | 95.2 | 95.9 |
| 24 months | 91.5 | 93.0 | 100.0 | 87.5 | 88.5 | 92.0 | 89.8 |
| 36 months | 84.7 | 85.5 | 100.0 | 80.2 | 83.8 | 85.2 | 84.7 |
CI, confidence interval; DFS, disease-free survival; NSCLC, non-small-cell lung cancer; OS, overall survival.
DFS and OS appear similar for exons 18, 19 deletion, exon 21 L585R EGFR mutations DFS and OS at 3 years of 71%/85%, 67%/87%, and 59%/85%, respectively), but worse for exon 20 insertion mutations (49–69%) (Table 4).
Table 4.
Patients’ follow-up status according to the NSCLC EGFR-mutated exon.
| Parameter | Total | Exon 18 | Exon 19 | Exon 20 | Exon 21 | Other exons |
|---|---|---|---|---|---|---|
| (N = 171) | (n = 15) | (n = 58) | (n = 28) | (n = 60) | (n = 2) | |
| Median follow-up (95% CI), months | 31.5 (29.6–33.1) | 25.2 (19.6–33.5) | 31.3 (29.3–33.2) | 28.9 (18.6–31.5) | 31.5 (27.5–34.9) | 32 (30.3–33.7) |
| Median OS (95% CI) | NR (NR–NR) | NR (NR–NR) | NR (NR–NR) | NR (24–NR) | NR (NR–NR) | NR (NR–NR) |
| Median DFS (95% CI), months | NR (35.7–NR) | NR (9–NR) | NR (35.7–NR) | 34.5 (18.6–NR) | 40 (34.9–NR) | NR (NR–NR) |
| % OS at | ||||||
| 12 months | 94.6 | 100 | 96.6 | 85.3 | 95.0 | 100 |
| 24 months | 91.5 | 85.1 | 96.6 | 69.3 | 93.3 | 100 |
| 36 months | 84.7 | 85.1 | 87.7 | 69.3 | 85.0 | 100 |
| % Survivors without progression at | ||||||
| 12 months | 85.1 | 100 | 93.0 | 74.2 | 86.7 | 100 |
| 24 months | 75.6 | 71.4 | 79.3 | 65.9 | 79.9 | 100 |
| 36 months | 60.0 | 71.4 | 67.3 | 49.4 | 59.4 | 100 |
CI, confidence interval; DFS, disease-free survival; EGFR, epidermal growth factor receptor; NR, not reached; NSCLC, non-small-cell lung cancer; OS, overall survival.
Discussion
In this retrospective, multicenter analysis of consecutive resected non-squamous NSCLCs (2018–2019), the EGFR mutation rate was 12.3%. Albeit slightly higher than for metastatic forms in France, it is consistent with previously published findings. 19 That analysis of the France biomarker database yielded a 10.2% EGFR mutation rate for the 854 surgically treated patients. Even though that rate is not strictly an incidence because patients were not included consecutively, it is consistent with ours.
Using Pan-cAnadian Lung cancEr Observational Study data (2012–2019), authors reported the results of a retrospective, multicenter, observational cohort study on stage IB–IIIA resected NSCLCs that had not received neoadjuvant therapy. Among the 535 patients whose tumor samples underwent reflex EGFR mutation testing, 23% were carriers, 15.9% with common, and 5.6% with uncommon mutations. 20 That higher rate could be explained by a larger Asian-ancestry population (35%) than ours.
The clinical characteristics of patients with localized EGFR-mutated NSCLCs are similar to those of metastatic forms, with a predominance of women and non-smokers. The high percentage of patients with PD-L1-negative tumor cells (68%) should also be noted. The activating mutations (in exons 19 and 21, L858R) represented the majority of the alterations, as in metastatic forms. Exon 20 mutation seemed to be overrepresented in our population and the Canadian series. 20 The findings also agreed with data from Asian populations.21,22 Similar results were reported based on a retrospective analysis of an Asian cohort (389 patients managed between 1 January 2010 and 30 June 2018, at a specialized cancer center in Singapore) for distributions of stages, surgical procedures, R0 rates, relapse rates, and DFS results. 22 The results were also very close for the Canadian series for stage distribution, surgery, and DFS. 20 At 2 years, the probability of being disease-free was 75% (95% CI: 65–87), 48% (95% CI: 36–66), and 38% (95% CI: 24–61), respectively, for stages IB, II, and IIIA, and 45% (95% CI: 35–58) for stages II–IIIA combined. 20 Finally, our results are also in agreement with the control arm of the ADAURA study, with 2-year DFS at 44% (95% CI: 37–51) for stage II–IIIA patients. 15
We emphasize, as did the Asian study, that outcomes for stage IA and IB NSCLCs were similar. That observation is worth noting, given that patients with stage IA NSCLCs were not included in the ADAURA study and are otherwise not eligible for osimertinib. Even among patients with very early-stage disease, nearly 20% of them still experience early relapse or death. This high rate of relapse in early-stage patients (stage I) was also observed in the Canadian study (stage Ia 19% and stage Ib 21%), but no difference was found between mutated and wild-type EGFR patients. 22
The prognostic impact of EGFR alterations on early-stage NSCLC outcomes is conflicting, and factors associated with relapse risk in patients with EGFR-mutated NSCLCs need further elucidation.23,24 In an Asian cohort, prognostic EGFR mutation impact on DFS for patients with pT1a and pT1b invasive lung non-squamous cancers after surgical resection did not differ from that of patients whose tumors expressed wild-type EGFR; however, among all patients, OS was significantly longer for those with EGFR-mutated NSCLCs, and N0 and N1–2-stage subgroups. 21 That observation is probably explained by the number of effective targeted treatment options for metastatic EGFR-mutated NSCLCs. Uni- and multivariate analyses of wild-type EGFR-expressing NSCLCs found only more advanced stage and lymphovascular invasion to be significantly associated with relapse. By contrast, univariate and multivariate analyses of patients with EGFR-mutated NSCLCs identified more advanced stage, non-acinar and non-lepidic non-squamous subtype, sub-lobar resection, positive resection margins, and lymphovascular invasion were significantly associated with relapse. 24 Exploratory whole-exome and transcriptome-sequencing analyses of a subgroup of 85 patients with EGFR-mutated NSCLCs found alterations in rhophilin-2 (RHPN2) and β-catenin-1 (CTNNB1), and micropapillary subtype increased the risk of relapse, while loss of retinoblastoma-1 (RB1) was associated with a lower risk. 25 Confirmation of those preliminary results would contribute to better identification of the patients at the highest risk of relapse.
This analysis has several unavoidable limitations given its retrospective nature. One of the main limitations is that of the interpretation of DFS results in a real-world study. Indeed, disease relapse was defined here by the investigators according to their usual clinical practices, which does not imply systematic achievement of the objective Response Evaluation Criteria In Solid Tumor 1.1. In this study, the proportion of early-stage patients (stage I) is high but correctly reflects surgical activity. 26 Also, not all patients had a complete NGS which may underestimate the proportion of co-mutations.
Conclusion
The incidence of surgically resected, early-stage, EGFR-mutated NSCLCs in France is slightly higher than for advanced NSCLC stages. The findings based on this consecutive series agree with previous research findings that relapse rates of those EGFR-mutated NSCLCs are high, including for stage IA. Identifying individual risk features could facilitate tailored surveillance and adjuvant treatment strategies for early-stage EGFR-mutated NSCLCs.
Supplemental Material
Supplemental material, sj-docx-1-tam-10.1177_17588359241236451 for Resected EGFR-mutated non-small-cell lung cancers: incidence and outcomes in a European population (GFPC Exerpos Study) by Jean-Bernard Auliac, Pascal-Alexandre Thomas, Olivier Bylicki, Florian Guisier, Hubert Curcio, AlainVegnenègre, Aurelie Swalduz, Marie Wislez, Jacques Le Treut, Chantal Decroisette, Victor Basse, Lionel Falchero, Gonzague De Chabot, Diane Moreau, Eric Huchot, Audrey Lupo Mansuet, Helene Blons, Christos Chouaïd and Laurent Greillier in Therapeutic Advances in Medical Oncology
Acknowledgments
None.
Footnotes
ORCID iDs: Jean-Bernard Auliac 
https://orcid.org/0000-0002-6400-7506
Florian Guisier
https://orcid.org/0000-0002-8166-7303
Christos Chouaïd
https://orcid.org/0000-0002-4290-5524
Supplemental material: Supplemental material for this article is available online.
Contributor Information
Jean-Bernard Auliac, Service de Pneumologie, Pneumology Department, CHI Créteil, 40 Avenue de Verdun, Creteil 94010, France.
Pascal-Alexandre Thomas, Thoracic Surgery Department, Assistance Publique Hopitaux de Marseille, Marseille, France.
Olivier Bylicki, Pneumology Department, Hôpital d’instruction des Armées Sainte-Anne, Toulon, France.
Florian Guisier, Service de Pneumologie, Oncologie Thoracique et Soins Intensifs Respiratoires, CHU Rouen, Rouen, France.
Hubert Curcio, Oncology Department, Centre Francois Baclesse, Caen, France.
AlainVegnenègre, Pneumology Department, CHU Limoges – Hopital Dupuytren, Limoges, France.
Aurelie Swalduz, Department of Pneumology, Comprehensive Cancer Centre Léon Bérard, Lyon, France.
Marie Wislez, Pneumology Department, Hôpital Cochin, AP-HP, Paris, France.
Jacques Le Treut, Pneumology Department, Hôpital Européen Marseille, Marseille, France.
Chantal Decroisette, Pneumology Department, Le Centre Hospitalier Annecy Genevois, Metz-Tessy, France.
Victor Basse, Oncology Department, Clinique Saint-Yves, Vannes, France.
Lionel Falchero, Pneumology Department, Hospital Center De Villefranche-Sur-Saône, Gleizé, France.
Gonzague De Chabot, Oncology Department, Centre Hospitalier Bretagne Atlantique, Vannes, France.
Diane Moreau, Pneumology Department, Centre Hospitalier Universitaire de Saint Pierre de la Réunion, Saint-Pierre, Reunion Islands.
Eric Huchot, Pneumology Department, Centre Hospitalier Universitaire Felix-Guyon, Saint Denis, France.
Audrey Lupo Mansuet, Service d’Anatomie-Pathologique, Hôpital Cochin, Université de Paris, AP-HP, Paris, France.
Helene Blons, HEGP Biochimie, UF de Pharmacogénétique et Oncologie Moléculaire, Paris, France.
Christos Chouaïd, Pneumology Department, CHI Créteil, Créteil, France.
Laurent Greillier, Multidisciplinary Oncology and Therapeutic Innovations, Hopital St. Marguerite Assistance Publique Hopitaux de Marseille, Marseille, France.
Declarations
Ethics approval and consent to participate: The study received Ethics Committee approval (Comité de Protection des Personnes, Sud-Est) on 06/04/2021 (no. ID RCB: 2020-A03528-31).A written informed consent was obtained from all patients.
Consent for publication: Not applicable.
Author contributions: Jean-Bernard Auliac: Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Project administration; Resources; Supervision; Validation; Writing – original draft; Writing – review & editing.
Pascal-Alexandre Thomas: Investigation; Supervision; Writing – original draft; Writing – review & editing.
Olivier Bylicki: Formal analysis; Investigation; Supervision; Validation; Writing – review & editing.
Florian Guisier: Investigation; Visualization; Writing – review & editing.
Hubert Curcio: Investigation; Resources; Writing – review & editing.
AlainVegnenègre: Investigation; Supervision; Writing – review & editing.
Aurelie Swalduz: Investigation; Supervision; Writing – review & editing.
Marie Wislez: Investigation; Validation; Writing – review & editing.
Jacques Le Treut: Investigation; Validation; Writing – review & editing.
Chantal Decroisette: Investigation; Validation; Writing – review & editing.
Victor Basse: Investigation; Validation; Writing – review & editing.
Lionel Falchero: Investigation; Validation; Writing – review & editing.
Gonzague De Chabot: Investigation; Validation; Writing – review & editing.
Diane Moreau: Investigation; Resources; Validation; Writing – review & editing.
Eric Huchot: Investigation; Validation; Writing – review & editing.
Audrey Lupo Mansuet: Methodology; Resources; Validation; Writing – review & editing.
Helene Blons: Investigation; Resources; Writing – review & editing.
Christos Chouaïd: Conceptualization; Investigation; Methodology; Software; Visualization; Writing – original draft; Writing – review & editing.
Laurent Greillier: Conceptualization; Investigation; Methodology; Project administration; Resources; Writing – review & editing.
Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by an academic grant from ASTRA ZENECA.
J-BA: In the last 5 years, J-BA has received honoraria for attending scientific meetings, speaking, organizing research, or consulting, from Boehringer Ingelheim, Hoffman-Roche, Takeda, BMS, MSD, Astra Zeneca, Amgen, and Pfizer.
Availability of data and materials: Not applicable.
References
- 1. Debieuvre D, Molinier O, Falchero L, et al.; Study Group KBP-2020-CPHG; KBP-2020-CPHG. Lung cancer trends and tumor characteristic changes over 20 years (2000–2020): results of three French consecutive nationwide prospective cohorts’ studies. Lancet Reg Health Eur 2022; 22: 100492. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Postmus PE, Kerr KM, Oudkerk M, et al.; on Behalf of the ESMO Guidelines Committee. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017; 28: iv1–iv21. [DOI] [PubMed] [Google Scholar]
- 3. Singh N, Temin S, Baker S, Jr, et al. Therapy for stage IV non-small cell lung cancer with driver alterations: ASCO living guideline. J Clin Oncol 2022; 40: 3310–3322. [DOI] [PubMed] [Google Scholar]
- 4. Pignon JP. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 2008; 26: 3552–3559. [DOI] [PubMed] [Google Scholar]
- 5. Le Pechoux C, Pourel N, Barlesi F, et al. Postoperative radiotherapy versus no postoperative radiotherapy in patients with completely resected non-small-cell lung cancer and proven mediastinal N2 involvement (lung ART): an open-label, randomised, phase 3 trial. Lancet Oncol 2022; 23: 104–114. [DOI] [PubMed] [Google Scholar]
- 6. Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 2009; 361: 958–967. [DOI] [PubMed] [Google Scholar]
- 7. 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 nation wide programme of the French Cooperative Thoracic Intergroup (IFCT). Lancet 2016; 387: 1415–1426. [DOI] [PubMed] [Google Scholar]
- 8. Mok TS, Wu Y, Ahn MJ, et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med 2017; 376: 629–640. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013; 31: 3327–3334. [DOI] [PubMed] [Google Scholar]
- 10. Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med 2020; 382: 41–50. [DOI] [PubMed] [Google Scholar]
- 11. Sharma SV, Bell DW, Settleman J, et al. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 2007; 7: 169–181. [DOI] [PubMed] [Google Scholar]
- 12. Kelly K, Altorki NK, Eberhardt W, 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. J Clin Oncol 2015; 33: 4007–4014. [DOI] [PubMed] [Google Scholar]
- 13. 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. J Clin Oncol 2019; 37: 97–91. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Zhong WZ1, Wang Q, Mao WM, et al.; ADJUVANT Investigators. 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. Lancet Oncol 2018; 19: 139–148. [DOI] [PubMed] [Google Scholar]
- 15. Herbst RS, Wu YL, John T, et al. Adjuvant osimertinib for resected EGFR-mutated stage IB–IIIA non-small-cell lung cancer: updated results from the phase III randomized ADAURA trial. J Clin Oncol 2023; 41: 1830–1840. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Herbst RS, Tsuboi M, John T, et al. Overall survival analysis from the ADAURA trial of adjuvant osimertinib in patients with resected EGFR-mutated (EGFRm) stage IB–IIIA non-small cell lung cancer (NSCLC). N Engl J Med 2023; 389: 137–147.37272535 [Google Scholar]
- 17.Panorama des cancers INCA e-cancer.fr. [Google Scholar]
- 18. Von Elm E, Altman DG, Egger M, et al.; STROBE Initiative. Strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol 2007; 61: 344–349. [DOI] [PubMed] [Google Scholar]
- 19. Mordant P, Brosseau S, Milleron B, et al. Outcome of patients with resected early-stage non-small cell lung cancer and EGFR mutations: results from the IFCT Biomarkers France Study. Clin Lung Cancer 2022; S1525–S7304: 97–98. [DOI] [PubMed] [Google Scholar]
- 20. Sara Kuruvilla M, Liu G, Syed I, et al. EGFR mutation prevalence, real-world treatment patterns, and outcomes among patients with resected, early-stage, non-small cell lung cancer in Canada. Lung Cancer 2022; 173: 58–66. [DOI] [PubMed] [Google Scholar]
- 21. Yang XN, Yan HH, Wang J, et al. Real-world survival outcomes based on EGFR mutation status in Chinese patients with lung adenocarcinoma after complete resection: results from the ICAN study. JTO Clin Res Rep 2021; 3: 100257. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Saw SPL, Zhou S, Chen J, et al. Association of clinicopathologic and molecular tumor features with recurrence in resected early-stage epidermal growth factor receptor-positive non-small cell lung cancer. JAMA Netw Open 2021; 4: e2131892. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Zhang Z, Wang T, Zhang J, et al. Prognostic value of epidermal growth factor receptor mutations in resected non-small cell lung cancer: a systematic review with meta-analysis. PLoS One 2014; 9: e106053. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Chen S, Yang S, Zhang Y, et al. Clinicopathologic features and prognostic value of epidermal growth factor receptor mutation inpatients with pT1a and pT1b invasive lung adenocarcinoma after surgical resection. J Thorac Dis 2021; 13: 5496–5507. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Jao K, Tomasini P, Kamel-Reid S, et al. The prognostic effect of single and multiple cancer-related somatic mutations in resected non-small-cell lung cancer. Lung Cancer 2018; 123: 22–29. [DOI] [PubMed] [Google Scholar]
- 26. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228–247. [DOI] [PubMed] [Google Scholar]
Associated Data
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Supplementary Materials
Supplemental material, sj-docx-1-tam-10.1177_17588359241236451 for Resected EGFR-mutated non-small-cell lung cancers: incidence and outcomes in a European population (GFPC Exerpos Study) by Jean-Bernard Auliac, Pascal-Alexandre Thomas, Olivier Bylicki, Florian Guisier, Hubert Curcio, AlainVegnenègre, Aurelie Swalduz, Marie Wislez, Jacques Le Treut, Chantal Decroisette, Victor Basse, Lionel Falchero, Gonzague De Chabot, Diane Moreau, Eric Huchot, Audrey Lupo Mansuet, Helene Blons, Christos Chouaïd and Laurent Greillier in Therapeutic Advances in Medical Oncology