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Wang X, Huang J, Xu C, Zhang L, Su J, Liu J, Shen L, Luan L, Hou Y. FGFR3 amplification is predictive of poor prognosis in esophageal squamous cell carcinoma patients. Virchows Arch 2025:10.1007/s00428-024-03884-8. [PMID: 40418326 DOI: 10.1007/s00428-024-03884-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 06/17/2024] [Accepted: 07/27/2024] [Indexed: 05/27/2025]
Abstract
Identification and verification of clinically actionable molecular variations to refine currently adopted risk-stratified treatment strategy for esophageal squamous cell carcinoma (ESCC) is urgently needed. Here, we evaluated FGFR3 amplification status by fluorescence in situ hybridization (FISH) performed on tissue microarrays and its prognostic value in 526 ESCC patients. FGFR3 amplification was found in 3.0% (16/526) of ESCC patients enrolled in this study cohort. Intratumor heterogeneity and metastatic heterogeneity of FGFR3 amplification were found in 10% (2/20) and 40% (2/5) FGFR3 amplified ESCC cases, respectively. No statistically significant associations were found between FGFR3 amplification status and common clinicopathological features. Survival analyses demonstrated that FGFR3 amplification was associated with a worse disease-free survival (DFS) and overall survival (OS) (DFS, P = 0.008; OS, P = 0.027). Univariate and multivariate analyses revealed that invasive depth was significantly associated with DFS (P = 0.001, HR: 1.498, 95% CI: 1.172-1.914) and OS (P = 0.002, HR: 1.482, 95% CI: 1.159-1.894), and FGFR3 amplification was significantly associated with DFS (P = 0.020, HR: 2.065, 95% CI: 1.120-3.808) and tend to associate with OS (P = 0.070, HR: 1.756, 95% CI: 0.954-3.233). Furthermore, when patients were stratified into stage I-II group and stage III-IV group, the adverse effect of FGFR3 amplification on prognosis was presented in stage III-IV patients (DFS, P = 0.0047; OS, P = 0.029) rather than stage I-II patients (DFS, P = 0.46; OS, P = 0.53), indicating that the prognostic value of FGFR3 amplification may relying on clinical stage. Our findings might provide a better understanding of the FGFR3 amplification status in ESCC patients and add further insights into its potential prognostic value.
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Affiliation(s)
- Xiang Wang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jie Huang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chen Xu
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lili Zhang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jieakesu Su
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jia Liu
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Licheng Shen
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lijuan Luan
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Yingyong Hou
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.
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Lyu SI, Plum PS, Fretter C, Simon AG, Bedau T, Knipper K, Thomas MN, Stippel D, Wagner BJ, Bruns C, Waldschmidt D, Büttner R, Drebber U, Quaas A. Therapy-relevant MDM2 amplification in cholangiocarcinomas in Caucasian patients. Ther Adv Med Oncol 2024; 16:17588359241288123. [PMID: 39525665 PMCID: PMC11550496 DOI: 10.1177/17588359241288123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 09/13/2024] [Indexed: 11/16/2024] Open
Abstract
Background Cholangiocarcinomas (CCA) are a group of aggressive malignancies with poor prognosis. The distinct subtypes are related to different etiologies and genetic aberrations that are subject to targeted therapies. Mouse double minute 2 homolog (MDM2) is a potent inhibitor of tumor suppressor p53 and is proven to be altered in certain carcinomas. Novel targeted drugs, such as the MDM2-p53 antagonist Brigimadlin, have shown promising results for therapeutic efficacy in patients with MDM2 amplification and wild-type TP53. Objectives This study therefore aimed to characterize CCAs regarding their MDM2 status, compare the concordance between fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) methods, and elucidate the role of MDM2 amplification in prognosis and other clinicopathological characteristics. Design Retrospective cohort study. Methods All patients (n = 52) were diagnosed with CCA and received surgical resection with curative intention at the University Hospital of Cologne. Samples were analyzed retrospectively for MDM2 amplification with FISH and IHC. We correlated results with pre-existing molecular as well as clinical data. Results We included 52 patients with primary CCA, three of which showed positive MDM2 amplification (5.8%). MDM2 amplification was present only in the intrahepatic CCA type and all patients with positive MDM2 amplification exhibited normal p53 status. Among the large-duct subtypes of intrahepatic CCAs, patients with positive MDM2 amplification demonstrated better survival than patients with negative MDM2 amplification (p = 0.041). Of the patients with MDM2 amplification, two underwent adjuvant therapy post-surgery (66.7%). There was a strong correlation between MDM2 amplification and positive protein expression in IHC. There were no identifiable molecular co-alterations of MDM2 with FGFR2 or SWI/SNF complex alterations. Conclusion Real-world evidence in our Caucasian patient population confirmed that a significant number of intrahepatic CCAs showcase MDM2 amplification, qualifying for a personalized therapy option with Brigimadlin. MDM2 amplification must therefore be considered in the context of personalized molecular testing in CCA.
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Affiliation(s)
- Su Ir Lyu
- Faculty of Medicine and University Hospital of Cologne, Institute of Pathology, University of Cologne, Kerpener Str. 62, Cologne 50937, Germany
| | - Patrick Sven Plum
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Caroline Fretter
- Faculty of Medicine and University Hospital of Cologne, Institute of Pathology, University of Cologne, Cologne, Germany
| | - Adrian Georg Simon
- Faculty of Medicine and University Hospital of Cologne, Institute of Pathology, University of Cologne, Cologne, Germany
| | - Tillmann Bedau
- Faculty of Medicine and University Hospital of Cologne, Institute of Pathology, University of Cologne, Cologne, Germany
| | - Karl Knipper
- Faculty of Medicine and University Hospital of Cologne, Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany
| | - Michael N. Thomas
- Faculty of Medicine and University Hospital of Cologne, Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany
| | - Dirk Stippel
- Faculty of Medicine and University Hospital of Cologne, Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany
| | - Britta Janina Wagner
- Faculty of Medicine and University Hospital of Cologne, Institute of Pathology, University of Cologne, Cologne, Germany
| | - Christiane Bruns
- Faculty of Medicine and University Hospital of Cologne, Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany
| | - Dirk Waldschmidt
- Faculty of Medicine and University Hospital of Cologne, Department of Gastroenterology and Hepatology, University of Cologne, Cologne, Germany
| | - Reinhard Büttner
- Faculty of Medicine and University Hospital of Cologne, Institute of Pathology, University of Cologne, Cologne, Germany
| | - Uta Drebber
- Faculty of Medicine and University Hospital of Cologne, Institute of Pathology, University of Cologne, Cologne, Germany
| | - Alexander Quaas
- Faculty of Medicine and University Hospital of Cologne, Institute of Pathology, University of Cologne, Cologne, Germany
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Kim Y, Jee S, Kim H, Paik SS, Choi D, Yoo SH, Shin SJ. EGFR, HER2, and MET gene amplification and protein expression profiles in biliary tract cancer and their prognostic significance. Oncologist 2024; 29:e1051-e1060. [PMID: 38709907 PMCID: PMC11299936 DOI: 10.1093/oncolo/oyae076] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 04/03/2024] [Indexed: 05/08/2024] Open
Abstract
BACKGROUND There are limited conventional chemotherapy options for biliary tract cancers (BTCs), a heterogenous group of lethal, rare malignancies. The receptor tyrosine kinase (RTK) is closely associated with the progression of human malignancies through the regulation of cell cycle. Overexpression or amplification of RTKs has been investigated as a potential biomarker and therapeutic target in BTC; herein, we investigate the value of such interventions. MATERIALS AND METHODS Overexpression of RTK proteins was examined by immunohistochemistry in 193 BTC samples, of which 137 were gallbladder carcinoma, 29 were perihilar cholangiocarcinoma, and 27 were intrahepatic cholangiocarcinoma. Silver in situ hybridization of MET and HER2 was performed to assess gene amplification. RESULTS In the entire cancer group, gallbladder, perihilar, and intrahepatic, MET amplification rates were 15.7%, 19.0%, 3.4%, and 14.8%, respectively, and of HER2 amplification rates were 22.4%, 27.2%, 17.2%, and 3.7%, respectively. MET and HER2 protein expressions were significantly correlated with their gene amplification status. RTKs were significantly associated with adverse clinicopathologic features such as advanced pT category and lymph node metastasis. Overall survival was significantly shorter in MET-amplified (P = .024) and EGFR-overexpressed cases (P = .045). Recurrence-free survival was significantly correlated with HER2-amplified (P = .038) and EGFR-overexpressed cases (P = .046) in all patient groups. Overall and recurrence-free survival were significantly shorter in patients who were double positive for HER2 and EGFR. CONCLUSION Our data suggested that MET, HER2, and EGFR might be potential therapeutic targets and that their co-expression is a strong prognostic factor for BTCs.
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Affiliation(s)
- Yeseul Kim
- Department of Pathology, University of Korea College of Medicine, Anam Hospital, Seoul, Republic of Korea
| | - Seungyun Jee
- Departments of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Hyunsung Kim
- Department of Pathology, College of Medicine, Hanyang University, Seoul, Republic of Korea
| | - Seung Sam Paik
- Department of Pathology, College of Medicine, Hanyang University, Seoul, Republic of Korea
| | - Dongho Choi
- Department of Surgery, College of Medicine, Hanyang University, Seoul, Republic of Korea
| | - Su Hyun Yoo
- Department of Pathology, National Police Hospital, Seoul, Republic of Korea
| | - Su-Jin Shin
- Departments of Pathology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
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Barzaga ADA, Perias GAS, Reyes LAE, Moreno PGG, Relacion PR, Manalo RAM, Ronquillo YC, Heralde FM. Molecular Biomarkers Detected Using Fluorescence in situ Hybridization in a Filipino with Retinoblastoma. ACTA MEDICA PHILIPPINA 2024; 58:99-107. [PMID: 38939426 PMCID: PMC11199350 DOI: 10.47895/amp.vi0.7666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/29/2024]
Abstract
Background and Objective Retinoblastoma is one of the most common intraocular cancers among children usually caused by the loss of retinoblastoma protein function. Despite being a highly heritable disease, conventional diagnostic and prognostic methods depend on clinical examination, with limited consideration of cancer genetics in the standard of care. CD133, KRT19, and MUC1 are commonly explored genes for their utility in liquid biopsies of cancer including lung adenocarcinoma. To date, there are few extensive molecular studies on retinoblastoma in Filipino patients. To this end, the study aimed to describe the copy number of CD133, KRT19, and MUC1 in retinoblastoma samples from a Filipino patient and quantitate the respective expression level of these genes. Methods Hematoxylin & Eosin (H&E) staining was utilized to characterize the retinoblastoma tissue while fluorescence in situ hybridization (FISH) using probes specific to CD133, KRT19, and MUC1 was performed to determine the copy number of genes in retinoblastoma samples from a Filipino patient (n = 1). The gene expression of CD133, MUC1, and KRT19 was quantitated using RT-qPCR. Results The H&E staining in the retinoblastoma tissue shows poorly differentiated cells with prominent basophilic nuclei. CD133 was approximately 1.5-fold overexpressed in the retinoblastoma tissue with respect to the normal tissue, while MUC1 and KRT19 are only slightly expressed. Multiple intense signals of each probe were localized in the same nuclear areas throughout the retinoblastoma tissue, with high background noise. Conclusion These findings suggest that CD133 is a potential biomarker for the staging and diagnosis of retinoblastoma in Filipino cancer patients. However, further optimization of the hybridization procedures is recommended.
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Affiliation(s)
- Arnold Dominic A. Barzaga
- Department of Biochemistry and Molecular Biology, College of Medicine, University of the Philippines Manila
| | | | - Lia Angela E. Reyes
- Department of Biochemistry and Molecular Biology, College of Medicine, University of the Philippines Manila
| | - Patrick Gabriel G. Moreno
- Department of Biochemistry and Molecular Biology, College of Medicine, University of the Philippines Manila
| | - Patrick R. Relacion
- Department of Biochemistry and Molecular Biology, College of Medicine, University of the Philippines Manila
- Department of Medical Technology, Faculty of Pharmacy, University of Santo Tomas, Manila
| | | | - Yasmyne C. Ronquillo
- Hoopes Durrie Rivera Research
- Department of Biology, University of Utah, Salt Lake City, Utah
| | - Francisco M. Heralde
- Department of Biochemistry and Molecular Biology, College of Medicine, University of the Philippines Manila
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Priesterbach-Ackley LP, van Kuik J, Tops BBJ, Lasorella A, Iavarone A, van Hecke W, Robe PA, Wesseling P, de Leng WWJ. RT-PCR assay to detect FGFR3::TACC3 fusions in formalin-fixed, paraffin-embedded glioblastoma samples. Neurooncol Pract 2024; 11:142-149. [PMID: 38496910 PMCID: PMC10940835 DOI: 10.1093/nop/npad081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/19/2024] Open
Abstract
Background One targeted treatment option for isocitrate dehydrogenase (IDH)-wild-type glioblastoma focuses on tumors with fibroblast growth factor receptor 3::transforming acidic coiled-coil-containing protein 3 (FGFR3::TACC3) fusions. FGFR3::TACC3 fusion detection can be challenging, as targeted RNA next-generation sequencing (NGS) is not routinely performed, and immunohistochemistry is an imperfect surrogate marker. Fusion status can be determined using reverse transcription polymerase chain reaction (RT-PCR) on fresh frozen (FF) material, but sometimes only formalin-fixed, paraffin-embedded (FFPE) tissue is available. Aim To develop an RT-PCR assay to determine FGFR3::TACC3 status in FFPE glioblastoma samples. Methods Twelve tissue microarrays with 353 historical glioblastoma samples were immunohistochemically stained for FGFR3. Samples with overexpression of FGFR3 (n = 13) were subjected to FGFR3::TACC3 RT-PCR on FFPE, using 5 primer sets for the detection of 5 common fusion variants. Fusion-negative samples were additionally analyzed with NGS (n = 6), FGFR3 Fluorescence In Situ Hybridization (n = 6), and RNA sequencing (n = 5). Results Using RT-PCR on FFPE material of the 13 samples with FGFR3 overexpression, we detected an FGFR3::TACC3 fusion in 7 samples, covering 3 different fusion variants. For 5 of these FF was available, and the presence of the fusion was confirmed through RT-PCR on FF. With RNA sequencing, 1 additional sample was found to harbor an FGFR3::TACC3 fusion (variant not covered by current RT-PCR for FFPE). The frequency of FGFR3::TACC3 fusion in this cohort was 9/353 (2.5%). Conclusions RT-PCR for FGFR3::TACC3 fusions can successfully be performed on FFPE material, with a specificity of 100% and (due to limited primer sets) a sensitivity of 83.3%. This assay allows for the identification of potential targeted treatment options when only formalin-fixed tissue is available.
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Affiliation(s)
| | - Joyce van Kuik
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Bastiaan B J Tops
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | - Anna Lasorella
- Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Florida, USA
| | - Antonio Iavarone
- Department of Neurological Surgery, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Florida, USA
| | - Wim van Hecke
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Pierre A Robe
- Department of Neurosurgery, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Pieter Wesseling
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
- Department of Pathology, Amsterdam University Medical Centers/VUmc & Brain Tumor Center Amsterdam, Amsterdam, The Netherlands
| | - Wendy W J de Leng
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
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Friedlaender A, Perol M, Banna GL, Parikh K, Addeo A. Oncogenic alterations in advanced NSCLC: a molecular super-highway. Biomark Res 2024; 12:24. [PMID: 38347643 PMCID: PMC10863183 DOI: 10.1186/s40364-024-00566-0] [Citation(s) in RCA: 39] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 01/17/2024] [Indexed: 02/15/2024] Open
Abstract
Lung cancer ranks among the most common cancers world-wide and is the first cancer-related cause of death. The classification of lung cancer has evolved tremendously over the past two decades. Today, non-small cell lung cancer (NSCLC), particularly lung adenocarcinoma, comprises a multitude of molecular oncogenic subsets that change both the prognosis and management of disease.Since the first targeted oncogenic alteration identified in 2004, with the epidermal growth factor receptor (EGFR), there has been unprecedented progress in identifying and targeting new molecular alterations. Almost two decades of experience have allowed scientists to elucidate the biological function of oncogenic drivers and understand and often overcome the molecular basis of acquired resistance mechanisms. Today, targetable molecular alterations are identified in approximately 60% of lung adenocarcinoma patients in Western populations and 80% among Asian populations. Oncogenic drivers are largely enriched among non-smokers, east Asians, and younger patients, though each alteration has its own patient phenotype.The current landscape of druggable molecular targets includes EGFR, anaplastic lymphoma kinase (ALK), v-raf murine sarcoma viral oncogene homolog B (BRAF), ROS proto-oncogene 1 (ROS1), Kirstin rat sarcoma virus (KRAS), human epidermal receptor 2 (HER2), c-MET proto-oncogene (MET), neurotrophic receptor tyrosine kinase (NTRK), rearranged during transfection (RET), neuregulin 1 (NRG1). In addition to these known targets, others including Phosphoinositide 3-kinases (PI3K) and fibroblast growth factor receptor (FGFR) have garnered significant attention and are the subject of numerous ongoing trials.In this era of personalized, precision medicine, it is of paramount importance to identify known or potential oncogenic drivers in each patient. The development of targeted therapy is mirrored by diagnostic progress. Next generation sequencing offers high-throughput, speed and breadth to identify molecular alterations in entire genomes or targeted regions of DNA or RNA. It is the basis for the identification of the majority of current druggable alterations and offers a unique window into novel alterations, and de novo and acquired resistance mechanisms.In this review, we discuss the diagnostic approach in advanced NSCLC, focusing on current oncogenic driver alterations, through their pathophysiology, management, and future perspectives. We also explore the shortcomings and hurdles encountered in this rapidly evolving field.
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Affiliation(s)
- Alex Friedlaender
- Clinique Générale Beaulieu, Geneva, Switzerland
- Oncology Department, University Hospital Geneva, Rue Gentil Perret 4. 1205, Geneva, Switzerland
| | - Maurice Perol
- Department of Medical Oncology, Centre Léon Bérard, Lyon, France
| | - Giuseppe Luigi Banna
- Portsmouth Hospitals University NHS Trust, Portsmouth, UK
- Faculty of Science and Health, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK
| | | | - Alfredo Addeo
- Oncology Department, University Hospital Geneva, Rue Gentil Perret 4. 1205, Geneva, Switzerland.
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Malchers F, Nogova L, van Attekum MH, Maas L, Brägelmann J, Bartenhagen C, Girard L, Bosco G, Dahmen I, Michels S, Weeden CE, Scheel AH, Meder L, Golfmann K, Schuldt P, Siemanowski J, Rehker J, Merkelbach-Bruse S, Menon R, Gautschi O, Heuckmann JM, Brambilla E, Asselin-Labat ML, Persigehl T, Minna JD, Walczak H, Ullrich RT, Fischer M, Reinhardt HC, Wolf J, Büttner R, Peifer M, George J, Thomas RK. Somatic rearrangements causing oncogenic ectodomain deletions of FGFR1 in squamous cell lung cancer. J Clin Invest 2023; 133:e170217. [PMID: 37606995 PMCID: PMC10617767 DOI: 10.1172/jci170217] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 08/17/2023] [Indexed: 08/23/2023] Open
Abstract
The discovery of frequent 8p11-p12 amplifications in squamous cell lung cancer (SQLC) has fueled hopes that FGFR1, located inside this amplicon, might be a therapeutic target. In a clinical trial, only 11% of patients with 8p11 amplification (detected by FISH) responded to FGFR kinase inhibitor treatment. To understand the mechanism of FGFR1 dependency, we performed deep genomic characterization of 52 SQLCs with 8p11-p12 amplification, including 10 tumors obtained from patients who had been treated with FGFR inhibitors. We discovered somatically altered variants of FGFR1 with deletion of exons 1-8 that resulted from intragenic tail-to-tail rearrangements. These ectodomain-deficient FGFR1 variants (ΔEC-FGFR1) were expressed in the affected tumors and were tumorigenic in both in vitro and in vivo models of lung cancer. Mechanistically, breakage-fusion-bridges were the source of 8p11-p12 amplification, resulting from frequent head-to-head and tail-to-tail rearrangements. Generally, tail-to-tail rearrangements within or in close proximity upstream of FGFR1 were associated with FGFR1 dependency. Thus, the genomic events shaping the architecture of the 8p11-p12 amplicon provide a mechanistic explanation for the emergence of FGFR1-driven SQLC. Specifically, we believe that FGFR1 ectodomain-deficient and FGFR1-centered amplifications caused by tail-to-tail rearrangements are a novel somatic genomic event that might be predictive of therapeutically relevant FGFR1 dependency.
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Affiliation(s)
- Florian Malchers
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany Germany
| | - Lucia Nogova
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn, Cologne Duesseldorf, Cologne, Germany
| | - Martijn H.A. van Attekum
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany Germany
| | - Lukas Maas
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany Germany
| | - Johannes Brägelmann
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany Germany
- Mildred Scheel School of Oncology, Cologne, University Hospital Cologne, Medical Faculty, Cologne, Germany
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Cologne, Germany
| | - Christoph Bartenhagen
- Department of Experimental Pediatric Oncology, University Children’s Hospital of Cologne, University Hospital Cologne, Medical Faculty, Cologne, Germany
| | - Luc Girard
- University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Graziella Bosco
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany Germany
| | - Ilona Dahmen
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany Germany
| | - Sebastian Michels
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn, Cologne Duesseldorf, Cologne, Germany
| | - Clare E. Weeden
- Personalized Oncology Division, Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, The University of Melbourne, Parkville, Australia
| | - Andreas H. Scheel
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Cologne, Germany
| | - Lydia Meder
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn, Cologne Duesseldorf, Cologne, Germany
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Cologne, Germany
| | - Kristina Golfmann
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn, Cologne Duesseldorf, Cologne, Germany
| | - Philipp Schuldt
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn, Cologne Duesseldorf, Cologne, Germany
| | - Janna Siemanowski
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Cologne, Germany
| | - Jan Rehker
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Cologne, Germany
| | - Sabine Merkelbach-Bruse
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Cologne, Germany
| | | | - Oliver Gautschi
- University of Berne and Cantonal Hospital of Lucerne, Cantonal Hospital of Lucerne, Lucerne, Switzerland
| | | | | | - Marie-Liesse Asselin-Labat
- Personalized Oncology Division, Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, The University of Melbourne, Parkville, Australia
| | - Thorsten Persigehl
- Institute for Diagnostic and Interventional Radiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - John D. Minna
- University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Henning Walczak
- Institute of Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany
- CECAD Cluster of Excellence, University of Cologne, Cologne, Germany
- Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, London, United Kingdom
| | - Roland T. Ullrich
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn, Cologne Duesseldorf, Cologne, Germany
| | - Matthias Fischer
- Department of Experimental Pediatric Oncology, University Children’s Hospital of Cologne, University Hospital Cologne, Medical Faculty, Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), Cologne, Germany
| | - Hans Christian Reinhardt
- Department of Hematology and Stem Cell Transplantation, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Jürgen Wolf
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn, Cologne Duesseldorf, Cologne, Germany
| | - Reinhard Büttner
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Cologne, Germany
| | - Martin Peifer
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany Germany
- Center for Molecular Medicine Cologne (CMMC), Cologne, Germany
| | - Julie George
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany Germany
- Department of Head and Neck Surgery, Medical Faculty, University Hospital Cologne, Cologne, Germany
| | - Roman K. Thomas
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany Germany
- University of Cologne, Faculty of Medicine and University Hospital Cologne, Institute of Pathology, Cologne, Germany
- German Cancer Consortium (DKTK), partner site Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany
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Ilié M, Hofman V, Bontoux C, Goffinet S, Benzaquen J, Heeke S, Boutros J, Lassalle S, Long-Mira E, Zahaf K, Lalvée S, Lespinet-Fabre V, Bordone O, Tanga V, Gómez-Caro A, Cohen C, Berthet JP, Marquette CH, Hofman P. Lack of correlation between MET and PD-L1 expression in non-small cell lung cancer revealed by comparative study of matched biopsies and surgical resection samples. Lung Cancer 2023; 181:107230. [PMID: 37150140 DOI: 10.1016/j.lungcan.2023.107230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 04/24/2023] [Accepted: 04/30/2023] [Indexed: 05/09/2023]
Abstract
INTRODUCTION Both MET expression and the PD-L1 tumor proportion score (TPS) are companion diagnostics for treatment of advanced non-small cell lung carcinoma (aNSCLC) patients. We evaluated the rate of correlation between MET expression and the PD-L1 TPS in matched biopsies and surgically resected specimens from NSCLC patients. PATIENTS AND METHODS This retrospective analysis assessed the prevalence and correlation between MET expression (SP44 clone) and the PD-L1 TPS (22C3 clone) by immunohistochemistry together with molecular alterations determined by targeted next-generation sequencing in matched lung biopsy and surgically lung resected specimens from 70 patients with NSCLC. RESULTS The study found a significant correlation between the MET H-score in surgical samples and matched biopsies (P-value < 0.0001), as well as between the PD-L1 TPS in paired biopsies and surgical samples (P-value < 0.0001). However, there was no significant correlation between the MET H-score or expression subgroups and the PD-L1 TPS in both types of paired samples (P-value = 0.47, and P-value = 0.90). The MET H-score was significantly higher in adenocarcinoma compared to squamous cell carcinoma (P-value < 0.0001). A mutational analysis showed that the MET H-score was significantly higher in NSCLC cases with targetable molecular alterations (P-value = 0.0095), while no significant correlation was found for the PD-L1 TPS. CONCLUSIONS Our study found no significant correlation between PD-L1 and MET expression in samples from NSCLC patients, highlighting the importance of personalized treatment strategies based on individual expression profiles. These findings provide valuable insight into the development of effective immunotherapy and targeted therapy for NSCLC patients.
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Affiliation(s)
- Marius Ilié
- Laboratory of Clinical and Experimental Pathology, Hôpital Pasteur, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France; Hospital-integrated Biobank (BB-0033-00025), Hôpital Pasteur, Nice, France; FHU OncoAge, Hôpital Pasteur, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France; Team 4, Inserm U1081, CNRS UMR 7413, Institute for Research on Cancer and Aging, Nice, France
| | - Véronique Hofman
- Laboratory of Clinical and Experimental Pathology, Hôpital Pasteur, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France; Hospital-integrated Biobank (BB-0033-00025), Hôpital Pasteur, Nice, France; FHU OncoAge, Hôpital Pasteur, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France; Team 4, Inserm U1081, CNRS UMR 7413, Institute for Research on Cancer and Aging, Nice, France
| | - Christophe Bontoux
- Laboratory of Clinical and Experimental Pathology, Hôpital Pasteur, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France
| | - Samantha Goffinet
- Laboratory of Clinical and Experimental Pathology, Hôpital Pasteur, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France
| | - Jonathan Benzaquen
- FHU OncoAge, Hôpital Pasteur, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France; Team 4, Inserm U1081, CNRS UMR 7413, Institute for Research on Cancer and Aging, Nice, France; Department of Pulmonary Medicine and Thoracic Oncology, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France
| | - Simon Heeke
- Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Jacques Boutros
- FHU OncoAge, Hôpital Pasteur, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France; Department of Pulmonary Medicine and Thoracic Oncology, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France
| | - Sandra Lassalle
- Laboratory of Clinical and Experimental Pathology, Hôpital Pasteur, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France; Hospital-integrated Biobank (BB-0033-00025), Hôpital Pasteur, Nice, France; FHU OncoAge, Hôpital Pasteur, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France; Team 4, Inserm U1081, CNRS UMR 7413, Institute for Research on Cancer and Aging, Nice, France
| | - Elodie Long-Mira
- Laboratory of Clinical and Experimental Pathology, Hôpital Pasteur, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France; Hospital-integrated Biobank (BB-0033-00025), Hôpital Pasteur, Nice, France; FHU OncoAge, Hôpital Pasteur, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France; Team 4, Inserm U1081, CNRS UMR 7413, Institute for Research on Cancer and Aging, Nice, France
| | - Katia Zahaf
- Laboratory of Clinical and Experimental Pathology, Hôpital Pasteur, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France
| | - Salomé Lalvée
- Laboratory of Clinical and Experimental Pathology, Hôpital Pasteur, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France
| | - Virginie Lespinet-Fabre
- Laboratory of Clinical and Experimental Pathology, Hôpital Pasteur, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France
| | - Olivier Bordone
- Laboratory of Clinical and Experimental Pathology, Hôpital Pasteur, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France
| | - Virginie Tanga
- Hospital-integrated Biobank (BB-0033-00025), Hôpital Pasteur, Nice, France
| | - Abel Gómez-Caro
- Department of Thoracic Surgery, Hôpital Pasteur, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France
| | - Charlotte Cohen
- Department of Thoracic Surgery, Hôpital Pasteur, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France
| | - Jean-Philippe Berthet
- Department of Thoracic Surgery, Hôpital Pasteur, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France
| | - Charles-Hugo Marquette
- FHU OncoAge, Hôpital Pasteur, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France; Team 4, Inserm U1081, CNRS UMR 7413, Institute for Research on Cancer and Aging, Nice, France; Department of Pulmonary Medicine and Thoracic Oncology, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France
| | - Paul Hofman
- Laboratory of Clinical and Experimental Pathology, Hôpital Pasteur, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France; Hospital-integrated Biobank (BB-0033-00025), Hôpital Pasteur, Nice, France; FHU OncoAge, Hôpital Pasteur, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France; Team 4, Inserm U1081, CNRS UMR 7413, Institute for Research on Cancer and Aging, Nice, France.
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Ellinghaus P, Neureiter D, Nogai H, Stintzing S, Ocker M. Patient Selection Approaches in FGFR Inhibitor Trials-Many Paths to the Same End? Cells 2022; 11:3180. [PMID: 36231142 PMCID: PMC9563413 DOI: 10.3390/cells11193180] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 10/04/2022] [Accepted: 10/06/2022] [Indexed: 12/16/2022] Open
Abstract
Inhibitors of fibroblast growth factor receptor (FGFR) signaling have been investigated in various human cancer diseases. Recently, the first compounds received FDA approval in biomarker-selected patient populations. Different approaches and technologies have been applied in clinical trials, ranging from protein (immunohistochemistry) to mRNA expression (e.g., RNA in situ hybridization) and to detection of various DNA alterations (e.g., copy number variations, mutations, gene fusions). We review, here, the advantages and limitations of the different technologies and discuss the importance of tissue and disease context in identifying the best predictive biomarker for FGFR targeting therapies.
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Affiliation(s)
- Peter Ellinghaus
- Global Clinical Development Oncology, Merck Healthcare KGaA, 64293 Darmstadt, Germany
| | - Daniel Neureiter
- Institute of Pathology, University Clinics Salzburg, Paracelsus Medical University, 5020 Salzburg, Austria
- Cancer Cluster Salzburg, 5020 Salzburg, Austria
| | | | - Sebastian Stintzing
- Division of Hematology, Oncology, and Tumor Immunology (Campus Charité Mitte), Medical Department, Charité University Medicine Berlin, 10117 Berlin, Germany
| | - Matthias Ocker
- Division of Hematology, Oncology, and Tumor Immunology (Campus Charité Mitte), Medical Department, Charité University Medicine Berlin, 10117 Berlin, Germany
- Anji Pharmaceuticals, Cambridge, MA 02142, USA
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10
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Addeo A, Rothschild SI, Schneider M, Waibel C, Haefliger S, Mark M, Fernandez E, Mach N, Mauti L, Jermann PM, Alborelli I, Calgua B, Savic-Prince S, Joerger M, Früh M. Fibroblast growth factor receptor (FGFR) inhibitor rogaratinib in patients with advanced pretreated squamous-cell non-small cell lung cancer over-expressing FGFR mRNA: the SAKK 19/18 phase II study. Lung Cancer 2022; 172:154-159. [DOI: 10.1016/j.lungcan.2022.08.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/08/2022] [Accepted: 08/24/2022] [Indexed: 10/15/2022]
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11
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Reissig TM, Uhrig S, Jost PJ, Luchini C, Vicentini C, Liffers ST, Allgäuer M, Adsay V, Scarpa A, Lawlor RT, Fröhling S, Stenzinger A, Klöppel G, Schildhaus HU, Siveke JT. MCL1 as putative target in pancreatoblastoma. Virchows Arch 2022; 481:265-272. [PMID: 35668118 PMCID: PMC9343273 DOI: 10.1007/s00428-022-03349-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 04/26/2022] [Accepted: 05/23/2022] [Indexed: 12/05/2022]
Abstract
Pancreatoblastoma (PB) is a rare tumor of the pancreas. In case of metastases, the treatment options are sparse and targeted approaches are not developed. We here evaluate MCL1 amplification as a putative target in PB.Thirteen samples from adult (10/13) and pediatric patients (3/13) were collected. Three of these samples had been previously subjected to whole-exome sequencing (2 cases) or whole-genome sequencing (1 case) within a precision oncology program (NCT/DKTK MASTER), and this analysis had shown copy number gains of MCL1 gene. We established a fluorescence in situ hybridization (FISH) test to assess the copy number alterations of MCL1 gene in 13 formalin-fixed paraffin-embedded PBs, including the 3 cases assessed by genome sequencing. FISH analysis showed the amplification of MCL1 in 2 cases (both were adult PB), one of which was a case with the highest copy number gain at genomic analysis. In both cases, the average gene copy number per cell was ≥ 5.7 and the MCL1/1p12 ratio was ≥ 2.4. Our data support MCL1 as a putative target in PB. Patients with MCL1-amplified PB might benefit from MCL1 inhibition. Sequencing data is useful to screen for amplification; however, the established FISH for MCL1 can help to determine the level and cellular heterogeneity of MCL1 amplification more accurately.
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Affiliation(s)
- Timm M Reissig
- Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Hufelandstrasse 55, 45147, Essen, Germany
- Division of Solid Tumor Translational Oncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Heidelberg, Germany
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany
- German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany
| | - Sebastian Uhrig
- Computational Oncology Group, Molecular Diagnostics Program, NCT Heidelberg and DKFZ, Heidelberg, Germany
- Division of Applied Bioinformatics, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany
- German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Philipp J Jost
- Department of Medicine III, Klinikum rechts der Isar, TUM School of Medicine, Technical University of Munich, Munich, Germany
- Division of Clinical Oncology, Department of Medicine, Medical University of Graz, Graz, Austria
| | - Claudio Luchini
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
- ARC-NET Research Centre, University of Verona, Verona, Italy
| | - Caterina Vicentini
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Sven-Thorsten Liffers
- Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Hufelandstrasse 55, 45147, Essen, Germany
- Division of Solid Tumor Translational Oncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Heidelberg, Germany
- German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany
| | - Michael Allgäuer
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Volkan Adsay
- Department of Pathology and Research Center for Translational Medicine (KUTTAM), Koç University, Istanbul, Turkey
| | - Aldo Scarpa
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
- ARC-NET Research Centre, University of Verona, Verona, Italy
| | | | - Stefan Fröhling
- German Cancer Consortium (DKTK), Heidelberg, Germany
- Division of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Albrecht Stenzinger
- German Cancer Consortium (DKTK), Heidelberg, Germany
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Günter Klöppel
- Department of Pathology, Technical University of Munich, Munich, Germany
| | - Hans-Ulrich Schildhaus
- German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany.
- Institute of Pathology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Hufelandstrasse 55, 45147, Essen, Germany.
| | - Jens T Siveke
- Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Hufelandstrasse 55, 45147, Essen, Germany.
- Division of Solid Tumor Translational Oncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Heidelberg, Germany.
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany.
- German Cancer Consortium (DKTK), Partner Site University Hospital Essen, Essen, Germany.
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12
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Activation of CD44/PAK1/AKT signaling promotes resistance to FGFR1 inhibition in squamous-cell lung cancer. NPJ Precis Oncol 2022; 6:52. [PMID: 35853934 PMCID: PMC9296622 DOI: 10.1038/s41698-022-00296-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 06/08/2022] [Indexed: 12/24/2022] Open
Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide. Fibroblast growth factor receptor 1 (FGFR1) gene amplification is one of the most prominent and potentially targetable genetic alterations in squamous-cell lung cancer (SQCLC). Highly selective tyrosine kinase inhibitors have been developed to target FGFR1; however, resistance mechanisms originally existing in patients or acquired during treatment have so far led to limited treatment efficiency in clinical trials. In this study we performed a wide-scale phosphoproteomic mass-spectrometry analysis to explore signaling pathways that lead to resistance toward FGFR1 inhibition in lung cancer cells that display (i) intrinsic, (ii) pharmacologically induced and (iii) mutationally induced resistance. Additionally, we correlated AKT activation to CD44 expression in 175 lung cancer patient samples. We identified a CD44/PAK1/AKT signaling axis as a commonly occurring resistance mechanism to FGFR1 inhibition in lung cancer. Co-inhibition of AKT/FGFR1, CD44/FGFR1 or PAK1/FGFR1 sensitized ‘intrinsically resistant’ and ‘induced-resistant’ lung-cancer cells synergetically to FGFR1 inhibition. Furthermore, strong CD44 expression was significantly correlated with AKT activation in SQCLC patients. Collectively, our phosphoproteomic analysis of lung-cancer cells resistant to FGFR1 inhibitor provides a large data library of resistance-associated phosphorylation patterns and leads to the proposal of a common resistance pathway comprising CD44, PAK1 and AKT activation. Examination of CD44/PAK1/AKT activation could help to predict response to FGFR1 inhibition. Moreover, combination between AKT and FGFR1 inhibitors may pave the way for an effective therapy of patients with treatment-resistant FGFR1-dependent lung cancer.
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13
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Genomic and transcriptomic analyses reveal a tandem amplification unit of 11 genes and mutations in mismatch repair genes in methotrexate-resistant HT-29 cells. Exp Mol Med 2021; 53:1344-1355. [PMID: 34521988 PMCID: PMC8492700 DOI: 10.1038/s12276-021-00668-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 06/04/2021] [Accepted: 06/21/2021] [Indexed: 12/16/2022] Open
Abstract
DHFR gene amplification is commonly present in methotrexate (MTX)-resistant colon cancer cells and acute lymphoblastic leukemia. In this study, we proposed an integrative framework to characterize the amplified region by using a combination of single-molecule real-time sequencing, next-generation optical mapping, and chromosome conformation capture (Hi-C). We identified an amplification unit spanning 11 genes, from the DHFR gene to the ATP6AP1L gene position, with high adjusted interaction frequencies on chromosome 5 (~2.2 Mbp) and a twenty-fold tandemly amplified region, and novel inversions at the start and end positions of the amplified region as well as frameshift insertions in most of the MSH and MLH genes were detected. These mutations might stimulate chromosomal breakage and cause the dysregulation of mismatch repair. Characterizing the tandem gene-amplified unit may be critical for identifying the mechanisms that trigger genomic rearrangements. These findings may provide new insight into the mechanisms underlying the amplification process and the evolution of drug resistance. Sequencing a large region of DNA containing many surplus copies of genes linked to drug resistance in colon cancer cells may illuminate how these genomic rearrangements arise. Such regions of gene amplification are highly repetitive, making them impossible to sequence using ordinary methods, and little is known about how they are generated. Using advanced methods, Jeong-Sun Seo at Seoul National University Bundang Hospital in South Korea and co-workers sequenced a region of gene amplification in colon cancer cells. The amplified region was approximately 20 times the length of that in healthy cells and contained many copies of an eleven-gene segment, including a gene implicated in drug resistance. The region also contained mutations in chromosomal repair genes which would disrupt repair pathways. These results illuminate the genetic changes that lead to gene amplification and drug resistance in cancer cells.
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14
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Hanke B, Jünger ST, Kirches E, Waldt N, Schreiber J, Lücke E, Franke S, Sandalcioglu IE, Warnke JP, Meisel HJ, Prell J, Scheller C, Braunsdorf WEK, Preusser M, Schildhaus HU, Mawrin C. Frequency of actionable molecular drivers in lung cancer patients with precocious brain metastases. Clin Neurol Neurosurg 2021; 208:106841. [PMID: 34343913 DOI: 10.1016/j.clineuro.2021.106841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 07/16/2021] [Accepted: 07/20/2021] [Indexed: 11/27/2022]
Abstract
Brain metastases frequently occur during the course of disease in patients suffering from lung cancer. Occasionally, neurological symptoms caused by brain metastases (BM) might represent the first sign of systemic tumor disease (so called precocious metastases), leading to the detection of the primary lung tumor. The biological basis of precocious BM is largely unknown, and treatment options are not well established for this subgroup of patients. Therefore, we retrospectively analyzed 33 patients (24 non-small cell lung cancer (NSCLC)), 9 small cell lung cancer (SCLC)) presenting with precocious BM focusing on molecular alterations potentially relevant for the tumor's biology and treatment. We found five FGFR1 amplifications (4 adenocarcinoma, 1 SCLC) among 31 analyzed patients (16.1%), eight MET amplifications among 30 analyzed tumors (7 NSCLC, 1 SCLC; 26.7%), three EGFR mutations within 33 patients (all adenocarcinomas, 9.1%), and five KRAS mutations among 32 patients (all adenocarcinomas; 15.6%). No ALK, ROS1 or RET gene rearrangements were detected. Our findings suggest that patients with precocious BM of lung cancer harbor EGFR mutations, MET amplifications or FGFR1 amplifications as potential targeted treatment options.
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Affiliation(s)
- Benjamin Hanke
- Department of Neuropathology, Otto-von-Guericke University Magdeburg, Germany
| | - Stephanie T Jünger
- Centre for Neurosurgery, Department of General Neurosurgery, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Elmar Kirches
- Department of Neuropathology, Otto-von-Guericke University Magdeburg, Germany
| | - Natalie Waldt
- Department of Neuropathology, Otto-von-Guericke University Magdeburg, Germany
| | - Jens Schreiber
- Department of Pneumonology, Otto-von-Guericke University Magdeburg, Germany
| | - Eva Lücke
- Department of Pneumonology, Otto-von-Guericke University Magdeburg, Germany
| | - Sabine Franke
- Department of Pathology, Otto-von-Guericke University Magdeburg, Germany
| | | | - Jan-Peter Warnke
- Department of Neurosurgery, Paracelsus Hospital Zwickau, Germany
| | - Hans-Jörg Meisel
- Department of Neurosurgery, Bergmannstrost Hospital Halle/Saale, Germany
| | - Julian Prell
- Department of Neurosurgery, University Hospital Halle/Saale, Germany
| | | | | | - Matthias Preusser
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Austria
| | | | - Christian Mawrin
- Department of Neuropathology, Otto-von-Guericke University Magdeburg, Germany.
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15
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Bogatyrova O, Mattsson JSM, Ross EM, Sanderson MP, Backman M, Botling J, Brunnström H, Kurppa P, La Fleur L, Strell C, Wilm C, Zimmermann A, Esdar C, Micke P. FGFR1 overexpression in non-small cell lung cancer is mediated by genetic and epigenetic mechanisms and is a determinant of FGFR1 inhibitor response. Eur J Cancer 2021; 151:136-149. [PMID: 33984662 DOI: 10.1016/j.ejca.2021.04.005] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 03/11/2021] [Accepted: 04/06/2021] [Indexed: 02/06/2023]
Abstract
Amplification of fibroblast growth factor receptor 1 (FGFR1) in non-small cell lung cancer (NSCLC) has been considered as an actionable drug target. However, pan-FGFR tyrosine kinase inhibitors did not demonstrate convincing clinical efficacy in FGFR1-amplified NSCLC patients. This study aimed to characterise the molecular context of FGFR1 expression and to define biomarkers predictive of FGFR1 inhibitor response. In this study, 635 NSCLC samples were characterised for FGFR1 protein expression by immunohistochemistry and copy number gain (CNG) by in situ hybridisation (n = 298) or DNA microarray (n = 189). FGFR1 gene expression (n = 369) and immune cell profiles (n = 309) were also examined. Furthermore, gene expression, methylation and microRNA data from The Cancer Genome Atlas (TCGA) were compared. A panel of FGFR1-amplified NSCLC patient-derived xenograft (PDX) models were tested for response to the selective FGFR1 antagonist M6123. A minority of patients demonstrated FGFR1 CNG (10.5%) or increased FGFR1 mRNA (8.7%) and protein expression (4.4%). FGFR1 CNG correlated weakly with FGFR1 gene and protein expression. Tumours overexpressing FGFR1 protein were typically devoid of driver alterations (e.g. EGFR, KRAS) and showed reduced infiltration of T-lymphocytes and lower PD-L1 expression. Promoter methylation and microRNA were identified as regulators of FGFR1 expression in NSCLC and other cancers. Finally, NSCLC PDX models demonstrating FGFR1 amplification and FGFR1 protein overexpression were sensitive to M6123. The unique molecular and immune features of tumours with high FGFR1 expression provide a rationale to stratify patients in future clinical trials of FGFR1 pathway-targeting agents.
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MESH Headings
- Animals
- Antineoplastic Agents/pharmacology
- B7-H1 Antigen/metabolism
- Carcinoma, Non-Small-Cell Lung/drug therapy
- Carcinoma, Non-Small-Cell Lung/genetics
- Carcinoma, Non-Small-Cell Lung/immunology
- Carcinoma, Non-Small-Cell Lung/metabolism
- DNA Methylation
- Epigenesis, Genetic
- Female
- Gene Amplification
- Gene Expression Regulation, Neoplastic
- Humans
- Lung Neoplasms/drug therapy
- Lung Neoplasms/genetics
- Lung Neoplasms/immunology
- Lung Neoplasms/metabolism
- Lymphocytes, Tumor-Infiltrating/immunology
- Lymphocytes, Tumor-Infiltrating/metabolism
- Mice, Inbred NOD
- Mice, SCID
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Molecular Targeted Therapy
- Receptor, Fibroblast Growth Factor, Type 1/antagonists & inhibitors
- Receptor, Fibroblast Growth Factor, Type 1/genetics
- Receptor, Fibroblast Growth Factor, Type 1/metabolism
- T-Lymphocytes/immunology
- T-Lymphocytes/metabolism
- Tumor Microenvironment
- Xenograft Model Antitumor Assays
- Mice
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Affiliation(s)
- Olga Bogatyrova
- Translational Innovation Platform Oncology & Immuno-Oncology, Merck KGaA, Darmstadt, Germany
| | - Johanna S M Mattsson
- Dept. of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Edith M Ross
- Translational Medicine, Merck KGaA, Darmstadt, Germany
| | - Michael P Sanderson
- Translational Innovation Platform Oncology & Immuno-Oncology, Merck KGaA, Darmstadt, Germany
| | - Max Backman
- Dept. of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Johan Botling
- Dept. of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Hans Brunnström
- Division of Pathology, Lund University, Skåne University Hospital, Lund, Sweden
| | - Pinja Kurppa
- Dept. of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Linnéa La Fleur
- Dept. of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Carina Strell
- Dept. of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Claudia Wilm
- Translational Innovation Platform Oncology & Immuno-Oncology, Merck KGaA, Darmstadt, Germany
| | - Astrid Zimmermann
- Translational Innovation Platform Oncology & Immuno-Oncology, Merck KGaA, Darmstadt, Germany
| | - Christina Esdar
- Translational Innovation Platform Oncology & Immuno-Oncology, Merck KGaA, Darmstadt, Germany
| | - Patrick Micke
- Dept. of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
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Pacini L, Jenks AD, Lima NC, Huang PH. Targeting the Fibroblast Growth Factor Receptor (FGFR) Family in Lung Cancer. Cells 2021; 10:1154. [PMID: 34068816 PMCID: PMC8151052 DOI: 10.3390/cells10051154] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 05/05/2021] [Accepted: 05/07/2021] [Indexed: 12/12/2022] Open
Abstract
Lung cancer is the most common cause of cancer-related deaths globally. Genetic alterations, such as amplifications, mutations and translocations in the fibroblast growth factor receptor (FGFR) family have been found in non-small cell lung cancer (NSCLC) where they have a role in cancer initiation and progression. FGFR aberrations have also been identified as key compensatory bypass mechanisms of resistance to targeted therapy against mutant epidermal growth factor receptor (EGFR) and mutant Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) in lung cancer. Targeting FGFR is, therefore, of clinical relevance for this cancer type, and several selective and nonselective FGFR inhibitors have been developed in recent years. Despite promising preclinical data, clinical trials have largely shown low efficacy of these agents in lung cancer patients with FGFR alterations. Preclinical studies have highlighted the emergence of multiple intrinsic and acquired resistance mechanisms to FGFR tyrosine kinase inhibitors, which include on-target FGFR gatekeeper mutations and activation of bypass signalling pathways and alternative receptor tyrosine kinases. Here, we review the landscape of FGFR aberrations in lung cancer and the array of targeted therapies under clinical evaluation. We also discuss the current understanding of the mechanisms of resistance to FGFR-targeting compounds and therapeutic strategies to circumvent resistance. Finally, we highlight our perspectives on the development of new biomarkers for stratification and prediction of FGFR inhibitor response to enable personalisation of treatment in patients with lung cancer.
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Affiliation(s)
| | | | | | - Paul H. Huang
- Division of Molecular Pathology, The Institute of Cancer Research, London SM2 5NG, UK; (L.P.); (A.D.J.); (N.C.L.)
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17
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Guerini-Rocco E, Gray KP, Fumagalli C, Reforgiato MR, Leone I, Rafaniello Raviele P, Munzone E, Kammler R, Neven P, Hitre E, Jerusalem G, Simoncini E, Gombos A, Deleu I, Karlsson P, Aebi S, Chirgwin J, Di Lauro V, Thompson A, Graas MP, Barber M, Fontaine C, Loibl S, Gavilá J, Kuroi K, Müller B, O'Reilly S, Di Leo A, Goldhirsch A, Viale G, Barberis M, Regan MM, Colleoni M. Genomic Aberrations and Late Recurrence in Postmenopausal Women with Hormone Receptor-positive Early Breast Cancer: Results from the SOLE Trial. Clin Cancer Res 2020; 27:504-512. [PMID: 33082214 DOI: 10.1158/1078-0432.ccr-20-0126] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2020] [Revised: 06/10/2020] [Accepted: 10/15/2020] [Indexed: 11/16/2022]
Abstract
PURPOSE Women with hormone receptor-positive early breast cancers have a persistent risk of relapse and biomarkers for late recurrence are needed. We sought to identify tumor genomic aberrations associated with increased late-recurrence risk. EXPERIMENTAL DESIGN In a secondary analysis of Study of Letrozole Extension trial, a case-cohort-like sampling selected 598 primary breast cancers for targeted next-generation sequencing analysis of gene mutations and copy-number gains (CNGs). Correlations of genomic aberrations with clinicopathologic factors and breast and distant recurrence-free intervals (BCFIs and DRFIs) were analyzed using weighted Cox models. RESULTS Analysis of mutations and CNGs was successfully performed for 403 and 350 samples, including 148 and 134 patients with breast cancer recurrences (median follow-up time, 5.2 years), respectively. The most frequent alterations were PIK3CA mutations (42%) and CNGs of CCND1 (15%), ERBB2 (10%), FGFR1 (8%), and MYC (8%). PIK3CA mutations and MYC CNGs were associated with lower (P = 0.03) and higher (P = 0.004) tumor grade, respectively; a higher Ki-67 was seen in tumor with CCND1, ERBB2, and MYC CNGs (P = 0.01, P < 0.001, and P = 0.03, respectively). FGFR1 CNG was associated with an increased risk of late events in univariate analyses [17/29 patients; BCFI: HR, 3.2; 95% confidence interval (CI), 1.48-6.92; P = 0.003 and DRFI: HR, 3.5; 95% CI, 1.61-7.75; P = 0.002) and in multivariable models adjusted for clinicopathologic factors. CONCLUSIONS Postmenopausal women with hormone receptor-positive early breast cancer harboring FGFR1 CNG had an increased risk of late recurrence despite extended therapy. FGFR1 CNG may represent a useful prognostic biomarker for late recurrence and a therapeutic target.
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Affiliation(s)
- Elena Guerini-Rocco
- Division of Pathology and Laboratory Medicine, IEO, European Institute of Oncology IRCCS, Milan and University of Milan, Department of Oncology and Hemato-Oncology, Milan, Italy.
| | - Kathryn P Gray
- International Breast Cancer Study Group Statistical Center, Frontier Science Foundation, and Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Caterina Fumagalli
- Division of Pathology and Laboratory Medicine, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Marta Rita Reforgiato
- Division of Pathology and Laboratory Medicine, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Isabella Leone
- Division of Pathology and Laboratory Medicine, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Paola Rafaniello Raviele
- Division of Pathology and Laboratory Medicine, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Elisabetta Munzone
- Division of Medical Senology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | | | - Patrick Neven
- Multidisciplinary Breast Center, University Hospitals, KU Leuven, Leuven, Belgium
| | - Erika Hitre
- National Institute of Oncology, Budapest, Hungary
| | | | | | | | | | - Per Karlsson
- Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy/Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden
| | - Stefan Aebi
- Lucerne Cantonal Hospital and University of Bern, Bern, Switzerland
| | - Jacquie Chirgwin
- Box Hill and Maroondah Hospitals, Monash University, Melbourne, Victoria, Australia
| | | | - Alastair Thompson
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas
| | | | | | | | | | - Joaquín Gavilá
- Fundación Instituto Valenciano de Oncologia, Valencia, Spain
| | - Katsumasa Kuroi
- Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Bunkyo City, Tokyo, Japan
| | - Bettina Müller
- Chilean Cooperative Group for Oncologic Research (GOCCHI), Santiago, Chile
| | | | | | - Aron Goldhirsch
- International Breast Cancer Study Group, Bern, Switzerland and MultiMedica, Milan, Italy
| | - Giuseppe Viale
- Division of Pathology and Laboratory Medicine, IEO, European Institute of Oncology IRCCS, Milan, International Breast Cancer Study Group Central Pathology Office and University of Milan, Department of Oncology and Hemato-Oncology, Milan, Italy
| | - Massimo Barberis
- Division of Pathology and Laboratory Medicine, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Meredith M Regan
- International Breast Cancer Study Group Statistical Center, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, Massachusetts
| | - Marco Colleoni
- Division of Medical Senology, European Institute of Oncology, and the International Breast Cancer Study Group, Milan, Italy
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18
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Qin J, Xie F, Wang F, Lu H. mRNA Expression of FGFR1 as Potential Marker for Predicting Prognosis of Surgical Resection of Small Cell Lung Cancer may be better than Protein Expression and Gene Amplification. J Cancer 2020; 11:4691-4699. [PMID: 32626515 PMCID: PMC7330682 DOI: 10.7150/jca.44476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Accepted: 05/12/2020] [Indexed: 11/10/2022] Open
Abstract
Purpose: Fibroblast growth factor receptor 1 (FGFR1) alterations have been described in many cancers, including lung cancer, but the role has not been elucidated specifically in small cell lung cancer (SCLC). The present study aimed to identify the frequency of FGFR1 alterations among Chinese patients with surgically resected SCLC and the association with the clinicopathological characteristics and the survival were also investigated. Methods: FGFR1 protein expression, FGFR1 amplification, FGFR1 mutations, and messenger RNA (mRNA) levels, were determined by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), polymerase chain reaction (PCR) and reverse transcription-polymerase chain reaction (RT-PCR), respectively in primary tumors from 33 patients with resected SCLC. Results: 7/33(21.2%) of the specimens were positive for FGFR1 protein expression. FGFR1 amplification was identified in 4/28 cases (14.3%). If the cut-off value was determined to be 3.5, FGFR1 mRNA positivity was considered in 7/33 cases (21.2%). However, no mutation was detected in the 33 SCLC postoperative tissue specimens. No significant association was observed between FGFR1 protein expression or amplification and clinicalcharacteristics or prognosis. There was a distinct trend for mRNA level and poor prognosis, including recurrence-free survival (RFS) (p = 0.07) and overall survival (OS) (p= 0.08), but they did not reach statistical significance. Conclusions: As novel FGFR1-targeted therapies are developed, FISH, IHC, especially mRNA were detected, which should be considered as biomarkers of FGFR1 pathway dysregulation in SCLC.
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Affiliation(s)
- Jing Qin
- Zhejiang Key Laboratory of Diagnosis and Treatment Technology on Thoracic Oncology (lung and esophagus), Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, 310022, P.R. China.,Department of Thoracic Medical Oncology, Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, 310022, P.R. China
| | - Fajun Xie
- Zhejiang Key Laboratory of Diagnosis and Treatment Technology on Thoracic Oncology (lung and esophagus), Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, 310022, P.R. China.,Department of Thoracic Medical Oncology, Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, 310022, P.R. China
| | - Fenfang Wang
- Graduate School, WenZhou Medical University, Wenzhou, 325035, P.R. China
| | - Hongyang Lu
- Graduate School, WenZhou Medical University, Wenzhou, 325035, P.R. China.,Zhejiang Key Laboratory of Diagnosis and Treatment Technology on Thoracic Oncology (lung and esophagus), Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, 310022, P.R. China.,Department of Thoracic Medical Oncology, Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, 310022, P.R. China
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19
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Bourrier C, Pierga JY, Xuereb L, Salaun H, Proudhon C, Speicher MR, Belic J, Heitzer E, Lockhart BP, Guigal-Stephan N. Shallow Whole-Genome Sequencing from Plasma Identifies FGFR1 Amplified Breast Cancers and Predicts Overall Survival. Cancers (Basel) 2020; 12:cancers12061481. [PMID: 32517171 PMCID: PMC7353062 DOI: 10.3390/cancers12061481] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 05/26/2020] [Accepted: 06/04/2020] [Indexed: 12/30/2022] Open
Abstract
Background: Focal amplification of fibroblast growth factor receptor 1 (FGFR1) defines a subgroup of breast cancers with poor prognosis and high risk of recurrence. We sought to demonstrate the potential of circulating cell-free DNA (cfDNA) analysis to evaluate FGFR1 copy numbers from a cohort of 100 metastatic breast cancer (mBC) patients. Methods: Formalin-fixed paraffin-embedded (FFPE) tissue samples were screened for FGFR1 amplification by FISH, and positive cases were confirmed with a microarray platform (OncoscanTM). Subsequently, cfDNA was evaluated by two approaches, i.e., mFAST-SeqS and shallow whole-genome sequencing (sWGS), to estimate the circulating tumor DNA (ctDNA) allele fraction (AF) and to evaluate the FGFR1 status. Results: Tissue-based analyses identified FGFR1 amplifications in 20/100 tumors. All cases with a ctDNA AF above 3% (n = 12) showed concordance for FGFR1 status between tissue and cfDNA. In one case, we were able to detect a high-level FGFR1 amplification, although the ctDNA AF was below 1%. Furthermore, high levels of ctDNA indicated an association with unfavorable prognosis based on overall survival. Conclusions: Screening for FGFR1 amplification in ctDNA might represent a viable strategy to identify patients eligible for treatment by FGFR inhibition, and mBC ctDNA levels might be used for the evaluation of prognosis in clinical drug trials.
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Affiliation(s)
- Chantal Bourrier
- Division of Biotechnology, Servier Research Institute, 125, Chemin de ronde, 78290 Croissy Sur-seine, France; (C.B.); (B.P.L.)
| | - Jean-Yves Pierga
- Department of Medical Oncology, Institut Curie, 26 rue d’Ulm, 75005 Paris, France; (J.-Y.P.); (H.S.)
- Circulating Tumor Biomarkers Laboratory, Institut Curie, PSL Research University, INSERM CIC 1428, 26 rue d’Ulm, 75005 Paris, France;
- Université de Paris, 75005 Paris, France
| | - Laura Xuereb
- Division of Methodology and Valorisation of Data, Servier Research and Development Institute, 50 rue carnot, 92150 Suresnes, France;
| | - Hélène Salaun
- Department of Medical Oncology, Institut Curie, 26 rue d’Ulm, 75005 Paris, France; (J.-Y.P.); (H.S.)
- Université de Paris, 75005 Paris, France
| | - Charlotte Proudhon
- Circulating Tumor Biomarkers Laboratory, Institut Curie, PSL Research University, INSERM CIC 1428, 26 rue d’Ulm, 75005 Paris, France;
| | - Michael R. Speicher
- Institute of Human Genetics, Diagnostic and Research Center for Molecular BioMedicine, Medical University of Graz, Neue Stiftingtalstrasse 6, 8010 Graz, Austria; (M.R.S.); (J.B.); (E.H.)
- BioTechMed-Graz, 8010 Graz, Austria
| | - Jelena Belic
- Institute of Human Genetics, Diagnostic and Research Center for Molecular BioMedicine, Medical University of Graz, Neue Stiftingtalstrasse 6, 8010 Graz, Austria; (M.R.S.); (J.B.); (E.H.)
| | - Ellen Heitzer
- Institute of Human Genetics, Diagnostic and Research Center for Molecular BioMedicine, Medical University of Graz, Neue Stiftingtalstrasse 6, 8010 Graz, Austria; (M.R.S.); (J.B.); (E.H.)
- BioTechMed-Graz, 8010 Graz, Austria
- Christian Doppler Laboratory for Liquid Biopsies for Early Detection of Cancer, 8010 Graz, Austria
| | - Brian Paul Lockhart
- Division of Biotechnology, Servier Research Institute, 125, Chemin de ronde, 78290 Croissy Sur-seine, France; (C.B.); (B.P.L.)
| | - Nolwen Guigal-Stephan
- Division of Biotechnology, Servier Research Institute, 125, Chemin de ronde, 78290 Croissy Sur-seine, France; (C.B.); (B.P.L.)
- Correspondence: ; Tel.: +33-155-722-532
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20
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Elakad O, Lois AM, Schmitz K, Yao S, Hugo S, Lukat L, Hinterthaner M, Danner BC, von Hammerstein-Equord A, Reuter-Jessen K, Schildhaus HU, Ströbel P, Bohnenberger H. Fibroblast growth factor receptor 1 gene amplification and protein expression in human lung cancer. Cancer Med 2020; 9:3574-3583. [PMID: 32207251 PMCID: PMC7288860 DOI: 10.1002/cam4.2994] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 02/18/2020] [Accepted: 03/02/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Targeting fibroblast growth factor receptor 1 (FGFR1) is a potential treatment for squamous cell lung cancer (SQCLC). So far, treatment decision in clinical studies is based on gene amplification. However, only a minority of patients have shown durable response. Furthermore, former studies have revealed contrasting results regarding the impact of FGFR1 amplification and expression on patient's prognosis. AIMS Here, we analyzed prevalence and correlation of FGFR1 gene amplification and protein expression in human lung cancer and their impact on overall survival. MATERIALS & METHODS: FGFR1 gene amplification and protein expression were analyzed by fluorescence in situ hybridization and immunohistochemistry (IHC) in 208 SQCLC and 45 small cell lung cancers (SCLC). Furthermore, FGFR1 protein expression was analyzed in 121 pulmonary adenocarcinomas (ACs). Amplification and expression were correlated to each other, clinicopathological characteristics, and overall survival. RESULTS FGFR1 was amplified in 23% of SQCLC and 8% of SCLC. Amplification was correlated to males (P = .027) but not to overall survival. Specificity of immunostaining was verified by cellular CRISPR/Cas9 FGFR1 knockout. FGFR1 was strongly expressed in 9% of SQCLC, 35% of AC, and 4% of SCLC. Expression was correlated to females (P = .0187) and to the absence of lymph node metastasis in SQCLC (P = .018) with no significant correlation to overall survival. Interestingly, no significant correlation between amplification and expression was detected. DISCUSSION FGFR1 gene amplification does not seem to correlate to protein expression. CONCLUSION We believe that patient selection for FGFR1 inhibitors in clinical studies should be reconsidered. Neither FGFR1 amplification nor expression influences patient's prognosis.
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MESH Headings
- Adenocarcinoma of Lung/drug therapy
- Adenocarcinoma of Lung/genetics
- Adenocarcinoma of Lung/metabolism
- Adenocarcinoma of Lung/pathology
- Adult
- Aged
- Aged, 80 and over
- Carcinoma, Squamous Cell/drug therapy
- Carcinoma, Squamous Cell/genetics
- Carcinoma, Squamous Cell/metabolism
- Carcinoma, Squamous Cell/pathology
- Female
- Gene Amplification
- Humans
- Lung Neoplasms/drug therapy
- Lung Neoplasms/genetics
- Lung Neoplasms/metabolism
- Lung Neoplasms/pathology
- Male
- Middle Aged
- Neoplasm Staging
- Prognosis
- Protein Kinase Inhibitors/therapeutic use
- Receptor, Fibroblast Growth Factor, Type 1/antagonists & inhibitors
- Receptor, Fibroblast Growth Factor, Type 1/genetics
- Receptor, Fibroblast Growth Factor, Type 1/metabolism
- Small Cell Lung Carcinoma/drug therapy
- Small Cell Lung Carcinoma/genetics
- Small Cell Lung Carcinoma/metabolism
- Small Cell Lung Carcinoma/pathology
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Affiliation(s)
- Omar Elakad
- Institute of Pathology, University Medical Center, Göttingen, Germany
| | - Anna-Maria Lois
- Institute of Pathology, University Medical Center, Göttingen, Germany
| | - Katja Schmitz
- Institute of Pathology, University Medical Center, Göttingen, Germany
| | - Sha Yao
- Institute of Pathology, University Medical Center, Göttingen, Germany
| | - Sara Hugo
- Institute of Pathology, University Medical Center, Göttingen, Germany
| | - Laura Lukat
- Institute of Pathology, University Medical Center, Göttingen, Germany
| | - Marc Hinterthaner
- Department of Thoracic and Cardiovascular Surgery, University Medical Center, Göttingen, Germany
| | - Bernhard C Danner
- Department of Thoracic and Cardiovascular Surgery, University Medical Center, Göttingen, Germany
| | | | | | | | - Philipp Ströbel
- Institute of Pathology, University Medical Center, Göttingen, Germany
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21
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Miao JL, Zhou JH, Cai JJ, Liu RJ. The association between fibroblast growth factor receptor 1 gene amplification and lung cancer: a meta-analysis. Arch Med Sci 2020; 16:16-26. [PMID: 32051701 PMCID: PMC6963147 DOI: 10.5114/aoms.2020.91284] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Accepted: 06/11/2017] [Indexed: 12/24/2022] Open
Abstract
INTRODUCTION Identifying target oncogenic alterations in lung cancer represents a major development in disease management. We examined the association of fibroblast growth factor receptor 1 (FGFR1) gene amplification with pathological characteristics and geographic region. MATERIAL AND METHODS We conducted a meta-analysis of studies published between January 2010 and October 2016. Relative risks (RR) and corresponding 95% confidence intervals (CI) were calculated regarding the rate of FGFR1 amplification in different lung cancer types and geographic region. RESULTS Twenty-three studies (5252 patients) were included. There was heterogeneity between studies. However, in subgroup analyses for squamous cell carcinoma (SCC), small cell lung cancer (SCLC), studies using the same definition of FGFR1 amplification, and those from Australia, no significant heterogeneity was detected. The prevalence of FGFR1 amplification in these studies ranged from 4.9% to 49.2% in non-small cell lung cancer (NSCLC), 5.1% to 41.5% in SCC, 0% to 14.7% in adenocarcinoma, and 0% to 7.8% in SCLC. The prevalence of FGFR1 amplification was significantly higher in SCC than in adenocarcinoma (RR = 5.2) and SCLC (RR = 4.2). The prevalence of FGFR1 amplification ranged from 5.6% to 22.2% in Europe, 4.1% to 18.2% in the United States, 7.8% to 49.2% in Asia, and 14.2% to 18.6% in Australia. The rate of FGFR1 amplification was higher in Asians than in non-Asians (RR = 1.9) in NSCLC. CONCLUSIONS These results suggest that FGFR1 amplification occurs more frequently in SCC and in Asians. FGFR1 amplification may be a potential new therapeutic target for specific patients and lung cancer subtypes.
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Affiliation(s)
- Jian-Long Miao
- Department of Respiratory Medicine, Shandong Jining No. 1 People's Hospital, Jining, Shandong, China
| | - Jin-Hua Zhou
- Department of Respiratory Medicine, Shandong Jining No. 1 People's Hospital, Jining, Shandong, China
| | - Jing-Jing Cai
- Department of Respiratory Medicine, Shandong Jining No. 1 People's Hospital, Jining, Shandong, China
| | - Rui-Juan Liu
- Department of Respiratory Medicine, Shandong Jining No. 1 People's Hospital, Jining, Shandong, China
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22
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Kron A, Alidousty C, Scheffler M, Merkelbach-Bruse S, Seidel D, Riedel R, Ihle MA, Michels S, Nogova L, Fassunke J, Heydt C, Kron F, Ueckeroth F, Serke M, Krüger S, Grohe C, Koschel D, Benedikter J, Kaminsky B, Schaaf B, Braess J, Sebastian M, Kambartel KO, Thomas R, Zander T, Schultheis AM, Büttner R, Wolf J. Impact of TP53 mutation status on systemic treatment outcome in ALK-rearranged non-small-cell lung cancer. Ann Oncol 2019; 29:2068-2075. [PMID: 30165392 PMCID: PMC6225899 DOI: 10.1093/annonc/mdy333] [Citation(s) in RCA: 129] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Background We analyzed whether co-occurring mutations influence the outcome of systemic therapy in ALK-rearranged non-small-cell lung cancer (NSCLC). Patients and methods ALK-rearranged stage IIIB/IV NSCLC patients were analyzed with next-generation sequencing and fluorescence in situ hybridization analyses on a centralized diagnostic platform. Median progression-free survival (PFS) and overall survival (OS) were determined in the total cohort and in treatment-related sub-cohorts. Cox regression analyses were carried out to exclude confounders. Results Among 216 patients with ALK-rearranged NSCLC, the frequency of pathogenic TP53 mutations was 23.8%, while other co-occurring mutations were rare events. In ALK/TP53 co-mutated patients, median PFS and OS were significantly lower compared with TP53 wildtype patients [PFS 3.9 months (95% CI: 2.4–5.6) versus 10.3 months (95% CI: 8.6–12.0), P < 0.001; OS 15.0 months (95% CI: 5.0–24.9) versus 50.0 months (95% CI: 22.9–77.1), P = 0.002]. This difference was confirmed in all treatment-related subgroups including chemotherapy only [PFS first-line chemotherapy 2.6 months (95% CI: 1.3–4.1) versus 6.2 months (95% CI: 1.8–10.5), P = 0.021; OS 2.0 months (95% CI: 0.0–4.6) versus 9.0 months (95% CI: 6.1–11.9), P = 0.035], crizotinib plus chemotherapy [PFS crizotinib 5.0 months (95% CI: 2.9–7.2) versus 14.0 months (95% CI: 8.0–20.1), P < 0.001; OS 17.0 months (95% CI: 6.7–27.3) versus not reached, P = 0.049] and crizotinib followed by next-generation ALK-inhibitor [PFS next-generation inhibitor 5.4 months (95% CI: 0.1–10.7) versus 9.9 months (95% CI: 6.4–13.5), P = 0.039; OS 7.0 months versus 50.0 months (95% CI: not reached), P = 0.001). Conclusions In ALK-rearranged NSCLC co-occurring TP53 mutations predict an unfavorable outcome of systemic therapy. Our observations encourage future research to understand the underlying molecular mechanisms and to improve treatment outcome of the ALK/TP53 co-mutated subgroup.
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Affiliation(s)
- A Kron
- Network Genomic Medicine, Cologne, Germany; Lung Cancer Group Cologne, Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany; Center for Integrated Oncology Köln Bonn, Cologne, Germany
| | - C Alidousty
- Network Genomic Medicine, Cologne, Germany; Center for Integrated Oncology Köln Bonn, Cologne, Germany; Institute of Pathology, University Hospital of Cologne, Cologne, Germany
| | - M Scheffler
- Network Genomic Medicine, Cologne, Germany; Lung Cancer Group Cologne, Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany; Center for Integrated Oncology Köln Bonn, Cologne, Germany
| | - S Merkelbach-Bruse
- Network Genomic Medicine, Cologne, Germany; Center for Integrated Oncology Köln Bonn, Cologne, Germany; Institute of Pathology, University Hospital of Cologne, Cologne, Germany
| | - D Seidel
- Center for Integrated Oncology Köln Bonn, Cologne, Germany; CECAD Cluster of Excellence, University of Cologne, Cologne, Germany
| | - R Riedel
- Network Genomic Medicine, Cologne, Germany; Lung Cancer Group Cologne, Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany; Center for Integrated Oncology Köln Bonn, Cologne, Germany
| | - M A Ihle
- Network Genomic Medicine, Cologne, Germany; Center for Integrated Oncology Köln Bonn, Cologne, Germany; Institute of Pathology, University Hospital of Cologne, Cologne, Germany
| | - S Michels
- Network Genomic Medicine, Cologne, Germany; Lung Cancer Group Cologne, Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany; Center for Integrated Oncology Köln Bonn, Cologne, Germany
| | - L Nogova
- Network Genomic Medicine, Cologne, Germany; Lung Cancer Group Cologne, Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany; Center for Integrated Oncology Köln Bonn, Cologne, Germany
| | - J Fassunke
- Network Genomic Medicine, Cologne, Germany; Center for Integrated Oncology Köln Bonn, Cologne, Germany; Institute of Pathology, University Hospital of Cologne, Cologne, Germany
| | - C Heydt
- Network Genomic Medicine, Cologne, Germany; Center for Integrated Oncology Köln Bonn, Cologne, Germany; Institute of Pathology, University Hospital of Cologne, Cologne, Germany
| | - F Kron
- Network Genomic Medicine, Cologne, Germany; Center for Integrated Oncology Köln Bonn, Cologne, Germany
| | - F Ueckeroth
- Network Genomic Medicine, Cologne, Germany; Center for Integrated Oncology Köln Bonn, Cologne, Germany; Institute of Pathology, University Hospital of Cologne, Cologne, Germany
| | - M Serke
- Network Genomic Medicine, Cologne, Germany; Department of Pneumology, Lungenklinik Hemer des Deutschen Gemeinschafts-Diakonieverbandes GmbH, Hemer, Germany
| | - S Krüger
- Network Genomic Medicine, Cologne, Germany; Department of Pneumology, Florence Nightingale Hospital, Düsseldorf, Germany
| | - C Grohe
- Network Genomic Medicine, Cologne, Germany; Department of Pneumology, Evangelische Lungenklinik Berlin (Paul Gerhardt Diakonie), Berlin, Germany
| | - D Koschel
- Network Genomic Medicine, Cologne, Germany; Department of Pneumology, Fachkrankenhaus Coswig, Coswig, Germany
| | - J Benedikter
- Network Genomic Medicine, Cologne, Germany; Department of Pneumology, Klinikum Bogenhausen, Munich, Germany
| | - B Kaminsky
- Network Genomic Medicine, Cologne, Germany; Department of Pneumology, Krankenhaus Bethanien, Solingen, Germany
| | - B Schaaf
- Network Genomic Medicine, Cologne, Germany; Lung Cancer Center, Klinikum Dortmund GmbH, Dortmund, Germany
| | - J Braess
- Network Genomic Medicine, Cologne, Germany; Department of Oncology and Hematology, Krankenhaus Barmherzige Brueder, Regensburg, Germany
| | - M Sebastian
- Network Genomic Medicine, Cologne, Germany; Department of Oncology and Hematology, University Hospital Frankfurt (Johannes-Wolfgang Goethe Institute), Frankfurt am Main, Germany
| | - K-O Kambartel
- Network Genomic Medicine, Cologne, Germany; Department of Pneumology, Bethanien Hospital Moers-Lungenzentrum, Moers, Germany
| | - R Thomas
- Network Genomic Medicine, Cologne, Germany; Cologne Center for Genomics, University Hospital of Cologne, Cologne, Germany
| | - T Zander
- Network Genomic Medicine, Cologne, Germany; Center for Integrated Oncology Köln Bonn, Cologne, Germany
| | - A M Schultheis
- Network Genomic Medicine, Cologne, Germany; Center for Integrated Oncology Köln Bonn, Cologne, Germany; Institute of Pathology, University Hospital of Cologne, Cologne, Germany
| | - R Büttner
- Network Genomic Medicine, Cologne, Germany; Center for Integrated Oncology Köln Bonn, Cologne, Germany; Institute of Pathology, University Hospital of Cologne, Cologne, Germany
| | - J Wolf
- Network Genomic Medicine, Cologne, Germany; Lung Cancer Group Cologne, Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany; Center for Integrated Oncology Köln Bonn, Cologne, Germany.
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Kim Y, Bang SS, Jee S, Park S, Shin SJ, Jang K. Prevalence and Clinicopathological Significance of MET Overexpression and Gene Amplification in Patients with Gallbladder Carcinoma. Cancer Res Treat 2019; 52:481-491. [PMID: 31645095 PMCID: PMC7176974 DOI: 10.4143/crt.2019.370] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Accepted: 10/23/2019] [Indexed: 12/14/2022] Open
Abstract
PURPOSE Mesenchymal epithelial transition (MET) is a proto-oncogene that encodes a heterodimeric transmembrane receptor tyrosine kinase for the hepatocyte growth factor. Aberrant MET signaling has been described in several solid tumors-especially non-small cell lung cancer- and is associated with tumor progression and adverse prognosis. As MET is a potential therapeutic target, information regarding its prevalence and clinicopathological relevance is crucial. MATERIALS AND METHODS We investigated MET expression and gene amplification in 113 gallbladder cancers using tissue microarray. Immunohistochemistry was used to evaluate MET overexpression, and silver/fluorescence in situ hybridization (ISH) was used to assess gene copy number. RESULTS MET overexpression was found in 37 cases of gallbladder carcinoma (39.8%), and gene amplification was present in 17 cases (18.3%). MET protein expression did not correlate with MET amplification. MET amplification was significantly associated with aggressive clinicopathological features, including high histological grade, advanced pT category, lymph node metastasis, and advanced American Joint Committee on Cancer stage. There was no significant correlation between any clinicopathological factors and MET overexpression. No difference in survival was found with respect to MET overexpression and amplification status. CONCLUSION Our data suggested that MET might be a potential therapeutic target for targeted therapy in gallbladder cancer, because MET amplification was found in a subset of tumors associated with adverse prognostic factors. Detection of MET amplification by ISH might be a useful predictive biomarker test for anti-MET therapy.
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Affiliation(s)
- Yeseul Kim
- Department of Pathology, Hanyang University College of Medicine, Seoul, Korea
| | - Seong Sik Bang
- Department of Pathology, Hanyang University College of Medicine, Seoul, Korea
| | - Seungyun Jee
- Department of Pathology, Hanyang University College of Medicine, Seoul, Korea
| | - Sungeon Park
- Department of Pathology, Hanyang University College of Medicine, Seoul, Korea
| | - Su-Jin Shin
- Department of Pathology, Hanyang University College of Medicine, Seoul, Korea
| | - Kiseok Jang
- Department of Pathology, Hanyang University College of Medicine, Seoul, Korea
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24
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Hui R, Pearson A, Cortes J, Campbell C, Poirot C, Azim HA, Fumagalli D, Lambertini M, Daly F, Arahmani A, Perez-Garcia J, Aftimos P, Bedard PL, Xuereb L, Scheepers ED, Vicente M, Goulioti T, Loibl S, Loi S, Pierrat MJ, Turner NC, Andre F, Curigliano G. Lucitanib for the Treatment of HR+/HER2− Metastatic Breast Cancer: Results from the Multicohort Phase II FINESSE Study. Clin Cancer Res 2019; 26:354-363. [DOI: 10.1158/1078-0432.ccr-19-1164] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 07/04/2019] [Accepted: 10/09/2019] [Indexed: 11/16/2022]
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25
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Morgensztern D, Karaseva N, Felip E, Delgado I, Burdaeva O, Dómine M, Lara P, Paik PK, Lassen U, Orlov S, Trigo J, Shomova M, Baker-Neblett K, Vasquez J, Wang X, Yan L, Mitrica I, DeYoung MP, Garrido P. An open-label phase IB study to evaluate GSK3052230 in combination with paclitaxel and carboplatin, or docetaxel, in FGFR1-amplified non-small cell lung cancer. Lung Cancer 2019; 136:74-79. [PMID: 31446228 DOI: 10.1016/j.lungcan.2019.08.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 07/11/2019] [Accepted: 08/13/2019] [Indexed: 11/29/2022]
Abstract
OBJECTIVES GSK3052230 (FP-1039) is a soluble fusion protein that acts as ligand trap sequestering fibroblast growth factors (FGFs) involved in tumor growth and angiogenesis, while sparing the hormonal FGFs. Because of this selectivity, the molecule is predicted to avoid toxicities associated with small molecule inhibitors of FGFR, including hyperphosphatemia and retinal, nail, and skin toxicities. Herein we report the results of a phase 1b study where GSK3052330 was administered with standard of care chemotherapy in FGFR1-amplified squamous non-small cell lung cancer (sqNSCLC) patients. METHODS AND METHODS Eligible patients with stage IV or recurrent metastatic sqNSCLC harboring FGFR1 gene amplification received escalating doses of GSK3052230 in combination with paclitaxel and carboplatin at the starting doses 200 mg/m2 and AUC of 6, respectively, in the first line setting (Arm A) or docetaxel 75 mg/m2 in second line (Arm B). The primary endpoints of the study were safety and tolerability, to identify a maximum tolerated dose (MTD), and to assess overall response rate (ORR) based on investigator assessment. RESULTS Twenty-nine patients were enrolled into the study, including 20 patients on Arm A and 9 patients on Arm B. There were no dose limiting toxicities in either Arm and the MTD was not reached. The most common adverse events (AEs) were compatible with the chemotherapy backbone used in each Arm, including neutropenia, alopecia, nausea, arthralgia, asthenia, diarrhea and peripheral neuropathy. The overall response rate and median progression-free survival were 47% and 5.5 months, respectively, for Arm A and 0% and 4.6 months, respectively, for Arm B. CONCLUSION GSK3052230 is a novel FGFR pathway inhibitor, which is well tolerated in combination with chemotherapy. Importantly, AEs associated with small molecule inhibitors of FGFR were not observed, as predicted by the unique mechanism of action of this drug.
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Affiliation(s)
| | - Nina Karaseva
- St. Petersburg City Oncology Dispensary, St. Petersburg, Russian Federation
| | - Enriqueta Felip
- Servicio de Oncologia, Hospital General Universitario Vall d'Hebron, Barcelona, Spain
| | | | - Olga Burdaeva
- Arkhangelsk Regional Oncology Dispensary, Arkhangelsk, Russian Federation
| | | | - Primo Lara
- University of California, Davis Medical Center, Sacramento, CA, USA
| | - Paul K Paik
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ulrik Lassen
- Department of Oncology Rigshospitalet, Copenhagen, Denmark
| | - Sergey Orlov
- First Pavlov State Medical University, St. Petersburg, Russian Federation
| | - José Trigo
- Hospital Universitario Virgen de la Victoria, Málaga, Spain
| | - Marina Shomova
- Regional Clinical Oncology Dispensary, Ryazan, Russian Federation
| | | | | | | | - Li Yan
- GlaxoSmithKline, Inc., Collegeville, PA, USA
| | | | | | - Pilar Garrido
- Medical Oncology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain.
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26
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Bordi P, Del Re M, Minari R, Rofi E, Buti S, Restante G, Squadrilli A, Crucitta S, Casartelli C, Gnetti L, Azzoni C, Bottarelli L, Petrini I, Cosenza A, Ferri L, Rapacchi E, Danesi R, Tiseo M. From the beginning to resistance: Study of plasma monitoring and resistance mechanisms in a cohort of patients treated with osimertinib for advanced T790M-positive NSCLC. Lung Cancer 2019; 131:78-85. [PMID: 31027702 DOI: 10.1016/j.lungcan.2019.03.017] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 03/16/2019] [Accepted: 03/18/2019] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Analysis of circulating tumor DNA (ctDNA) for the identification of T790M mutation in advanced EGFR-mutated NSCLC patients can replace tissue re-biopsy for resistance characterization and, being non-invasive, may be applied for disease monitoring. We analysed ctDNA during osimertinib treatment to correlate mutational levels with clinical outcome and to predict pattern of resistance. MATERIALS AND METHODS Forty patients with advanced NSCLC receiving osimertinib for T790M + disease after previous EGFR-TKI were enrolled in a pilot study to collect plasma at baseline and every 12 weeks until progression. Molecular analysis of ctDNA was performed by ddPCR and Therascreen®. When feasible at progression, tissue re-biopsy and NGS analysis were performed. RESULTS Thirty-eight patients had baseline plasma samples suitable for molecular analysis. Patients with low levels of the EGFR activating mutation in ctDNA [< 2200 copies/mL or allele frequency (AF) < 6.1%] showed better progression-free survival (17.8 or 17.8 months vs. 4.3 or 2.7, p = 0.022 or p = 0.018, respectively) and overall survival (23.6 or 23.6 vs. 7.7 or 7.3, p = 0.016 or p = 0.013, respectively) than patients with high levels (≥ 2200 copies/mL or AF ≥ 6.1%). Patients with detectable EGFR mutations in plasma (shedders) presented worse outcome than negative subjects (non-shedders). Low levels of T790M, higher T790M/activating mutation ratio and complete clearance after 2 months were associated with a trend towards better outcome. Tissue re-biopsy at resistance showed 3 patients with EGFR C797S, 1 with MET amplification, 1 with MYC amplification, 1 with PTEN loss, 3 with SCLC transformation. CONCLUSIONS The mutational analysis performed on plasma plays a significant role in prognostic stratification, especially for the EGFR activating mutation, since patients with absence or low levels of mutations presented a better outcome to osimertinib. At progression, tissue re-biopsy remains a crucial issue for the identification of resistance mechanisms.
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Affiliation(s)
- Paola Bordi
- Medical Oncology Unit, University Hospital of Parma, Italy
| | - Marzia Del Re
- Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Italy
| | - Roberta Minari
- Medical Oncology Unit, University Hospital of Parma, Italy.
| | - Eleonora Rofi
- Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Italy
| | | | - Giuliana Restante
- Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Italy
| | | | - Stefania Crucitta
- Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Italy
| | | | - Letizia Gnetti
- Pathology Unit, Department of Medicine and Surgery, University Hospital of Parma, Parma, Italy
| | - Cinzia Azzoni
- Pathology Unit, Department of Medicine and Surgery, University Hospital of Parma, Parma, Italy
| | - Lorena Bottarelli
- Pathology Unit, Department of Medicine and Surgery, University Hospital of Parma, Parma, Italy
| | - Iacopo Petrini
- Department of Translational Medicine and New Technologies, University of Pisa, Italy
| | - Agnese Cosenza
- Medical Oncology Unit, University Hospital of Parma, Italy
| | - Leonarda Ferri
- Medical Oncology Unit, University Hospital of Parma, Italy
| | - Elena Rapacchi
- Medical Oncology Unit, University Hospital of Parma, Italy
| | - Romano Danesi
- Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Italy
| | - Marcello Tiseo
- Medical Oncology Unit, University Hospital of Parma, Italy; Department of Medicine and Surgery, University of Parma, Parma, Italy
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Scheffler M, Ihle MA, Hein R, Merkelbach-Bruse S, Scheel AH, Siemanowski J, Brägelmann J, Kron A, Abedpour N, Ueckeroth F, Schüller M, Koleczko S, Michels S, Fassunke J, Pasternack H, Heydt C, Serke M, Fischer R, Schulte W, Gerigk U, Nogova L, Ko YD, Abdulla DSY, Riedel R, Kambartel KO, Lorenz J, Sauerland I, Randerath W, Kaminsky B, Hagmeyer L, Grohé C, Eisert A, Frank R, Gogl L, Schaepers C, Holzem A, Hellmich M, Thomas RK, Peifer M, Sos ML, Büttner R, Wolf J. K-ras Mutation Subtypes in NSCLC and Associated Co-occuring Mutations in Other Oncogenic Pathways. J Thorac Oncol 2018; 14:606-616. [PMID: 30605727 DOI: 10.1016/j.jtho.2018.12.013] [Citation(s) in RCA: 184] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 10/31/2018] [Accepted: 12/10/2018] [Indexed: 12/23/2022]
Abstract
INTRODUCTION Although KRAS mutations in NSCLC have been considered mutually exclusive driver mutations for a long time, there is now growing evidence that KRAS-mutated NSCLC represents a genetically heterogeneous subgroup. We sought to determine genetic heterogeneity with respect to cancer-related co-mutations and their correlation with different KRAS mutation subtypes. METHODS Diagnostic samples from 4507 patients with NSCLC were analyzed by next-generation sequencing by using a panel of 14 genes and, in a subset of patients, fluorescence in situ hybridization. Next-generation sequencing with an extended panel of 14 additional genes was performed in 101 patients. Molecular data were correlated with clinical data. Whole-exome sequencing was performed in two patients. RESULTS We identified 1078 patients with KRAS mutations, of whom 53.5% had at least one additional mutation. Different KRAS mutation subtypes showed different patterns of co-occurring mutations. Besides mutations in tumor protein p53 gene (TP53) (39.4%), serine/threonine kinase 11 gene (STK11) (19.8%), kelch like ECH associated protein 1 gene (KEAP1) (12.9%), and ATM serine/threonine kinase gene (ATM) (11.9%), as well as MNNG HOS Transforming gene (MET) amplifications (15.4%) and erb-b2 receptor tyrosine kinase 2 gene (ERBB2) amplifications (13.8%, exclusively in G12C), we found rare co-occurrence of targetable mutations in EGFR (1.2%) and BRAF (1.2%). Whole-exome sequencing of two patients with co-occurring phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA) mutation revealed clonality of mutated KRAS in one patient and subclonality in the second, suggesting different evolutionary backgrounds. CONCLUSION KRAS-mutated NSCLC represents a genetically heterogeneous subgroup with a high frequency of co-occurring mutations in cancer-associated pathways, partly associated with distinct KRAS mutation subtypes. This diversity might have implications for understanding the variability of treatment outcome in KRAS-mutated NSCLC and for future trial design.
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Affiliation(s)
- Matthias Scheffler
- University Hospital of Cologne, Lung Cancer Group Cologne, Department I of Internal Medicine, Cologne, Germany
| | - Michaela A Ihle
- University of Cologne, Cologne Institute of Pathology, Cologne, Germany
| | - Rebecca Hein
- University of Cologne, Institute of Medical Statistics, Informatics and Epidemiology, Cologne, Germany
| | | | - Andreas H Scheel
- University of Cologne, Cologne Institute of Pathology, Cologne, Germany
| | - Janna Siemanowski
- University of Cologne, Cologne Institute of Pathology, Cologne, Germany
| | - Johannes Brägelmann
- University of Cologne, Department for Translational Genomics, Cologne, Germany
| | - Anna Kron
- University Hospital of Cologne, Lung Cancer Group Cologne, Department I of Internal Medicine, Cologne, Germany
| | - Nima Abedpour
- University of Cologne, Department for Translational Genomics, Cologne, Germany
| | - Frank Ueckeroth
- University of Cologne, Cologne Institute of Pathology, Cologne, Germany
| | - Merle Schüller
- University Hospital of Cologne, Lung Cancer Group Cologne, Department I of Internal Medicine, Cologne, Germany
| | - Sophia Koleczko
- University Hospital of Cologne, Lung Cancer Group Cologne, Department I of Internal Medicine, Cologne, Germany
| | - Sebastian Michels
- University Hospital of Cologne, Lung Cancer Group Cologne, Department I of Internal Medicine, Cologne, Germany
| | - Jana Fassunke
- University of Cologne, Cologne Institute of Pathology, Cologne, Germany
| | - Helen Pasternack
- Pathology of the University Medical Center Schleswig-Holstein, Campus Luebeck and Research Center Borstel, Leibniz Center for Medicine and Biosciences
| | - Carina Heydt
- University of Cologne, Cologne Institute of Pathology, Cologne, Germany
| | - Monika Serke
- Lung Clinic Hemer, Department for Pulmonology and Thoracic Oncology, Hemer, Germany
| | - Rieke Fischer
- University Hospital of Cologne, Lung Cancer Group Cologne, Department I of Internal Medicine, Cologne, Germany
| | | | - Ulrich Gerigk
- GFO Clinics Bonn, Marien-Hospital Bonn, Bonn, Germany
| | - Lucia Nogova
- University Hospital of Cologne, Lung Cancer Group Cologne, Department I of Internal Medicine, Cologne, Germany
| | - Yon-Dschun Ko
- Evangelical Clinics of Bonn, Johanniter Hospital, Bonn, Germany
| | - Diana S Y Abdulla
- University Hospital of Cologne, Lung Cancer Group Cologne, Department I of Internal Medicine, Cologne, Germany
| | - Richard Riedel
- University Hospital of Cologne, Lung Cancer Group Cologne, Department I of Internal Medicine, Cologne, Germany
| | | | - Joachim Lorenz
- Hospital Lüdenscheid, Clinic for Pneumology, Internistic Intensive Medicine, Infectiology and Sleep Medicine, Lüdenscheid, Germany
| | - Imke Sauerland
- Hospital Lüdenscheid, Clinic for Pneumology, Internistic Intensive Medicine, Infectiology and Sleep Medicine, Lüdenscheid, Germany
| | - Winfried Randerath
- Bethanien Hospital Solingen, Clinic for Pulmonology and Allergology, Solingen, Germany
| | - Britta Kaminsky
- Bethanien Hospital Solingen, Clinic for Pulmonology and Allergology, Solingen, Germany
| | - Lars Hagmeyer
- Bethanien Hospital Solingen, Clinic for Pulmonology and Allergology, Solingen, Germany
| | - Christian Grohé
- Evangelic Lung Clinic Berlin, Department of Respiratory Diseases, Berlin, Germany
| | - Anna Eisert
- University Hospital of Cologne, Lung Cancer Group Cologne, Department I of Internal Medicine, Cologne, Germany
| | - Rieke Frank
- University Hospital of Cologne, Lung Cancer Group Cologne, Department I of Internal Medicine, Cologne, Germany
| | - Leonie Gogl
- University Hospital of Cologne, Lung Cancer Group Cologne, Department I of Internal Medicine, Cologne, Germany
| | - Carsten Schaepers
- University Hospital of Cologne, Lung Cancer Group Cologne, Department I of Internal Medicine, Cologne, Germany
| | - Alessandra Holzem
- University Hospital of Cologne, Lung Cancer Group Cologne, Department I of Internal Medicine, Cologne, Germany
| | - Martin Hellmich
- University of Cologne, Institute of Medical Statistics, Informatics and Epidemiology, Cologne, Germany
| | - Roman K Thomas
- University of Cologne, Department for Translational Genomics, Cologne, Germany
| | - Martin Peifer
- University of Cologne, Department for Translational Genomics, Cologne, Germany
| | - Martin L Sos
- University of Cologne, Department for Translational Genomics, Cologne, Germany
| | - Reinhard Büttner
- University of Cologne, Cologne Institute of Pathology, Cologne, Germany
| | - Jürgen Wolf
- University Hospital of Cologne, Lung Cancer Group Cologne, Department I of Internal Medicine, Cologne, Germany.
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Ryu HJ, Kim EK, Cho BC, Yoon SO. Characterization of head and neck squamous cell carcinoma arising in young patients: Particular focus on molecular alteration and tumor immunity. Head Neck 2018; 41:198-207. [DOI: 10.1002/hed.25507] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Revised: 05/08/2018] [Accepted: 07/12/2018] [Indexed: 12/16/2022] Open
Affiliation(s)
- Hyang Joo Ryu
- Department of PathologyYonsei University College of Medicine Seoul South Korea
| | - Eun Kyung Kim
- Department of PathologyYonsei University College of Medicine Seoul South Korea
- Department of PathologyNational Health Insurance Service Ilsan Hospital Goyang South Korea
| | - Byoung Chul Cho
- Division of Medical Oncology, Yonsei Cancer CenterYonsei University College of Medicine Seoul South Korea
| | - Sun Och Yoon
- Department of PathologyYonsei University College of Medicine Seoul South Korea
- Division of Medical Oncology, Yonsei Cancer CenterYonsei University College of Medicine Seoul South Korea
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29
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Fromme JE, Schmitz K, Wachter A, Grzelinski M, Zielinski D, Koppel C, Conradi LC, Homayounfar K, Hugo T, Hugo S, Lukat L, Rüschoff J, Ströbel P, Ghadimi M, Beißbarth T, Reuter-Jessen K, Bleckmann A, Schildhaus HU. FGFR3 mRNA overexpression defines a subset of oligometastatic colorectal cancers with worse prognosis. Oncotarget 2018; 9:32204-32218. [PMID: 30181810 PMCID: PMC6114946 DOI: 10.18632/oncotarget.25941] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Accepted: 07/12/2018] [Indexed: 12/31/2022] Open
Abstract
Objectives Metastatic colorectal cancer (CRC) remains a leading cause of cancer related deaths. Patients with oligometastatic liver disease represent a clinical subgroup with heterogeneous course. Until now, biomarkers to characterize outcome and therapeutic options have not been fully established. Methods We investigated the prevalence of FGFR alterations in a total of 140 primary colorectal tumors and 63 liver metastases of 55 oligometastatic CRC patients. FGF receptors (FGFR1-4) and their ligands (FGF3, 4 and 19) were analyzed for gene amplifications and rearrangements as well as for RNA overexpression in situ. Results were correlated with clinico-pathologic data and molecular subtypes. Results Primary tumors showed FGFR1 (6.3%) and FGF3,4,19 (2.2%) amplifications as well as FGFR1 (10.1%), FGFR2 (5.5%) and FGFR3 (16.2%) overexpression. In metastases, we observed FGFR1 amplifications (4.8%) as well as FGFR1 (8.5%) and FGFR3 (14.9%) overexpression. Neither FGFR2-4 amplifications nor gene rearrangements were observed. FGFR3 overexpression was significantly associated with shorter overall survival in metastases (mOS 19.9 vs. 47.4 months, HR=3.14, p=0.0152), but not in primary CRC (HR=1.01, p=0.985). Although rare, also FGFR1 amplification was indicative of worse outcome (mOS 12.6 vs. 47.4 months, HR=8.83, p=0.00111). Conclusions We provide the so far most comprehensive analysis of FGFR alterations in primary and metastatic CRC. We describe FGFR3 overexpression in 15% of CRC patients with oligometastatic liver disease as a prognosticator for poor outcome. Recently FGFR3 overexpression has been shown to be a potential therapeutic target. Therefore, we suggest focusing on this subgroup in upcoming clinical trials with FGFR-targeted therapies.
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Affiliation(s)
| | - Katja Schmitz
- Institute of Pathology, University Hospital Göttingen, Göttingen, Germany
| | - Astrid Wachter
- Department of Medical Statistics, University Medical Center Göttingen, Göttingen, Germany
| | | | | | | | - Lena-Christin Conradi
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Georg-August-University, Goettingen, Germany
| | - Kia Homayounfar
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Georg-August-University, Goettingen, Germany
| | - Tabea Hugo
- Institute of Pathology, University Hospital Göttingen, Göttingen, Germany
| | - Sara Hugo
- Institute of Pathology, University Hospital Göttingen, Göttingen, Germany
| | - Laura Lukat
- Institute of Pathology, University Hospital Göttingen, Göttingen, Germany
| | | | - Philipp Ströbel
- Institute of Pathology, University Hospital Göttingen, Göttingen, Germany
| | - Michael Ghadimi
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Georg-August-University, Goettingen, Germany
| | - Tim Beißbarth
- Department of Medical Statistics, University Medical Center Göttingen, Göttingen, Germany
| | | | - Annalen Bleckmann
- Department of Medical Statistics, University Medical Center Göttingen, Göttingen, Germany.,Department for Hematology and Medical Oncology, University Hospital Göttingen, Göttingen, Germany
| | - Hans-Ulrich Schildhaus
- Institute of Pathology, University Hospital Göttingen, Göttingen, Germany.,Targos Molecular Pathology Inc., Kassel, Germany
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Abstract
Unlike for adenocarcinomas of the lung, no molecular targeted therapies have yet been developed for squamous cell lung cancers, because targetable oncogenic aberrations are scarce in this tumor type. Recent discoveries have established that the fibroblast growth factor (FGF) signaling pathway plays a fundamental role in cancer development by supporting tumor angiogenesis and cancer cell proliferation via different mechanisms. Through comprehensive genomic studies, aberrations in the FGF pathway have been identified in various tumor types, including squamous cell lung cancer, making FGF receptor (FGFR) a potentially druggable target in this malignancy. Several multi-targeted tyrosine kinase inhibitors include FGFR in their target spectrum and a number of these compounds have been approved for clinical use in different cancers. Novel agents selectively targeting FGFRs have been developed and are currently under investigation in clinical trials, showing promising results. This article reviews FGFR aberrations and the clinical data involving selective and multikinase FGFR inhibitors in squamous cell lung cancer.
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31
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Mikesch JH, Hartmann W, Angenendt L, Huber O, Schliemann C, Arteaga MF, Wardelmann E, Rudack C, Berdel WE, Stenner M, Grünewald I. AAA+ ATPases Reptin and Pontin as potential diagnostic and prognostic biomarkers in salivary gland cancer - a short report. Cell Oncol (Dordr) 2018; 41:455-462. [PMID: 29873033 DOI: 10.1007/s13402-018-0382-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/09/2018] [Indexed: 12/19/2022] Open
Abstract
PURPOSE Salivary gland cancer (SGC) is a rare and heterogeneous disease with significant differences in recurrence and metastasis characteristics. As yet, little is known about the mechanisms underlying the initiation and/or progression of these diverse tumors. In recent years, the AAA+ ATPase family members Pontin (RuvBL1, Tip49a) and Reptin (RuvBL2, Tip49b) have been implicated in various processes, including transcription regulation, chromatin remodeling and DNA damage repair, that are frequently deregulated in cancer. The aim of this study was to assess the clinical and functional significance of Reptin and Pontin expression in SGC. METHODS Immunohistochemical staining of Pontin, Reptin, β-catenin, Cyclin D1, TP53 and MIB-1 was performed on a collection of 94 SGC tumor samples comprising 13 different histological subtypes using tissue microarrays. RESULTS We found that Reptin and Pontin were expressed in the majority of SGC samples across all histological subtypes. Patients with a high Reptin expression showed a significantly inferior 5-year overall survival rate compared to patients with a low Reptin expression (47.7% versus 78.3%; p = 0.033), whereas no such difference was observed for Pontin. A high Reptin expression strongly correlated with a high expression of the proliferation marker MIB-1 (p = 0.003), the cell cycle regulator Cyclin D1 (p = 0.006), accumulation of TP53 as a surrogate p53 mutation marker (p = 0.042) and cytoplasmic β-catenin expression (p = 0.002). Increased Pontin expression was found to significantly correlate with both cytoplasmic and nuclear β-catenin expression (p = 0.037 and p = 0.018, respectively), which is indicative for its oncogenic function. CONCLUSIONS Our results suggest a role of Reptin and Pontin in SGC tumor progression and/or patient survival. Therefore, SGC patients exhibiting a high Reptin expression may benefit from more aggressive therapeutic regimens. Future studies should clarify whether such patients may be considered for more radical surgery, extended adjuvant therapy and/or targeted therapy.
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Affiliation(s)
- Jan-Henrik Mikesch
- Department of Medicine A, University Hospital of Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany.
| | - Wolfgang Hartmann
- Gerhard-Domagk-Institute for Pathology, University Hospital of Münster, Albert Schweitzer Campus 1 D17, 48149, Münster, Germany
| | - Linus Angenendt
- Department of Medicine A, University Hospital of Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany
| | - Otmar Huber
- Department of Biochemistry II, Jena University Hospital, Nonnenplan 2, 07743, Jena, Germany
| | - Christoph Schliemann
- Department of Medicine A, University Hospital of Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany
| | - Maria Francisca Arteaga
- Department of Medicine A, University Hospital of Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany
| | - Eva Wardelmann
- Gerhard-Domagk-Institute for Pathology, University Hospital of Münster, Albert Schweitzer Campus 1 D17, 48149, Münster, Germany
| | - Claudia Rudack
- Department of Otorhinolaryngology, Head and Neck Surgery, School of Medicine, University Hospital of Münster, Kardinal-von-Galen-Ring 10, 48149, Münster, Germany
| | - Wolfgang E Berdel
- Department of Medicine A, University Hospital of Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany
| | - Markus Stenner
- Department of Otorhinolaryngology, Head and Neck Surgery, School of Medicine, University Hospital of Münster, Kardinal-von-Galen-Ring 10, 48149, Münster, Germany
| | - Inga Grünewald
- Gerhard-Domagk-Institute for Pathology, University Hospital of Münster, Albert Schweitzer Campus 1 D17, 48149, Münster, Germany.
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32
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Frank R, Scheffler M, Merkelbach-Bruse S, Ihle MA, Kron A, Rauer M, Ueckeroth F, König K, Michels S, Fischer R, Eisert A, Fassunke J, Heydt C, Serke M, Ko YD, Gerigk U, Geist T, Kaminsky B, Heukamp LC, Clement-Ziza M, Büttner R, Wolf J. Clinical and Pathological Characteristics of KEAP1- and NFE2L2-Mutated Non-Small Cell Lung Carcinoma (NSCLC). Clin Cancer Res 2018; 24:3087-3096. [PMID: 29615460 DOI: 10.1158/1078-0432.ccr-17-3416] [Citation(s) in RCA: 119] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Revised: 02/22/2018] [Accepted: 03/27/2018] [Indexed: 11/16/2022]
Abstract
Purpose:KEAP1 and NFE2L2 mutations are associated with impaired prognosis in a variety of cancers and with squamous cell carcinoma formation in non-small cell lung cancer (NSCLC). However, little is known about frequency, histology dependence, molecular and clinical presentation as well as response to systemic treatment in NSCLC.Experimental Design: Tumor tissue of 1,391 patients with NSCLC was analyzed using next-generation sequencing (NGS). Clinical and pathologic characteristics, survival, and treatment outcome of patients with KEAP1 or NFE2L2 mutations were assessed.Results:KEAP1 mutations occurred with a frequency of 11.3% (n = 157) and NFE2L2 mutations with a frequency of 3.5% (n = 49) in NSCLC patients. In the vast majority of patients, both mutations did not occur simultaneously. KEAP1 mutations were found mainly in adenocarcinoma (AD; 72%), while NFE2L2 mutations were more common in squamous cell carcinoma (LSCC; 59%). KEAP1 mutations were spread over the whole protein, whereas NFE2L2 mutations were clustered in specific hotspot regions. In over 80% of the patients both mutations co-occurred with other cancer-related mutations, among them also targetable aberrations like activating EGFR mutations or MET amplification. Both patient groups showed different patterns of metastases, stage distribution and performance state. No patient with KEAP1 mutation had a response on systemic treatment in first-, second-, or third-line setting. Of NFE2L2-mutated patients, none responded to second- or third-line therapy.Conclusions:KEAP1- and NFE2L2-mutated NSCLC patients represent a highly heterogeneous patient cohort. Both are associated with different histologies and usually are found together with other cancer-related, partly targetable, genetic aberrations. In addition, both markers seem to be predictive for chemotherapy resistance. Clin Cancer Res; 24(13); 3087-96. ©2018 AACR.
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Affiliation(s)
- Rieke Frank
- Lung Cancer Group Cologne, Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany.,Network Genomic Medicine (Lung Cancer), Cologne, Germany
| | - Matthias Scheffler
- Lung Cancer Group Cologne, Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany.,Network Genomic Medicine (Lung Cancer), Cologne, Germany
| | - Sabine Merkelbach-Bruse
- Network Genomic Medicine (Lung Cancer), Cologne, Germany.,Institute of Pathology, University Hospital of Cologne, Cologne, Germany
| | - Michaela A Ihle
- Network Genomic Medicine (Lung Cancer), Cologne, Germany.,Institute of Pathology, University Hospital of Cologne, Cologne, Germany
| | - Anna Kron
- Lung Cancer Group Cologne, Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany.,Institute of Pathology, University Hospital of Cologne, Cologne, Germany
| | - Michael Rauer
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.,Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD) Research Center and Systems Biology of Ageing Cologne, University of Cologne, Cologne, Germany
| | - Frank Ueckeroth
- Network Genomic Medicine (Lung Cancer), Cologne, Germany.,Institute of Pathology, University Hospital of Cologne, Cologne, Germany
| | - Katharina König
- Network Genomic Medicine (Lung Cancer), Cologne, Germany.,Institute of Pathology, University Hospital of Cologne, Cologne, Germany
| | - Sebastian Michels
- Lung Cancer Group Cologne, Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany.,Network Genomic Medicine (Lung Cancer), Cologne, Germany
| | - Rieke Fischer
- Lung Cancer Group Cologne, Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany.,Network Genomic Medicine (Lung Cancer), Cologne, Germany
| | - Anna Eisert
- Lung Cancer Group Cologne, Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany.,Network Genomic Medicine (Lung Cancer), Cologne, Germany
| | - Jana Fassunke
- Network Genomic Medicine (Lung Cancer), Cologne, Germany.,Institute of Pathology, University Hospital of Cologne, Cologne, Germany
| | - Carina Heydt
- Network Genomic Medicine (Lung Cancer), Cologne, Germany.,Institute of Pathology, University Hospital of Cologne, Cologne, Germany
| | - Monika Serke
- Network Genomic Medicine (Lung Cancer), Cologne, Germany.,Department for Pulmonology and Thoracic Oncology, Lung Clinic Hemer, Hemer, Germany
| | - Yon-Dschun Ko
- Network Genomic Medicine (Lung Cancer), Cologne, Germany.,Johanniter Hospital, Evangelical Clinics of Bonn, Bonn, Germany
| | - Ulrich Gerigk
- Network Genomic Medicine (Lung Cancer), Cologne, Germany.,Marien-Hospital Bonn, GFO Clinics Bonn, Bonn, Germany
| | - Thomas Geist
- Network Genomic Medicine (Lung Cancer), Cologne, Germany.,Center Practice for Lung and Bronchial Diseases, Düsseldorf, Germany
| | - Britta Kaminsky
- Network Genomic Medicine (Lung Cancer), Cologne, Germany.,Clinic for Pulmonology and Allergology, Bethanien Hospital Solingen, Solingen, Germany
| | - Lukas C Heukamp
- Network Genomic Medicine (Lung Cancer), Cologne, Germany.,Institute of Pathology, University Hospital of Cologne, Cologne, Germany
| | - Mathieu Clement-Ziza
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.,Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD) Research Center and Systems Biology of Ageing Cologne, University of Cologne, Cologne, Germany
| | - Reinhard Büttner
- Network Genomic Medicine (Lung Cancer), Cologne, Germany.,Institute of Pathology, University Hospital of Cologne, Cologne, Germany
| | - Jürgen Wolf
- Lung Cancer Group Cologne, Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany. .,Network Genomic Medicine (Lung Cancer), Cologne, Germany
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Park S, Lee M, Cho KJ, Kim SB, Roh JL, Choi SH, Nam SY, Kim SY, Song JS. Association Between Fibroblast Growth Factor Receptor 1 Gene Amplification and Human Papillomavirus Prevalence in Tonsillar Squamous Cell Carcinoma With Clinicopathologic Analysis. J Histochem Cytochem 2018; 66:511-522. [PMID: 29553868 DOI: 10.1369/0022155418761652] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Amplification of fibroblast growth factor receptor 1 ( FGFR1) has been reported in many squamous cell carcinomas, and human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma has been characterized as a distinct subset with favorable prognosis. Here, we investigated the FGFR1 amplification and HPV status in tonsillar squamous cell carcinoma (TSCC) and analyzed the clinical characteristics. HPV in situ hybridization (HPV ISH) and FGFR1 fluorescence in situ hybridization (FISH) were performed using tissue microarray from 89 cases of TSCC. Fourteen of 89 (15.7%) TSCC cases had FGFR1 amplification, and HPV was detected in 59 of 89 (66.3%) cases. FGFR1 amplification status was not associated with HPV positivity ( p=0.765). Outcomes were not significantly different between FGFR1 amplified and non-amplified patients. Although FGFR1 amplified patients ( n=4) in the HPV ISH-negative group ( n=30) had a tendency for poorer overall survival, no statistical significance was identified ( p=0.150, log-rank). FGFR1 protein overexpression showed better disease-free survival ( p=0.031, log-rank) in HPV-negative TSCC. This study suggests FGFR1 amplification may be important in the pathogenesis of TSCC regardless of HPV status.
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Affiliation(s)
- Soonchan Park
- Department of Radiology, Kyung Hee University Hospital at Gangdong, College of Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Miji Lee
- Department of Pathology, Veterans Health Service Medical Center, Seoul, Republic of Korea
| | - Kyung-Ja Cho
- Departments of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Sung Bae Kim
- Medical Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Jong-Lyel Roh
- Head and Neck Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Seung-Ho Choi
- Head and Neck Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Soon Yuhl Nam
- Head and Neck Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Sang Yoon Kim
- Head and Neck Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Joon Seon Song
- Departments of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
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Grünewald I, Trautmann M, Busch A, Bauer L, Huss S, Schweinshaupt P, Vollbrecht C, Odenthal M, Quaas A, Büttner R, Meyer MF, Beutner D, Hüttenbrink KB, Wardelmann E, Stenner M, Hartmann W. MDM2 and CDK4 amplifications are rare events in salivary duct carcinomas. Oncotarget 2018; 7:75261-75272. [PMID: 27662657 PMCID: PMC5342738 DOI: 10.18632/oncotarget.12127] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Accepted: 09/12/2016] [Indexed: 12/14/2022] Open
Abstract
Salivary duct carcinoma (SDC) is an aggressive adenocarcinoma of the salivary glands associated with poor clinical outcome. SDCs are known to carry TP53 mutations in about 50%, however, only little is known about alternative pathogenic mechanisms within the p53 regulatory network. Particularly, data on alterations of the oncogenes MDM2 and CDK4 located in the chromosomal region 12q13-15 are limited in SDC, while genomic rearrangements of the adjacent HMGA2 gene locus are well documented in subsets of SDCs. We here analyzed the mutational status of the TP53 gene, genomic amplification of MDM2, CDK4 and HMGA2 rearrangement/amplification as well as protein expression of TP53 (p53), MDM2 and CDK4 in 51 de novo and ex pleomorphic adenoma SDCs. 25 of 51 cases were found to carry TP53 mutations, associated with extreme positive immunohistochemical p53 staining levels in 13 cases. Three out of 51 tumors had an MDM2 amplification, one of them coinciding with a CDK4 amplification and two with a HMGA2 rearrangement/amplification. Two of the MDM2 amplifications occurred in the setting of a TP53 mutation. Two out of 51 cases showed a CDK4 amplification, one synchronously being MDM2 amplified and the other one displaying concurrent low copy number increases of both, MDM2 and HMGA2. In summary, we here show that subgroups of SDCs display genomic amplifications of MDM2 and/or CDK4, partly in association with TP53 mutations and rearrangement/amplification of HMGA2. Further research is necessary to clarify the role of chromosomal region 12q13-15 alterations in SDC tumorigenesis and their potential prognostic and therapeutic relevance.
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Affiliation(s)
- Inga Grünewald
- Department of Pathology, University Hospital Muenster, Muenster, Germany
| | - Marcel Trautmann
- Department of Pathology, University Hospital Muenster, Muenster, Germany
| | - Alina Busch
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Muenster, Muenster, Germany
| | - Larissa Bauer
- Department of Pathology, University Hospital Muenster, Muenster, Germany
| | - Sebastian Huss
- Department of Pathology, University Hospital Muenster, Muenster, Germany
| | | | - Claudia Vollbrecht
- Institute of Pathology, University Hospital Cologne, Cologne, Germany.,Current address: Institute of Pathology, Charité University Hospital Berlin, Berlin, Germany
| | | | - Alexander Quaas
- Institute of Pathology, University Hospital Cologne, Cologne, Germany
| | - Reinhard Büttner
- Institute of Pathology, University Hospital Cologne, Cologne, Germany
| | - Moritz F Meyer
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Cologne, Cologne, Germany
| | - Dirk Beutner
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Cologne, Cologne, Germany
| | - Karl-Bernd Hüttenbrink
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Cologne, Cologne, Germany
| | - Eva Wardelmann
- Department of Pathology, University Hospital Muenster, Muenster, Germany
| | - Markus Stenner
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Muenster, Muenster, Germany
| | - Wolfgang Hartmann
- Department of Pathology, University Hospital Muenster, Muenster, Germany
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Volpi CC, Gualeni AV, Pietrantonio F, Vaccher E, Carbone A, Gloghini A. Bright-field in situ hybridization detects gene alterations and viral infections useful for personalized management of cancer patients. Expert Rev Mol Diagn 2018; 18:259-277. [PMID: 29431533 DOI: 10.1080/14737159.2018.1440210] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Bright-field in situ hybridization (ISH) methods detect gene alterations that may improve diagnostic precision and personalized management of cancer patients. Areas covered: This review focuses on some bright-field ISH techniques for detection of gene amplification or viral infection that have already been introduced in tumor pathology, research and diagnostic practice. Other emerging ISH methods, for the detection of translocation, mRNA and microRNA have recently been developed and need both an optimization and analytical validation. The review also deals with their clinical applications and implications on the management of cancer patients. Expert commentary: The technology of bright-field ISH applications has advanced significantly in the last decade. For example, an automated dual-color assay was developed as a clinical test for selecting cancer patients that are candidates for personalized therapy. Recently an emerging bright-field gene-protein assay has been developed. This method simultaneously detects the protein, gene and centromeric targets in the context of tissue morphology, and might be useful in assessing the HER2 status particularly in equivocal cases or samples with heterogeneous tumors. The application of bright-field ISH methods has become the gold standard for the detection of tumor-associated viral infection as diagnostic or prognostic factors.
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Affiliation(s)
- Chiara C Volpi
- a Department of Pathology and Laboratory Medicine , Fondazione IRCCS, Istituto Nazionale dei Tumori , Milano , Italy
| | - Ambra V Gualeni
- a Department of Pathology and Laboratory Medicine , Fondazione IRCCS, Istituto Nazionale dei Tumori , Milano , Italy
| | - Filippo Pietrantonio
- b Department of Medical Oncology , Fondazione IRCCS, Istituto Nazionale dei Tumori , Milano , Italy
| | - Emanuela Vaccher
- c Department of Medical Oncology , Centro di Riferimento Oncologico, IRCCS, National Cancer Institute , Aviano , Italy
| | - Antonino Carbone
- d Department of Pathology , Centro di Riferimento Oncologico, IRCCS, National Cancer Institute , Aviano , Italy
| | - Annunziata Gloghini
- a Department of Pathology and Laboratory Medicine , Fondazione IRCCS, Istituto Nazionale dei Tumori , Milano , Italy
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36
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Baldia PH, Maurer A, Heide T, Rose M, Stoehr R, Hartmann A, Williams SV, Knowles MA, Knuechel R, Gaisa NT. Fibroblast growth factor receptor (FGFR) alterations in squamous differentiated bladder cancer: a putative therapeutic target for a small subgroup. Oncotarget 2018; 7:71429-71439. [PMID: 27669755 PMCID: PMC5342089 DOI: 10.18632/oncotarget.12198] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2016] [Accepted: 09/16/2016] [Indexed: 11/25/2022] Open
Abstract
Although drugable fibroblast growth factor receptor (FGFR) alterations in squamous cell carcinomas (SCC) of various entities are well known, little is known about FGFR modifications in squamous differentiated bladder cancer. Therefore, our study evaluated FGFR1-3 alterations as a putative therapeutic target in this subgroup. We analyzed 73 squamous differentiated bladder cancers (n = 10 pT2, n = 55 pT3, n = 8 pT4) for FGFR1-3 protein expression, FGFR1-3 copy number variations, FGFR3 chromosomal rearrangements (fluorescence in situ hybridization (FISH)) and FGFR3 mutations (SNapShot analysis). Only single cases displayed enhanced protein expression, most frequently FGFR3 overexpression (9.4% (6/64)). FISH showed no amplifications of FGFR1, 2 or 3. Break apart events were only slightly above the cut off in 12.1% (8/66) of cases and no FGFR3-TACC3 rearrangements could be proven by qPCR. FGFR3 mutations (p.S249C) were found in 8.5% (6/71) of tumors and were significantly associated with FGFR3 protein overexpression (p < 0.001), and unfavourable clinical outcome (p = 0.001). Our findings are consistent with the results of the TCGA data set for the “squamous-like” subtype of bladder cancer (n = 85), which revealed reduced overall expression of FGFR1 and FGFR2 in tumors compared to normal tissue, while expression of FGFR3 remained high. In the TCGA “squamous-like” subtype FGFR3 mutations were found in 4.9% and correlated with high FGFR3 RNA expression. Mutations of FGFR1 and FGFR2 were less frequent (2.4% and 1.2%). Hence, our comprehensive study provides novel insights into a subgroup of squamous differentiated bladder tumors that hold clues for novel therapeutic regimens and may benefit from FGFR3-targeted therapies.
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Affiliation(s)
| | - Angela Maurer
- Institute of Pathology, RWTH Aachen University, Aachen, Germany
| | - Timon Heide
- Institute of Pathology, RWTH Aachen University, Aachen, Germany
| | - Michael Rose
- Institute of Pathology, RWTH Aachen University, Aachen, Germany
| | - Robert Stoehr
- Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University, Erlangen-Nuremberg, Erlangen, Germany
| | - Arndt Hartmann
- Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University, Erlangen-Nuremberg, Erlangen, Germany
| | - Sarah V Williams
- Section of Molecular Oncology, Leeds Institute of Cancer and Pathology, University of Leeds, St. James's University Hospital, United Kingdom
| | - Margaret A Knowles
- Section of Molecular Oncology, Leeds Institute of Cancer and Pathology, University of Leeds, St. James's University Hospital, United Kingdom
| | - Ruth Knuechel
- Institute of Pathology, RWTH Aachen University, Aachen, Germany
| | - Nadine T Gaisa
- Institute of Pathology, RWTH Aachen University, Aachen, Germany
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37
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Monico J, Miller B, Rezeanu L, May W, Sullivan DC. Fibroblast growth factor receptor 1 amplification in laryngeal squamous cell carcinoma. PLoS One 2018; 13:e0186185. [PMID: 29351293 PMCID: PMC5774678 DOI: 10.1371/journal.pone.0186185] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Accepted: 09/26/2017] [Indexed: 12/17/2022] Open
Abstract
Fibroblast growth factor receptor 1 (FGFR1) has been noted to be amplified in a variety of squamous cell carcinomas (SCCa) of the head, neck, and lung and increased copy number (CN) is a predictor of poor outcomes. FGFR1 is a therapeutic target for lung SCCa and inhibition therapy is currently in clinical trials. Absolute quantification of FGFR1 from formalin fixed paraffin embedded (FFPE) tissue of laryngeal SCCa was examined in this retrospective study. A droplet digital polymerase chain reaction (ddPCR) was used for absolute quantitation of the FGFR1 gene CN. Of the 74 samples analyzed, FGFR1 CN analysis revealed 54% of samples had CN greater than 2 copies/cell (1.8-2.2 copies/cell), and 38% had CN values greater than 3. The mean and standard deviation FGFR1 CN was 4.17 ± 1.46 CN for African American patients (n = 41) and 3.78 ±1.85 CN for Caucasian patients (n = 31). Further, 60.9% of specimens from African Americans demonstrated increased FGFR1 CN compared to 48.4% of Caucasians. Two SCCA samples from Native American demonstrated increased FGFR1 CN (4.19 and 3.01 CN). The level of FGFR1 amplification did not correlate with tumor stage, lymph node staging, or metastasis. In this population, the proportion of patient samples with an FGFR1 amplification was three times higher than in reported for SCCA of the head and neck. Further, increased FGFR1 CN was observed in two racial groups not previously reported: African Americans and Native Americans. However, FGFR1 amplification is not prognostic in laryngeal squamous cell carcinomas.
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Affiliation(s)
- Jesus Monico
- Department of Pathology, University of Mississippi Medical Center, Jackson, Mississippi, United States of America
| | - Brandon Miller
- Department of Otolaryngology and Communicative Sciences, University of Mississippi Medical Center, Jackson, Mississippi, United States of America
| | - Luminita Rezeanu
- Department of Pathology, University of Mississippi Medical Center, Jackson, Mississippi, United States of America
| | - Warren May
- Department of Biostatistics, University of Mississippi Medical Center, Jackson, Mississippi, United States of America
| | - Donna C. Sullivan
- Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, United States of America
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38
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Tao D, Han X, Zhang N, Lin D, Wu D, Zhu X, Song W, Shi Y. Genetic alteration profiling of patients with resected squamous cell lung carcinomas. Oncotarget 2017; 7:36590-36601. [PMID: 27145277 PMCID: PMC5095023 DOI: 10.18632/oncotarget.9096] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2016] [Accepted: 04/17/2016] [Indexed: 12/28/2022] Open
Abstract
In this study, we analyzed the genetic profiles of squamous cell lung carcinoma (SqCLC) to identify potential therapeutic targets. Approximately 2,800 COSMIC mutations from 50 genes were determined by next-generation sequencing. Amplification/deletion of SOX2, CDKN2A, PTEN, FGFR1, EGFR, CCND1, HER2 and PDGFRA were detected by FISH and expression of VEGFR2, PD-L1 and PTEN were examined by IHC. One hundred and fifty-seven samples of SqCLC were collected. Somatic mutations was identified in 73.9% of cases, with TP53 (56.1%), CDKN2A (8.9%), PIK3CA (8.9%), KRAS (4.5%) and EGFR (3.2%). Gene copy number alterations were identified in 75.8% of cases, including SOX2 amplification (31.2%), CDKN2A deletion (21.7%), PTEN deletion (16.6%), FGFR1 amplification (15.9%), EGFR amplification (14.0%), CCND1 amplification (14.0%), HER2 amplification (9.6%) and PDGFRA amplification (7.6%). Positive expression of VEGFR2 and PD-L1 and loss of PTEN expression were observed in 80.5%, 47.2%, and 42.7% of cases, respectively. Multivariate analysis showed that positive expression of PD-L1 was an independent favorable prognostic factor for DFS (HR = 0.610; P = 0.044). In conclusion, nearly all (93.6%) SqCLC cases harbored at least one potential druggable target. The findings of this study could facilitate the identification of therapeutic target candidates for precision medicine of SqCLC.
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Affiliation(s)
- Dan Tao
- Department of Medical Oncology, National Cancer Center/Cancer Hospital, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xiaohong Han
- Department of Medical Oncology, National Cancer Center/Cancer Hospital, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Ningning Zhang
- Department of Medical Oncology, National Cancer Center/Cancer Hospital, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Dongmei Lin
- Department of Pathology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Di Wu
- Department of Medical Oncology, National Cancer Center/Cancer Hospital, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xinxin Zhu
- Department of Pathology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Wenya Song
- Department of Medical Oncology, National Cancer Center/Cancer Hospital, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yuankai Shi
- Department of Medical Oncology, National Cancer Center/Cancer Hospital, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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Flockerzi FA, Roggia C, Langer F, Holleczek B, Bohle RM. FGFR1 gene amplification in squamous cell carcinomas of the lung: a potential favorable prognostic marker for women and for patients with advanced cancer. Virchows Arch 2017; 472:759-769. [PMID: 29270870 DOI: 10.1007/s00428-017-2282-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Revised: 11/30/2017] [Accepted: 12/11/2017] [Indexed: 12/01/2022]
Abstract
In squamous cell carcinoma (SCC) of the lung, mutations within the genes of fibroblast growth factor receptors (FGFR) such as K660N/K660E in FGFR2 and R248C/S249C in FGFR3 and FGFR1 gene amplification have been described, but their prognostic relevance still remains unclear. In order to detect the mutation frequencies and to define their prognostic value for associated clinicopathologic features and survival of patients, resected ΔNp63/p40-positive SCC of the lung (n = 101) were screened for FGFR1 gene amplification by fluorescence in situ hybridization performed on formalin-fixed paraffin embedded tissues and for the presumed driver mutations in genes of FGFR2 and FGFR3 by PCR and Sanger sequencing. Twenty-two of 101 SCCs (22%) were positive for amplification based on a FGFR1/centromere (chromosome 8) ratio > 2.0 or higher. In advanced tumor stages (III-IV), the overall survival of patients carrying FGFR1 gene amplification was significantly higher (p = 0.006). Among women, FGFR1 gene amplification was significantly associated with longer overall survival (p = 0.023). The presence of FGFR1 gene amplification was associated with patient age (65 versus 69 years, p = 0.046), but not with gender, tumor stage, histologic subtype, tumor grade, or ΔNp63/p40 immunoreactivity. The S249C mutation in the FGFR3 gene was identified in one out of 101 SCCs (1%); the K600N, K660E, or R248C mutations were not identified. These results suggest that FGFR1 gene amplification is a frequent alteration in SCC of the lung and appears not to be a negative but rather a favorable prognostic marker for women and particularly for patients with advanced SCC of the lung (stage III-IV).
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Affiliation(s)
- Fidelis Andrea Flockerzi
- Department of Pathology, Saarland University Medical Center, Homburg, Building 26, 66421, Homburg, Germany.
| | - Cristiana Roggia
- Department of Pathology, Saarland University Medical Center, Homburg, Building 26, 66421, Homburg, Germany.,Department of Interdisciplinary Division of Neuro-Oncology, University Hospital Tübingen, Tübingen, Germany
| | - Frank Langer
- Department of Thoracic and Cardiovascular Surgery, Saarland University Medical Center, Homburg, Germany
| | | | - Rainer M Bohle
- Department of Pathology, Saarland University Medical Center, Homburg, Building 26, 66421, Homburg, Germany.,Cancer Center Saarland, Saarland University Medical Center, Homburg, Germany
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40
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Helbig D, Ihle MA, Pütz K, Tantcheva-Poor I, Mauch C, Büttner R, Quaas A. Oncogene and therapeutic target analyses in atypical fibroxanthomas and pleomorphic dermal sarcomas. Oncotarget 2017; 7:21763-74. [PMID: 26943575 PMCID: PMC5008321 DOI: 10.18632/oncotarget.7845] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Accepted: 02/21/2016] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Until now, almost nothing is known about the tumorigenesis of atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS). Our hypothesis is that AFX is the non-infiltrating precursor lesion of PDS. MATERIALS AND METHODS We performed the world-wide most comprehensive immunohistochemical and mutational analysis in well-defined AFX (n=5) and PDS (n=5). RESULTS In NGS-based mutation analyses of selected regions by a 17 hotspot gene panel of 102 amplicons we could detect TP53 mutations in all PDS as well as in the only analyzed AFX and PDS of the same patient. Besides, we detected mutations in the CDKN2A, HRAS, KNSTRN and PIK3CA genes.Performing immunohistochemistry for CTNNB1, KIT, CDK4, c-MYC, CTLA-4, CCND1, EGFR, EPCAM, ERBB2, IMP3, INI-1, MKI67, MDM2, MET, p40, TP53, PD-L1 and SOX2 overexpression of TP53, CCND1 and CDK4 was seen in AFX as well as in PDS. IMP3 was upregulated in 2 AFX (weak staining) and 4 PDS (strong staining).FISH analyses for the genes FGFR1, FGFR2 and FGFR3 revealed negative results in all tumors. CONCLUSIONS UV-induced TP53 mutations as well as CCND1/CDK4 changes seem to play essential roles in tumorigenesis of PDS. Furthermore, we found some more interesting mutated genes in other oncogene pathways (activating mutations of HRAS and PIK3CA). All AFX and PDS investigated immunohistochemically presented with similar oncogene expression profiles (TP53, CCND1, CDK4 overexpression) and the single case with an AFX and PDS showed complete identical TP53 and PIK3CA mutation profiles in both tumors. This reinforces our hypothesis that AFX is the non-infiltrating precursor lesion of PDS.
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Affiliation(s)
- Doris Helbig
- Department of Dermatology, University Hospital Cologne, Cologne, Germany
| | | | - Katharina Pütz
- Institute of Pathology, University Hospital Cologne, Cologne, Germany
| | | | - Cornelia Mauch
- Department of Dermatology, University Hospital Cologne, Cologne, Germany
| | - Reinhard Büttner
- Institute of Pathology, University Hospital Cologne, Cologne, Germany
| | - Alexander Quaas
- Institute of Pathology, University Hospital Cologne, Cologne, Germany
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Boxberg M, Steiger K, Lenze U, Rechl H, von Eisenhart-Rothe R, Wörtler K, Weichert W, Langer R, Specht K. PD-L1 and PD-1 and characterization of tumor-infiltrating lymphocytes in high grade sarcomas of soft tissue - prognostic implications and rationale for immunotherapy. Oncoimmunology 2017; 7:e1389366. [PMID: 29399389 DOI: 10.1080/2162402x.2017.1389366] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Revised: 10/01/2017] [Accepted: 10/02/2017] [Indexed: 10/18/2022] Open
Abstract
Therapies targeting programmed death 1-(PD-1) or its ligand (PD-L1), promoting antitumor T-cell activity have been successfully introduced into clinical practice. Clinical response correlates with PD-L1 expression by tumor cells or immune cells within the tumor microenvironment. The PD-L1/PD-1 axis and tumor microenvironment has been rarely studied in high-grade sarcomas of soft tissue (hSTS), a group of rare, genetically heterogenous and clinically aggressive tumors. We examined PD-L1 protein and CD274/PD-L1 gene copy number variations in 128 primary resected, therapy-naive hSTS using immunohistochemistry and fluorescence-in-situ hybridization. Frequency of tumoral PD-L1 expression varied widely in different disease subentities, with highest rates of positivity (40%) seen in undifferentiated pleomorphic sarcomas (UPS) and rare positivity detected in synovial sarcomas (6%). Amplification of the CD274/PD-L1 gene occurred in 14% of UPS and was rare in other subtypes. PD-L1 protein expression was significantly more frequent in CD274/PD-L1 amplified cases (p = 0.015). The subgroup of UPS was further characterized regarding the interaction between PD-L1 and the immunologic tumor microenvironment. High density of CD3+ and CD8+ tumor infiltrating lymphocytes (TILs) was significantly correlated with the presence of PD-L1 expression and seen more frequently in tumors with lower TNM stage (p = 0.024). Both, PD-L1 expression and high density lymphocytic infiltration were independent prognostic factors for a favorable overall (p = 0.001, HR 6.105 (2.041-8.258)), disease-specific (p = 0.003, HR 10.536 (2.186-50.774)) and disease-free survival (p = 0.020, HR 3.317 (1.209-9.106); values for CD8) in this particular subgroup of hSTS, whereas PD-L1 expression in TILs or CD274/PD-L1 gene amplification were not associated with outcome. These findings represent novel insights into the immune landscape of soft tissue sarcomas, in particular UPS and strengthen the rationale for immunotherapy, including targeting the PD-1/PD-L1 axis in these tumors.
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Affiliation(s)
- Melanie Boxberg
- Institute of Pathology, Technical University of Munich, Munich, Germany
| | - Katja Steiger
- Institute of Pathology, Technical University of Munich, Munich, Germany
| | - Ulrich Lenze
- Department of Orthopedics, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Hans Rechl
- Department of Orthopedics, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | | | - Klaus Wörtler
- Department of Radiology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Wilko Weichert
- Institute of Pathology, Technical University of Munich, Munich, Germany.,National Center of Tumor Diseases (NCT), Heidelberg, University of Heidelberg, Germany.,Department of Pathology, German Cancer Consortium (DKTK), Partner Site Munich, Technical University of Munich, Munich, Germany
| | - Rupert Langer
- Institute of Pathology, University of Bern, Bern, Switzerland
| | - Katja Specht
- Institute of Pathology, Technical University of Munich, Munich, Germany
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Song Q, Liu Y, Jiang D, Wang H, Huang J, Xu Y, Sujie A, Zeng H, Xu C, Hou Y. High amplification of FGFR1 gene is a delayed poor prognostic factor in early stage ESCC patients. Oncotarget 2017; 8:74539-74553. [PMID: 29088806 PMCID: PMC5650361 DOI: 10.18632/oncotarget.20215] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Accepted: 06/29/2017] [Indexed: 11/29/2022] Open
Abstract
Amplification of the fibroblast growth factor receptor 1 (FGFR1) is believed to predict response to FGFR inhibitors. The aim of this study was to investigate the frequency and the prognostic impact of FGFR1 amplification in patients with resected esophageal squamous cell carcinoma (ESCC) by using fluorescent in situ hybridization. Microarrayed paraffin embedded blocks were constructed, and the cohort of tissues came from 506 patients with ESCC. FGFR1 high amplification (FGFR1high) was defined by an FGFR1/centromere 8 ratio of ≥ 2.0, or average number of FGFR1 signals/tumor cell nucleus ≥ 6.0, or percentage of tumor cells containing ≥ 15 FGFR1 signals, or large cluster in ≥ 10% of cancer cells. FGFR1 low amplification was defined by ≥ 5 FGFR1 signals in ≥ 50% of cancer cells. Kaplan-Meier curves with log-rank tests and Cox proportional hazards model were used to analyze patients’ survival. Among 506 patients, high amplification, low amplification, and disomy were detected in 8.7%, 3.6% and 87.7%, respectively. In general, the FGFR1high group trended towards worse disease-free survival (DFS) and overall survival (OS) compared to the FGFR1 low amplification/disomy (FGFR1low/disomy) group (DFS, P=0.108; OS, P=0.112), but this trend was amplified for patients with DFS ≥ 30 months (DFS, P=0.009; OS, P=0.007). Furthermore, when patients were stratified into stage I-II and stage III-IV, the FGFR1high group directly presented with adverse DFS and OS than the FGFR1low/disomy group in stage I-II patients (DFS, P=0.019; OS, P=0.034), especially with DFS ≥ 30 months (DFS, P=0.002; OS, P=0.001). However, for patients in stage III-IV, FGFR1high had no effect on prognosis regardless of DFS time. FGFR1high occurs in a minority of ESCC, and it predicts delayed poor prognosis in stage I and II ESCC patients.
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Affiliation(s)
- Qi Song
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, P. R. China
| | - Yalan Liu
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, P. R. China
| | - Dongxian Jiang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, P. R. China
| | - Haixing Wang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, P. R. China
| | - Jie Huang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, P. R. China
| | - Yifan Xu
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, P. R. China
| | - Akesu Sujie
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, P. R. China
| | - Haiying Zeng
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, P. R. China
| | - Chen Xu
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, P. R. China
| | - Yingyong Hou
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, P. R. China.,Department of Pathology, School of Basic Medical Sciences & Zhongshan Hospital, Fudan University, Shanghai 200032, P. R. China
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Chae YK, Arya A, Chiec L, Shah H, Rosenberg A, Patel S, Raparia K, Choi J, Wainwright DA, Villaflor V, Cristofanilli M, Giles F. Challenges and future of biomarker tests in the era of precision oncology: Can we rely on immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) to select the optimal patients for matched therapy? Oncotarget 2017; 8:100863-100898. [PMID: 29246028 PMCID: PMC5725070 DOI: 10.18632/oncotarget.19809] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 04/11/2017] [Indexed: 12/22/2022] Open
Abstract
Molecular techniques have improved our understanding of the pathogenesis of cancer development. These techniques have also fueled the rational development of targeted drugs for patient populations stratified by their genetic characteristics. These novel methods have changed the classic paradigm of diagnostic pathology; among them are IHC, FISH, polymerase chain reaction (PCR) and microarray technology. IHC and FISH detection methods for human epidermal growth factor receptor-2 (HER2), epidermal growth factor receptor (EGFR) and programmed death ligand-1 (PD-L1) were recently approved by the Food and Drug Administration (FDA) as routine clinical practice for cancer patients. Here, we discuss general challenges related to the predictive power of these molecular biomarkers for targeted therapy in cancer medicine. We will also discuss the prospects of utilizing new biomarkers for fibroblast growth factor receptor (FGFR) and hepatocyte growth factor receptor (cMET/MET) targeted therapies for developing new and robust predictive biomarkers in oncology.
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Affiliation(s)
- Young Kwang Chae
- Developmental Therapeutics Program of the Division of Hematology Oncology, Chicago, IL, USA.,Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.,Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Ayush Arya
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
| | - Lauren Chiec
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
| | - Hiral Shah
- Developmental Therapeutics Program of the Division of Hematology Oncology, Chicago, IL, USA
| | - Ari Rosenberg
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
| | - Sandip Patel
- University of California San Diego, San Diego, CA, USA
| | - Kirtee Raparia
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.,Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Jaehyuk Choi
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.,Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Derek A Wainwright
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.,Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Victoria Villaflor
- Developmental Therapeutics Program of the Division of Hematology Oncology, Chicago, IL, USA.,Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.,Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Massimo Cristofanilli
- Developmental Therapeutics Program of the Division of Hematology Oncology, Chicago, IL, USA.,Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.,Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Francis Giles
- Developmental Therapeutics Program of the Division of Hematology Oncology, Chicago, IL, USA.,Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.,Northwestern University Feinberg School of Medicine, Chicago, IL, USA
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44
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Michael M, Bang YJ, Park YS, Kang YK, Kim TM, Hamid O, Thornton D, Tate SC, Raddad E, Tie J. A Phase 1 Study of LY2874455, an Oral Selective pan-FGFR Inhibitor, in Patients with Advanced Cancer. Target Oncol 2017; 12:463-474. [PMID: 28589492 DOI: 10.1007/s11523-017-0502-9] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND We report here a phase 1 study of LY2874455, a potent oral selective pan-fibroblast growth factor receptor (FGFR) inhibitor. OBJECTIVE The primary objective was to determine the recommended phase 2 dosing (RP2D). Secondary objectives included determining toxicity, antitumor activity, pharmacokinetics (PK), and pharmacodynamic (PD) properties of LY2874455. PATIENTS AND METHODS This study comprised two parts: (a) dose escalation with 3 + 3 cohorts in patients with solid tumors and (b) dose-expansion cohorts in patients with gastric cancer (GC) and non-small cell lung cancer (NSCLC). Part A: 36 patients in 11 dose cohorts ranging from 2 to 24 mg twice daily (BID). RP2D was 16 mg BID. Part B: GC cohort, 29 patients, NSCLC cohort, 27 patients, all treated at the RP2D. RESULTS LY2874455 was slowly absorbed and generally showed linear PK. The effective half-life was ∼12 h. PD properties of LY2874455 occurred at doses ≥10 mg by increases in serum phosphorus. Phosphate binders were administered to control serum phosphorus. LY2874455 was generally well tolerated; most toxicities were grade 1 or 2; most frequent were hyperphosphatemia, diarrhea, and stomatitis. EFFICACY part A: 24 patients evaluable: 1 patient in the 14-mg BID cohort with GC had a partial response (PR); 14 patients had stable disease (SD); part B: NSCLC cohort: 11 of 12 evaluable patients had SD; GC cohort: 15 patients evaluable: 1 patient with PR; 12 patients with SD. CONCLUSIONS LY2874455 has an RP2D of 16 mg BID and demonstrated good tolerability and activity in solid-organ cancer patients. The role of FGFR inhibition on tumor growth in patients requires further study. (NCT01212107).
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Affiliation(s)
- Michael Michael
- Division of Cancer Medicine, Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC, 3000, Australia.
| | - Yung-Jue Bang
- Seoul National University College of Medicine, Seoul, South Korea
| | - Young Suk Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Seoul, South Korea
| | - Yoon-Koo Kang
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Tae Min Kim
- Seoul National University Hospital, Seoul, South Korea
| | - Oday Hamid
- Eli Lilly and Company, Indianapolis, IN, USA
| | | | - Sonya C Tate
- Eli Lilly and Company, Basingstoke, Hampshire, UK
| | - Eyas Raddad
- Eli Lilly and Company, Indianapolis, IN, USA
| | - Jeanne Tie
- Division of Cancer Medicine, Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC, 3000, Australia
- Royal Melbourne Hospital, Melbourne, Australia
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45
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Miao JL, Liu RJ, Zhou JH, Meng SH. Fibroblast Growth Factor Receptor 1 Gene Amplification in Nonsmall Cell Lung Cancer. Chin Med J (Engl) 2017; 129:2868-2872. [PMID: 27901003 PMCID: PMC5146797 DOI: 10.4103/0366-6999.194649] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Objective: To review the prevalence and prognostic significance of fibroblast growth factor receptor 1 (FGFR1) amplification and to establish an association between FGFR1 amplification and the clinical characteristics of nonsmall cell lung cancer (NSCLC). Data Sources: We searched PubMed for English-language studies published between January 2010 and May 2016. Study Selection: We included all relevant articles, with no limitation of study design. Results: FGFR1 amplification was reported in 8.7–20.0% of NSCLC cases and was significantly more frequent in squamous cell carcinomas (SCCs) (9.7–28.3%) than in adenocarcinomas (ADCs) (0–15.0%). The rates of FGFR1 amplification were as follows: males, 13.9–22.1%; females, 0–20.1%; Stage I NSCLC, 9.3–24.1%; Stage II NSCLC, 12.9–25.0%; Stage III NSCLC, 8.2–19.5%; Stage IV NSCLC, 0–12.5%; current smokers, 13.3–29.0%; former smokers, 2.5–23.0%; and nonsmokers, 0–22.2%. Overall survival was 43.9–70.8 months in patients with FGFR1 amplification and 42.4–115.0 months in patients with no FGFR1 amplification; disease-free survival was 22.5–58.5 months and 52.4–94.6 months, respectively. Conclusions: FGFR1 amplification is more frequent in SCCs than in ADCs. The association between FGFR1 amplification and clinical characteristics (gender, smoking status, and disease stage) and the prognostic significance of FGFR1 amplification in NSCLC remain controversial.
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Affiliation(s)
- Jian-Long Miao
- Department of Respiratory Medicine, Shandong Jining No. 1 People's Hospital, Jining, Shandong 272000, China
| | - Rui-Juan Liu
- Department of Respiratory Medicine, Shandong Jining No. 1 People's Hospital, Jining, Shandong 272000, China
| | - Jin-Hua Zhou
- Department of Respiratory Medicine, Shandong Jining No. 1 People's Hospital, Jining, Shandong 272000, China
| | - Shu-Hua Meng
- Zouping County Institute for Tuberculosis Prevention and Control, Binzhou, Shandong 256200, China
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Shim HS, Choi YL, Kim L, Chang S, Kim WS, Roh MS, Kim TJ, Ha SY, Chung JH, Jang SJ, Lee GK. Molecular Testing of Lung Cancers. J Pathol Transl Med 2017; 51:242-254. [PMID: 28427247 PMCID: PMC5445209 DOI: 10.4132/jptm.2017.04.10] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Accepted: 04/09/2017] [Indexed: 12/25/2022] Open
Abstract
Targeted therapies guided by molecular diagnostics have become a standard treatment of lung cancer. Epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements are currently used as the best predictive biomarkers for EGFR tyrosine kinase inhibitors and ALK inhibitors, respectively. Besides EGFR and ALK, the list of druggable genetic alterations has been growing, including ROS1 rearrangements, RET rearrangements, and MET alterations. In this situation, pathologists should carefully manage clinical samples for molecular testing and should do their best to quickly and accurately identify patients who will benefit from precision therapeutics. Here, we grouped molecular biomarkers of lung cancers into three categories—mutations, gene rearrangements, and amplifications—and propose expanded guidelines on molecular testing of lung cancers.
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Affiliation(s)
- Hyo Sup Shim
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
| | - Yoon-La Choi
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Lucia Kim
- Department of Pathology, Inha University School of Medicine, Incheon, Korea
| | - Sunhee Chang
- Department of Pathology, Inje University Ilsan Paik Hospital, Inje University, Goyang, Korea
| | - Wan-Seop Kim
- Department of Pathology, Konkuk University School of Medicine, Seoul, Korea
| | - Mee Sook Roh
- Department of Pathology, Dong-A University College of Medicine, Busan, Korea
| | - Tae-Jung Kim
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seung Yeon Ha
- Department of Pathology, Gachon University Gil Medical Center, Incheon, Korea
| | - Jin-Haeng Chung
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Se Jin Jang
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Geon Kook Lee
- Department of Pathology, National Cancer Center, Goyang, Korea
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Chudasama P, Renner M, Straub M, Mughal SS, Hutter B, Kosaloglu Z, Schweßinger R, Scheffler M, Alldinger I, Schimmack S, Persigehl T, Kobe C, Jäger D, von Kalle C, Schirmacher P, Beckhaus MK, Wolf S, Heining C, Gröschel S, Wolf J, Brors B, Weichert W, Glimm H, Scholl C, Mechtersheimer G, Specht K, Fröhling S. Targeting Fibroblast Growth Factor Receptor 1 for Treatment of Soft-Tissue Sarcoma. Clin Cancer Res 2017; 23:962-973. [PMID: 27535980 DOI: 10.1158/1078-0432.ccr-16-0860] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Revised: 07/12/2016] [Accepted: 07/28/2016] [Indexed: 11/16/2022]
Abstract
Purpose: Altered FGFR1 signaling has emerged as a therapeutic target in epithelial malignancies. In contrast, the role of FGFR1 in soft-tissue sarcoma (STS) has not been established. Prompted by the detection and subsequent therapeutic inhibition of amplified FGFR1 in a patient with metastatic leiomyosarcoma, we investigated the oncogenic properties of FGFR1 and its potential as a drug target in patients with STS.Experimental Design: The frequency of FGFR1 amplification and overexpression, as assessed by FISH, microarray-based comparative genomic hybridization and mRNA expression profiling, SNP array profiling, and RNA sequencing, was determined in three patient cohorts. The sensitivity of STS cell lines with or without FGFR1 alterations to genetic and pharmacologic FGFR1 inhibition and the signaling pathways engaged by FGFR1 were investigated using viability assays, colony formation assays, and biochemical analysis.Results: Increased FGFR1 copy number was detected in 74 of 190 (38.9%; cohort 1), 13 of 79 (16.5%; cohort 2), and 80 of 254 (31.5%; cohort 3) patients. FGFR1 overexpression occurred in 16 of 79 (20.2%, cohort 2) and 39 of 254 (15.4%; cohort 3) patients. Targeting of FGFR1 by RNA interference and small-molecule inhibitors (PD173074, AZD4547, BGJ398) revealed that the requirement for FGFR1 signaling in STS cells is dictated by FGFR1 expression levels, and identified the MAPK-ERK1/2 axis as critical FGFR1 effector pathway.Conclusions: These data identify FGFR1 as a driver gene in multiple STS subtypes and support FGFR1 inhibition, guided by patient selection according to the FGFR1 expression and monitoring of MAPK-ERK1/2 signaling, as a therapeutic option in this challenging group of diseases. Clin Cancer Res; 23(4); 962-73. ©2016 AACR.
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Affiliation(s)
- Priya Chudasama
- Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Marcus Renner
- Department of General Pathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Melanie Straub
- Institute of Pathology, Technische Universität München, Munich, Germany
| | - Sadaf S Mughal
- Division Applied Bioinformatics, DKFZ and NCT Heidelberg, Heidelberg, Germany
| | - Barbara Hutter
- Division Applied Bioinformatics, DKFZ and NCT Heidelberg, Heidelberg, Germany
| | - Zeynep Kosaloglu
- Clinical Cooperation Unit Applied Tumor Immunity, DKFZ and NCT Heidelberg, Heidelberg, Germany
| | - Ron Schweßinger
- Division Applied Bioinformatics, DKFZ and NCT Heidelberg, Heidelberg, Germany
| | - Matthias Scheffler
- Department of Internal Medicine I, Center for Integrated Oncology, Cologne University Hospital, Cologne, Germany
| | - Ingo Alldinger
- Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Simon Schimmack
- Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | | | - Carsten Kobe
- Department of Nuclear Medicine, Cologne University Hospital, Cologne, Germany
| | - Dirk Jäger
- Clinical Cooperation Unit Applied Tumor Immunity, DKFZ and NCT Heidelberg, Heidelberg, Germany.,Department of Internal Medicine VI, Heidelberg University Hospital, Heidelberg, Germany
| | - Christof von Kalle
- Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.,Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany.,German Cancer Consortium, Heidelberg, Germany.,DKFZ-Heidelberg Center for Personalized Oncology (HIPO), Heidelberg, Germany
| | - Peter Schirmacher
- Department of General Pathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.,German Cancer Consortium, Heidelberg, Germany
| | | | - Stephan Wolf
- German Cancer Consortium, Heidelberg, Germany.,Genomics and Proteomics Core Facility, DKFZ, Heidelberg, Germany
| | - Christoph Heining
- Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.,Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany
| | - Stefan Gröschel
- Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.,Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany
| | - Jürgen Wolf
- Department of Internal Medicine I, Center for Integrated Oncology, Cologne University Hospital, Cologne, Germany
| | - Benedikt Brors
- Division Applied Bioinformatics, DKFZ and NCT Heidelberg, Heidelberg, Germany.,German Cancer Consortium, Heidelberg, Germany
| | - Wilko Weichert
- Institute of Pathology, Technische Universität München, Munich, Germany.,German Cancer Consortium, Munich, Germany
| | - Hanno Glimm
- Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.,Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany.,German Cancer Consortium, Heidelberg, Germany
| | - Claudia Scholl
- Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.,German Cancer Consortium, Heidelberg, Germany
| | - Gunhild Mechtersheimer
- Department of General Pathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Katja Specht
- Institute of Pathology, Technische Universität München, Munich, Germany.,German Cancer Consortium, Munich, Germany
| | - Stefan Fröhling
- Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany. .,Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany.,German Cancer Consortium, Heidelberg, Germany
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48
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Pu D, Liu J, Li Z, Zhu J, Hou M. Fibroblast Growth Factor Receptor 1 (FGFR1), Partly Related to Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) and Microvessel Density, is an Independent Prognostic Factor for Non-Small Cell Lung Cancer. Med Sci Monit 2017; 23:247-257. [PMID: 28088809 PMCID: PMC5260665 DOI: 10.12659/msm.899005] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Background This study aimed to explore the correlation between FGFR1 and clinical features, including survival analysis and the promotion of angiogenesis by fibroblast growth factor receptor 1 (FGFR1) and vascular endothelial growth factor receptor 2 (VEGFR2). FGFR1 gene amplification has been found in non-small cell lung cancer (NSCLC). However, the prognostic value of FGFR1 and the correlation between FGFR1 and clinical features are still controversial. Material/Methods A total of 92 patients with NSCLC who underwent R0 resection between July 2006 and July 2008 were enrolled in the study. The expression of FGFR1, VEGFR2, and CD34 was detected by immunohistochemistry. The correlations between the aforementioned markers and the patients’ clinical features were analyzed by the chi-square test. The impact factors of prognosis were evaluated by Cox regression analyses. Results The expression ratios of FGFR1 and VEGFR2 were 26.1% and 43.4%, respectively. The intensity of FGFR1 expression was related to VEGFR2 and histopathology. To some extent, the average microvessel density (MVD) had correlation to the expression of FGFR1 and VGEFR2. The pathological stages III–IV and high expression of FGFR1 were found to be independent prognostic factors. Conclusions The expression intensity of FGFR1 and VEGFR2 was associated with MVD, and the expression of FGFR1 is one of the independent prognostic indicators for NSCLC.
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Affiliation(s)
- Dan Pu
- Lung Cancer Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China (mainland)
| | - Jiewei Liu
- Lung Cancer Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China (mainland)
| | - Zhixi Li
- Lung Cancer Centre, West China Hospital of Sichuan University, Chengdu, Sichuan, China (mainland)
| | - Jiang Zhu
- Department of Oncology, West China Hospital of Sichuan University, Chengdu, Sichuan, China (mainland)
| | - Mei Hou
- Lung Cancer Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China (mainland)
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49
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Kwon D, Yun JY, Keam B, Kim YT, Jeon YK. Prognostic implications of FGFR1 and MYC status in esophageal squamous cell carcinoma. World J Gastroenterol 2016; 22:9803-9812. [PMID: 27956804 PMCID: PMC5124985 DOI: 10.3748/wjg.v22.i44.9803] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2016] [Revised: 09/20/2016] [Accepted: 09/28/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the clinicopathological features and prognostic implications of combined MYC and fibroblast growth factor receptor 1 (FGFR1) status in esophageal squamous cell carcinomas (ESCCs).
METHODS All patients with ESCC (n = 180) underwent surgical resection at Seoul National University Hospital sometime between 2000 and 2013. A tissue microarray was constructed using cores obtained from representative tumor areas of formalin-fixed, paraffin-embedded tissue blocks. FGFR1 and MYC copy numbers were quantified using fluorescence in situ hybridization. The level of MYC expression was determined using immunohistochemistry. FGFR1 and MYC amplification status was compared between primary and metastatic lymph nodes. Univariate and multivariate survival analyses were performed according to adjuvant therapy status.
RESULTS FGFR1 and MYC amplifications were observed in 21.4% (37/173) and 54.2% (91/168) of patients, respectively, while MYC expression was observed in 58.9% (106/180) of patients. There was a positive correlation between MYC amplification and overexpression (P = 0.002). Although FGFR1 amplification was not associated with MYC amplification or expression, 12.3% (20/163) of patients exhibited both FGFR1 amplification and MYC expression. There was also a correlation in FGFR1 amplification status between matched primary tumors and metastatic lymph nodes (P < 0.001). MYC expression was higher in ESCCs with pT1 (P < 0.001) and in those with no lymph node metastasis (P = 0.023). MYC expression was associated with prolonged disease-free survival (P = 0.036) and overall survival (OS) (P = 0.017) but was not an independent prognostic factor. FGFR1 amplification was an independent predictor for prolonged OS in all patients (P = 0.029) and in those who did not receive adjuvant therapy (P = 0.013). Combined FGFR1 amplification and MYC expression predicted better OS in patients who did not receive adjuvant therapy (P = 0.034) but not in those who did receive adjuvant therapy.
CONCLUSION FGFR1 amplification and MYC expression have prognostic implications in resected ESCCs with respect to adjuvant therapy. The role of FGFR1-targeted therapy in ESCC remains to be explored.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Biomarkers, Tumor/genetics
- Carcinoma, Squamous Cell/genetics
- Carcinoma, Squamous Cell/mortality
- Carcinoma, Squamous Cell/pathology
- Carcinoma, Squamous Cell/therapy
- Chemoradiotherapy, Adjuvant
- Chemotherapy, Adjuvant
- Esophageal Neoplasms/genetics
- Esophageal Neoplasms/mortality
- Esophageal Neoplasms/pathology
- Esophageal Neoplasms/therapy
- Esophageal Squamous Cell Carcinoma
- Esophagectomy
- Female
- Gene Amplification
- Gene Dosage
- Genetic Predisposition to Disease
- Humans
- Immunohistochemistry
- In Situ Hybridization, Fluorescence
- Kaplan-Meier Estimate
- Lymphatic Metastasis
- Male
- Middle Aged
- Multivariate Analysis
- Neoadjuvant Therapy
- Phenotype
- Proportional Hazards Models
- Proto-Oncogene Proteins c-myc/genetics
- Radiotherapy, Adjuvant
- Receptor, Fibroblast Growth Factor, Type 1/genetics
- Retrospective Studies
- Risk Factors
- Time Factors
- Tissue Array Analysis
- Treatment Outcome
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50
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Chang H, Oh J, Zhang X, Kim YJ, Lee JH, Lee CT, Chung JH, Lee JS. EGFR protein expression using a specific intracellular domain antibody and PTEN and clinical outcomes in squamous cell lung cancer patients with EGFR-tyrosine kinase inhibitor therapy. Onco Targets Ther 2016; 9:5153-62. [PMID: 27578983 PMCID: PMC4998034 DOI: 10.2147/ott.s107291] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Purpose The aim of this research was to examine the molecular and clinical features that are related with EGFR-tyrosine kinase inhibitor (EGFR-TKI) efficacy in previously treated patients with squamous cell carcinoma of the lung (SCCL). Materials and methods This retrospective study included 67 SCCL patients with obtainable lung cancer tissue and records on EGFR-TKI treatment response and survival. EGFR protein expression in lung cancer tissue was measured by immunohistochemistry with a specific antibody that recognizes the intracellular domain (ID) of EGFR. PTEN expression in lung cancer tissue was also evaluated with immunohistochemistry. PI3KCA gene amplification was detected by quantitative real-time polymerase chain reaction, and FGFR1 amplification was assessed by fluorescent in situ hybridization. Results EGFR ID expression (hazard ratio [HR] 0.53, P=0.022) and Eastern Cooperative Oncology Group (ECOG) performance status (PS) (HR 0.43, P=0.022) were significantly related with progression-free survival following EGFR-TKIs treatment. PTEN expression (HR 0.52, P=0.025) was significantly related to overall survival. The group of EGFR-positive or PTEN-positive patients with ECOG PS of 0 or 1 had better clinical outcomes than patients who were EGFR-negative and PTEN-negative or who had poor ECOG PS with longer median progression-free survival (2.1 vs 1.0 months, P=0.05) and overall survival (6.2 vs 2.1 months, P=0.05). Conclusion EGFR expression using an ID-specific antibody and PTEN protein expression may be used to identify SCCL patients who might benefit from EGFR-TKI treatment.
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Affiliation(s)
- Hyun Chang
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam; Division of Medical Oncology, Department of Internal Medicine, International St Mary's Hospital, College of Medicine, Catholic Kwandong University, Incheon
| | - Jisu Oh
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam; Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Xianglan Zhang
- Department of Pathology, Yanbian University Hospital, Yanji, People's Republic of China
| | - Yu Jung Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam
| | - Jae Ho Lee
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam
| | - Choon-Taek Lee
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam
| | - Jin-Haeng Chung
- Department of Pathology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Jong-Seok Lee
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam
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