Dataset Information

Antiestrogen fulvestrant enhances the antiproliferative effects of epidermal growth factor receptor inhibitors in human non-small-cell lung cancer.

ABSTRACT:

Introduction

Estrogen receptor (ER) signaling and its interaction with epidermal growth factor receptor (EGFR) is a potential therapeutic target in non-small-cell lung cancer (NSCLC). To explore cross-communication between ER and EGFR, we have correlated ER pathway gene and protein expression profiles and examined effects of antiestrogens with or without EGFR inhibitors in preclinical models of human NSCLC.

Methods

We evaluated 54 NSCLC cell lines for growth inhibition with EGFR inhibitors, antiestrogen treatment, or the combination. Each line was evaluated for baseline ER pathway protein expression. The majority were also evaluated for baseline ER pathway gene expression. Human NSCLC xenografts were evaluated for effects of inhibition of each pathway, either individually, or in combination.

Results

The specific antiestrogen fulvestrant has modest single agent activity in vitro, but in many lines, fulvestrant adds to effects of EGFR inhibitors, including synergy in the EGFR-mutant, erlotinib-resistant H1975 line. ER?, ER?, progesterone receptor-A, progesterone receptor-B, and aromatase proteins are expressed in all lines to varying degrees, with trends toward lower aromatase in more sensitive cell lines. Sensitivity to fulvestrant correlates with greater baseline ER? gene expression. Tumor stability is achieved in human tumor xenografts with either fulvestrant or EGFR inhibitors, but tumors regress significantly when both pathways are inhibited.

Conclusions

These data provide a rationale for further investigation of the antitumor activity of combined therapy with antiestrogen and anti-EGFR agents in the clinic. Future work should also evaluate dual ER and EGFR inhibition in the setting of secondary resistance to EGFR inhibition.

SUBMITTER: Garon EB

PROVIDER: S-EPMC3573351 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Publications

Antiestrogen fulvestrant enhances the antiproliferative effects of epidermal growth factor receptor inhibitors in human non-small-cell lung cancer.

Garon Edward B EB Pietras Richard J RJ Finn Richard S RS Kamranpour Naeimeh N Pitts Sharon S Márquez-Garbán Diana C DC Desai Amrita J AJ Dering Judy J Hosmer Wylie W von Euw Erika M EM Dubinett Steven M SM Slamon Dennis J DJ

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 20130301 3

<h4>Introduction</h4>Estrogen receptor (ER) signaling and its interaction with epidermal growth factor receptor (EGFR) is a potential therapeutic target in non-small-cell lung cancer (NSCLC). To explore cross-communication between ER and EGFR, we have correlated ER pathway gene and protein expression profiles and examined effects of antiestrogens with or without EGFR inhibitors in preclinical models of human NSCLC.<h4>Methods</h4>We evaluated 54 NSCLC cell lines for growth inhibition with EGFR i ...[more]

PMID: 23399957

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Project description:BackgroundChoroidal metastases are the most common eye metastatic site. The prevalence of choroidal metastases in NSCLC patients has been reported to vary from 0.2 to 7% in historical series. Although previously reported, little is known about choroidal metastasis in Epidermal Growth Factor Receptor (EGFR)-mutant Non-small cell lung cancer (NSCLC). This study sought to describe the prevalence of choroidal metastases among patients with EGFR-mutated NSCLC and their characteristics, and to estimate their impact on prognosis.MethodsWe conducted a single-center retrospective study including all consecutive metastatic EGFR-mutant NSCLC patients, from Sept. 2015 to Oct. 2018. The EGFR-mutant NSCLC patients were identified via the Department of Genetics' files. Patients who exhibited choroidal metastases were compared to patients without choroidal metastases. Kaplan-Meier analysis and log-rank test were conducted to assess median overall survival (OS) from diagnosis for the two groups. The study was approved by the IRB as CEPRO number #2020-010.ResultsPrevalence of choroidal metastases in EGFR-mutated NSCLCs was 8.4% (7/83). Five were women, and four current or former smokers. Molecular analysis showed three tumors with exon 19 deletion, three with L858R mutation, and one with complex exon 21 mutation. The choroidal metastases were symptomatic in six/seven patients. Visual disturbances decreased in all but one symptomatic cases upon EGFR TKI, and the choroidal response was maintained over time. Median follow-up was 42.2 mo (95%CI [37.2-47.1]). Median OS in the choroidal metastasis group was 23.4 mo (95%CI [0.1-51.4]) versus 27.9 mo (95%CI [16.9-38.9]) in the non-choroidal metastasis group (p = 0.32). In the choroidal metastasis group, 2-year and 5-year OS were 47.6 and 0%, respectively, versus 55.8 and 26.3% in the non-choroidal metastasis subset.ConclusionsChoroidal metastases in NSCLC EGFR-mutant patients are rare but should be systematically suspected in case of visual disturbance. TKIs are efficient for treating visual symptoms. Whether choroidal metastases confer a worse prognosis remains unclear owing to the third-generation EGFR TKI osimertinib first-line registration.

Dataset Information

Antiestrogen fulvestrant enhances the antiproliferative effects of epidermal growth factor receptor inhibitors in human non-small-cell lung cancer.

Introduction

Methods

Results

Conclusions

Publications

Antiestrogen fulvestrant enhances the antiproliferative effects of epidermal growth factor receptor inhibitors in human non-small-cell lung cancer.

Similar Datasets

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