Elsevier

Lung Cancer

Volume 81, Issue 3, September 2013, Pages 462-467
Lung Cancer

Fibroblast growth factor receptor 1 (FGFR1) copy number is an independent prognostic factor in non-small cell lung cancer

https://doi.org/10.1016/j.lungcan.2013.05.015Get rights and content

Abstract

Fibroblast growth factor receptor 1 (FGFR1) is an oncogene that can potentially be targeted by tyrosine kinase inhibitors. We aimed to investigate the prevalence and prognostic significance of alterations in FGFR1 copy number in non-small cell lung cancer (NSCLC). FGFR1 status was evaluated by chromogenic silver in situ hybridisation (ISH) in tissue microarray sections from a retrospective cohort of 304 surgically resected NSCLCs and results were correlated with the clinicopathological features and overall survival. High FGFR1 gene copy number (amplification or high-level polysomy) was significantly more frequent in squamous cell carcinomas (SCC) (24.8%) and large cell carcinomas (LCC) (25%) compared to adenocarcinomas (11.3%) (p = 0.01 and p = 0.03 respectively). Among NSCLC there was no significant correlation between FGFR1-positive status and other clinicopathological features including age, gender, smoking history, tumour size, lymph node status, stage, grade, vascular, lymphatic or perineural invasion. FGFR1-positive patients showed a tendency to longer overall survival in univariate analysis (p = 0.14). Multivariate survival analysis using Cox regression model confirmed FGFR1-positive patients had a significant reduction in the risk of death compared to FGFR1-negative patients (HR 0.6; p = 0.02). High FGFR1 gene copy number is a common finding in SCC and LCC and is an independent favourable prognostic factor.

Introduction

Our understanding of the molecular origins of non-small cell lung cancer (NSCLC) has progressed significantly over the past decade due to the identification of driver events such as mutations of KRAS, EGFR, BRAF, PIK3CA, ALK rearrangement, or MET amplification [1], [2]. A growing number of targeted therapies, primarily tyrosine kinase inhibitors, are now in routine clinical use for lung adenocarcinomas (ADC) harbouring specific mutations, however, prospects for personalised and molecularly targeted therapy have not impacted on other subtypes of NSCLC [3]. While molecular abnormalities in specific subsets of lung adenocarcinomas have been well characterised [4], it is only recently that comprehensive genomic characterisation of squamous cell lung cancers has identified potentially targetable mutations [5]. Fibroblast growth factor receptor 1 (FGFR1) has been identified as one of the emerging molecular targets for the treatment of squamous cell carcinomas of the lung [6], [7] and several early phase clinical trials of FGFR inhibitors are currently being undertaken in NSCLC [8], [9].

FGFRs belongs to the super-family of receptor tyrosine kinases and are encoded by 4 genes (FGFR1, FGFR2, FGFR3, and FGFR4) [10]. FGFR acts as a cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation and migration [11]. Alterations of the FGFR gene have been recognised in many epithelial malignancies including amplifications in gastric, breast, oral squamous cell, ovarian and bladder carcinomas [10], [12], [13] and more recently in squamous NSCLC [6], promising a novel therapeutic target in these tumours. Previous studies of FGFR1 amplification in lung cancer have focussed on squamous cell carcinoma (SCC) [14] or SCC and ADC [6], [7], [15], [16] with little data available on undifferentiated large cell carcinomas (LCC). We have undertaken a comprehensive evaluation of FGFR1 gene copy status in the main subtypes of NSCLC in a study designed to investigate the prevalence and prognostic significance of alterations in FGFR1 copy number in NSCLC. We also comprehensively report a comparison of FGFR1 status in primary tumours and matched lymph node metastases.

Section snippets

Patient cohort and tissue microarray construction

This retrospective study was conducted in a cohort of 261 NSCLC patients who underwent resection of a primary NSCLC at the Royal Prince Alfred Hospital, Sydney, Australia. Surgery was performed by the one cardiothoracic surgeon (B.M.) from 1994 to 2002. In order to extend the sample size for correlative analyses between primary and lymph node metastatic tumours as well as clinicopathological features, an additional cohort of 43 NSCLC lymph node metastatic stage patients from 2010 to 2012 was

FGFR1 ISH analyses and clinicopathological correlations

A total of 304 cases were evaluated for FGFR1 gene copy number in which 264 cases (87%) were scorable. The clinicopathological features of all 264 patients are summarised in Table 1. The majority of patients were male (64%), with early pathological stage tumours (35.6% stage I and 48.9% stage II), and a median age of 66.5 ± 8.7 years. Amongst all NSCLC, the mean FGFR1 gene copy number was 2.88 (range 1.1–20.4) and mean CEP8 was 1.78 (range 1.0–3.9). Only 3% of tumours had mean CEP8 scores  3

Discussion

There is increasing interest in characterisation of key molecular alterations in lung cancers that may provide opportunities for targeted therapeutic interventions. Deregulation of the FGFR signalling pathway has been described in many epithelial tumours, predominantly through receptor overexpression or more rarely through activating somatic mutations of the receptor gene [10]. In vitro and in vivo studies have shown FGFR1-mediated signalling plays an important role in NSCLC cell growth,

Conflict of interest statement

S. O’Toole has received honoraria for participating in an Advisory Board for Roche.

Funding sources

This study was supported by a grant from The Sydney Foundation for Medical Research. SOT – Cancer Institute NSW, Sydney Breast Cancer Foundation, CINSW Programme Grant.

MKC is a Cancer Institute NSW Fellow.

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