EGFRMutations Predict Survival Benefit From Gefitinib in Patients With Advanced Lung Adenocarcinoma: A Historical Comparison of Patients Treated Before and After Gefitinib Approval in Japan

PurposeThis study evaluated whether the presence of epidermal growth factor receptor (EGFR) mutations is a predictive marker for survival benefit from gefitinib and/or a prognostic marker in patients with advanced lung adenocarcinoma.Patients and MethodsOverall survival (OS) was compared between patients with advanced lung adenocarcinoma who began first-line systemic therapy before and after gefitinib approval in Japan (January 1999 to July 2001 and July 2002 to December 2004, respectively). Deletional mutations in exon 19 or the L858R mutation in exon 21 of EGFR were evaluated using high-resolution melting analysis.ResultsEGFR mutations were detected in 136 (41%) of the 330 patients included in this study. OS was significantly longer among the EGFR-mutant patients treated after gefitinib approval compared with the OS of patients treated before gefitinib approval (median survival time [MST], 27.2 v 13.6 months, respectively; P < .001), whereas no significant survival improvement was observed in patients without EGFR mutations (MST, 13.2 v 10.4 months, respectively; P = .13). A significant interaction between the presence of EGFR mutations and a survival improvement was seen (P = .045). Among patients treated before gefitinib approval, those with EGFR mutations lived longer than those without EGFR mutations (MST, 13.6 v 10.4 months, respectively; P = .034). The response rates to first-line cytotoxic chemotherapy were not significantly different between patients with and without EGFR mutations (31% v 28%, respectively; P = .50).ConclusionEGFR mutations significantly predict both a survival benefit from gefitinib and a favorable prognosis in patients with advanced lung adenocarcinoma.

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Better Progression-Free Survival in Elderly Patients with Stage IV Lung Adenocarcinoma Harboring Uncommon Epidermal Growth Factor Receptor Mutations Treated with the First-line Tyrosine Kinase Inhibitors

Cancers ◽

10.3390/cancers10110434 ◽

2018 ◽

Vol 10 (11) ◽

pp. 434 ◽

Cited By ~ 4

Author(s):

Ming-Ju Tsai ◽

Jen-Yu Hung ◽

Mei-Hsuan Lee ◽

Chia-Yu Kuo ◽

Yu-Chen Tsai ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Kinase Inhibitors ◽

Growth Factor Receptor ◽

Stage Iv ◽

Progression Free Survival ◽

Egfr Mutations ◽

First Line ◽

Free Survival ◽

Younger Patients ◽

Epidermal Growth

Patients with lung adenocarcinoma harboring common epidermal growth factor receptor (EGFR) mutations usually have a good response rate (RR) and longer progression-free survival (PFS) to EGFR tyrosine kinase inhibitors (TKIs). However, the treatment efficacy to uncommon EGFR mutations remains controversial. We, therefore, performed a retrospective study, screening 2958 patients. A total of 67 patients with lung adenocarcinoma harboring uncommon EGFR mutations were enrolled and 57 patients with stage IV diseases receiving a first-line EGFR TKI were included for further analyses. The patients were classified into 27 (47%) “a single sensitizing uncommon mutation”, 7 (12%) “multiple sensitizing mutations”, 5 (9%) “a sensitizing mutation and a resistant uncommon mutation”, and 18 (32%) “other resistant uncommon mutations”. No significant difference was noted in PFS or overall survival (OS) between groups. Patients receiving different first-line EGFR TKIs had similar PFS and OS. The elder patients had a significantly poorer performance status than the younger patients but a significantly longer PFS than the younger patients (median PFS: 10.5 vs. 5.5 months, p = 0.0320). In conclusion, this is the first study to identify that elderly patients with stage IV lung adenocarcinoma harboring uncommon EGFR mutation might have a longer PFS. Large-scale prospective studies are mandatory to prove our findings.

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Brain metastases in lung adenocarcinoma: impact of EGFR mutation status on incidence and survival

Radiology and Oncology ◽

10.2478/raon-2014-0016 ◽

2014 ◽

Vol 48 (2) ◽

pp. 173-183 ◽

Cited By ~ 31

Author(s):

Karmen Stanic ◽

Matjaz Zwitter ◽

Nina Turnsek Hitij ◽

Izidor Kern ◽

Aleksander Sadikov ◽

...

Keyword(s):

Brain Metastases ◽

Lung Adenocarcinoma ◽

Cumulative Incidence ◽

Egfr Mutation ◽

Growth Factor Receptor ◽

Egfr Mutations ◽

Mutation Status ◽

Course Of Disease ◽

Epidermal Growth ◽

Egfr Mutant

AbstractBackground. The brain represents a frequent progression site in lung adenocarcinoma. This study was designed to analyse the association between the epidermal growth factor receptor (EGFR) mutation status and the frequency of brain metastases (BM) and survival in routine clinical practice.Patients and methods. We retrospectively analysed the medical records of 629 patients with adenocarcinoma in Slovenia who were tested for EGFR mutations in order to analyse the cumulative incidence of BM, the time from the diagnosis to the development of BM (TDBM), the time from BM to death (TTD) and the median survival.Results. Out of 629 patients, 168 (27%) had BM, 90 patients already at the time of diagnosis. Additional 78 patients developed BM after a median interval of 14.3 months; 25.8 months in EGFR positive and 11.8 months in EGFR negative patients, respectively (p = 0.002). EGFR mutations were present in 47 (28%) patients with BM. The curves for cumulative incidence of BM in EGFR positive and negative patients demonstrate a trend for a higher incidence of BM in EGFR mutant patients at diagnosis (19% vs. 13%, p = 0.078), but no difference later during the course of the disease. The patients with BM at diagnosis had a statistically longer TTD (7.3 months) than patients who developed BM later (3.1 months). The TTD in EGFR positive patients with BM at diagnosis was longer than in EGFR negative patients (12.6 vs. 6.8, p = 0.005), while there was no impact of EGFR status on the TTD of patients who developed BM later.Conclusions. Except for a non-significant increase of frequency of BM at diagnosis in EGFR positive patients, EGFR status had no influence upon the cumulative incidence of BM. EGFR positive patients had a longer time to CNS progression. While EGFR positive patients with BM at diagnosis had a longer survival, EGFR status had no influence on TTD in patients who developed BM later during the course of disease.

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Updated survival outcomes of NEJ005/TCOG0902, a randomized phase II study of concurrent (C) versus sequential alternating (S) gefitinib and chemotherapy in previously untreated non-small cell lung cancer (NSCLC) with sensitive epidermal growth factor receptor (EGFR) mutations.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.9038 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 9038-9038 ◽

Cited By ~ 2

Author(s):

Satoshi Oizumi ◽

Shunichi Sugawara ◽

Koichi Minato ◽

Toshiyuki Harada ◽

Akira Inoue ◽

...

Keyword(s):

Overall Survival ◽

Kinase Inhibitor ◽

Growth Factor Receptor ◽

Progression Free Survival ◽

Egfr Mutations ◽

Combination Therapies ◽

First Line ◽

North East ◽

Egfr Mutant

9038 Background: North East Japan Study Group (NEJ) 005/ Tokyo Cooperative Oncology Group (TCOG) 0902 study has demonstrated that first-line concurrent (C) and sequential alternating (S) combination therapies of EGFR tyrosine kinase inhibitor (gefitinib) plus platinum-based doublet chemotherapy (carboplatin/pemetrexed) offer promising efficacy with predictable toxicities for patients with EGFR-mutant NSCLC (ASCO2014, Ann Oncol 2015). However, overall survival (OS) data were insufficient because of the lack of death events in the primary report. Methods: Progression-free survival (PFS) and OS were re-evaluated at the final data cutoff point (November 2016) for the entire population (N = 80). Results: At the median follow-up time of 35.6 months, 88.8% of patients had progressive disease and 72.5% of patients had died. Median PFS was 17.5 months for the C regimen and 15.3 months for the S regimen (p = 0.13). Median OS time was 43.3 with the C regimen and 30.7 months with the S regimen (p = 0.018). Updated response rates were similar in both groups (90.2% and 82.1%, respectively; p = 0.34). Patients who had common mutations showed no significant differences in PFS according to type of mutation. Patients with Del19 displayed relatively better OS (median: 45.3 and 33.3 months for C and S regimens) than those with L858R (31.4 and 28.9 months). No severe adverse events including interstitial lung disease have occurred during the follow-up period since the primary report. Conclusions: This updated analysis has confirmed that PFS is improved with first-line combination therapies compared to that with gefitinib monotherapy, and the C regimen in particular offers an overall survival benefit of 43 months in the EGFR-mutated setting. Our on-going NEJ009 study will clarify whether this combinational strategy can be incorporated into routine clinical practice. Clinical trial information: UMIN000002789.

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Effect of WW Domain-Containing Oxidoreductase Gene Polymorphism on Clinicopathological Characteristics of Patients with EGFR Mutant Lung Adenocarcinoma in Taiwan

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph182413136 ◽

2021 ◽

Vol 18 (24) ◽

pp. 13136

Author(s):

Ju-Pi Li ◽

Jinghua Tsai Chang ◽

Po-Chung Ju ◽

Ming-Hong Hsieh ◽

Yu-Hua Chao ◽

...

Keyword(s):

Lung Cancer ◽

Lung Adenocarcinoma ◽

Growth Factor Receptor ◽

Egfr Mutations ◽

Genotype Distribution ◽

Nucleotide Polymorphisms ◽

Primary Tumors ◽

Ww Domain ◽

Significant Difference ◽

Egfr Mutant

Lung adenocarcinoma is the most common histological type of non-small cell lung cancer, which accounts for the majority of lung cancers. Previous studies have showed that dysregulation of WW domain-containing oxidoreductase (WWOX) participates in the generation of several cancer types, including lung cancer. However, whether these WWOX polymorphisms are related to the clinical risk of epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma is worthy of investigation. The present study examined the relationship between the WWOX single-nucleotide polymorphisms (SNPs; rs11545028, rs12918952, rs3764340, rs73569323, and rs383362) and the clinicopathological factors in lung adenocarcinoma patients with or without EGFR mutations. We found that there was no significant difference in the genotype distribution of WWOX polymorphism between EGFR wild-type and EGFR mutant in patients with lung adenocarcinoma. Our results demonstrated that the presence of at least one G genotype (CG and GG) allele on WWOX rs3764340 was associated with a significantly higher risk of nearby lymph node involvement in those patients harboring EGFR mutations (odds ratio (OR) = 3.881, p = 0.010) compared with the CC genotype. Furthermore, in the subgroup of lung adenocarcinoma patients with the EGFR-L858R mutation, both WWOX rs3764340 C/G (OR = 5.209, p = 0.023) and rs73569323 C/T polymorphisms (OR = 3.886, p = 0.039) exhibited significant associations with the size of primary tumors and the invasion of adjacent tissues. In conclusion, these data indicate that WWOX SNPs may help predict tumor growth and invasion in patients with EGFR mutant lung adenocarcinoma, especially those with the EGFR-L858R mutant in Taiwan.

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MCPH1 (BRIT1) and outcome to erlotinib in non-small cell lung cancer (NSCLC) patients (p) harboring EGFR mutations.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e18131 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e18131-e18131 ◽

Cited By ~ 1

Author(s):

M. Rosario Garcia-Campelo ◽

Miquel Taron ◽

Susana Benlloch ◽

Jose Javier Sanchez ◽

Carlota Costa ◽

...

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Expression System ◽

Progression Free Survival ◽

Predictive Marker ◽

Egfr Mutations ◽

Damage Response ◽

Low Levels ◽

L858r Mutation ◽

Egfr Mutant

e18131 Background: Progression-free survival (PFS) in EGFR-mutant NSCLC p treated with erlotinib can range from a few months (m) to more than two years, but genetic influences on the duration of response remain unclear. The cytotoxic effect of erlotinib has been related to several proteins that regulate DNA damage response (eg, BRCA1, BRCA2). MCPH1 contains 3 BRCT domains which are conserved in important molecules involved in DNA damage signaling, including BRCA1, MDC1 and 53BP1. MCPH1 binds to BRCA2 and regulates the localization of BRCA2 and Rad51 at sites of DNA damage. MCPH1 also regulates the ATP-dependent SWI-SNF chromatin remodeling complex during DNA repair. Methods: We used the NanoString nCounter gene expression system, which captures and counts individual mRNA transcripts, to analyze the expression of 44 selected genes, many of which are involved in DNA damage response, in 55 erlotinib-treated NSCLC p. We identified MCPH1 and correlated expression levels with clinical outcomes. Results: p characteristics: 16 males, 39 females (70.9%); 39 never-smokers (70.9%), 12 former smokers, 4 current smokers; 34 with EGFR deletion in exon 19 (61.8%), 21 with L858R mutation (38.2%). PFS was not reached for patients with high MCPH1, while it was 19 m for those with intermediate levels and 9 m for those with low levels (P=0.01). Median survival was 31 m for p with high levels, not reached for p with intermediate levels and 17 m for p with low levels (P=0.004). Conclusions: The enhanced effect of erlotinib in the presence of elevated MCPH1 could be due to the fact that MCPH1 can interfere with the function of MDC1 and 53BP1. The role of MCPH1 merits validation as a predictive marker of erlotinib response.

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The effectiveness of afatinib in patients with lung adenocarcinoma harboring complex epidermal growth factor receptor mutation

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835920946156 ◽

2020 ◽

Vol 12 ◽

pp. 175883592094615

Author(s):

Shang-Gin Wu ◽

Chong-Jen Yu ◽

James Chih-Hsin Yang ◽

Jin-Yuan Shih

Keyword(s):

Lung Cancer ◽

Lung Adenocarcinoma ◽

Growth Factor Receptor ◽

Egfr Mutations ◽

Line Treatment ◽

First Line ◽

Tissue Samples ◽

Epidermal Growth ◽

Egfr Tkis ◽

First Line Treatment

Background and aims: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are effective against classical EGFR mutations in lung cancer. However, their effectiveness and the prognosis of lung cancer patients with complex EGFR mutations are not well delineated. Therefore, we aimed to investigate the treatment effectiveness of different EGFR TKIs in patients with complex EGFR mutations. Patients and methods: From 2005 to 2020, we collected lung adenocarcinoma tissue samples for EGFR mutation analysis using direct Sanger sequencing. Patients with EGFR mutations treated with EGFR TKIs as first-line treatment were enrolled. Clinical characteristics, EGFR mutation status, treatment response, progression-free survival (PFS), and overall survival (OS) were analyzed. Results: Among 2675 patients with EGFR mutations, 239 (8.9%) had complex EGFR mutations, of whom 125 received EGFR TKI treatment as first-line treatment. Multivariate analysis revealed that afatinib was a more favorable factor for PFS than gefitinib [hazard ratio (HR), 2.01; 95% confidence interval (CI), 1.11–3.62] and erlotinib (HR, 2.61; 95% CI, 1.31–5.22), especially in patients with uncommon mutation patterns. Afatinib treatment as first-line treatment was also associated with longer OS compared with erlotinib (HR, 2.48; 95% CI, 1.20–5.12). Classical mutation pattern was associated with longer PFS ( p = 0.001) and OS ( p = 0.020). Secondary T790M was detected in 22 of 52 (42.3%) patients who had re-biopsied tissue samples after acquiring resistance to EGFR TKIs. There was no significant difference in secondary T790M formation after acquired resistance to the three EGFR TKIs ( p = 0.261). Furthermore, three (5.8%) patients had small-cell lung cancer transformation. Conclusion: Afatinib is an effective first-line treatment for patients with lung adenocarcinoma harboring complex EGFR mutations, especially those with uncommon mutation patterns.

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Two different patterns of lung adenocarcinoma with concomitant EGFR mutation and ALK rearrangement

Tumori Journal ◽

10.1177/03008916211005546 ◽

2021 ◽

pp. 030089162110055

Author(s):

Dashi Zhao ◽

Jun Fan ◽

Li Peng ◽

Bo Huang ◽

Yili Zhu ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Egfr Mutation ◽

Growth Factor Receptor ◽

Egfr Mutations ◽

Alk Rearrangement ◽

Molecular Alterations ◽

Anaplastic Lymphoma ◽

Sporadic Cases ◽

Epidermal Growth ◽

Rare Group

Epidermal growth factor receptor ( EGFR) mutations and anaplastic lymphoma kinase ( ALK) rearrangements are considered mutually exclusive in non-small cell lung cancer (NSCLC), especially in lung adenocarcinoma (LUAC). However, sporadic cases harboring concomitant EGFR and ALK alterations have been increasingly reported. There is no consensus opinion regarding the treatment of patients positive for both molecular alterations. NSCLC with EGFR/ ALK coalterations should be separated into two subtypes: unifocal and multifocal LUAC. Here, we present an overview of the available literature regarding this rare group of patients to provide useful suggestions for therapeutic strategies.

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Vasculogenic mimicry, a negative indicator for progression free survival of lung adenocarcinoma irrespective of first line treatment and epithelial growth factor receptor mutation status

BMC Cancer ◽

10.1186/s12885-021-07863-z ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Xuejun He ◽

Jijun You ◽

Haibing Ding ◽

Zhisheng Zhang ◽

Lin Cui ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Target Therapy ◽

Vasculogenic Mimicry ◽

Therapy Response ◽

Progression Free Survival ◽

Egfr Mutations ◽

Line Treatment ◽

First Line ◽

Free Survival ◽

First Line Treatment

Abstract Background Vascular mimicry (VM) was associated with the prognosis of cancers. The aim of the study was to explore the association between VM and anticancer therapy response in patients with lung adenocarcinoma. Methods This was a single-center retrospective study of patients with lung adenocarcinoma between March 1st, 2013, to April 1st, 2019, at the Second People’s Hospital of Taizhou City. All included patients were divided into the VM and no-VM groups according to whether VM was observed or not in the specimen. Vessels with positive PAS and negative CD34 staining were confirmed as VM. The main outcome was progression-free survival (PFS). Results Sixty-six (50.4%) patients were male. Eighty-one patients received chemotherapy as the first-line treatment, and 50 patients received TKIs. Forty-five (34.4%) patients were confirmed with VM. There was no difference regarding the first-line treatment between the VM and no-VM groups (P = 0.285). The 86 patients without VM had a median PFS of 279 (range, 90–1095) days, and 45 patients with VM had a median PFS of 167 (range, 90–369) days (P < 0.001). T stage (hazard ratio (HR) = 1.37, 95% confidence interval (CI): 1.10–1.71), N stage (HR = 1.43, 95%CI: 1.09–1.86), M stage (HR = 2.85, 95%CI: 1.76–4.61), differentiation (HR = 1.85, 95%CI: 1.29–2.65), therapy (HR = 0.32, 95%CI: 0.21–0.49), VM (HR = 2.12, 95%CI: 1.33–3.37), and ECOG (HR = 1.41, 95%CI: 1.09–1.84) were independently associated with PFS. Conclusion The benefits of first-line TKIs for NSCLC with EGFR mutation are possibly better than those of platinum-based regimens in patients without VM, but there is no difference in the benefit of chemotherapy or target therapy for VM-positive NSCLC harboring EGFR mutations.

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First-Line Gefitinib for Patients With Advanced Non–Small-Cell Lung Cancer Harboring Epidermal Growth Factor Receptor Mutations Without Indication for Chemotherapy

Journal of Clinical Oncology ◽

10.1200/jco.2008.18.7658 ◽

2009 ◽

Vol 27 (9) ◽

pp. 1394-1400 ◽

Cited By ~ 330

Author(s):

Akira Inoue ◽

Kunihiko Kobayashi ◽

Kazuhiro Usui ◽

Makoto Maemondo ◽

Shoji Okinaga ◽

...

Keyword(s):

Lung Cancer ◽

Epidermal Growth Factor Receptor ◽

Nucleic Acid ◽

Growth Factor ◽

Growth Factor Receptor ◽

Small Cell ◽

Egfr Mutations ◽

Small Cell Lung ◽

First Line ◽

Epidermal Growth

Purpose This multicenter phase II study was undertaken to investigate the efficacy and feasibility of gefitinib for patients with advanced non–small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations without indication for chemotherapy as a result of poor performance status (PS). Patients and Methods Chemotherapy-naïve patients with poor PS (patients 20 to 74 years of age with Eastern Cooperative Oncology Group PS 3 to 4, 75 to 79 years of age with PS 2 to 4, and ≥ 80 years of age with PS 1 to 4) who had EGFR mutations examined by the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method were enrolled and received gefitinib (250 mg/d) alone. Results Between February 2006 and May 2007, 30 patients with NSCLC and poor PS, including 22 patients with PS 3 to 4, were enrolled. The overall response rate was 66% (90% CI, 51% to 80%), and the disease control rate was 90%. PS improvement rate was 79% (P < .00005); in particular, 68% of the 22 patients improved from ≥ PS 3 at baseline to ≤ PS 1. The median progression-free survival, median survival time, and 1-year survival rate were 6.5 months, 17.8 months, and 63%, respectively. No treatment-related deaths were observed. Conclusion This is the first report indicating that EGFR mutation-positive patients with extremely poor PS benefit from first-line gefitinib. Because there previously has been no standard treatment for these patients with short life expectancy other than best supportive care, examination of EGFR mutations as a biomarker is recommended in this patient population.

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