https://www.hal.inserm.fr/inserm-00561753/document

International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Classification of Lung Adenocarcinoma

Screening for Epidermal Growth Factor Receptor Mutations in Lung Cancer

All patients with metastatic lung, colorectal, pancreatic or head and neck cancers who initially benefit from epidermal growth factor receptor (EGFR)-targeted therapies eventually develop resistance. An increasing understanding of the number and complexity of resistance mechanisms highlights the Herculean challenge of killing tumors that are resistant to EGFR inhibitors. Our growing knowledge of resistance pathways provides an opportunity to develop new mechanism-based inhibitors and combination therapies to prevent or overcome therapeutic resistance in tumors. We present a comprehensive review of resistance pathways to EGFR-targeted therapies in lung, colorectal and head and neck cancers and discuss therapeutic strategies that are designed to circumvent resistance.

/pdf/the-quest-to-overcome-resistance-to-egfr-targeted-therapies-2d5tjuoeck.pdf

The quest to overcome resistance to EGFR-targeted therapies in cancer

// Yue-Lun Zhang 1, 2 , Jin-Qiu Yuan 1, 2 , Kai-Feng Wang 3 , Xiao-Hong Fu 1, 2 , Xiao-Ran Han 1, 2 , Diane Threapleton 1 , Zu-Yao Yang 1, 2 , Chen Mao 1, 2 , Jin-Ling Tang 1, 2 1 Division of Epidemiology, The Jockey Club School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong Kong, China 2 Shenzhen Municipal Key Laboratory for Health Risk Analysis, Shenzhen Research Institute of The Chinese University of Hong Kong, Shenzhen, Guangdong Province, China 3 Division of Epidemiology, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, Guangdong Province, China Correspondence to: Chen Mao, email: maochen@cuhk.edu.hk Jin-Ling Tang, email: jltang@cuhk.edu.hk Keywords: non-small cell lung cancer, epidermal growth factor receptor, prevalence, systematic review, meta-analysis Received: May 17, 2016     Accepted: September 25, 2016     Published: October 12, 2016 ABSTRACT Objectives: Estimate the epidermal growth factor receptor ( EGFR ) mutation prevalence in all non-small cell lung cancer (NSCLC) patients and patient subgroups. Results: A total of 456 studies were included, reporting 30,466 patients with EGFR mutation among 115,815 NSCLC patients. The overall pooled prevalence for EGFR mutations was 32.3% (95% CI 30.9% to 33.7%), ranging from 38.4% (95% CI: 36.5% to 40.3%) in China to 14.1% (95% CI: 12.7% to 15.5%) in Europe. The pooled prevalence of EGFR mutation was higher in females (females vs. males: 43.7% vs. 24.0%; OR: 2.7, 95% CI: 2.5 to 2.9), non-smokers (non-smokers vs. past or current smokers: 49.3% vs. 21.5%; OR: 3.7, 95% CI: 3.4 to 4.0), and patients with adenocarcinoma (adenocarcinoma vs. non-adenocarcinoma: 38.0% vs. 11.7%; OR: 4.1, 95% CI: 3.6 to 4.8). Materials and Methods: PubMed, EMBASE, and the Cochrane Library were searched to June 2013. Eligible studies reported EGFR mutation prevalence and the association with at least one of the following factors: gender, smoking status and histology. Random-effects models were used to pool EGFR mutation prevalence data. Conclusion: This study provides the exact prevalence of EGFR mutations in different countries and NSCLC patient subgroups.

/pdf/the-prevalence-of-egfr-mutation-in-patients-with-non-small-2zch4vyl3c.pdf

The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis

Purpose: Clinical features of epidermal growth factor receptor (EGFR) mutations, L858R, deletions in exon 19, T790M, and insertions in exon 20, in non–small cell lung cancer (NSCLC) are well known. The clinical significance of other uncommon EGFR mutations, such as their association with the effectiveness of EGFR tyrosine kinase inhibitors (TKI), is not well understood. This study aimed to improve the understanding of these uncommon EGFR mutations of unknown clinical significance. Patients and Methods: Specimens from 1,261 patients were tested for EGFR mutations. We surveyed the clinical data and the effectiveness of gefitinib and erlotinib in NSCLC patients with uncommon EGFR mutations. Results: Of the 1,261 patients, 627 (49.8%) had EGFR mutations. This included 258 patients with deletions in exon 19, 260 patients with L858R, 25 patients with insertions or duplications in exon 20, 6 patients with de novo T790M, and 78 (12.4%) patients with uncommon mutations. Of the 78 patients, 62 received either gefitinib or erlotinib treatment. The response rate of TKIs treatment was 48.4%, and the median progression-free survival (PFS) was 5.0 months. Mutations on G719 and L861 composed a major part (28 of 62) of uncommon mutations, and were associated with a favorable effectiveness of EGFR TKIs (response rate, 57.1%; median PFS, 6.0 months). Mutations other than G719 and L861 led to a worse response to EGFR TKIs (response rate, 20.0%; median PFS, 1.6 months). Conclusions: Uncommon EGFR mutations constituted a distinct part of the whole group of EGFR mutations. Their composition was heterogeneous, and their associations with EGFR TKIs differed. Clin Cancer Res; 17(11); 3812–21. ©2011 AACR .

https://clincancerres.aacrjournals.org/content/clincanres/17/11/3812.full.pdf

Effectiveness of Tyrosine Kinase Inhibitors on “Uncommon” Epidermal Growth Factor Receptor Mutations of Unknown Clinical Significance in Non–Small Cell Lung Cancer

Rationale: Gefitinib is effective in treating patients with non–small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Deletions in exon 19 and L858R in exon 21 are the best-documented EGFR mutations that are associated with effective gefitinib responsiveness.Objectives: To clarify the influence of gefitinib timing, we conducted a study to compare the outcomes of different lines of gefitinib treatment in patients with exon 19 deletions or L858R.Methods: We surveyed the clinical data and mutational studies of patients with NSCLC with EGFR mutations in the National Taiwan University Hospital (Taipei, Taiwan).Measurements and Main Results: Three hundred and twenty-eight patients, who received gefitinib for stage IIIb or IV NSCLC, were adequately sequenced for EGFR mutations; 192 patients had mutant EGFR, including 77 patients with exon 19 deletions and 75 patients with L858R. The 152 patients with exon 19 deletions or L858R and who were receiving gefitinib were classified into...

First- or Second-line Therapy with Gefitinib Produces Equal Survival in Non–Small Cell Lung Cancer

Purpose: Several deletions in exon 19 of epidermal growth factor receptor ( EGFR ) gene have been reported in non–small cell lung cancer (NSCLC) It is unknown if deletions occurring at different amino acid positions or of different sizes are associated with different clinical outcome to EGFR tyrosine kinase inhibitors (TKI) Experimental Design: This study enrolled NSCLC patients with deletions in EGFR exon 19 Patients who had received EGFR TKIs for advanced NSCLC were further evaluated for response rate (RR), progression-free survival (PFS), and overall survival (OS) Results: In 308 patients with deletions in EGFR exon 19, 298 had deletions encompassing the entire amino acid string from L747 through E749 (LRE deletions) EGFR TKIs were used in 204 patients with advanced NSCLC Patients with non-LRE deletions had the least RR, compared with those with deletions from E746 or L747 (429%, 682%, and 796%, respectively; P = 0022) Patients with non-LRE deletions had relatively short median PFS, though not significantly different from those with deletions from E746 or L747 (59, 98, and 105 months, respectively; P = 0665) The OS was not different among patients with deletions occurring at different amino acid positions ( P = 0776) Deletions in exon 19 of different sizes were not associated with different RR, PFS, or OS Conclusions: Non-LRE deletions in exon 19 were associated with worse response to EGFR TKIs, compared with LRE deletions Therefore, the expected clinical outcome under EGFR TKIs depends on not only the existence but also the types of deletions in exon 19 Clin Cancer Res; 18(12); 3470–7 ©2012 AACR 

https://clincancerres.aacrjournals.org/content/clincanres/18/12/3470.full.pdf

Clinical Outcomes in Non–Small Cell Lung Cancers Harboring Different Exon 19 Deletions in EGFR

Objective Epidermal growth factor receptor (EGFR) mutations in lung adenocarcinoma are involved in the tumorigenesis and regulation of cell metabolism via Akt signaling. F-18 fluorodeoxyglucose-positron emission tomography ([18F]FDG PET), a functional imaging modality, can be used to measure tumor cell metabolism. Thus, in this study, we hypothesize that there exist correlations between EGFR mutation status and [18F]FDG uptake of advanced lung adenocarcinoma. Methods From May 2004 to April 2008, patients with stage IIIB or IV lung adenocarcinoma who underwent [18F]FDG PET and EGFR mutation analysis before receiving any treatment were eligible to participate in this study. The association of EGFR mutation status with patient characteristics and the SUVMAX from the [18F]FDG PET was evaluated. Multivariate logistic regression analysis was used to analyze predictors of EGFR mutations. Results Seventy-seven lung adenocarcinoma patients were included in this study. EGFR mutations were identified in 49 (64%) of the patients. The [18F]FDG uptake was significantly higher in EGFR-mutant (mean SUVMAX = 10.5 ± 4.7) than wild-type (8.0 ± 3.3) lung adenocarcinoma patients (P = 0.008). The median SUVMAX was 9.5, and patients with an SUVMAX ≥ 9.5 were more likely to harbor EGFR mutations (P = 0.009). In the multivariate analysis, an SUVMAX ≥ 9.5 remained a statistically significant predictor of EGFR mutations (P = 0.005). Conclusions Among Asian patients with advanced lung adenocarcinoma, those with higher SUVMAX on the [18F]FDG PET are more likely to carry EGFR mutations.

Correlation of F-18 fluorodeoxyglucose-positron emission tomography maximal standardized uptake value and EGFR mutations in advanced lung adenocarcinoma.

https://www.jto.org/article/S1556-0864(15)33264-0/pdf

Pin-Fei Wei

Papers

First- or Second-line Therapy with Gefitinib Produces Equal Survival in Non–Small Cell Lung Cancer

Clinical Outcomes in Non–Small Cell Lung Cancers Harboring Different Exon 19 Deletions in EGFR

Correlation of F-18 fluorodeoxyglucose-positron emission tomography maximal standardized uptake value and EGFR mutations in advanced lung adenocarcinoma.

Effusion immunocytochemistry as an alternative approach for the selection of first-line targeted therapy in advanced lung adenocarcinoma.