Response to EGFR tyrosine kinase inhibitor (TKI) retreatment after a drug-free interval in EGFR-mutant advanced non-small cell lung cancer (NSCLC) with acquired resistance.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7525-7525 ◽  
Author(s):  
Stephanie Heon ◽  
Mizuki Nishino ◽  
Sarah B. Goldberg ◽  
Jennifer Porter ◽  
Lecia V. Sequist ◽  
...  
Keyword(s):  
Egfr Mutation ◽  
Advanced Nsclc ◽  
Single Agent ◽  
Acquired Resistance ◽  
Egfr Mutations ◽  
Free Interval ◽  
Egfr Mutant ◽  
The Impact ◽  
Drug Free ◽  
Egfr Tki

7525 Background: Patients (pts) with advanced NSCLC and sensitizing EGFR mutations who initially respond to gefitinib or erlotinib eventually develop acquired resistance to the TKIs. Anecdotal and retrospective reports suggest that EGFR-TKI resistant cancers can respond again to gefitinib or erlotinib after an interval off the TKI. This retrospective study was undertaken to investigate the impact of EGFR-TKI retreatment after a drug-free interval in EGFR mutant NSCLC with acquired resistance to gefitinib or erlotinib. Methods: Pts with stage IV or relapsed NSCLC with sensitizing EGFR mutations and acquired resistance to EGFR-TKI seen at the DFCI/MGH between 8/00 and 8/11 who were retreated with single agent gefitinib or erlotinib after an EGFR-TKI-free interval were identified from a prospective trial. The objective tumor response (CR, PR, SD, PD) was determined using RECIST 1.1. Results: 19 pts were eligible and had adequate scans for radiographic assessments after the reinstitution of an EGFR-TKI. The response rate and median PFS to the initial course of gefitinib (n=4) or erlotinib (n=15) were 16/19 (84%) and 9.8 months (95% CI, 7.8-11.3) respectively. All pts were retreated with erlotinib after 1 to 4 intervening systemic regimens. The median interval from EGFR-TKI discontinuation to erlotinib retreatment was 11 months (range, 2-46). 4 of the 19 pts (21%) had PD as the best response to erlotinib retreatment, 14 (74%) had SD for at least 1 month, and 1 (5%) had a PR. The median PFS was 4.4 months (95% CI, 3.0-6.7). 3 pts remained on erlotinib without progression for 6 months. 3 pts had their tumors rebiopsied before (n=2) or during (n=1) erlotinib retreatment; 1 of the 3 had EGFR T790M in association with the initial sensitizing EGFR mutation, and another had a secondary PIK3CA mutation. Conclusions: Our findings suggest that erlotinib retreatment is an option for EGFR mutated NSCLC with acquired resistance to EGFR-TKI after a drug-free interval and progression on intervening therapy. Additional advanced NSCLC pts without a documented EGFR mutation who fulfill the clinical definition of acquired resistance are undergoing review to expand our cohort.

scholarly journals Efficacy and Acquired Resistance of EGFR-TKI Combined with Chemotherapy as First-Line Treatment for Chinese Patients with Advanced Non-Small Cell Lung Cancer in a Real-world Setting

2020 ◽  
Author(s):  
Qianqian Wang ◽  
Wen Gao ◽  
Fangyan Gao ◽  
Shidai Jin ◽  
Tianyu Qu ◽  
...  
Keyword(s):  
Egfr Mutation ◽  
Advanced Nsclc ◽  
Acquired Resistance ◽  
Small Cell ◽  
Combination Group ◽  
Monotherapy Group ◽  
Small Cell Lung ◽  
T790m Mutation ◽  
Nsclc Patients ◽  
Egfr Tki

Abstract Background To compare the benefits and explore the cause of acquired resistance of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and its combination with chemotherapy in advanced non-small-cell lung cancer (NSCLC) patients harboring EGFR mutation in a real-life setting.Methods This retrospective analysis included 117 advanced NSCLC patients with EGFR mutation who underwent next-generation sequencing (NGS) prior to treatment. The combination group included 50 patients who received the regimen of EGFR-TKI combined with chemotherapy, while the EGFR-TKI monotherapy group included 67 patients treated with TKI only. The primary endpoint of this study was progression-free survival (PFS); the secondary endpoints were overall survival (OS), response rate, and toxicity.Results The median PFS was significantly longer in the combination group than in the EGFR-TKI monotherapy group (19.00 months [95% CI, 14.674-23.326] vs. 11.70 months [95% CI, 10.807-12.593], p = 0.000). Subgroup analysis showed a similar trend of results. The median OS was not reached in the combination group and was 38.50 (95% CI, 35.300-41.700) months in the EGFR-TKI monotherapy group (p = 0.586). Patients in the combination group were more likely to experience adverse events, most of which showed the severity of grade 1 or 2. T790M mutation remains the main reason for acquired resistance, and the frequency of T790M mutation was similar between the two groups (p = 0.898). Conclusions Compared with EGFR-TKI monotherapy, EGFR-TKI combined with chemotherapy significantly improved PFS in advanced NSCLC patients with EGFR mutation, with acceptable toxicity.

Quantitative test of mutant EGFR and its effect on efficacy of EGFR TKI in advanced NSCLC.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e22186-e22186
Author(s):  
Caicun Zhou ◽  
Xuefei Li ◽  
Shengxiang Ren ◽  
Guohua Yang ◽  
Wei He
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Egfr Mutation ◽  
Advanced Nsclc ◽  
Progression Free Survival ◽  
Egfr Mutations ◽  
Conserved Sequence ◽  
Egfr Tki ◽  
Mutant Egfr

e22186 Background: It is reported that abundance of EGFR mutation is related with efficacy of EGFR TKI in advanced NSCLC patients with positive EGFR mutations. This study was designed to investigate influence of EGFR mutations and their abundance on efficacy of EGFR TKI. Methods: 141 advanced NSCLC treated with EGFR TKI and available tissue for EGFR mutations were enrolled into the study. EGFR mutation was detected with the kit of AmoyDx ARMS and concentration of mutant EGFR was detected with the method of a quantitative competitive allele specific Taqman PCR technology (qCAST). In this assay, copies from EGFR mutants were calibrated by standard curve respectively, and the mutation rates were estimated through normalizing by copies of a conserved sequence in EGFR exon2. The relationship between abundance of EGFR mutations and efficacy of EGFR TKI was analyzed. Results: The median age of patients was 59 years old, and in which 54.3% were male, 71.7% ex-somkers. Among all of the patients, adenocarcinoma accounted for 57.7%, squamous cell carcinoma 27.2%, adeno-squamous cell carcinoma 7.6%, and others 7.6%. 46.7% of patients harbored EGFR mutations, and in which 48.7% existed more than 20% abundance of EGFR mutations. Overall response rate was 31.4% and progression free survival was 5.0 months. The final analysis data will be reported at the conference. Conclusions: The abundance of EGFR mutations might affect the efficacy of EGFR-TKI, and quantitation of mutant EGFR may better predict for efficacy of EGFR TKI in advanced NSCLC.

Chemoimmunotherapy combination: Potential option for metastatic NSCLC patients with EGFR mutation resistant to osimertinib.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20618-e20618
Author(s):  
Bo Yang ◽  
Yaping Long ◽  
Yi Hu
Keyword(s):  
Egfr Mutation ◽  
Acquired Resistance ◽  
Progression Free Survival ◽  
Egfr Mutations ◽  
Combination Group ◽  
Metastatic Nsclc ◽  
Number Of Patients ◽  
Grade 3 ◽  
Egfr Mutant ◽  
Nsclc Patients

e20618 Background: Osimertinib has been emerged as the standard selection in EGFR T790M-positive NSCLC patients who failed prior treatment with EGFR TKIs. However, acquired resistance to osimertinib is a growing clinical challenge. Despite the significant antitumor activity of Chemoimmunotherapy (CIT) combinations in NSCLC, clinical benefit in patients with EGFR mutations has not been shown obviously. Our objective was to assess the effectiveness and tolerability of CIT for metastatic EGFR-mutant NSCLC patients with acquired resistance to Osimertinib. Methods: We conducted a retrospective study in patients with sensitizing EGFR-mutant NSCLC who were resistant to Osimertinib and received anti-PD1 immunotherapy combined with chemotherapy at Chinese PLA General Hospital. Progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and toxicities were examined. Results: Between Oct 2015 and Nov 2018, 11 patients were available for analysis, 45.5% male, 45.5% ECOG PS 0-1, median age 54 years, all pts who failed treatment with Osimertinib had received previously targeted therapies. In this CIT combination group, 6 [54.5%] of 11 pts received pembrolizumab and 5[54.5%] of 11 pts received Nivolumab anti-PD1 therapy, 8 [72.7%] of 11 pts received mono-chemotherapy and 3 [27.3%] of 11 pts received platinum-based doublet chemotherapy. The median PFS was 7.47 months (95% CI 3.04 to 11.89). Despite Median OS was not reached, the OS rate at one year was 6 [54.5%] of 11. The ORR was 5 [45.5%] of 11. Treatment-related adverse events (TRAE) of grade 3 or higher were reported in 6 [54.5%] of 11 patients. The most common grade 3 or worse TRAEs were fatigue (3 [27.3%] of 11) and anemia (3 [27.3%] of 11); The following ≥Grade 3 TRAEs occurred once: decreased neutrophil count, acute kidney injury, gastrointestinal bleeding. One patient discontinued treatment because of immune-associated gastroenteritis. Conclusions: In metastatic NSCLC patients with activating EGFR mutation resistant to Osimertinib, our single institution real-world experience in Chemoimmunotherapy combination shows promising activity and acceptable toxicity profile. Given the small number of patients studied, further clinical trials are warranted.

Rebiopsy of patients (pts) with acquired resistance to epidermal growth factor tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8025-8025 ◽  
Author(s):  
M. E. Arcila ◽  
G. J. Riely ◽  
M. F. Zakowski ◽  
M. G. Kris ◽  
M. Ladanyi ◽  
...  
Keyword(s):  
Median Time ◽  
Progressive Disease ◽  
Kinase Inhibitors ◽  
Egfr Mutation ◽  
Acquired Resistance ◽  
Egfr Mutations ◽  
Met Amplification ◽  
Metastatic Sites ◽  
Egfr Tki ◽  
Egfr Tkis

8025 Background: The EGFR-TKIs erlotinib and gefitinib produce dramatic regressions of tumor in ∼ 70% of NSCLC patients with activating mutations in the EGFR-TK domain. After a median time to progression of ∼1 year, most pts have progressive disease. We undertook this study to search for mechanisms of “acquired resistance” to EGFR-TKIs, to determine the spectrum and frequency of secondary EGFR mutations which arose, and to determine the feasibility of rebiopsy in this setting. Methods: All pts had metastatic or recurrent NSCLC and prior treatment with EGFR-TKI and progressive disease while on EGFR-TKI. Pts must also have had an activating EGFR mutation OR radiographic response (RECIST or WHO) to EGFR-TKI OR significant and durable improvement in cancer-related symptoms as judged by patient's physician. Core biopsies were performed and studied for EGFR mutation (exons 18–21 including PCR-based test for T790M) and MET amplification. Results: From 8/04–12/08 98 pts were consented for rebiopsy and 85 underwent the procedure. Demographics Female/Male=59/39; median age 62 (range 28–88); smoking: never=59, former/current=39. Primary EGFR mutation was exon 19 del-39; exon 21 L858R-11, other/WT-28, pending-7. Median time on EGFR-TKI before biopsy was 12 months (7–28 months). Secondary EGFR mutations: T790M-33, other-2, none detected-31, indeterminate-10, pending-9. MET amplification in 2/16 studied to date. Conclusions: 1) Rebiopsy of patients with NSCLC and acquired resistance to EGFR TKIs is feasible and well-received by pts. 2) Knowledge of EGFR genotype including EGFR T790M and MET status can inform clinical trials of targeted therapies in this population 3) More complete annotation of MET status and exploratory analyses of profiles of specimens by metastatic sites and prior EGFR-TKI versus chemo and EGFR-TKI is ongoing. Supported by the Doris Duke Foundation, the LaBrecque Foundation, Steps for Breath, NIH, and an anonymous donor. No significant financial relationships to disclose.

Small cell lung cancer (SCLC) among patients who are never smokers.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7593-7593
Author(s):  
Anna M. Varghese ◽  
Helena Alexandra Yu ◽  
Helen H. Won ◽  
Camelia S. Sima ◽  
Gregory J. Riely ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Egfr Mutation ◽  
De Novo ◽  
Egfr Mutations ◽  
Kras Mutations ◽  
Lung Cancers ◽  
Never Smokers ◽  
Egfr Mutant ◽  
Egfr Tki ◽  
Generation Sequencing

7593 Background: Although most patients (pts) with SCLC are current or former smokers, SCLC has been reported in pts who are never smokers, most recently in pts with EGFR-mutant lung cancers who develop acquired resistance (AR) to EGFR tyrosine kinase inhibitors (TKIs). We describe clinical, pathologic, and molecular characteristics of never-smoking pts with SCLC at diagnosis and in the AR setting. Methods: We identified cases through systematic review of pts seen at MSKCC from 2005 – 2012. Smoking history was obtained prospectively. SCLC diagnosis was confirmed by expert pathology review. We collected age, sex, stage, treatment, and survival data. EGFR, KRAS, PIK3CA, and ALK testing and next generation sequencing of 279 cancer genes was performed on available samples. Results: 2.2% (23/1040, 95% CI 1.5 to 3.3%) of pts with SCLC seen at MSKCC were never smokers: 61% women, median 64 years, 74% extensive stage, and 22% with brain metastases at diagnosis. 83% (19/23) had de novo SCLC, whereas only 17% had SCLC as AR to EGFR TKI after treatment for EGFR-mutant lung cancers, all of whom had persistent EGFR mutation confirmed at resistance. Median survival from SCLC diagnosis is 23 months (95%CI: 11-26) for all pts and 23 months (95% CI: 8–27) for the 19 pts with de novo SCLC. Pathologic review demonstrated 19 cases of pure SCLC and 4 mixed histology cases with SCLC and other histologies. Treatment history was available for 15/19 pts with de novo SCLC: 53% etoposide-platinum sensitive. ALK rearrangement and KRAS mutations were identified in 0/5 and 0/10, respectively. One pt with de novo mixed SCLC and adenocarcinoma had an EGFR mutation and another pt with de novo pure SCLC had EGFR and PIK3CA mutations. Mutations were identified in p53 and Rb1 with amplification in TERT in 1 sample to date tested with next generation sequencing. Conclusions: 2% of pts with SCLC are never smokers. While transformation to SCLC can occur in the setting of AR to EGFR TKI, de novo SCLC occurs in the majority of our never smokers with this disease. EGFR mutations uniformly exist in SCLC in the AR setting. EGFR mutations were rare, and we found no KRAS mutations or ALK rearrangements. Comprehensive, multiplexed genotyping can aid in providing optimal care and facilitate research in this unique population.

scholarly journals A preliminary results of integrated chemotherapy with EGFR receptor tyrosine kinase inhibitors in patients with non-small-cell-lung cancer harboring EGFR mutation

2019 ◽  
pp. 110-114
Author(s):  
K. K. Laktionov ◽  
D. I. Yudin ◽  
V. V. Breder ◽  
E. V. Reutova ◽  
K. P. Laktionov ◽  
...  
Keyword(s):  
Receptor Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Egfr Mutation ◽  
Advanced Nsclc ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
Free Survival ◽  
Single Center Study ◽  
One Year ◽  
Drug Free

In the open prospective non-randomized single-center study we recruited patients with advanced NSCLC harboring EGFR mutations. Initially there were two months of treatment by gefitinib 250 mg daily. Then, after a 2-week drug-free period, 3 cycles of paclitaxel 175 mg / m2 and carboplatin AUC5 were administrated at days 71-113. Thereafter, gefitinib was re-started on day 135 and continued until disease progression. The primary endpoint was progressive free survival (PFS) time. One-year PFS in all patients group included in the study at the time of the preliminary analysis was 79.8%, median PFS was 17 months (13.5–23, CI 95%). In the group of integrated chemotherapy one-year PFS was 89.3%, median PFS was 19 months (14–23.5, CI 95%).

Phase IB study of olaparib (AZD2281) plus gefitinib in EGFR-mutant patients (p) with advanced non-small-cell lung cancer (NSCLC) (NCT01513174/GECP-GOAL).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2581-2581 ◽  
Author(s):  
Rosario García Campelo ◽  
Enriqueta Felip ◽  
Bartomeu Massuti ◽  
Margarita Majem ◽  
Enric Carcereny ◽  
...  
Keyword(s):  
Dose Level ◽  
Advanced Nsclc ◽  
Egfr Mutations ◽  
Clinical Activity ◽  
Phase Ib ◽  
Treatment Naïve ◽  
Previously Treated ◽  
Egfr Mutant ◽  
Dose Levels ◽  
Egfr Tki

2581 Background: Progression-free survival (PFS) and response to EGFR tyrosine kinase inhibitors (TKIs) vary in p with NSCLC driven by EGFR mutations. In our experience, high BRCA1 mRNA expression was associated with shorter PFS in EGFR-mutant p treated with erlotinib. We hypothesized that since olaparib downregulates BRCA1 expression, the addition of olaparib to gefitinib could improve PFS in these p. Methods: This is a Phase IB dose escalation study to identify the maximum tolerated dose (MTD), dose limiting toxicity (DLT), pharmacokinetics, and clinical activity of orally administered olaparib in combination with gefitinib in EGFR-mutant advanced NSCLC p. In a standard 3+3 design, p were treated with gefitinib 250mg once daily plus olaparib tablets at escalating doses ranging from 100mg BID to 250mg TDS during a 28-day cycle. Results: 18 p have been included across four dose levels of olaparib: 100mg BID (3), 200mg BID (6), 200mg TDS (3) and 250mg TDS (6). Median age, 69; male, 4; PS 0, 17; EGFR TKI treatment-naïve, 10. Toxicities: anemia (66.6%), leucopenia (33.3%), nausea (33.3%), diarrhea (33.3%), asthenia (27.7%), rash (22.2%) vomiting (11%), decreased appetite (16%), and hyperlipasemia (5.5%). Most toxicities were G1-2; G3 drug-related events included leucopenia (1) and anemia (3). No DLT at dose levels 1, 2, and 3; 1 DLT at dose level 4 (G3 anemia and repeated blood transfusion within 4-6 weeks). Few dose reductions or interruptions were needed. 1 p died due to pulmonary embolism unrelated to treatment. Partial responses (PR) were observed in 7 p (41.1%), all EGFR TKI-naïve; stable disease (SD) in 7 (41.1%), most previously treated; progressive disease (PD) in 3 (17.6%), all previously treated. Durable PR and SD were observed in EGFR TKI-naïve and previously treated p. 8 patients are still on treatment. Enrollment to dose level 4 will be completed in February 2013. Conclusions: This phase IB trial of gefitinib plus olaparib, has confirmed the activity and tolerability of the combination. The final recommended dose of olaparib is expected to be between 200 and 250 mg TDS. A phase II randomized trial in treatment-naïve EGFR-mutant advanced NSCLC will be opened in 2013. Clinical trial information: NCT0151317.

Afatinib in the treatment of advanced NSCLC with EGFR mutation: An observational real-world study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20518-e20518
Author(s):  
Yun Li ◽  
Xiaohua Wang ◽  
Li Wang ◽  
Yingying Kou ◽  
Xianglei Ma ◽  
...  
Keyword(s):  
Adverse Events ◽  
Mutation Rate ◽  
Real World ◽  
Egfr Mutation ◽  
Advanced Nsclc ◽  
Egfr Mutations ◽  
Third Generation ◽  
Efficacy And Safety ◽  
The Third ◽  
Egfr Tki

e20518 Background: Compared with the first generation of EGFR-TKI, Afatinib has a broader spectrum of activity and can better inhibit tumor growth. At present, the therapeutic effects of Afatinib varies on patients with different EGFR mutations and studies on the mechanism of acquired Afatinib resistance are limited. The aim of this study was to evaluate the efficacy and safety of Afatinib in the treatment of EGFR-mutation NSCLC who hadn’t received EGFR-TKI in the past. Methods: 88 patients with advanced NSCLC who had EGFR mutations were enrolled and given oral 40 mg Afatinib daily until disease progression or adverse events that could not be handled by dosage reduction. Efficacy and safety in different subgroups were analyzed. Results: Among 88 patients, the common mutation rate of EGFR was 79.5%, and the rare mutation rate was 20.5%. The objective remission rate (ORR) was 54.5%, and the disease control rate (DCR) was 92.0%. The median progression-free survival (PFS) was 14.2 months (95% CI 11.4-18.5), 27 patients (30.7%) continued Afatinib treatment after tumor progression, and the median time to progression of clinical symptoms (TTSP) was 16.3 months (95% CI 12.7-19.3). A total of 13 patients (14.8%) reduced Afatinib dosage of due to adverse events. Subgroup analysis showed that Afatinib had better effect on patients harboring common EGFR mutation but not exon 20 mutation, and was not affected by brain metastasis, dosage and lines of therapy. Among patients who progressed on Afatinib, 65.4% harbored T790M mutation. Most T790M patients received the third generation EGFR-TKI including AZD9291 and oxetinib treatment. The most common adverse reactions were diarrhea, rash, paronychia and stomatitis. Conclusions: Afatinib showed good efficacy and tolerance in advanced NSCLC patients with EGFR mutations. Continuation of Afatinib treatment after cancer progression could delay the progression of disease symptoms. The third generation EGFR-TKI could become a treatment option after Afatinib resistance. These findings reflected the real-world clinical practice of Afatinib.

scholarly journals Switching from first or second generation EGFR-TKI to osimertinib in EGFR mutation-positive NSCLC

2020 ◽  
Vol 9 (2) ◽  
pp. LMT29
Author(s):  
Fumio Imamura ◽  
Takako Inoue ◽  
Kei Kunimasa ◽  
Aki Kubota ◽  
Hanako Kuhara ◽  
...  
Keyword(s):  
Egfr Mutation ◽  
Acquired Resistance ◽  
Progression Free Survival ◽  
Egfr Mutations ◽  
Free Survival ◽  
Combination Strategies ◽  
Sequential Combination ◽  
Clinical Records ◽  
Egfr Tki ◽  
Egfr Tkis

Aim: We evaluated the efficacy of a novel switch protocol for EGFR-TKIs for EGFR mutation-positive NSCLC. Materials & methods: Clinical records were collected from the patients who had received one of two sequential combination strategies of EGFR-TKIs: Salvage use of osimertinib for T790M-mediated acquired resistance to an prior EGFR-TKI or switch use of osimertinib where an EGFR-TKI was switched to osimertinib before disease progression. Results: Progression-free survival of osimertinib and time from the start of treatment until progression to osimertinib was comparable between the salvage use and switch use of osimertinib. Conclusion: Switch use of osimertinib seemed to produce improved efficacy for patients with activating EGFR mutations, because of the lack of patient selection via T790M.

Cytoplasmic ERß expression to predict efficacy and survival of EGFR-TKI in EGFR-mutant NSCLC.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e19067-e19067
Author(s):  
Zhijie Wang ◽  
Jie Wang ◽  
Xiaodong Wang ◽  
Zhirong Shen ◽  
Xiaosheng Ding ◽  
...  
Keyword(s):  
Egfr Mutation ◽  
Growth Factor Receptor ◽  
Stage Iv ◽  
Fold Increase ◽  
Estrogen Receptor Pathway ◽  
Tissue Specimens ◽  
Egfr Mutant ◽  
Nsclc Patients ◽  
The Impact ◽  
Egfr Tki

e19067 Background: Estrogen receptor pathway has been reported to be interacted with epidermal growth factor receptor (EGFR) signal pathway. This study focused on the impact of intracellular ERβ localization (cytoplasmic or nuclear) on efficacy of EGFR-TKI. Methods: Tumor tissue specimens from 149 stage IV NSCLC patients treated with EGFR-TKI were analyzed using immunohistochemistry (IHC) for ER expression (ERα or β) and their associations with clinicopathological variables and clinical outcomes. Significance of cyto-ERβ expression was further examined in NSCLC cell lines. Results: The expression of ERα and ERβ was detected in 15% and 28.9% of the patients, respectively. Cyto-ERβ positive cases showed shortened PFS compared with negative ones (3.1 months vs. 7.3 months, p=0.061). In the EGFR-mutant subgroup, differences of PFS were enlarged with significant statistics (4.7 months vs. 10.9 months, p=0.042). COX’s proportional hazard model showed that female, EGFR mutation and c-ERβ status were independent predictors for PFS. PC-9 cells present ERβ in cytoplasma and nucleus. Estrodial (E2) induced PC-9 cells moderately resistant to erlotinib with a 3-fold increase of IC50, and the resistance can be reversed by ER blocker (fulvestrant) or siRNA directed to ESR2. The E2 function was accomplished by nongenomic activation (MAPK phosphorylation) caused by E2 via cyto-ERβ. Combination treatment with erlotinib and fulvestrant turned out to be far more effective than either treatment alone in PC-9 cells. Conclusions: Cyto-ERβ expression may predict relatively poor efficacy to EGFR-TKI compared with non- cyto-ERβ expression in NSCLC patients harboring EGFR mutation.

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