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1
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Jeyaprakash K, Kumaran M, Kim U, Santhi R, Muthukkaruppan V, Devarajan B, Vanniarajan A. Investigating druggable kinases for targeted therapy in retinoblastoma. J Hum Genet 2024; 69:467-474. [PMID: 38956221 DOI: 10.1038/s10038-024-01267-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 04/04/2024] [Accepted: 06/14/2024] [Indexed: 07/04/2024]
Abstract
Retinoblastoma (RB) is a childhood retinal neoplasm and commonly treated with cytotoxic chemotherapeutic agents. However, these therapeutic approaches often lead to diverse adverse effects. A precise molecular therapy will alleviate these side effects and offer better treatment outcomes. Over the years, kinases have become potential drug targets in cancer therapy. Hence, we aimed to investigate genetic alterations of putative kinase drug targets in RB. Targeted exome sequencing was performed on 35 RB tumors with paired blood samples using a gene panel consisting of 29 FDA-approved kinase genes. Single nucleotide variants were analyzed for pathogenicity using an in-house pipeline and copy number variations (CNVs) were detected by a depth of coverage and CNVPanelizer. The correlation between genetic changes and clinicopathological features was assessed using GraphPad Prism. Three somatic mutations, two in ERBB4 and one in EGFR were identified. Two of these mutations (ERBB4 c.C3836A & EGFR c.A1196T) were not reported earlier. CNV analysis revealed recurrent gains of ALK, MAP2K2, SRC, STK11, and FGFR3 as well as frequent losses of ATM, PI3KCA and ERBB4. Notably, nonresponsive tumors had a higher incidence of amplifications in clinically actionable genes such as ALK. Moreover, ALK gain and ATM loss were strongly correlated with optic nerve head invasion. In conclusion, our study revealed genetic alterations of druggable kinases in RB, providing preliminary insights for the exploration of kinase-targeted therapy in RB.
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Affiliation(s)
- Kumar Jeyaprakash
- Department of Molecular Genetics, Aravind Medical Research Foundation, Madurai, India
- Department of Molecular Biology, Aravind Medical Research Foundation, Affiliated to Alagappa University, Karaikudi, Tamil Nadu, India
| | - Manojkumar Kumaran
- Department of Bioinformatics, Aravind Medical Research Foundation, Madurai, India
| | - Usha Kim
- Department of Orbit, Oculoplasty and Oncology, Aravind Eye Hospital, Madurai, India
| | | | | | | | - Ayyasamy Vanniarajan
- Department of Molecular Genetics, Aravind Medical Research Foundation, Madurai, India.
- Department of Molecular Biology, Aravind Medical Research Foundation, Affiliated to Alagappa University, Karaikudi, Tamil Nadu, India.
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2
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La Salvia A, Meyer ML, Hirsch FR, Kerr KM, Landi L, Tsao MS, Cappuzzo F. Rediscovering immunohistochemistry in lung cancer. Crit Rev Oncol Hematol 2024; 200:104401. [PMID: 38815876 DOI: 10.1016/j.critrevonc.2024.104401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 05/23/2024] [Indexed: 06/01/2024] Open
Abstract
Several observations indicate that protein expression analysis by immunohistochemistry (IHC) remains relevant in individuals with non-small-cell lung cancer (NSCLC) when considering targeted therapy, as an early step in diagnosis and for therapy selection. Since the advent of next-generation sequencing (NGS), the role of IHC in testing for NSCLC biomarkers has been forgotten or ignored. We discuss how protein-level investigations maintain a critical role in defining sensitivity to lung cancer therapies in oncogene- and non-oncogene-addicted cases and in patients eligible for immunotherapy, suggesting that IHC testing should be reconsidered in clinical practice. We also argue how a panel of IHC tests should be considered complementary to NGS and other genomic assays. This is relevant to current clinical diagnostic practice but with potential future roles to optimize the selection of patients for innovative therapies. At the same time, strict validation of antibodies, assays, scoring systems, and intra- and interobserver reproducibility is needed.
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Affiliation(s)
- Anna La Salvia
- National Center for Drug Research and Evaluation, National Institute of Health (ISS), Rome 00161, Italy
| | - May-Lucie Meyer
- Center for Thoracic Oncology/Tisch Cancer Institute and Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Fred R Hirsch
- Center for Thoracic Oncology/Tisch Cancer Institute and Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Keith M Kerr
- Aberdeen University School of Medicine & Aberdeen Royal Infirmary, Aberdeen, UK
| | - Lorenza Landi
- Medical Oncology, Istituto Nazionale Tumori IRCCS "Regina Elena", Rome, Italy
| | - Ming-Sound Tsao
- University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
| | - Federico Cappuzzo
- Medical Oncology, Istituto Nazionale Tumori IRCCS "Regina Elena", Rome, Italy.
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3
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Sposito M, Belluomini L, Pontolillo L, Tregnago D, Trestini I, Insolda J, Avancini A, Milella M, Bria E, Carbognin L, Pilotto S. Adjuvant Targeted Therapy in Solid Cancers: Pioneers and New Glories. J Pers Med 2023; 13:1427. [PMID: 37888038 PMCID: PMC10608226 DOI: 10.3390/jpm13101427] [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: 08/24/2023] [Revised: 09/19/2023] [Accepted: 09/20/2023] [Indexed: 10/28/2023] Open
Abstract
Targeted therapy (TT) has revolutionized cancer treatment, successfully applied in various settings. Adjuvant TT in resected early-stage gastrointestinal stromal tumors (GIST), melanoma, non-small cell lung cancer (NSCLC), and breast cancer has led to practice-changing achievements. In particular, standard treatments include BRAF inhibitors for melanoma, osimertinib for NSCLC, hormone therapy or HER2 TT for breast cancer, and imatinib for GIST. Despite the undeniable benefit derived from adjuvant TT, the optimal duration of TT and the appropriate managing of the relapse remain open questions. Furthermore, neoadjuvant TT is emerging as valuable, particularly in breast cancer, and ongoing studies evaluate TT in the perioperative setting for early-stage NSCLC. In this review, we aim to collect and describe the large amount of data available in the literature about adjuvant TT across different histologies, focusing on epidemiology, major advances, and future directions.
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Affiliation(s)
- Marco Sposito
- Section of Innovation Biomedicine—Oncology Area, Department of Engineering for Innovation Medicine (DIMI), University of Verona and University and Hospital Trust (AOUI) of Verona, 37134 Verona, Italy; (M.S.); (L.B.); (D.T.); (I.T.); (J.I.); (A.A.); (M.M.)
| | - Lorenzo Belluomini
- Section of Innovation Biomedicine—Oncology Area, Department of Engineering for Innovation Medicine (DIMI), University of Verona and University and Hospital Trust (AOUI) of Verona, 37134 Verona, Italy; (M.S.); (L.B.); (D.T.); (I.T.); (J.I.); (A.A.); (M.M.)
| | - Letizia Pontolillo
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Roma, Italy; (L.P.); (E.B.)
- Medical Oncology, Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Roma, Italy
| | - Daniela Tregnago
- Section of Innovation Biomedicine—Oncology Area, Department of Engineering for Innovation Medicine (DIMI), University of Verona and University and Hospital Trust (AOUI) of Verona, 37134 Verona, Italy; (M.S.); (L.B.); (D.T.); (I.T.); (J.I.); (A.A.); (M.M.)
| | - Ilaria Trestini
- Section of Innovation Biomedicine—Oncology Area, Department of Engineering for Innovation Medicine (DIMI), University of Verona and University and Hospital Trust (AOUI) of Verona, 37134 Verona, Italy; (M.S.); (L.B.); (D.T.); (I.T.); (J.I.); (A.A.); (M.M.)
| | - Jessica Insolda
- Section of Innovation Biomedicine—Oncology Area, Department of Engineering for Innovation Medicine (DIMI), University of Verona and University and Hospital Trust (AOUI) of Verona, 37134 Verona, Italy; (M.S.); (L.B.); (D.T.); (I.T.); (J.I.); (A.A.); (M.M.)
| | - Alice Avancini
- Section of Innovation Biomedicine—Oncology Area, Department of Engineering for Innovation Medicine (DIMI), University of Verona and University and Hospital Trust (AOUI) of Verona, 37134 Verona, Italy; (M.S.); (L.B.); (D.T.); (I.T.); (J.I.); (A.A.); (M.M.)
| | - Michele Milella
- Section of Innovation Biomedicine—Oncology Area, Department of Engineering for Innovation Medicine (DIMI), University of Verona and University and Hospital Trust (AOUI) of Verona, 37134 Verona, Italy; (M.S.); (L.B.); (D.T.); (I.T.); (J.I.); (A.A.); (M.M.)
| | - Emilio Bria
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Roma, Italy; (L.P.); (E.B.)
- Medical Oncology, Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Roma, Italy
| | - Luisa Carbognin
- Gynecology Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCSS, 00168 Roma, Italy;
| | - Sara Pilotto
- Section of Innovation Biomedicine—Oncology Area, Department of Engineering for Innovation Medicine (DIMI), University of Verona and University and Hospital Trust (AOUI) of Verona, 37134 Verona, Italy; (M.S.); (L.B.); (D.T.); (I.T.); (J.I.); (A.A.); (M.M.)
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4
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Uchida S, Sugino T. ERBB2-Mutant Gastrointestinal Tumors Represent Heterogeneous Molecular Biology, Particularly in Microsatellite Instability, Tumor Mutation Burden, and Co-Mutated Genes: An In Silico Study. Curr Issues Mol Biol 2023; 45:7404-7416. [PMID: 37754252 PMCID: PMC10528499 DOI: 10.3390/cimb45090468] [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: 08/11/2023] [Revised: 09/09/2023] [Accepted: 09/10/2023] [Indexed: 09/28/2023] Open
Abstract
During recent years, activating mutations in ERBB2 have been reported in solid tumors of various organs, and clinical trials targeting ERBB2-mutant tumors have been conducted. However, no effective treatment has been established for gastrointestinal tumors targeting ERBB2 mutations. ERBB2-mutant tumors have a higher tumor mutation burden (TMB) and microsatellite instability (MSI) than ERBB2 non-mutant tumors, but not all ERBB2-mutant tumors are TMB- and MSI-high. Thus, a more detailed classification of ERBB2-mutant tumors based on the underlying molecular mechanisms is required. Herein, we classified ERBB2 mutations into three groups-group 1: both ERBB2 mutations and amplifications; group 2: ERBB2 mutations annotated as putative driver mutations but without amplifications; group 3: ERBB2 mutations annotated as non-driver mutations (passenger mutations or unknown significance) and those that were not amplified in gastrointestinal tumors. Esophageal adenocarcinoma, gastric cancer, and colorectal cancer presented significantly higher MSI and TMB in the ERBB2-mutant group than in the ERBB2-wild-type group. The proportions of TMB- and MSI-high tumors and frequency of co-mutated downstream genes differed among the groups. We identified TMB- and MSI-high groups; this classification is considered important for guiding the selection of drugs for ERBB2-mutant tumors with downstream genetic mutations.
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Affiliation(s)
- Shiro Uchida
- Division of Diagnostic Pathology, Kikuna Memorial Hospital, 4-4-27, Kikuna, Kohoku-ku, Yokohama 222-0011, Japan
- Division of Pathology, Shizuoka Cancer Center, Shizuoka 411-8777, Japan;
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Takashi Sugino
- Division of Pathology, Shizuoka Cancer Center, Shizuoka 411-8777, Japan;
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Rosner S, Valdivia A, Hoe HJ, Murray JC, Levy B, Felip E, Solomon BJ. Antibody-Drug Conjugates for Lung Cancer: Payloads and Progress. Am Soc Clin Oncol Educ Book 2023; 43:e389968. [PMID: 37163707 DOI: 10.1200/edbk_389968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/12/2023]
Abstract
Antibody Drug Conjugates (ADCs) are a novel class of therapeutic that structurally comprise an antibody directed at a tumor epitope connected via a linker to a cytotoxic payload that have shown significant antitumor activity across a range of malignancies including lung cancer. In this article we review the pharmacology of ADCs, describe results of trials with ADCs directed at targets in lung cancer including Trophoblast cell-surface antigen 2(TROP2), HER3, MET, Carcinoembryonic antigen-related cell adhesion molecular 5(CECAM-5) and HER2. Trastuzumab Deruxtecan (also known as DS-8201a or T-DXd) an ADC directed at HER2 recently became the first ADC to receive FDA approval in lung cancer, on the basis of its activity in tumors with HER2 mutations, demonstrated in the Destiny-Lung01 and Lung02 trials.
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Affiliation(s)
- Samuel Rosner
- Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD
| | - Augusto Valdivia
- Oncology Department, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona, Spain
| | - Hui Jing Hoe
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | | | - Benjamin Levy
- Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD
| | - Enriqueta Felip
- Oncology Department, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona, Spain
| | - Benjamin J Solomon
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
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Deciphering the Impact of HER2 Alterations on Non-Small-Cell Lung Cancer: From Biological Mechanisms to Therapeutic Approaches. J Pers Med 2022; 12:jpm12101651. [PMID: 36294789 PMCID: PMC9605102 DOI: 10.3390/jpm12101651] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 09/26/2022] [Accepted: 09/29/2022] [Indexed: 11/16/2022] Open
Abstract
Despite the recent increase in the number of types of treatments, non-small-cell lung cancer (NSCLC) remains the major cause of death from cancer worldwide. So, there is an urgent need to develop new therapeutic strategies. The HER2 gene codes for tyrosine kinase receptor whose alterations are known to drive carcinogenesis. HER2 alterations, including amplification, mutations, and overexpression, have been mainly described in breast and gastric cancers, but up to 4% of NSCLC harbor actionable HER2 mutations. HER2-targeted therapy for NSCLC with trastuzumab, pertuzumab, and trastuzumab emtansine has failed to demonstrate an improvement in survival. Nevertheless, recent data from phase II trials have shed light on promising specific therapies for HER2-mutant NSCLC such as trastuzumab deruxtecan. Herein, we aimed to provide an updated review on the biology, epidemiology, molecular testing, and therapeutic strategies for NSCLC with HER2 molecular alterations.
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Metro G, De Giglio A, Ricciuti B, Siringo M, Marinelli D, Gelibter A, Pecci F, Berardi R, Cantini L, Di Federico A, Andrini E, Mosca M, Lamberti G, Brambilla M, Mountzios G. Advanced non-small-cell lung cancer: how to manage EGFR and HER2 exon 20 insertion mutation-positive disease. Drugs Context 2022; 11:2022-3-9. [PMID: 35975031 PMCID: PMC9354707 DOI: 10.7573/dic.2022-3-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Accepted: 07/04/2022] [Indexed: 11/21/2022] Open
Abstract
EGFR exon 20 insertion mutations (Ex20ins) and HER2 mutations characterize an oncogene-addicted subtype of non-small-cell lung cancer (NSCLC) typically associated with a never or light smoking history, female sex, and adenocarcinoma histology. Nevertheless, Ex20ins-mutant and HER2-mutant advanced NSCLCs are still difficult to treat for various reasons. First, there is a need for sophisticated diagnostic tools (e.g. next-generation sequencing) that could allow the identification of these relatively rare molecular drivers. Second, highly active targeted drugs that might support a significant change in patients' prognosis when used as first-line therapy are required. In fact, although a few targeted drugs have so far demonstrated antitumour activity for these patients, mainly selective human epidermal receptor-tyrosine kinase inhibitors such as poziotinib and mobocertinib (for both molecular alterations), monoclonal antibodies such as amivantamab (for Ex20ins), and antibody-drug conjugates such as trastuzumab deruxtecan (for HER2 mutants), they are mostly confined for clinical use in pretreated patients. Finally, Ex20ins-targeted or HER2-targeted drugs might be difficult to access in different countries or regions worldwide. In the present review, we provide a concise but comprehensive summary of the challenges that lie ahead as we move towards personalized treatment of Ex20ins-mutant and HER2-mutant advanced NSCLC, also suggesting a treatment algorithm that could be followed for patients with these genetic aberrations.
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Affiliation(s)
- Giulio Metro
- Medical Oncology, Santa Maria della Misericordia Hospital, Azienda Ospedaliera di Perugia, Perugia, Italy
| | - Andrea De Giglio
- Department of Experimental, Diagnostic & Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria of Bologna, Bologna, Italy
| | - Biagio Ricciuti
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Marco Siringo
- Division of Medical Oncology B, Policlinico Umberto I, ‘La Sapienza’ University, Rome, Italy
| | - Daniele Marinelli
- Division of Medical Oncology B, Policlinico Umberto I, ‘La Sapienza’ University, Rome, Italy
| | - Alain Gelibter
- Division of Medical Oncology B, Policlinico Umberto I, ‘La Sapienza’ University, Rome, Italy
| | - Federica Pecci
- Department of Medical Oncology, Università Politecnica delle Marche, AOU Ospedali Riuniti di Ancona, Ancona, Italy
| | - Rossana Berardi
- Department of Medical Oncology, Università Politecnica delle Marche, AOU Ospedali Riuniti di Ancona, Ancona, Italy
| | - Luca Cantini
- Department of Medical Oncology, Università Politecnica delle Marche, AOU Ospedali Riuniti di Ancona, Ancona, Italy
| | - Alessandro Di Federico
- Department of Experimental, Diagnostic & Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria of Bologna, Bologna, Italy
| | - Elisa Andrini
- Department of Experimental, Diagnostic & Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria of Bologna, Bologna, Italy
| | - Mirta Mosca
- Department of Experimental, Diagnostic & Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria of Bologna, Bologna, Italy
| | - Giuseppe Lamberti
- Department of Experimental, Diagnostic & Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria of Bologna, Bologna, Italy
| | - Marta Brambilla
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Giannis Mountzios
- Fourth Department of Medical Oncology and Clinical Trials Unit, Henry Dunant Hospital Center, Athens, Greece
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Waliany S, Wakelee H, Ramchandran K, Das M, Huang J, Myall N, Li C, Pagtama J, Tisch AH, Neal JW. Characterization of ERBB2 (HER2) Alterations in Metastatic Non-small Cell Lung Cancer and Comparison of Outcomes of Different Trastuzumab-based Regimens. Clin Lung Cancer 2022; 23:498-509. [PMID: 35753988 DOI: 10.1016/j.cllc.2022.05.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 05/30/2022] [Accepted: 05/31/2022] [Indexed: 11/17/2022]
Abstract
INTRODUCTION About 3%-5% of mNSCLC have ERBB2 (HER2) alterations, but currently, there are no FDA-approved targeted therapies for this indication. We compared treatment response between trastuzumab-based and non-targeted regimens in ERBB2-mutant mNSCLC. METHODS This retrospective, single-institution study included patients with mNSCLC with ERBB2 alterations identified by next-generation sequencing. Best overall response was determined using Response Evaluation Criteria in Solid Tumors 1.1. RESULTS We identified 3 groups of patients: ERBB2-mutant/EGFR-wildtype mNSCLC (n = 33), ERBB2-amplified/EGFR-wildtype mNSCLC without concurrent ERBB2 mutations (n = 6), and ERBB2-altered/EGFR-mutant mNSCLC (n = 8). Observed mutations included A775_G776insYVMA (n = 23), Gly778_Pro780dup (n = 4), Ser310Phe (n = 3), and others (n = 5). Among the 33 with ERBB2-mutant/EGFR-wildtype mNSCLC, those with and without A775_G776insYVMA had significantly different median overall survival (OS) of 17.7 and 52.9 months, respectively (Cox regression multivariable HR: 5.03, 95% CI: 1.37-18.51, P = .02). In those with mNSCLC with A775_G776insYVMA, trastuzumab-based therapies were associated with greater OS (20.3 vs. 9.8 months; multivariable HR: 0.19, 95% CI: 0.04-0.87, P = .032). Objective response and disease control rates (median tumor size change) in the 33 patients with ERBB2-mutant/EGFR-wildtype mNSCLC were 40.0% and 80.0% (-35.8%), respectively, for patients treated with trastuzumab deruxtecan; 0% and 30.0% (-5.2%) for trastuzumab emtansine; and 7.1% and 50.0% (-13.0%) for trastuzumab/chemotherapy combinations. CONCLUSION In ERBB2-mutant/EGFR-wildtype mNSCLC, while most trastuzumab-based regimens had modest activity in this real-world analysis, trastuzumab deruxtecan had highest response rates and best tumor size reduction. Receipt of any trastuzumab-based regimen was associated with greater OS with A775_G776insYVMA. There remains an unmet need for approved targeted therapies for ERBB2-mutant/EGFR-wildtype NSCLC.
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Affiliation(s)
- Sarah Waliany
- Department of Medicine, Stanford University School of Medicine, Stanford, CA
| | - Heather Wakelee
- Department of Medicine, Stanford University School of Medicine, Stanford, CA; Division of Oncology, Stanford University School of Medicine, Stanford, CA; Stanford Cancer Institute, Stanford, CA
| | - Kavitha Ramchandran
- Department of Medicine, Stanford University School of Medicine, Stanford, CA; Division of Oncology, Stanford University School of Medicine, Stanford, CA; Stanford Cancer Institute, Stanford, CA
| | - Millie Das
- Department of Medicine, Stanford University School of Medicine, Stanford, CA; Division of Oncology, Stanford University School of Medicine, Stanford, CA; Stanford Cancer Institute, Stanford, CA; Department of Medicine, VA Palo Alto Health Care System, Palo Alto, CA
| | - Jane Huang
- Department of Medicine, Stanford University School of Medicine, Stanford, CA; Division of Oncology, Stanford University School of Medicine, Stanford, CA; Stanford Cancer Institute, Stanford, CA
| | - Nathaniel Myall
- Department of Medicine, Stanford University School of Medicine, Stanford, CA; Division of Oncology, Stanford University School of Medicine, Stanford, CA; Stanford Cancer Institute, Stanford, CA
| | - Connie Li
- Stanford Cancer Institute, Stanford, CA
| | | | | | - Joel W Neal
- Department of Medicine, Stanford University School of Medicine, Stanford, CA; Division of Oncology, Stanford University School of Medicine, Stanford, CA; Stanford Cancer Institute, Stanford, CA.
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9
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Ettinger DS, Wood DE, Aisner DL, Akerley W, Bauman JR, Bharat A, Bruno DS, Chang JY, Chirieac LR, D'Amico TA, DeCamp M, Dilling TJ, Dowell J, Gettinger S, Grotz TE, Gubens MA, Hegde A, Lackner RP, Lanuti M, Lin J, Loo BW, Lovly CM, Maldonado F, Massarelli E, Morgensztern D, Ng T, Otterson GA, Pacheco JM, Patel SP, Riely GJ, Riess J, Schild SE, Shapiro TA, Singh AP, Stevenson J, Tam A, Tanvetyanon T, Yanagawa J, Yang SC, Yau E, Gregory K, Hughes M. Non-Small Cell Lung Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2022; 20:497-530. [PMID: 35545176 DOI: 10.6004/jnccn.2022.0025] [Citation(s) in RCA: 793] [Impact Index Per Article: 264.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommended management for patients with NSCLC, including diagnosis, primary treatment, surveillance for relapse, and subsequent treatment. Patients with metastatic lung cancer who are eligible for targeted therapies or immunotherapies are now surviving longer. This selection from the NCCN Guidelines for NSCLC focuses on targeted therapies for patients with metastatic NSCLC and actionable mutations.
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Affiliation(s)
| | - Douglas E Wood
- Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance
| | | | | | | | - Ankit Bharat
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | - Debora S Bruno
- Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute
| | - Joe Y Chang
- The University of Texas MD Anderson Cancer Center
| | | | | | | | | | | | | | | | | | | | | | | | - Jules Lin
- University of Michigan Rogel Cancer Center
| | | | | | | | | | - Daniel Morgensztern
- Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
| | - Thomas Ng
- The University of Tennessee Health Science Center
| | - Gregory A Otterson
- The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute
| | | | | | | | | | | | | | - Aditi P Singh
- Abramson Cancer Center at the University of Pennsylvania
| | - James Stevenson
- Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute
| | - Alda Tam
- The University of Texas MD Anderson Cancer Center
| | | | | | - Stephen C Yang
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
| | - Edwin Yau
- Roswell Park Comprehensive Cancer Center; and
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10
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Batra U, Sharma M, Dewan A, Diwan H, Nathany S. A narrative review of ERBB2 in non-small cell lung carcinoma. CANCER RESEARCH, STATISTICS, AND TREATMENT 2022. [DOI: 10.4103/crst.crst_323_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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11
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Riudavets M, Sullivan I, Abdayem P, Planchard D. Targeting HER2 in non-small-cell lung cancer (NSCLC): a glimpse of hope? An updated review on therapeutic strategies in NSCLC harbouring HER2 alterations. ESMO Open 2021; 6:100260. [PMID: 34479034 PMCID: PMC8414039 DOI: 10.1016/j.esmoop.2021.100260] [Citation(s) in RCA: 102] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 08/02/2021] [Accepted: 08/05/2021] [Indexed: 12/16/2022] Open
Abstract
Non-small-cell lung cancer (NSCLC) harbouring HER2 alterations is now considered a distinct molecular subtype. The activation of HER2 in NSCLC occurs via three mechanisms, i.e. gene mutation (1%-4% of cases), gene amplification (2%-5%) and protein overexpression (2%-30%), with different prognostic and predictive outcomes. So far, non-selective tyrosine kinase inhibitors (TKIs) have shown a minor benefit in HER2-mutant NSCLC patients with objective response rates (ORRs) ranging from 0% to 19%. Trastuzumab-based chemotherapy was not found to be superior to chemotherapy alone [median progression-free survival (PFS) 6.1 versus 7 months, respectively] and dual HER2 antibody blockade with trastuzumab and pertuzumab had limited efficacy (ORR 13%-21%). In contrast, novel more selective HER2 TKIs such as poziotinib and pyrotinib have shown a promising activity in HER2-mutant pre-treated NSCLC patients, with response rates up to 38% and 44%, respectively. The most encouraging data come from phase II studies that evaluated the antibody–drug conjugates (ADCs) ado-trastuzumab–emtansine and trastuzumab–deruxtecan in patients with HER2-mutant NSCLC, with response rates of 50% and 62%, respectively. These agents are bringing hope to the management of HER2-altered NSCLC. Moreover, a paradigm shift from monotherapies towards combinations of agents with distinct mechanisms of action, such as ADCs with irreversible TKIs or immune checkpoint inhibitors, is already taking place and will change the therapeutic landscape of HER2-driven NSCLC. This paper provides a practical, concise and updated review on the therapeutic strategies in NSCLC with HER2 molecular alterations.
Activation of Her2 in NSCLC occurs via gene mutation, amplification or protein overexpression. Selective Her2 TKIs like poziotinib and pyrotinib induced responses in up to 44% of pre-treated Her2-mutant NSCLC patients. ADCs trastuzumab–emtansine and trastuzumab–deruxtecan showed impressive response rates in 62% of Her2-mutant NSCLC patients. Ongoing studies evaluating combination strategies may help improve the therapeutic landscape in Her2-dependent NSCLC.
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Affiliation(s)
- M Riudavets
- Department of Cancer Medicine, Gustave Roussy Cancer Campus, Villejuif, France
| | - I Sullivan
- Medical Oncology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - P Abdayem
- Department of Cancer Medicine, Gustave Roussy Cancer Campus, Villejuif, France
| | - D Planchard
- Department of Cancer Medicine, Gustave Roussy Cancer Campus, Villejuif, France.
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12
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Rolfo C, Russo A. HER2 Mutations in Non-Small Cell Lung Cancer: A Herculean Effort to Hit the Target. Cancer Discov 2021; 10:643-645. [PMID: 32357968 DOI: 10.1158/2159-8290.cd-20-0225] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Over the last two decades HER2 aberrations have been thoroughly investigated as potential therapeutic targets in advanced non-small cell lung cancer, with relatively modest results. Two articles published in this issue of Cancer Discovery further expand the knowledge on therapeutic exploitation of HER2 in lung cancer, addressing a large unmet medical need.See related article by Li et al., p. 674.See related article by Tsurutani et al., p. 688.
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Affiliation(s)
- Christian Rolfo
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland.
| | - Alessandro Russo
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland
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13
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Prabhash K. Treatment of advanced nonsmall cell lung cancer: First line, maintenance and second line - Indian consensus statement update. South Asian J Cancer 2020; 8:1-17. [PMID: 30766843 PMCID: PMC6348782 DOI: 10.4103/sajc.sajc_227_18] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
The management of advanced nonsmall cell lung cancer (NSCLC) patients is becoming increasingly complex with the identification of driver mutations/rearrangements and development/availability of appropriate targeted therapies. In 2017, an expert group of medical oncologists with expertise in treating lung cancer used data from published literature and experience to arrive at practical consensus recommendations on treatment of advanced NSCLC for use by the community oncologists. This was published subsequently in the Indian Journal of Cancer with a plan to be updated annually. The present document is an update to the 2017 document.
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Affiliation(s)
- Kumar Prabhash
- Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
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14
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Singh SS, Dahal A, Shrestha L, Jois SD. Genotype Driven Therapy for Non-Small Cell Lung Cancer: Resistance, Pan Inhibitors and Immunotherapy. Curr Med Chem 2020; 27:5274-5316. [PMID: 30854949 DOI: 10.2174/0929867326666190222183219] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 01/25/2019] [Accepted: 02/14/2019] [Indexed: 12/14/2022]
Abstract
Eighty-five percent of patients with lung cancer present with Non-small Cell Lung Cancer (NSCLC). Targeted therapy approaches are promising treatments for lung cancer. However, despite the development of targeted therapies using Tyrosine Kinase Inhibitors (TKI) as well as monoclonal antibodies, the five-year relative survival rate for lung cancer patients is still only 18%, and patients inevitably become resistant to therapy. Mutations in Kirsten Ras Sarcoma viral homolog (KRAS) and epidermal growth factor receptor (EGFR) are the two most common genetic events in lung adenocarcinoma; they account for 25% and 20% of cases, respectively. Anaplastic Lymphoma Kinase (ALK) is a transmembrane receptor tyrosine kinase, and ALK rearrangements are responsible for 3-7% of NSCLC, predominantly of the adenocarcinoma subtype, and occur in a mutually exclusive manner with KRAS and EGFR mutations. Among drug-resistant NSCLC patients, nearly half exhibit the T790M mutation in exon 20 of EGFR. This review focuses on some basic aspects of molecules involved in NSCLC, the development of resistance to treatments in NSCLC, and advances in lung cancer therapy in the past ten years. Some recent developments such as PD-1-PD-L1 checkpoint-based immunotherapy for NSCLC are also covered.
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Affiliation(s)
- Sitanshu S Singh
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe LA 71201, United States
| | - Achyut Dahal
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe LA 71201, United States
| | - Leeza Shrestha
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe LA 71201, United States
| | - Seetharama D Jois
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe LA 71201, United States
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15
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New insights into affinity proteins for HER2-targeted therapy: Beyond trastuzumab. Biochim Biophys Acta Rev Cancer 2020; 1874:188448. [PMID: 33039514 DOI: 10.1016/j.bbcan.2020.188448] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 10/06/2020] [Accepted: 10/06/2020] [Indexed: 12/31/2022]
Abstract
Human epidermal growth factor receptor 2 (HER2) is known as a potential target for both cancer treatment and diagnosis. One of the most interesting HER2-targeted therapeutics is an affinity protein which selectively recognizes and binds to a defined target. Trastuzumab is a monoclonal antibody which has been approved as the first affinity proteins for treatment of some HER2-positive cancers including breast cancer. Despite initial response to trastuzumab, the majority of patients with metastatic HER2-positive breast cancer still show resistance to the therapy. Recently, various anti-HER2 affinity proteins, including antibodies, antibody fragments (e.g., Fab and scFv) and other protein scaffolds (e.g., affibody and DARPin), alone or fused/conjugated with therapeutic agents (e.g., proteins, drugs and radioisotopes) have been developed to overcome the trastuzumab resistance. Here, we review these engineered affinity proteins which are either clinically approved or under evaluation. Modern technologies and future prospects for their clinical applications in cancer treatment are also discussed.
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16
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中国临床肿瘤学会非小细胞肺癌专家委员会. [Chinese Expert Consensus on Next Generation Sequencing Diagnosis
for Non-small Cell Lung Cancer (2020 Edition)]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2020; 23:741-761. [PMID: 32957170 PMCID: PMC7519957 DOI: 10.3779/j.issn.1009-3419.2020.101.45] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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17
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Del Re M, Cucchiara F, Petrini I, Fogli S, Passaro A, Crucitta S, Attili I, De Marinis F, Chella A, Danesi R. erbB in NSCLC as a molecular target: current evidences and future directions. ESMO Open 2020; 5:e000724. [PMID: 32820012 PMCID: PMC7443272 DOI: 10.1136/esmoopen-2020-000724] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 06/06/2020] [Accepted: 06/08/2020] [Indexed: 12/13/2022] Open
Abstract
A number of treatments have been developed for HER1, 2 and 3-driven non-small cell lung cancer (NSCLC), of which the most successful have been the epidermal growth factor receptor-tyrosine kinase inhibitors in HER1-mutant tumours resulting in highly improved progression-free survival. Human epidermal growth factor (HER)2 and 3-driven tumours represent the minority of NSCLC, and effective therapies in these patients still represent an unmet medical need. The encouraging results seen with anti-HER2 and anti-HER3 monoclonal antibodies need to be validated in larger studies, even if the greatest obstacle is represented by the exiguous number of patients bearing deregulated HER2/3 system and abnormalities of signal transduction pathway. Considering NSCLC tumour heterogeneity, which affects response and resistance to treatment, combined multiparametric approaches, such as liquid biopsy together with radiomics, may provide a better understanding of the tumour dynamics and clonal selection during the treatments.
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Affiliation(s)
- Marzia Del Re
- Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy
| | - Federico Cucchiara
- Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy
| | - Iacopo Petrini
- Translational Research and New Technologies in Medicine, University Hospital of Pisa, Pisa, Italy
| | - Stefano Fogli
- Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy
| | - Antonio Passaro
- Division of Thoracic Oncology, European Institute of Oncology - IRCCS, Milan, Italy
| | - Stefania Crucitta
- Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy
| | - Ilaria Attili
- Division of Thoracic Oncology, European Institute of Oncology - IRCCS, Milan, Italy
| | - Filippo De Marinis
- Division of Thoracic Oncology, European Institute of Oncology - IRCCS, Milan, Italy
| | - Antonio Chella
- Translational Research and New Technologies in Medicine, University Hospital of Pisa, Pisa, Italy
| | - Romano Danesi
- Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy
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18
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Zhang X, Lv J, Wu Y, Qin N, Ma L, Li X, Nong J, Zhang H, Zhang Q, Yang X, Shi H, Wang J, Zhang S. HER2 Exon 20 Insertion Mutations in Lung Adenocarcinoma: Case Series and Response to Pyrotinib. Front Oncol 2020; 10:1162. [PMID: 32850330 PMCID: PMC7411254 DOI: 10.3389/fonc.2020.01162] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 06/09/2020] [Indexed: 12/17/2022] Open
Abstract
HER2 mutations have emerged as oncogenic driver gene mutations in non-small cell lung cancer (NSCLC), which have not been described in detail like other driver gene mutations. Here, 295 patients with advanced lung adenocarcinoma were retrospectively screened for HER2 mutations using next-generation sequencing (NGS), and the positive cases were validated by Sanger sequencing. We identified five cases with HER2 exon 20 insertions, representing 1.7% of 295 lung adenocarcinomas. Among them, four different subtypes of HER2 exon 20 insertions were identified, including a rare subtype G778_S779insCPG never reported before with a partial response (PR) to pyrotinib and progression-free survival (PFS) of 12.8 months. Our findings reveal that HER2 exon 20 insertion mutations were detected in a small subset of lung adenocarcinomas. Given the different drug sensitivities, determining the mutation subtype by next-generation sequencing at the time of diagnosis might make sense.
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Affiliation(s)
- Xinyong Zhang
- Department of Medical Oncology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Jialin Lv
- Department of Medical Oncology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Yuhua Wu
- Department of Medical Oncology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Na Qin
- Department of Medical Oncology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Li Ma
- Department of Medical Oncology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Xi Li
- Department of Medical Oncology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Jingying Nong
- Department of Medical Oncology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Hui Zhang
- Department of Medical Oncology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Quan Zhang
- Department of Medical Oncology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Xinjie Yang
- Department of Medical Oncology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Huibo Shi
- Organ Transplantation Research Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jinghui Wang
- Department of Medical Oncology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Shucai Zhang
- Department of Medical Oncology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, China
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19
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Russo A, Lopes AR, McCusker MG, Garrigues SG, Ricciardi GR, Arensmeyer KE, Scilla KA, Mehra R, Rolfo C. New Targets in Lung Cancer (Excluding EGFR, ALK, ROS1). Curr Oncol Rep 2020; 22:48. [PMID: 32296961 DOI: 10.1007/s11912-020-00909-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
PURPOSE OF REVIEW Over the last two decades, the identification of targetable oncogene drivers has revolutionized the therapeutic landscape of non-small cell lung cancer (NSCLC). The extraordinary progresses made in molecular biology prompted the identification of several rare molecularly defined subgroups. In this review, we will focus on the novel and emerging actionable oncogenic drivers in NSCLC. RECENT FINDINGS Recently, novel oncogene drivers emerged as promising therapeutic targets besides the well-established EGFR mutations, and ALK/ROS1 rearrangements, considerably expanding the list of potential exploitable genetic aberrations. However, the therapeutic algorithm in these patients is far less defined. The identification of uncommon oncogene drivers is reshaping the diagnostic and therapeutic approach to NSCLC. The introduction of novel highly selective inhibitors is expanding the use of targeted therapies to rare and ultra-rare subsets of patients, further increasing the therapeutic armamentarium of advanced NSCLC.
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Affiliation(s)
- Alessandro Russo
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, 22 S Greene Street Rm. N9E08, Baltimore, MD, 21201, USA.,Medical Oncology Unit, A.O. Papardo & Department of Human Pathology, University of Messina, Contrada Papardo, 98158, Messina, Italy
| | - Ana Rita Lopes
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, 22 S Greene Street Rm. N9E08, Baltimore, MD, 21201, USA.,Portuguese Institute of Oncology (IPO), Porto, Portugal
| | - Michael G McCusker
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, 22 S Greene Street Rm. N9E08, Baltimore, MD, 21201, USA
| | - Sandra Gimenez Garrigues
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, 22 S Greene Street Rm. N9E08, Baltimore, MD, 21201, USA
| | - Giuseppina R Ricciardi
- Medical Oncology Unit, A.O. Papardo & Department of Human Pathology, University of Messina, Contrada Papardo, 98158, Messina, Italy
| | - Katherine E Arensmeyer
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, 22 S Greene Street Rm. N9E08, Baltimore, MD, 21201, USA
| | - Katherine A Scilla
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, 22 S Greene Street Rm. N9E08, Baltimore, MD, 21201, USA
| | - Ranee Mehra
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, 22 S Greene Street Rm. N9E08, Baltimore, MD, 21201, USA
| | - Christian Rolfo
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, 22 S Greene Street Rm. N9E08, Baltimore, MD, 21201, USA.
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20
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The force of HER2 - A druggable target in NSCLC? Cancer Treat Rev 2020; 86:101996. [PMID: 32135383 DOI: 10.1016/j.ctrv.2020.101996] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 02/20/2020] [Accepted: 02/25/2020] [Indexed: 01/26/2023]
Abstract
Since several years targeted therapy has been part of treatment in NSCLC in subsets of patients with specific genetic alterations. One of these alterations involves HER2, a member of the ERBB family of tyrosine kinase receptors. Despite that HER2 alterations in NSCLC have been studied for years, there is still no consensus about subgroup definitions. In this review HER2 alterations in NSCLC are discussed, including diagnostic challenges and treatment strategies. Three principal mechanisms of HER2 alterations can be identified: HER2 protein overexpression, HER2 gene amplification and HER2 gene mutations. There are several methods for the detection of HER2 "positivity" in NSCLC, but no gold standard has been established. Laboratory methods for assessment of HER2 positivity in NSCLC include immunohistochemistry (IHC) for protein overexpression and fluorescent in situ hybridization (FISH) and next generation sequencing (NGS) for genetic alterations. Many trials testing HER2 targeted therapy in HER2 altered NSCLC has not lead to a renewed standard of care for this group of patients. Therefore, today the (re)search on how to analyse, define and treat HER2 alterations in NSCLC continues. Still there is no consensus about HER2 subgroup definitions and results of the many trials studying possible treatment strategies are inconclusive. Future research should focus on the most important missing link, whether all HER2 alterations are relevant oncogenic drivers and whether it should be considered as a therapeutic target in NSCLC.
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21
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Baraibar I, Mezquita L, Gil-Bazo I, Planchard D. Novel drugs targeting EGFR and HER2 exon 20 mutations in metastatic NSCLC. Crit Rev Oncol Hematol 2020; 148:102906. [PMID: 32109716 DOI: 10.1016/j.critrevonc.2020.102906] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 02/06/2020] [Accepted: 02/07/2020] [Indexed: 02/03/2023] Open
Abstract
Approximately 4% of epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) present EGFR exon 20 in-frame insertions, accounting for 0.3 %-3.7 % of NSCLC. In addition, 2 %-4 % of patients with NSCLC harbor human epidermal growth factor receptor 2 gene (HER2) mutations, being the 90 % of them exon 20 insertions. These mutations confer intrinsic resistance to available EGFR tyrosine kinase inhibitors (TKIs) and anti-HER2 treatments, as they result in steric hindrance of the drug-binding pocket. Therefore, no targeted therapies have been approved for NSCLC patients with EGFR or HER2 exon 20- activating mutations to date and remain an unmet clinical need. Promising efforts to novel treatment development have been made. Early data provide encouraging activity of novel drugs targeting EGFR and HER2 mutations in metastatic NSCLC. In this review we will summarize all the data reported to date about these driver molecular alterations and potential targeted therapies.
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Affiliation(s)
- Iosune Baraibar
- Department of Oncology, Clínica Universidad de Navarra, Pamplona, Spain; Program of Solid Tumors, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
| | | | - Ignacio Gil-Bazo
- Department of Oncology, Clínica Universidad de Navarra, Pamplona, Spain; Program of Solid Tumors, Center for Applied Medical Research, University of Navarra, Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
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22
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Zhu Q, Dong H, Bukhari AAS, Zhao A, Li M, Sun Y, Zhang X, Cao C, Su D, Liang X. HUWE1 promotes EGFR ubiquitination and degradation to protect against renal tubulointerstitial fibrosis. FASEB J 2020; 34:4591-4601. [PMID: 32017279 DOI: 10.1096/fj.201902751r] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 01/08/2020] [Accepted: 01/18/2020] [Indexed: 12/13/2022]
Abstract
Injury of renal tubular epithelial cells is a key feature of the pathogenicity associated with tubulointerstitial fibrosis and other kidney diseases. HUWE1, an E3 ubiquitin ligase, acts by participating in ubiquitination and degradation of its target proteins. However, the detailed mechanisms by which HUWE1 might regulate fibrosis in renal tubular epithelial cells have not been established. Here, the possible regulation of renal tubulointerstitial fibrosis by HUWE1 was investigated by examining the expression of HUWE1 and EGFR in unilateral ureteral obstruction (UUO) mice. Markedly consistent reciprocal changes in HUWE1 and EGFR expression were observed at the protein and mRNA levels in the kidney after UUO injury. Expression of HUWE1 inhibited TGF-β-induced injury to HK-2 cells, while HUWE1 overexpression decreased the expression of EGFR. Further analysis indicated that HUWE1 physically interacted with EGFR and promoted its ubiquitination and degradation. HUWE1 expression also showed clinical relevance in renal disease, as it notably decreased in multiple types of clinical nephropathy, while EGFR expression significantly increased when compared to the normal kidney. Therefore, this study demonstrated that HUWE1, which serves as an E3 ubiquitin ligase specific for EGFR, promotes EGFR ubiquitination and degradation, thereby regulating EGFR expression and providing protection against kidney injury.
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Affiliation(s)
- Qian Zhu
- Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Hao Dong
- Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | | | - Anran Zhao
- Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Min Li
- Department of Pathology, Nanjing Medical University, Nanjing, China
| | - Yifei Sun
- Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Xue Zhang
- Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Changchun Cao
- Department of Nephrology, The Affiliated Sir Run Run Hospital of Nanjing Medical University, Nanjing, China
| | - Dongming Su
- Department of Pathology, Nanjing Medical University, Nanjing, China.,Center of Pathology and Clinical Laboratory, The Affiliated Sir Run Run Hospital of Nanjing Medical University, Nanjing, China
| | - Xiubin Liang
- Department of Pathophysiology, Nanjing Medical University, Nanjing, China.,Department of Nephrology, The Affiliated Sir Run Run Hospital of Nanjing Medical University, Nanjing, China
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23
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Liu WJ, Du Y, Wen R, Yang M, Xu J. Drug resistance to targeted therapeutic strategies in non-small cell lung cancer. Pharmacol Ther 2019; 206:107438. [PMID: 31715289 DOI: 10.1016/j.pharmthera.2019.107438] [Citation(s) in RCA: 125] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 11/06/2019] [Indexed: 02/07/2023]
Abstract
Rapidly developing molecular biology techniques have been employed to identify cancer driver genes in specimens from patients with non-small cell lung cancer (NSCLC). Inhibitors and antibodies that specifically target driver gene-mediated signaling pathways to suppress tumor growth and progression are expected to extend the survival time and further improve the quality of life of patients. However, the health of patients with advanced and metastatic NSCLC presents significant challenges due to treatment resistance, mediated by cancer driver gene alteration, epigenetic alteration, and tumor heterogeneity. In this review, we discuss two different resistance mechanisms in NSCLC targeted therapies, namely changes in the targeted oncogenes (on-target resistance) and changes in other related signaling pathways (off-target resistance) in tumor cells. We highlight the conventional mechanisms of drug resistance elicited by the complex heterogeneous microenvironment of NSCLC during targeted therapy, including mutations in epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), the receptor tyrosine kinase ROS proto-oncogene 1 (ROS1), and the serine/threonine-protein kinase BRAF (v-Raf murine sarcoma viral oncogene homolog B). We also discuss the mechanism of action of less common oncoproteins, as in-depth understanding of these molecular mechanisms is important for optimizing treatment strategies.
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Affiliation(s)
- Wen-Juan Liu
- Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, China
| | - Yue Du
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Ru Wen
- Department of Medicine, Stanford University School of Medicine, California, USA
| | - Ming Yang
- Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, China.
| | - Jian Xu
- Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
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24
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Kurzrock R, Gurski LA, Carlson RW, Ettinger DS, Horwitz SM, Kumar SK, Million L, von Mehren M, Benson AB. Level of evidence used in recommendations by the National Comprehensive Cancer Network (NCCN) guidelines beyond Food and Drug Administration approvals. Ann Oncol 2019; 30:1647-1652. [PMID: 31373348 PMCID: PMC6857604 DOI: 10.1093/annonc/mdz232] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND A previous analysis of 113 National Comprehensive Cancer Network® (NCCN®) recommendations reported that NCCN frequently recommends beyond Food and Drug Administration (FDA)-approved indications (44 off-label recommendations) and claimed that the evidence for these recommendations was weak. METHODS In order to determine the strength of the evidence, we carried out an in-depth re-analysis of the 44 off-label recommendations listed in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). RESULTS Of the 44 off-label recommendations, 14 were later approved by the FDA and/or are supported by randomized controlled trial (RCT) data. In addition, 13 recommendations were either very minor extrapolations from the FDA label (n = 8) or were actually on-label (n = 5). Of the 17 remaining extrapolations, 8 were for mechanism-based agents applied in rare cancers or subsets with few available treatment options (median response rate = 43%), 7 were based on non-RCT data showing significant efficacy (>50% response rates), and 2 were later removed from the NCCN Guidelines because newer therapies with better activity and/or safety became available. CONCLUSION Off-label drug use is a frequent component of care for patients with cancer in the United States. Our findings indicate that when the NCCN recommends beyond the FDA-approved indications, the strength of the evidence supporting such recommendations is robust, with a significant subset of these drugs later becoming FDA approved or supported by RCT. Recommendations without RCT data are often for mechanism-based drugs with high response rates in rare cancers or subsets without effective therapies.
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Affiliation(s)
- R Kurzrock
- Center for Personalized Cancer Therapy, University of California San Diego, Moores Cancer Center, San Diego, USA.
| | - L A Gurski
- National Comprehensive Cancer Network, Plymouth Meeting, Pennsylvania, USA
| | - R W Carlson
- National Comprehensive Cancer Network, Plymouth Meeting, Pennsylvania, USA; Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA; Stanford Cancer Institute, Stanford, California, USA
| | - D S Ettinger
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
| | - S M Horwitz
- Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - S K Kumar
- Mayo Clinic Cancer Center, Rochester, Minnesota, USA
| | - L Million
- Stanford Cancer Institute, Stanford, California, USA
| | - M von Mehren
- Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
| | - A B Benson
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA
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Ralki M, Maes B, Pat K, Wynants J, Cuppens K. Triple Trouble: A Case of Multiple Resistance Mechanisms after First Generation EGFR-TKI in NSCLC. Case Rep Oncol 2019; 12:625-630. [PMID: 31543779 PMCID: PMC6738260 DOI: 10.1159/000502214] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Accepted: 07/11/2019] [Indexed: 01/02/2023] Open
Abstract
Epidermal growth factor receptor (EGFR)-targeted therapy has become standard of care in advanced stages EGFR-mutant non-small cell lung cancer. Acquired resistance to first-line EGFR-tyrosine kinase inhibitor (TKI) and subsequent disease progression is a common problem and mostly due to a secondary mutation (T790M) in EGFR. We report a case of a patient with EGFR-mutated lung adenocarcinoma who developed a complex resistance profile: T790M mutation, HER2 mutation and HER2 amplification after first-line EGFR-TKI. This patient was safely treated with a combination of osimertinib and trastuzumab and achieved a clinically meaningful and clear molecular response. This is the first reported case of acquired resistance to first-line EGFR-TKI based on three resistance mechanisms, treated with molecular targeted combination therapy.
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Affiliation(s)
- Mike Ralki
- Department of Pulmonology and Thoracic Oncology, Jessa Hospital, Hasselt, Belgium
| | - Brigitte Maes
- Department of Pathology and Molecular Biology, Jessa Hospital, Hasselt, Belgium
| | - Karin Pat
- Department of Pulmonology and Thoracic Oncology, Jessa Hospital, Hasselt, Belgium
| | - Jokke Wynants
- Department of Pulmonology and Thoracic Oncology, Jessa Hospital, Hasselt, Belgium
| | - Kristof Cuppens
- Department of Pulmonology and Thoracic Oncology, Jessa Hospital, Hasselt, Belgium
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Subramanian J, Katta A, Masood A, Vudem DR, Kancha RK. Emergence of ERBB2 Mutation as a Biomarker and an Actionable Target in Solid Cancers. Oncologist 2019; 24:e1303-e1314. [PMID: 31292270 DOI: 10.1634/theoncologist.2018-0845] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2018] [Accepted: 05/25/2019] [Indexed: 02/06/2023] Open
Abstract
The oncogenic role ERBB2 amplification is well established in breast and gastric cancers. This has led to the development of a well-known portfolio of monoclonal antibodies and kinase inhibitors targeting the ERBB2 kinase. More recently, activating mutations in the ERBB2 gene have been increasingly reported in multiple solid cancers and were shown to play an oncogenic role similar to that of ERBB2 amplification. Thus, ERBB2 mutations define a distinct molecular subtype of solid tumors and serve as actionable targets. However, efforts to target ERBB2 mutation has met with limited clinical success, possibly because of their low frequency, inadequate understanding of the biological activity of these mutations, and difficulty in separating the drivers from the passenger mutations. Given the current impetus to deliver molecularly targeted treatments for cancer, there is an important need to understand the therapeutic potential of ERBB2 mutations. Here we review the distribution of ERBB2 mutations in different tumor types, their potential as a novel biomarker that defines new subsets in many cancers, and current data on preclinical and clinical efforts to target these mutations. IMPLICATIONS FOR PRACTICE: A current trend in oncology is to identify novel genomic drivers of solid tumors and developing precision treatments that target them. ERBB2 amplification is an established therapeutic target in breast and gastric cancers, but efforts to translate this finding to other solid tumors with ERBB2 amplification have not been effective. Recently the focus has turned to targeting activating ERBB2 mutations. The year 2018 marked an important milestone in establishing ERBB2 mutation as an important actionable target in multiple cancer types. There have been several recent preclinical and clinical studies evaluating ERBB2 mutation as a therapeutic target with varying success. With increasing access to next-generation sequencing technologies in the clinic, oncologists are frequently identifying activating ERBB2 mutations in patients with cancer. There is a significant need both from the clinician and bench scientist perspectives to understand the current state of affairs for ERBB2 mutations.
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Affiliation(s)
- Janakiraman Subramanian
- Division of Oncology, Saint Luke's Cancer Institute, Kansas City, Missouri, USA
- Center for Precision Oncology, Saint Luke's Cancer Institute, Kansas City, Missouri, USA
| | - Archana Katta
- Molecular Medicine and Therapeutics Laboratory, Centre for Plant Molecular Biology, Osmania University, Hyderabad, India
| | - Ashiq Masood
- Division of Oncology, Saint Luke's Cancer Institute, Kansas City, Missouri, USA
- Center for Precision Oncology, Saint Luke's Cancer Institute, Kansas City, Missouri, USA
| | - Dashavantha Reddy Vudem
- Molecular Biology Laboratory, Centre for Plant Molecular Biology, Osmania University, Hyderabad, India
| | - Rama Krishna Kancha
- Molecular Medicine and Therapeutics Laboratory, Centre for Plant Molecular Biology, Osmania University, Hyderabad, India
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27
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Afatinib in NSCLC With HER2 Mutations: Results of the Prospective, Open-Label Phase II NICHE Trial of European Thoracic Oncology Platform (ETOP). J Thorac Oncol 2019; 14:1086-1094. [DOI: 10.1016/j.jtho.2019.02.017] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 01/23/2019] [Accepted: 02/21/2019] [Indexed: 01/15/2023]
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Gao P, Zhang R, Li Z, Ding J, Xie J, Li J. Challenges of Providing Concordant Interpretation of Somatic Variants in Non-Small Cell Lung Cancer: A Multicenter Study. J Cancer 2019; 10:1814-1824. [PMID: 31205538 PMCID: PMC6547979 DOI: 10.7150/jca.29535] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 02/21/2019] [Indexed: 12/13/2022] Open
Abstract
Background: Success of multiple-gene mutation tests by next-generation sequencing (NGS), associated with molecular targeting therapies for cancers, depending on the accuracy and consistency of interpreting variants. Here, we summarized reports from clinical laboratories for cases with non-small cell lung cancer (NSCLC) and discussed conflicting interpretations of somatic variants. Methods: Three mimetic DNA samples, containing six somatic mutations, were prepared based on three clinical case reports of NSCLC. Clinical reports and genetic testing questionnaires were collected from 67 laboratories enrolled in this investigation. Results: Thirty-four laboratories with correct variant results identified two variants, based on FDA approval of targeted drugs for the same tumor, consistently, with strong clinical significance, whereas the other variants were classified with conflicting interpretations. Discordant interpretations were reported for ERBB2 with three different classifications, including strong clinical significance (53.0%, 18/34), potential clinical significance (38.2%, 13/34), and unknown significance (8.8%, 3/34). In the variant therapeutic drug recommendation section, 32.4% of the laboratories (11/34) did not recommend all the available therapeutic drugs designated by the National Comprehensive Cancer Network (NCCN). In the remaining group of 33 laboratories with incorrect variant results, less correct classifications were acquired for the variants with strong clinical significance. Conclusions: Owing to numerous reasons, the interpretation of variants differed greatly, which might in turn lead to the inappropriate clinical care of patients with NSCLC. By analyzing the limitations of different databases used by laboratories, we integrated various types of databases with different levels of evidence to form a comprehensive and detailed variant interpretation pipeline, aiming to standardize the variant classification and provide accurate and sufficient therapeutic drug recommendation to clinicians for minimal-inappropriate therapeutic options.
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Affiliation(s)
- Peng Gao
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Beijing, People's Republic of China
- Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, People's Republic of China
| | - Rui Zhang
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Beijing, People's Republic of China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, People's Republic of China
| | - Ziyang Li
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Beijing, People's Republic of China
- Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, People's Republic of China
| | - Jiansheng Ding
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Beijing, People's Republic of China
- Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, People's Republic of China
| | - Jiehong Xie
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Beijing, People's Republic of China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, People's Republic of China
| | - Jinming Li
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Beijing, People's Republic of China
- Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, People's Republic of China
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Jin J, Wu X, Yin J, Li M, Shen J, Li J, Zhao Y, Zhao Q, Wu J, Wen Q, Cho CH, Yi T, Xiao Z, Qu L. Identification of Genetic Mutations in Cancer: Challenge and Opportunity in the New Era of Targeted Therapy. Front Oncol 2019; 9:263. [PMID: 31058077 PMCID: PMC6477148 DOI: 10.3389/fonc.2019.00263] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 03/22/2019] [Indexed: 01/01/2023] Open
Abstract
The introduction of targeted therapy is the biggest success in the treatment of cancer in the past few decades. However, heterogeneous cancer is characterized by diverse molecular alterations as well as multiple clinical profiles. Specific genetic mutations in cancer therapy targets may increase drug sensitivity, or more frequently result in therapeutic resistance. In the past 3 years, several novel targeted therapies have been approved for cancer treatment, including drugs with new targets (i.e., anti-PD1/PDL1 therapies and CDK4/6 inhibitors), mutation targeting drugs (i.e., the EGFR T790M targeting osimertinib), drugs with multiple targets (i.e., the EGFR/HER2 dual inhibitor neratinib) and drug combinations (i.e., encorafenib/binimetinib and dabrafenib/trametinib). In this perspective, we focus on the most up-to-date knowledge of targeted therapy and describe how genetic mutations influence the sensitivity of targeted therapy, highlighting the challenges faced within this era of precision medicine. Moreover, the strategies that deal with mutation-driven resistance are further discussed. Advances in these areas would allow for more targeted and effective therapeutic options for cancer patients.
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Affiliation(s)
- Jing Jin
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Jianhua Yin
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Jing Li
- Department of Oncology and Hematology, Hospital (T.C.M) Affiliated to Southwest Medical University, Luzhou, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Qijie Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Jingbo Wu
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, China
| | - Qinglian Wen
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, China
| | - Chi Hin Cho
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.,South Sichuan Institute of Translational Medicine, Luzhou, China
| | - Tao Yi
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Liping Qu
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Abstract
Fulfilling the promises of precision medicine will depend on our ability to create patient-specific treatment regimens. Therefore, being able to translate genomic sequencing into predicting how a patient will respond to a given drug is critical. In this chapter, we review common bioinformatics approaches that aim to use sequencing data to predict sample-specific drug susceptibility. First, we explain the importance of customized drug regimens to the future of medical care. Second, we discuss the different public databases and community efforts that can be leveraged to develop new methods for identifying new predictive biomarkers. Third, we cover the basic methods that are currently used to identify markers or signatures of drug response, without any prior knowledge of the drug's mechanism of action. We further discuss how one can integrate knowledge about drug targets, mechanisms, and predictive markers to better estimate drug response in a diverse set of samples. We begin this section with a primer on popular methods to identify targets and mechanism of action for new small molecules. This discussion also includes a set of computational methods that incorporate other drug features, which do not relate to drug-induced genetic changes or sequencing data such as drug structures, side-effects, and efficacy profiles. Those additional drug properties can aid in gaining higher accuracy for the identification of drug target and mechanism of action. We then progress to discuss using these targets in combination with disease-specific expression patterns, known pathways, and genetic interaction networks to aid drug choice. Finally, we conclude this chapter with a general overview of machine learning methods that can integrate multiple pieces of sequencing data along with prior drug or biological knowledge to drastically improve response prediction.
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31
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Valentino F, Borra G, Allione P, Rossi L. Emerging targets in advanced non-small-cell lung cancer. Future Oncol 2018; 14:61-72. [PMID: 29989453 DOI: 10.2217/fon-2018-0099] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
New therapeutic options in non-small-cell lung cancer have been available through a great in-depth and genomic research, improving preclinical disease patterns and identifying the specific toxicity of target therapy. The multidisciplinary approach, increasingly practiced among clinicians, researchers, pharmaceutical companies and ethics committees has allowed the emergence of a new generation of translational clinical trials and the adoption of new technologies (e.g., point-of-care sequencing), then speeding up the development and trade of these new drugs. Consequently, there is a long list of therapeutic candidates that need to be efficiently evaluated early in the context of Phase I clinical trials. In this review, we discuss some of the key developments and novelties in the main histological groups.
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32
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Zhang P, Nie X, Wang B, Li L. Combined therapy with osimertinib and afatinib in a lung adenocarcinoma patient with EGFR T790M mutation and multiple HER2 alterations after resistance to icotinib: A case report. Thorac Cancer 2018; 9:1774-1777. [PMID: 30295016 PMCID: PMC6275817 DOI: 10.1111/1759-7714.12889] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2018] [Revised: 09/06/2018] [Accepted: 09/06/2018] [Indexed: 11/27/2022] Open
Abstract
Acquired resistance inevitably occurs after initial treatment with first-generation EGFR-tyrosine kinase inhibitors (TKIs). Several mechanisms have been identified, including EGFR T790M mutation and HER2 amplification. Herein, we present the case of a patient who progressed on first-generation EGFR-TKIs and developed EGFR T790M mutation, HER2 amplification, and HER2 mutation. The administration of single-agent osimertinib yielded an inconsistent response, with worsened pleural effusion and a reduction to lung metastases, but remarkably, a partial response was achieved after four weeks of treatment with combined osimertinib and afatinib, with grade 1 rash and grade 2 diarrhea. Our findings indicate an overlap of T790M, HER2 amplification, and HER2 mutation, which is rarely reported. Moreover, HER2 mutation was identified during the development of resistance, suggesting that HER2 mutation may cause resistance to first-generation EGFR-TKIs.
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Affiliation(s)
- Ping Zhang
- Department of Oncology, Beijing Hospital, National Center of Gerontology, Beijing, China
| | - Xin Nie
- Department of Oncology, Beijing Hospital, National Center of Gerontology, Beijing, China
| | - Bing Wang
- Department of In Vitro Diagnostic Testing, Beijing Institute of Medical Device Testing, Beijing, China
| | - Lin Li
- Department of Oncology, Beijing Hospital, National Center of Gerontology, Beijing, China
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33
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Peters S, Stahel R, Bubendorf L, Bonomi P, Villegas A, Kowalski DM, Baik CS, Isla D, Carpeno JDC, Garrido P, Rittmeyer A, Tiseo M, Meyenberg C, de Haas S, Lam LH, Lu MW, Stinchcombe TE. Trastuzumab Emtansine (T-DM1) in Patients with Previously Treated HER2-Overexpressing Metastatic Non–Small Cell Lung Cancer: Efficacy, Safety, and Biomarkers. Clin Cancer Res 2018; 25:64-72. [DOI: 10.1158/1078-0432.ccr-18-1590] [Citation(s) in RCA: 109] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 07/30/2018] [Accepted: 09/07/2018] [Indexed: 12/27/2022]
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34
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Oh IJ, Hur JY, Park CK, Kim YC, Kim SJ, Lee MK, Kim HJ, Lee KY, Lee JC, Choi CM. Clinical Activity of Pan-HER Inhibitors Against HER2-Mutant Lung Adenocarcinoma. Clin Lung Cancer 2018; 19:e775-e781. [DOI: 10.1016/j.cllc.2018.05.018] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Revised: 03/17/2018] [Accepted: 05/28/2018] [Indexed: 01/18/2023]
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35
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Concordance analysis between HER2 immunohistochemistry and in situ hybridization in non-small cell lung cancer. Int J Biol Markers 2018; 33:49-54. [PMID: 28478639 DOI: 10.5301/ijbm.5000271] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE This study aimed to elucidate the concordance between human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) and in situ hybridization (ISH) and the diagnostic accuracy of HER2 IHC in non-small cell lung cancer (NSCLC) through a meta-analysis and diagnostic test accuracy review. METHODS Seven eligible studies and 1,217 patients with NSCLC were included in the review. The concordance between HER2 IHC and ISH was analyzed. To confirm the diagnostic accuracy of HER2 IHC, the sensitivity and specificity were analyzed and the area under the curve (AUC) in the summary receiver operating characteristic (SROC) curve was calculated. RESULTS The concordance rate between HER2 IHC and ISH was 0.795 (95% confidence interval [CI] 0.534-0.929). In the HER2 IHC-negative (score 0/1+) subgroup, the concordance rate was 0.975 (95% CI 0.854-0.996). The concordance rates of the HER2 IHC score 2+ and 3+ subgroups were 0.091 (95% CI 0.039-0.197) and 0.665 (95% CI 0.446-0.830), respectively. In diagnostic test accuracy review, the pooled sensitivity and specificity were 0.67 (95% CI 0.54-0.78) and 0.89 (95% CI 0.87-0.91), respectively. The AUC in the SROC curve was 0.891 and the diagnostic odds ratio was 16.99 (95% CI 5.08-56.76). CONCLUSIONS HER2 IHC was largely in agreement with ISH in cases of HER2 IHC score 0/1+. Because the concordance rates of HER2 IHC score 2/3+ cases were lower than that of HER2 IHC score 0/1+ cases, further studies for detailed analysis criteria for HER2 IHC score 2+ or 3+ are required.
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36
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Peters S, Curioni-Fontecedro A, Nechushtan H, Shih JY, Liao WY, Gautschi O, Spataro V, Unk M, Yang JCH, Lorence RM, Carrière P, Cseh A, Chang GC. Activity of Afatinib in Heavily Pretreated Patients With ERBB2 Mutation-Positive Advanced NSCLC: Findings From a Global Named Patient Use Program. J Thorac Oncol 2018; 13:1897-1905. [PMID: 30096481 DOI: 10.1016/j.jtho.2018.07.093] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Revised: 07/03/2018] [Accepted: 07/31/2018] [Indexed: 10/28/2022]
Abstract
INTRODUCTION Approximately 1% to 4% of NSCLC tumors harbor erb-b2 receptor tyrosine kinase 2 (ERBB2) mutation; there is no approved targeted treatment for this subgroup. METHODS Patients with stage IV NSCLC that progressed after clinical benefit on erlotinib/gefitinib and/or had activating EGFR or ERBB2 mutations, had exhausted other treatments, and were ineligible for afatinib trials were enrolled in a named patient use program, receiving afatinib 30 to 50 mg/d on a compassionate basis within routine clinical practice. Efficacy and safety were retrospectively assessed in the subgroup with ERBB2 mutation-positive NSCLC. RESULTS Twenty-eight heavily pretreated patients in the named patient use program had a documented ERBB2 mutation by local testing. Median time-to-treatment failure (TTF; time from treatment initiation to discontinuation for any reason) was 2.9 months; eight patients (29%) had TTF greater than 1 year. Objective response rate was 19% (3 of 16 patients with response data achieved partial response) and disease control rate (DCR) was 69% (11 of 16). Among 12 patients for whom type of ERBB2 mutation was specified, 10 had a p.A775_G776insYVMA insertion in exon 20, four of whom (40%) remained on afatinib for more than 1 year. This subgroup had median TTF of 9.6 months, objective response rate of 33% (two of six), and disease control rate of 100% (six of six). CONCLUSIONS This analysis of patients treated in clinical practice provides further evidence of the activity of afatinib in ERBB2 mutation-positive NSCLC, and suggests that identification of specific subgroups with certain mutations, such as p.A775_G776ins/YVMA insertion in exon 20, could help optimize outcomes with ErbB2-targeted treatment.
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Affiliation(s)
- Solange Peters
- Oncology Department, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
| | | | - Hovav Nechushtan
- Sharett Institute of Oncology, Hadassah Hebrew University Medical Center, Kiryat Hadassah, Jerusalem, Israel
| | - Jin-Yuan Shih
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Wei-Yu Liao
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Oliver Gautschi
- Medical Oncology, Cantonal Hospital Lucerne, Lucerne, Switzerland
| | - Vito Spataro
- Department of Medical Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
| | - Mojca Unk
- Department for Medical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia
| | | | - Robert M Lorence
- Oncology Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Philippe Carrière
- Risk Management Oncology, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
| | - Agnieszka Cseh
- Medical Department, Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, Austria
| | - Gee-Chen Chang
- Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan; and the Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
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Indian consensus statement for treatment of advanced non small cell lung cancer: First line, maintenance, and second line. Indian J Cancer 2018; 54:89-103. [PMID: 29199671 DOI: 10.4103/ijc.ijc_136_17] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
The management of advanced nonsmall cell lung cancer (NSCLC) patients is becoming complex with the identification of driver mutations and targeted therapies. The expert group of academic medical oncologists used data from published literature, practical experience to arrive at practical consensus recommendations to treat advanced NSCLC for use by the community oncologists.
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38
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Yu HA, Planchard D, Lovly CM. Sequencing Therapy for Genetically Defined Subgroups of Non-Small Cell Lung Cancer. Am Soc Clin Oncol Educ Book 2018; 38:726-739. [PMID: 30231382 PMCID: PMC10172876 DOI: 10.1200/edbk_201331] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/29/2023]
Abstract
The practice of precision medicine for patients with metastatic non-small cell lung cancer (NSCLC), particularly those patients with adenocarcinoma histology (the predominant subtype of NSCLC), has become the accepted standard of care worldwide. Implementation of prospective tumor molecular profiling and rational therapeutic decision-making based on the presence of recurrently detected oncogenic "driver" alterations in the tumor genome has revolutionized the way that lung cancer is diagnosed and treated in the clinic. Over the past two decades, there has been a deluge of therapeutically actionable driver alterations and accompanying small molecule inhibitors to target these drivers. Herein, we synthesize a large and rapidly growing body of literature regarding therapeutic inhibition of driver mutations. We focus on established targets, including EGFR, anaplastic lymphoma kinase (ALK), ROS1, BRAF, RET, MET, HER2, and neurotrophic tyrosine kinase receptor (NTRK), with a particular emphasis on the sequencing of small molecule inhibitors in these genetically defined cohorts of patients with lung cancer.
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Affiliation(s)
- Helena A Yu
- From the Department of Medicine, Memorial Sloan Kettering Cancer Center, Weil Cornell Medical College, New York, NY; Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France; Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Vanderbilt Ingram Cancer Center, Nashville, TN
| | - David Planchard
- From the Department of Medicine, Memorial Sloan Kettering Cancer Center, Weil Cornell Medical College, New York, NY; Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France; Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Vanderbilt Ingram Cancer Center, Nashville, TN
| | - Christine M Lovly
- From the Department of Medicine, Memorial Sloan Kettering Cancer Center, Weil Cornell Medical College, New York, NY; Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France; Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Vanderbilt Ingram Cancer Center, Nashville, TN
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Meedendorp AD, Ter Elst A, 't Hart NA, Groen HJM, Schuuring E, van der Wekken AJ. Response to HER2 Inhibition in a Patient With Brain Metastasis With EGFR TKI Acquired Resistance and an HER2 Amplification. Front Oncol 2018; 8:176. [PMID: 29872644 PMCID: PMC5972286 DOI: 10.3389/fonc.2018.00176] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Accepted: 05/04/2018] [Indexed: 01/23/2023] Open
Abstract
A 62-year-old man was referred to our university hospital for treatment of advanced adenocarcinoma of the lung after disease progression on two lines of EGFR TKI and one line of chemotherapy. Fluorescent in situ hybridization analysis upon progression showed an HER2 amplification. At our weekly Molecular Tumor Board (MTB), a decision was made to treat this patient with afatinib, which resulted in a partial response. However, progression was observed with a facial nerve paresis due to a metastasis in the skull. A biopsy of a location in the thorax revealed the presence of an EGFR-T790M mutation associated with acquired resistance, after which treatment with osimertinib was started. After 6 months, disease progression was observed, and a new biopsy was taken from the pelvic bone, which revealed the original amplification of HER2 together with the EGFR-L858R mutation, the EGFR-T790M mutation was not detected. The MTB decided to treat the patient with trastuzumab/paclitaxel. A partial response was observed in different bone lesions, while the skull metastasis with ingrowth in the brain remained stable for 6 months. Because of progression of the bone metastases after 6 months, a biopsy of a lesion in the thorax wall was taken. In this lesion, the EGFR-T790M mutation could be detected again. The MTB advised to start treatment with a combination of osimertinib and afatinib. This resulted in an impressive clinical improvement and a partial response of the bone metastases on the most recent 18-fluorodeoxyglucose positron emission tomography and computer tomography-scan. In conclusion, adjusting treatment to the mutational make-up of the tumor is a great challenge. For optimal treatment response multiple biopsies and re-biopsy upon progression are imperative. As more genes are investigated, treatment decision becomes increasingly difficult, therefore, expert opinions from an MTB is essential.
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Affiliation(s)
- Arenda D Meedendorp
- University of Groningen and University Medical Center Groningen, Groningen, Netherlands
| | - Arja Ter Elst
- University of Groningen and University Medical Center Groningen, Groningen, Netherlands
| | - Nils A 't Hart
- University of Groningen and University Medical Center Groningen, Groningen, Netherlands
| | - Harry J M Groen
- University of Groningen and University Medical Center Groningen, Groningen, Netherlands
| | - Ed Schuuring
- University of Groningen and University Medical Center Groningen, Groningen, Netherlands
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Abstract
Targeted therapy and immunotherapy have changed the treatment paradigm of non-small cell lung cancer (NSCLC). Distinct molecular subtypes of NSCLC have been described over the past 20 years, enabling the emergence of treatments specific to that subtype. Agents targeting the driver mutations in NSCLC have revolutionized the approach to patients with metastatic disease, because oncologists now select a treatment based on the profile of that particular tumor. More recently, an understanding of immune checkpoints has led to the development of checkpoint inhibitors that enable the host immune system to better recognize tumor cells as foreign and to destroy them.
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Affiliation(s)
- Evan C Naylor
- Hematology and Oncology, Southern Ocean Medical Center, Meridian Cancer Care, 1140 Route 72 West, Manahawkin, NJ 08050, USA.
| | - Jatin K Desani
- Hematology and Oncology, Southern Ocean Medical Center, Meridian Cancer Care, 1140 Route 72 West, Manahawkin, NJ 08050, USA
| | - Paul K Chung
- Hematology and Oncology, Southern Ocean Medical Center, Meridian Cancer Care, 1140 Route 72 West, Manahawkin, NJ 08050, USA
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Li J, You W, Zheng D, Yan B, Ma X, Pan Y, Zhang Y, Li Y, Shen X, Cheng X, Sun Y, Chen H. A comprehensive evaluation of clinicopathologic characteristics, molecular features and prognosis in lung adenocarcinoma with solid component. J Cancer Res Clin Oncol 2018; 144:725-734. [PMID: 29368062 DOI: 10.1007/s00432-018-2588-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2017] [Accepted: 01/17/2018] [Indexed: 10/18/2022]
Abstract
PURPOSE We have reported that solid predominant lung adenocarcinoma according to the IASLC/ATS/ERS classification was associated with poor prognosis. However, the correlation of solid component with clinicopathological, molecular features, and prognosis in all lung adenocarcinoma patients remains unexplored. METHODS Surgically resected lung adenocarcinomas were divided into three groups, solid predominant (solid component accounting for at least 50%), solid minor (solid component accounting for 5-45%) and solid negative. Patients' clinicopathological characteristics, disease free survival (DFS), overall survival (OS) and molecular alterations, including EGFR, KRAS, FGFR, etc., were analyzed. RESULTS Of 1098 lung adenocarcinomas, 198 were solid predominant, 132 were solid minor, and 768 were solid negative. Solid positive patients, including solid predominant and solid minor, had significantly worse DFS (p < 0.0001) and OS (p < 0.0001) compared with solid negative group, so were solid minor patients (both p < 0.0001). Cox multivariate analysis revealed that solid positive pattern was an independent predictor for DFS [hazard ratio (HR) 1.495, 95% confidence interval (CI) 1.004-2.233; p = 0.034] and OS [HR 1.561, 95% CI 1.03-2.342; p = 0.016]. The frequency of FGFR fusions was significantly higher in solid positive lung adenocarcinomas than in solid negative group (1.5 vs. 0.3%, p = 0.048). The response rate to EGFR-tyrosine kinase inhibitors (TKIs) was 66.7% in EGFR-mutated solid positive patients after recurrence. CONCLUSIONS This study represents the first comprehensive clinical investigation of solid component in lung adenocarcinomas, identifying solid positive pattern as an independent poor prognostic indicator in lung adenocarcinoma.
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Affiliation(s)
- Jing Li
- Department of Internal Medicine, Shandong Police Hospital, Jinan, China
- Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Dong-An Road 270#, Shanghai, 200032, China
| | - Wenjie You
- Department of Respiratory Medicine, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China
| | - Difan Zheng
- Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Dong-An Road 270#, Shanghai, 200032, China
| | - Bei Yan
- Department of Internal Medicine, Shandong Police Hospital, Jinan, China
| | - Xiao Ma
- Department of Internal Medicine, Shanghai Pulmonary Hospital, Shanghai, China
| | - Yunjian Pan
- Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Dong-An Road 270#, Shanghai, 200032, China
| | - Yang Zhang
- Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Dong-An Road 270#, Shanghai, 200032, China
| | - Yuan Li
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Xuxia Shen
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Xinghua Cheng
- Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Dong-An Road 270#, Shanghai, 200032, China
| | - Yihua Sun
- Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Dong-An Road 270#, Shanghai, 200032, China
| | - Haiquan Chen
- Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Dong-An Road 270#, Shanghai, 200032, China.
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Ross JS, Fakih M, Ali SM, Elvin JA, Schrock AB, Suh J, Vergilio J, Ramkissoon S, Severson E, Daniel S, Fabrizio D, Frampton G, Sun J, Miller VA, Stephens PJ, Gay LM. Targeting HER2 in colorectal cancer: The landscape of amplification and short variant mutations in ERBB2 and ERBB3. Cancer 2018; 124:1358-1373. [PMID: 29338072 PMCID: PMC5900732 DOI: 10.1002/cncr.31125] [Citation(s) in RCA: 150] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Revised: 09/28/2017] [Accepted: 10/06/2017] [Indexed: 12/20/2022]
Abstract
BACKGROUND In contrast to lung cancer, few precision treatments are available for colorectal cancer (CRC). One rapidly emerging treatment target in CRC is ERBB2 (human epidermal growth factor receptor 2 [HER2]). Oncogenic alterations in HER2, or its dimerization partner HER3, can underlie sensitivity to HER2-targeted therapies. METHODS In this study, 8887 CRC cases were evaluated by comprehensive genomic profiling for genomic alterations in 315 cancer-related genes, tumor mutational burden, and microsatellite instability. This cohort included both colonic (7599 cases; 85.5%) and rectal (1288 cases; 14.5%) adenocarcinomas. RESULTS A total of 569 mCRCs were positive for ERBB2 (429 cases; 4.8%) and/or ERBB3 (148 cases; 1.7%) and featured ERBB amplification, short variant alterations, or a combination of the 2. High tumor mutational burden (≥20 mutations/Mb) was significantly more common in ERBB-mutated samples, and ERBB3-mutated CRCs were significantly more likely to have high microsatellite instability (P<.002). Alterations affecting KRAS (27.3%) were significantly underrepresented in ERBB2-amplified samples compared with wild-type CRC samples (51.8%), and ERBB2- or ERBB3-mutated samples (49.0% and 60.8%, respectively) (P<.01). Other significant differences in mutation frequency were observed for genes in the PI3K/MTOR and mismatch repair pathways. CONCLUSIONS Although observed less often than in breast or upper gastrointestinal carcinomas, indications for which anti-HER2 therapies are approved, the percentage of CRC with ERBB genomic alterations is significant. Importantly, 32% of ERBB2-positive CRCs harbor short variant alterations that are undetectable by routine immunohistochemistry or fluorescence in situ hybridization testing. The success of anti-HER2 therapies in ongoing clinical trials is a promising development for patients with CRC. Cancer 2018;124:1358-73. © 2018 Foundation Medicine, Inc. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.
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Affiliation(s)
- Jeffrey S. Ross
- Foundation Medicine IncCambridgeMassachusetts
- Department of PathologyAlbany Medical CenterAlbanyNew York
| | - Marwan Fakih
- Department of Medical Oncology and Therapeutics Research City of HopeDuarteCalifornia
| | | | | | | | - James Suh
- Foundation Medicine IncCambridgeMassachusetts
| | | | | | | | | | | | | | - James Sun
- Foundation Medicine IncCambridgeMassachusetts
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Cappuzzo F, Landi L. HER2 Deregulation in Lung Cancer: Right Time to Adopt an Orphan? Clin Cancer Res 2018; 24:2470-2472. [DOI: 10.1158/1078-0432.ccr-18-0198] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Revised: 02/13/2018] [Accepted: 02/27/2018] [Indexed: 11/16/2022]
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Tomasello C, Baldessari C, Napolitano M, Orsi G, Grizzi G, Bertolini F, Barbieri F, Cascinu S. Resistance to EGFR inhibitors in non-small cell lung cancer: Clinical management and future perspectives. Crit Rev Oncol Hematol 2018; 123:149-161. [DOI: 10.1016/j.critrevonc.2018.01.013] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2017] [Revised: 11/09/2017] [Accepted: 01/31/2018] [Indexed: 12/18/2022] Open
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Cappuzzo F, Toschi L, Finocchiaro G, Ligorio C, Santoro A. Surrogate Predictive Biomarkers for Response to Anti-EGFR Agents: State of the Art and Challenges. Int J Biol Markers 2018; 22:10-23. [DOI: 10.1177/17246008070221s403] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
The epidermal growth factor receptor (EGFR) plays a key role in cancer development and progression in several human malignancies including non-small cell lung cancer (NSCLC). Several strategies aimed at inhibiting the EGFR have been investigated in the last years, including the use of small tyrosine kinase inhibitors (TKIs) directed against the intracellular domain of the receptor and monoclonal antibodies targeting its extracellular portion. Subgroups of patients who are more likely to respond to TKIs have been identified based on both clincal and biological features. Never-smoking history has emerged as the most relevant clinical characteristic predictive of response to TKIs in NSCLC, while presence of drug-sensitive EGFR mutations and EGFR gene gain represent critical biological variables associated with an improved outcome for patients exposed to these agents. Recent studies have highlighted the existence of biological factors involved in intrinsic and acquired resistance to TKIs, including k-ras, HER-2 and EGFR exon 20 mutations. Increasing knowledge of EGFR biology and drug-receptor interactions will allow to identify individuals who are likely to derive a clinical benefit from the proposed targeted therapy, sparing refractory patients expensive and potentially toxic treatment.
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Affiliation(s)
- F. Cappuzzo
- Department of Oncology-Hematology, Istituto Clinico Humanitas IRCCS, Rozzano, Milan - Italy
| | - L. Toschi
- Department of Oncology-Hematology, Istituto Clinico Humanitas IRCCS, Rozzano, Milan - Italy
| | - G. Finocchiaro
- Department of Oncology-Hematology, Istituto Clinico Humanitas IRCCS, Rozzano, Milan - Italy
| | - C. Ligorio
- Department of Oncology-Hematology, Istituto Clinico Humanitas IRCCS, Rozzano, Milan - Italy
| | - A. Santoro
- Department of Oncology-Hematology, Istituto Clinico Humanitas IRCCS, Rozzano, Milan - Italy
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Hainsworth JD, Meric-Bernstam F, Swanton C, Hurwitz H, Spigel DR, Sweeney C, Burris H, Bose R, Yoo B, Stein A, Beattie M, Kurzrock R. Targeted Therapy for Advanced Solid Tumors on the Basis of Molecular Profiles: Results From MyPathway, an Open-Label, Phase IIa Multiple Basket Study. J Clin Oncol 2018; 36:536-542. [PMID: 29320312 DOI: 10.1200/jco.2017.75.3780] [Citation(s) in RCA: 358] [Impact Index Per Article: 51.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Purpose Detection of specific molecular alterations in tumors guides the selection of effective targeted treatment of patients with several types of cancer. These molecular alterations may occur in other tumor types for which the efficacy of targeted therapy remains unclear. The MyPathway study evaluates the efficacy and safety of selected targeted therapies in tumor types that harbor relevant genetic alterations but are outside of current labeling for these treatments. Methods MyPathway ( ClinicalTrials.gov identifier: NCT02091141) is a multicenter, nonrandomized, phase IIa multiple basket study. Patients with advanced refractory solid tumors harboring molecular alterations in human epidermal growth factor receptor-2, epidermal growth factor receptor, v-raf murine sarcoma viral oncogene homolog B1, or the Hedgehog pathway are treated with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. The primary end point is investigator-assessed objective response rate within each tumor-pathway cohort. Results Between April 1, 2014 and November 1, 2016, 251 patients with 35 different tumor types received study treatment. The efficacy population contains 230 treated patients who were evaluated for response or discontinued treatment before evaluation. Fifty-two patients (23%) with 14 different tumor types had objective responses (complete, n = 4; partial, n = 48). Tumor-pathway cohorts with notable objective response rates included human epidermal growth factor receptor-2-amplified/overexpressing colorectal (38% [14 of 37]; 95% CI, 23% to 55%) and v-raf murine sarcoma viral oncogene homolog B1 V600-mutated non-small-cell lung cancer (43% [six of 14]; 95% CI, 18% to 71%). Conclusion The four currently approved targeted therapy regimens in the MyPathway study produced meaningful responses when administered without chemotherapy in several refractory solid tumor types not currently labeled for these agents.
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Affiliation(s)
- John D Hainsworth
- John D. Hainsworth, David R. Spigel, and Howard Burris, Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN; Funda Meric-Bernstam, University of Texas MD Anderson Cancer Center, Houston, TX; Charles Swanton, Francis Crick Institute, London, United Kingdom; Herbert Hurwitz, Duke University Medical Center, Durham, NC; Christopher Sweeney, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Ron Bose, Washington University School of Medicine, St Louis, MO; Bongin Yoo, Alisha Stein, and Mary Beattie, Genentech, South San Francisco; and Razelle Kurzrock, Moores Cancer Center, University of California San Diego, San Diego, CA
| | - Funda Meric-Bernstam
- John D. Hainsworth, David R. Spigel, and Howard Burris, Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN; Funda Meric-Bernstam, University of Texas MD Anderson Cancer Center, Houston, TX; Charles Swanton, Francis Crick Institute, London, United Kingdom; Herbert Hurwitz, Duke University Medical Center, Durham, NC; Christopher Sweeney, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Ron Bose, Washington University School of Medicine, St Louis, MO; Bongin Yoo, Alisha Stein, and Mary Beattie, Genentech, South San Francisco; and Razelle Kurzrock, Moores Cancer Center, University of California San Diego, San Diego, CA
| | - Charles Swanton
- John D. Hainsworth, David R. Spigel, and Howard Burris, Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN; Funda Meric-Bernstam, University of Texas MD Anderson Cancer Center, Houston, TX; Charles Swanton, Francis Crick Institute, London, United Kingdom; Herbert Hurwitz, Duke University Medical Center, Durham, NC; Christopher Sweeney, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Ron Bose, Washington University School of Medicine, St Louis, MO; Bongin Yoo, Alisha Stein, and Mary Beattie, Genentech, South San Francisco; and Razelle Kurzrock, Moores Cancer Center, University of California San Diego, San Diego, CA
| | - Herbert Hurwitz
- John D. Hainsworth, David R. Spigel, and Howard Burris, Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN; Funda Meric-Bernstam, University of Texas MD Anderson Cancer Center, Houston, TX; Charles Swanton, Francis Crick Institute, London, United Kingdom; Herbert Hurwitz, Duke University Medical Center, Durham, NC; Christopher Sweeney, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Ron Bose, Washington University School of Medicine, St Louis, MO; Bongin Yoo, Alisha Stein, and Mary Beattie, Genentech, South San Francisco; and Razelle Kurzrock, Moores Cancer Center, University of California San Diego, San Diego, CA
| | - David R Spigel
- John D. Hainsworth, David R. Spigel, and Howard Burris, Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN; Funda Meric-Bernstam, University of Texas MD Anderson Cancer Center, Houston, TX; Charles Swanton, Francis Crick Institute, London, United Kingdom; Herbert Hurwitz, Duke University Medical Center, Durham, NC; Christopher Sweeney, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Ron Bose, Washington University School of Medicine, St Louis, MO; Bongin Yoo, Alisha Stein, and Mary Beattie, Genentech, South San Francisco; and Razelle Kurzrock, Moores Cancer Center, University of California San Diego, San Diego, CA
| | - Christopher Sweeney
- John D. Hainsworth, David R. Spigel, and Howard Burris, Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN; Funda Meric-Bernstam, University of Texas MD Anderson Cancer Center, Houston, TX; Charles Swanton, Francis Crick Institute, London, United Kingdom; Herbert Hurwitz, Duke University Medical Center, Durham, NC; Christopher Sweeney, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Ron Bose, Washington University School of Medicine, St Louis, MO; Bongin Yoo, Alisha Stein, and Mary Beattie, Genentech, South San Francisco; and Razelle Kurzrock, Moores Cancer Center, University of California San Diego, San Diego, CA
| | - Howard Burris
- John D. Hainsworth, David R. Spigel, and Howard Burris, Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN; Funda Meric-Bernstam, University of Texas MD Anderson Cancer Center, Houston, TX; Charles Swanton, Francis Crick Institute, London, United Kingdom; Herbert Hurwitz, Duke University Medical Center, Durham, NC; Christopher Sweeney, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Ron Bose, Washington University School of Medicine, St Louis, MO; Bongin Yoo, Alisha Stein, and Mary Beattie, Genentech, South San Francisco; and Razelle Kurzrock, Moores Cancer Center, University of California San Diego, San Diego, CA
| | - Ron Bose
- John D. Hainsworth, David R. Spigel, and Howard Burris, Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN; Funda Meric-Bernstam, University of Texas MD Anderson Cancer Center, Houston, TX; Charles Swanton, Francis Crick Institute, London, United Kingdom; Herbert Hurwitz, Duke University Medical Center, Durham, NC; Christopher Sweeney, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Ron Bose, Washington University School of Medicine, St Louis, MO; Bongin Yoo, Alisha Stein, and Mary Beattie, Genentech, South San Francisco; and Razelle Kurzrock, Moores Cancer Center, University of California San Diego, San Diego, CA
| | - Bongin Yoo
- John D. Hainsworth, David R. Spigel, and Howard Burris, Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN; Funda Meric-Bernstam, University of Texas MD Anderson Cancer Center, Houston, TX; Charles Swanton, Francis Crick Institute, London, United Kingdom; Herbert Hurwitz, Duke University Medical Center, Durham, NC; Christopher Sweeney, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Ron Bose, Washington University School of Medicine, St Louis, MO; Bongin Yoo, Alisha Stein, and Mary Beattie, Genentech, South San Francisco; and Razelle Kurzrock, Moores Cancer Center, University of California San Diego, San Diego, CA
| | - Alisha Stein
- John D. Hainsworth, David R. Spigel, and Howard Burris, Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN; Funda Meric-Bernstam, University of Texas MD Anderson Cancer Center, Houston, TX; Charles Swanton, Francis Crick Institute, London, United Kingdom; Herbert Hurwitz, Duke University Medical Center, Durham, NC; Christopher Sweeney, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Ron Bose, Washington University School of Medicine, St Louis, MO; Bongin Yoo, Alisha Stein, and Mary Beattie, Genentech, South San Francisco; and Razelle Kurzrock, Moores Cancer Center, University of California San Diego, San Diego, CA
| | - Mary Beattie
- John D. Hainsworth, David R. Spigel, and Howard Burris, Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN; Funda Meric-Bernstam, University of Texas MD Anderson Cancer Center, Houston, TX; Charles Swanton, Francis Crick Institute, London, United Kingdom; Herbert Hurwitz, Duke University Medical Center, Durham, NC; Christopher Sweeney, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Ron Bose, Washington University School of Medicine, St Louis, MO; Bongin Yoo, Alisha Stein, and Mary Beattie, Genentech, South San Francisco; and Razelle Kurzrock, Moores Cancer Center, University of California San Diego, San Diego, CA
| | - Razelle Kurzrock
- John D. Hainsworth, David R. Spigel, and Howard Burris, Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN; Funda Meric-Bernstam, University of Texas MD Anderson Cancer Center, Houston, TX; Charles Swanton, Francis Crick Institute, London, United Kingdom; Herbert Hurwitz, Duke University Medical Center, Durham, NC; Christopher Sweeney, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Ron Bose, Washington University School of Medicine, St Louis, MO; Bongin Yoo, Alisha Stein, and Mary Beattie, Genentech, South San Francisco; and Razelle Kurzrock, Moores Cancer Center, University of California San Diego, San Diego, CA
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Park CK, Hur JY, Choi CM, Kim TO, Cho HJ, Shin HJ, Lim JH, Choi YD, Kim YC, Oh IJ. Efficacy of Afatinib in a Previously-Treated Patient with Non-Small Cell Lung Cancer Harboring HER2 Mutation: Case Report. J Korean Med Sci 2018; 33:e7. [PMID: 29215816 PMCID: PMC5729642 DOI: 10.3346/jkms.2018.33.e7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2016] [Accepted: 09/03/2016] [Indexed: 12/18/2022] Open
Abstract
Human epidermal growth factor receptor 2 (HER2) mutation in non-small cell lung cancer (NSCLC) is an oncogenic driver that possibly becomes a druggable target to HER2-targeted therapy. The benefit of HER2-targeted therapy is much less defined especially in eastern populations. We provide evidence of clinical benefit of afatinib in a 50-year-old Asian woman with HER2-mutant NSCLC who previously failed cytotoxic chemotherapy and gefitinib treatment. Next-generation sequencing of the tumor tissue revealed a HER2 exon 20 mutation (c.2437A>G), which has never been reported. The patient was treated with afatinib for more than four months. She showed rapid radiologic response within a month, and maintained stable state until the last dose of afatinib.
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Affiliation(s)
- Cheol Kyu Park
- Department of Internal Medicine, Chonnam National University Hwasun Hospital, Hwasun, Korea
- Lung and Esophageal Cancer Clinic, Chonnam National University Hwasun Hospital, Hwasun, Korea
| | - Jae Young Hur
- Department of Pathology, Konkuk University Hospital, Seoul, Korea
| | - Chang Min Choi
- Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Tae Ok Kim
- Department of Internal Medicine, Chonnam National University Hwasun Hospital, Hwasun, Korea
| | - Hyun Ju Cho
- Department of Internal Medicine, Chonnam National University Hwasun Hospital, Hwasun, Korea
- Lung and Esophageal Cancer Clinic, Chonnam National University Hwasun Hospital, Hwasun, Korea
| | - Hong Joon Shin
- Department of Internal Medicine, Chonnam National University Hwasun Hospital, Hwasun, Korea
| | - Jung Hwan Lim
- Department of Internal Medicine, Chonnam National University Hwasun Hospital, Hwasun, Korea
- Lung and Esophageal Cancer Clinic, Chonnam National University Hwasun Hospital, Hwasun, Korea
| | - Yoo Duk Choi
- Lung and Esophageal Cancer Clinic, Chonnam National University Hwasun Hospital, Hwasun, Korea
- Department of Pathology, Chonnam National University Medical School, Gwangju, Korea
| | - Young Chul Kim
- Department of Internal Medicine, Chonnam National University Hwasun Hospital, Hwasun, Korea
- Lung and Esophageal Cancer Clinic, Chonnam National University Hwasun Hospital, Hwasun, Korea
| | - In Jae Oh
- Department of Internal Medicine, Chonnam National University Hwasun Hospital, Hwasun, Korea
- Lung and Esophageal Cancer Clinic, Chonnam National University Hwasun Hospital, Hwasun, Korea.
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Abdel-Fatah TMA, Rees RC, Pockley AG, Moseley P, Ball GR, Chan SYT, Ellis IO, Miles AK. The localization of pre mRNA splicing factor PRPF38B is a novel prognostic biomarker that may predict survival benefit of trastuzumab in patients with breast cancer overexpressing HER2. Oncotarget 2017; 8:112245-112257. [PMID: 29348822 PMCID: PMC5762507 DOI: 10.18632/oncotarget.22496] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Accepted: 10/28/2017] [Indexed: 11/25/2022] Open
Abstract
Cancer biomarkers that can define disease status and provide a prognostic insight are essential for the effective management of patients with breast cancer (BC). The prevalence, clinicopathological and prognostic significance of PRPF38B expression in a consecutive series of 1650 patients with primary invasive breast carcinoma were examined using immunohistochemistry. Furthermore, the relationship(s) between clinical outcome and PRPF38B expression was explored in 627 patients with ER-negative (oestrogen receptor) disease, and 322 patients with HER2-overexpressing disease. Membranous expression of PRPF38B was observed in 148/1388 (10.7%) cases and was significantly associated with aggressive clinicopathological features, including high grade, high mitotic index, pleomorphism, invasive ductal carcinoma of no specific type (IDC-NST), ER-negative, HER2-overexpression and p53 mutational status (all p < 0.01). In patients with ER-negative disease receiving chemotherapy, nuclear expression of PRPF38B was significantly associated with a reduced risk of relapse (p = 0.0004), whereas membranous PRPF38B expression was significantly associated with increased risk of relapse (p = 0.004; respectively) at a 5 year follow-up. When patients were stratified according to ER-negative/HER2-positive status, membranous PRPF38B expression was associated with a higher risk of relapse in those patients that did not receive trastuzumab therapy (p = 0.02), whereas in those patients with ER-negative/HER2-positive disease that received trastuzumab adjuvant therapy, membranous PRPF38B expression associated with a lower risk of relapse (p = 0.00018). Nuclear expression of PRPF38B is a good prognostic indicator in both ER-negative patients and ER-negative/HER2-positive BC (breast cancer) patients, whereas membranous localisation of PRPF38B is a poor prognostic biomarker that predicts survival benefit from trastuzumab therapy in patients with ER-negative/HER2-overexpressing BC.
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Affiliation(s)
- Tarek M A Abdel-Fatah
- Department of Clinical Oncology, Nottingham City Hospital, Nottingham University Hospitals NHS Trust, Nottingham, NG5 1PB, UK
| | - Robert C Rees
- The John van Geest Cancer Research Centre, Nottingham Trent University, Nottingham, NG11 8NS, UK
| | - A Graham Pockley
- The John van Geest Cancer Research Centre, Nottingham Trent University, Nottingham, NG11 8NS, UK
| | - Paul Moseley
- Department of Clinical Oncology, Nottingham City Hospital, Nottingham University Hospitals NHS Trust, Nottingham, NG5 1PB, UK
| | - Graham R Ball
- The John van Geest Cancer Research Centre, Nottingham Trent University, Nottingham, NG11 8NS, UK
| | - Stephen Y T Chan
- Department of Clinical Oncology, Nottingham City Hospital, Nottingham University Hospitals NHS Trust, Nottingham, NG5 1PB, UK
| | - Ian O Ellis
- Department of Histopathology, Nottingham City Hospital, Nottingham University Hospitals NHS Trust, Nottingham, NG5 1PB, UK
| | - Amanda K Miles
- The John van Geest Cancer Research Centre, Nottingham Trent University, Nottingham, NG11 8NS, UK
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Connell CM, Doherty GJ. Activating HER2 mutations as emerging targets in multiple solid cancers. ESMO Open 2017; 2:e000279. [PMID: 29209536 PMCID: PMC5708307 DOI: 10.1136/esmoopen-2017-000279] [Citation(s) in RCA: 117] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Revised: 10/22/2017] [Accepted: 10/23/2017] [Indexed: 12/15/2022] Open
Abstract
The epidermal growth factor receptor (EGFR) family of transmembrane receptor tyrosine kinases activates signalling pathways regulating cellular proliferation and survival. HER2 is a non-ligand-binding member of this family and exerts its activity through heterodimerisation with other EGFR family members. HER2 functional activation promotes oncogenesis, leading to the investigation of HER2-directed agents in cancers with HER2 alterations. This has been best characterised in the context of HER2 gene amplification in breast and gastro-oesophageal cancers, for which HER2-directed drugs form part of standard treatment regimens. More recently, somatic HER2 gene mutations have been detected in a range of human cancer types. Preclinical data suggest that functionally activating HER2 mutations may drive and maintain cancers in a manner analogous to HER2 gene amplification and that HER2 mutations may similarly confer sensitivity to HER2-directed drugs. Here, we critically review the emerging roles for HER2-directed drugs in HER2 mutant cancers. We review data from experimental models, where our knowledge of the underlying biology of HER2 mutational activation remains incomplete. We discuss clinical data from Phase I and II clinical trials which evaluate HER2-directed agents (tyrosine kinase inhibitors and antibody-based drugs) in several cancer types. We highlight the heterogeneity of HER2 mutations in human cancers, differences in the clinical efficacy of HER2-directed drugs between cancer types and possible mechanisms of primary and acquired resistance, in order to guide clinical practice and future drug development.
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Affiliation(s)
- Claire M Connell
- Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
- Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK
| | - Gary J Doherty
- Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
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Imperial R, Toor OM, Hussain A, Subramanian J, Masood A. Comprehensive pancancer genomic analysis reveals (RTK)-RAS-RAF-MEK as a key dysregulated pathway in cancer: Its clinical implications. Semin Cancer Biol 2017; 54:14-28. [PMID: 29175106 DOI: 10.1016/j.semcancer.2017.11.016] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Accepted: 11/19/2017] [Indexed: 02/07/2023]
Abstract
Recent advances in Next Generation Sequencing (NGS) have provided remarkable insights into the genomic characteristics of human cancers that have spurred a revolution in the field of oncology. The mitogen-activated protein kinase pathway (MAPK) and its activating cell receptor, the receptor tyrosine kinases (RTKs), which together encompass the (RTK)-RAS-RAF-MEK-ERK axis, are central to oncogenesis. A pan-cancer genomics analysis presented in this review is made possible by large collaborative projects, including The Cancer Genome Atlas (TCGA), the International Cancer Genome Consortium (ICGC), and others. Landmark studies contributing to these projects have revealed alterations in cell signaling cascades that vary between cancer types and within tumors themselves. We review several of these studies in major tumor types to highlight recent advances in our understanding of the role of (RTK)-RAS-RAF alterations in cancer. Further studies are needed to increase the statistical power to detect clinically relevant low-frequency mutations, in addition to the known (RTK)-RAS-RAF pathway alterations, and to refine the resolution of the genomic landscape that defines these cancer mutations. The (RTK)-RAS-RAF-MEK-ERK mutation status, and their prognostic value, are also examined and correlated with clinical phenotypes. Treatments targeting various components of this pathway are ongoing, and are often effective initially in defined subgroups of patients. However, resistance to these agents can develop through adaptive mechanisms. With our steady increase in understanding the molecular biology of cancer, ongoing evaluation and monitoring through genomic analysis will continue to provide important information to the clinician in the context of treatment selection, response, resistance and outcomes.
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Affiliation(s)
- Robin Imperial
- Department of Medicine, University of Missouri Kansas City School of Medicine, Kansas City, MO 64108, USA
| | - Omer M Toor
- Department of Medicine, University of Missouri Kansas City School of Medicine, Kansas City, MO 64108, USA; Division of Oncology, Saint Luke's Cancer Institute, Kansas City, MO 64111, USA; Center for Precision Oncology, Saint Luke's Cancer Institute, Kansas City, MO 64111, USA
| | - Arif Hussain
- Division of Oncology, University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA; The Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, USA
| | - Janakiraman Subramanian
- Department of Medicine, University of Missouri Kansas City School of Medicine, Kansas City, MO 64108, USA; Division of Oncology, Saint Luke's Cancer Institute, Kansas City, MO 64111, USA; Center for Precision Oncology, Saint Luke's Cancer Institute, Kansas City, MO 64111, USA
| | - Ashiq Masood
- Department of Medicine, University of Missouri Kansas City School of Medicine, Kansas City, MO 64108, USA; Division of Oncology, Saint Luke's Cancer Institute, Kansas City, MO 64111, USA; Center for Precision Oncology, Saint Luke's Cancer Institute, Kansas City, MO 64111, USA.
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