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Byoung Chul Cho, M.D., Ph.D. Yonsei Cancer Center Yonsei University College of Medicine JE-UK Laboratory of Molecular Cancer Therapeutics FALCON (Fight.

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Presentation on theme: "Byoung Chul Cho, M.D., Ph.D. Yonsei Cancer Center Yonsei University College of Medicine JE-UK Laboratory of Molecular Cancer Therapeutics FALCON (Fight."— Presentation transcript:

1 Byoung Chul Cho, M.D., Ph.D. Yonsei Cancer Center Yonsei University College of Medicine JE-UK Laboratory of Molecular Cancer Therapeutics FALCON (Fight Against Lung Cancer Oncology Network) Fibroblast Growth Factor Receptor 1 Gene Amplification Is Associated with Poor Survival and Cigarette Smoking Dosage in Resected Squamous Cell Lung Cancer

2 Lung Cancer Mutation Consortium Incidence of Driver Mutations in Adenocarcinoma Mutation found in 54% (280/516) of tumors completely tested (CI 50-59%) Kris et al ASCO 2011 ROS1

3 Squamous Cell Carcinoma of Lung Lung squamous cell carcinoma (SqCC) accounts for ~30% of non-small cell lung cancer Currently, lung SqCC lacks any druggable target ~90% are male smokers (Korean Cancer Registry) Despite advances in personalized treatment of adenocarcinoma, effective targeted therapies for SqCC has remained elusive

4 Frequencies of Potential Driver Mutations in Lung Frequencies of Potential Driver Mutations in Lung Squamous Cell Carcinoma Lancet oncol 2011;12:175 MutationFrequency (%) EGFR<5 ALK<5 HER20 BRAF0 KRAS<5 PIK3CA<5 AKT1<5 MAP2K10 MET<5 ~70% unknown

5 FGFR1 is Amplified in Lung Squamous Cell Carcinoma Weiss J. Sci Transl Med p.12 By FISH, high FGFR1 amplification (≥ 9 copies): 22% (34/153)

6 FGFR1 amplifications are associated with FGFR inhibitor activity Weiss J. Sci Transl Med 2010

7 To investigate the frequency and the prognostic impact of FGFR1 amplification in surgically resected lung SqCC To evaluate the association between smoking does and FGFR1-amplification Study Purpose

8 Patient and Method SqCC patients that underwent radical resection of a primary lung cancer at Severance Hospital between 1998 and Selection criteria (n= 262): availability of tumor tissue from the primary lung cancer, smoking-data, and survival data Construct a tissue-microarray with 2-mm diameter cores (3 cores per tumor)

9 FGFR1 FISH assay was performed on the tissue- microarrays using FGFR1-probe that hybridizes to the band 8p12-8p11.23 with Spectrum Orange (red) and CEP 8 with Spectrum Green (Abbott Molecular ® ) Prespecified Criteria 1  “high-amplification” FGFR1 copy number ≥ 9  “low-amplification” FGFR1 copy number >2 or <9  “disomy” FGFR1 copy number = 2 Gene Copy Number 1 Weiss J et al. Sci Transl Med 2010

10 FGFR1 protein & mRNA Expression IHC analysis was performed using FGFR1 Ab (Epitomics, Burlingame, CA) IHC analysis was performed using FGFR1 Ab (Epitomics, Burlingame, CA)  Only clear membranous staining of the tumor cells was considered positive and cytoplasmic or granular staining was considered negative or trace  Scoring system (0-400): % of positive tumor cells (0% to 100%) X dominant staining pattern (1: negative or trace, 2: weak, 3: moderate, 4: intense) mRNA expression analysis was performed by QuantiGene Reagent Systems in FFPE tissue samples

11 Patient characteristics according to FGFR1 gene amplification by FISH

12 FGFR1 IHC staining & Gene Copy Number by FISH 34 (13%) 105 (40.1%)123 (46.9%)

13 Association between FGFR1 GCN and FGFR1 protein & mRNA Expression

14 FGFR1 Amplification Is Associated with Poor Survival in Resected Lung SqCC Patients FGFR1 high amp Kim HR, Soo RA, Cho BC. J Clin Oncol 2012

15 VariableCategoryDisease-free survivalOverall survival HR95% CIPHR95% CIP Sex Female vs. male Pathologic stageIII vs. I+II < < Smoking Smoker vs. never smoker Adjuvant therapyYes vs. no FGFR1 FISHFGFR1 amp + vs FGFR1 amp < Multivariate Survival Analyses

16 Treatment outcome to EGFR-TKI according to FGFR1 Amplification Independent dataset of unresectable, previously treated lung SqCC (N= 47)

17 FGFR1 Amplification is a Smoking- associated Oncogenic Mutation P value was tested by χ 2 test for linear trend Kim HR, Soo RA, Cho BC. J Clin Oncol 2012

18 Intratumoral Heterogeneity? Whole tissue section FISH in 51 randomly selected tumors (31 high FGFR1-amp, 10 low FGFR1-amp and 10 disomy tumors)

19 Homogenous FGFR1 distribution in high amplified tumors - at least 80% of nuclei per area exhibited ≥ 9 copies of FGFR1 Majority of areas displayed low amplified FGFR1 signals In low amplified tumors Two FGFR1 signals were homogenously distributed in disomy cases No FGFR1 amplification in peritumoral normal tissue High correlation of FGFR1 GCN between primary & metastatic lesion 1 Summary of Whole Tissue Section FISH 1 Friederike Goeke et al. Chest Apr 12, 2012 FGFR1 amplification may be involved not in early tumorigenesis, but in early disease progression

20 Conclusion: FGFR1 Amplification- A New “Druggable” Target in SqCC The first high-frequency (13%) therapeutic target of smoking-associated SqCC The first high-frequency (13%) therapeutic target of smoking-associated SqCC FGFR1 amplification induced a strong FGFR1 dependency in FGFR1 amplified SqCC FGFR1 amplification induced a strong FGFR1 dependency in FGFR1 amplified SqCC FGFR1 amplification is a negative prognostic factor in resected lung SqCC FGFR1 amplification is a negative prognostic factor in resected lung SqCC FGFR1-amplification is associated with cigarette- smoking in a dose-dependent manner FGFR1-amplification is associated with cigarette- smoking in a dose-dependent manner  Strongly implies that FGFR1-amplification is an oncogenic-aberration caused by tobacco-carcinogen


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