Definition of a fluorescence in-situ hybridization score identifies high- and low-level FGFR1 amplification types in squamous cell lung cancer

Abstract

We recently reported fibroblast growth factor receptor-type 1 (FGFR1) amplification to be associated with therapeutically tractable FGFR1 dependency in squamous cell lung cancer. This makes FGFR1 a novel target for directed therapy in these tumors. To reproducibly identify patients for clinical studies, we developed a standardized reading and evaluation strategy for FGFR1 fluorescence in-situ hybridization (FISH) and propose evaluation criteria, describe different patterns of low- and high-level amplifications and report on the prevalence of FGFR1 amplifications in pulmonary carcinomas. A total of 420 lung cancer patients including 307 squamous carcinomas, 100 adenocarcinomas of the lung and 13 carcinomas of other types were analyzed for FGFR1 amplification using a dual color FISH. We found heterogeneous and different patterns of gene copy numbers. FGFR1 amplifications were observed in 20% of pulmonary squamous carcinomas but not in adenocarcinomas. High-level amplification (as defined by an FGFR1/centromer 8 (CEN8) ratio ≥2.0, or average number of FGFR1 signals per tumor cell nucleus ≥6, or the percentage of tumor cells containing ≥15 FGFR1 signals or large clusters ≥10%) was detected at a frequency of 16% and low-level amplification (as defined by ≥5 FGFR1 signals in ≥50% of tumor cells) at a frequency of 4%. We conclude that FGFR1 amplification is one of the most frequent therapeutically tractable genetic lesions in pulmonary carcinomas. Standardized reporting of FGFR1 amplification in squamous carcinomas of the lung will become increasingly important to correlate therapeutic responses with FGFR1 inhibitors in clinical studies. Thus, our reading and evaluation strategy might serve as a basis for identifying patients for ongoing and upcoming clinical trials.

Fibroblast growth factor receptor 1 (FGFR1) amplification is a potential therapeutic target in small-cell lung cancer

“…5,6,15,17 This is a clinically important finding since until now current therapies are very limited. So far no positive data about FGFR1 FISH analysis in SCLC have been described in the literature.…”

“…Evaluation was carried out according to previously established FGFR1 amplification criteria. 5 Figure 1 summarizes the evaluation algorithm.…”

“…The technical failure rate in SCLC is, therefore, higher than in pulmonary squamous cell carcinomas, which we reported recently to be o5%. 5 Analysis was stopped after a third ineffective attempt of evaluation. Fifty-one samples of nonevaluable cases were specimens from biopsies (ie, core needle biopsy, transbronchial and mediastinal lymph node biopsies), four samples from total lobectomy and one sample from wedge resection.…”

“…1 Over the last 30 years, medical treatment for advanced SCLC has mainly remained unchanged, consisting of a platinum-based chemotherapy regimen with optional radiation therapy depending on tumor stage. 2 Although targeted therapeutic options have been established for pulmonary adenocarcinomas, including EGFR (epidermal growth factor receptor) and ALK (anaplastic lymphoma kinase) inhibitors, 1,3,4 and recently also for squamous cell carcinomas, 5,6 small-cell carcinomas still lack therapeutically exploitable genetic alterations. So far no single molecularly targeted drug has yet shown any significant clinical activity in SCLC.…”

“…Our group could show an oncogene dependency for a focal FGFR1 amplification in a large subset of pulmonary carcinomas, a finding that was reproduced by subsequent studies. 5,6,15 Furthermore, FGFR1 amplification represents a therapeutically tractable molecular event, as a selective inhibitor of the FGFR activity caused G1 growth arrest in breast cancer cell lines. 10 In SCLC, inhibition of the FGFR resulted in blockade of tumor growth, suggesting the important role of the FGF-FGFR signaling pathway for SCLC growth 16 and a recent survey of potential oncogenic driver mutations also suggested FGFR1 as a potential therapeutic target.…”