Cryobiopsy increases the EGFR detection rate in non-small cell lung cancer
Introduction
Lung cancer ranks among the most common cancers worldwide with approximately 1.8 million patients in 2012 [1,2]. Non small cell lung cancer (NSCLC) represents 75–85 % of all lung cancers. 2/3 of these patients are in non-curable stage III and IV at the time of diagnosis, and are usually treated systemically [3]. The current management of non-curable NSCLC has become more and more individualized and is based on immunohistochemical and molecular tumor characterization [4]. In this context, EGFR mutation is currently the most relevant molecular-genetic alteration [5] since target therapies directed to activating EGFR mutation not only have a much better side effect profile [6], but also lead to an improved clinical response [7], an improved progression free survival, and an improved overall survival in certain subgroups (e.g. with deletion in Exon 19 [[8], [9], [10], [11], [12], [13], [14]]).
As a consequence, precise and correct molecular characterization of advanced stage III and IV NSCLC is crucial for ensuring optimal treatment, and missing any targetable alteration may result in suboptimal therapy. Therefore, representative tumour tissue of adequate volume and quality forms the basis for optimal histological and molecular evaluation. EGFR testing lays the cornerstone for current NSCLC treatment in advanced stages [15]. Apart from surgical resection and radiologically guided biopsies, the standard techniques to obtain tissue samples in patients with suspected lung cancer are bronchoscopic forceps biopsy and fine needle aspiration [16]. However, there has been no detailed evaluation of the quality of biopsy specimen required for molecular testing, nor has there been an evaluation as to which biopsy technique provides the best material for molecular testing. As a result, guidelines on molecular testing of NSCLC do not discuss the quality of biopsy specimens required for EGFR testing, and limit their recommendations to statements like “a sufficient cancer cell content and appropriate DNA quantity and quality” [17,18] are required. This had led to the imprecise advice that each laboratory defines its own criteria [17]. Even in prospective large multicentre trials evaluating the effect of targeted therapies, criteria addressing the quality of biopsy specimens needed for molecular testing are usually not specified [19].
The recently developed technique of cryobiopsy for the diagnosis of patients with endobronchial tumor has revealed a significantly higher diagnostic yield for lung cancer than conventional forceps biopsy [20]. In addition, cryobiopsy samples are of sufficiently large size to routinely allow immunohistological staining [21]. Cryobiopsy provides better tissue preservation without biopsy artifacts. Nevertheless, it cannot be ruled out that physical alterations caused by the freezing and thawing cycle during cryobiopsy could influence the diagnostic value on a molecular level.
We have therefore evaluated the detection rate of EGFR mutations in cryobiopsies and compared these to other biopsy techniques in patients with pathologically proven non small cell lung cancer.
Section snippets
Study design and population
This retrospective single center study was performed at the Department of Internal Medicine II in collaboration with the Institute of Pathology at the University of Tuebingen, Germany. All malignant tissue samples from the University Hospital which had been examined for EGFR mutations between March 2008 and July 2014 were included in this study. A total of 483 tissue samples were analyzed for mutations of the EGFR gene on exon 18, 19, 20, 21 using Sanger sequencing [22]. 60 tumor samples were
Patient characteristics
Demographic data of the cryobiopsy group and the non-cryobiopsy group were comparable with regard to age and gender, as shown in Table 1. Almost all patients were Causasian (>99 %). Due to the retrospective study design smoking status was unknown in a large proportion of patients, but when known, it did not differ between both groups.
Tumor characteristics
Tumor characteristics for both groups are shown in Table 2. Cryobiopsy was used more frequently for sampling of central tumors (85.6 %), while non-cryobiopsy
Discussion
To our knowledge, this is the first analysis to study the influence of biopsy techniques on the rate of EGFR mutation detection in patients with NSCLC. Our restrospective analysis indicates that sampling by bronchoscopic cryobiopsy increased the detection rate of molecular genetic alterations in NSCLC in comparison to other biopsy techniques (21.6 % vs 13.8 % (p < 0.05). Thus cryobiopsy might be able to substantially increase the number of patients who go on to receive targeted therapy.
EGFR
Authors’ contributions
MH contributed to the concept, performed the bronchoscopic procedures, analyzed the data, performed statistical analysis and wrote the main part of the manuscript. MB contributed to the concept and performed the bronchoscopic procedures. AE analyzed the data and contributed to the manuscript. RW analyzed the data and performed statistical analysis. W.S. performed the bronchoscopic procedures. V.S. performed the surgical procedures. H.B. and F.F. did the histopathological evaluation. MHo
Declaration of Competing Interest
JH has received personal fees from Erbe Elektromedizin GmbH for workshops and presentations. MH and MB have received personal fees from Erbe Elektromedizin GmbH for Workshops. AE, RW, WS, VS, HB, MHo, RAL, FF, LK, IB have no conflict of interest to declare.
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