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Michelon I, Vilbert M, do Rego Castro CE, Stecca C, Dacoregio MI, Rizzo M, Cláudio Cordeiro de Lima V, Cavalcante L. EGFR-Tyrosine Kinase Inhibitor Retreatment in Non-Small-Cell Lung Cancer Patients Previously Exposed to EGFR-TKI: A Systematic Review and Meta-Analysis. J Pers Med 2024; 14:752. [PMID: 39064005 PMCID: PMC11277985 DOI: 10.3390/jpm14070752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Revised: 07/08/2024] [Accepted: 07/09/2024] [Indexed: 07/28/2024] Open
Abstract
We performed a systematic review and meta-analysis to assess the efficacy of EGFR-tyrosine kinase inhibitors (TKI) retreatment in advanced/metastatic non-small-cell lung cancer (NSCLC) patients. We systematically searched PubMed, Embase, Cochrane databases, ASCO, and ESMO websites for studies evaluating EGFR-TKI retreatment in advanced/metastatic NSCLC patients. All analyses were performed using R software (v.4.2.2). We included 19 studies (9 CTs and 10 retrospective cohorts) with a total of 886 patients. In a pooled analysis of all patients during retreatment with TKI, median OS was 11.7 months (95% confidence interval [CI] 10.2-13.4 months) and PFS was 3.2 months (95% CI 2.5-3.9 months). ORR was 15% (95% CI 10-21%) and DCR was 61% (95% CI 53-67%). The subanalysis by generation of TKI in the rechallenge period revealed a slightly better ORR for patients on 3rd generation TKI (p = 0.05). Some limitations include the high heterogeneity of some of the analyses and inability to perform certain subanalyses. Our results unequivocally support the benefit of EGFR-TKI rechallenge in EGFR-mutated NSCLC patients progressing on TKI treatment after a TKI-free interval. These findings may be especially valuable in areas where access to novel therapeutic drugs and clinical trials is limited.
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Affiliation(s)
- Isabella Michelon
- Department of Medicine, Catholic University of Pelotas, Pelotas 96015-560, Brazil
| | - Maysa Vilbert
- Massachusetts General Hospital Cancer Center, Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA;
| | | | - Carlos Stecca
- Department of Medicine, Parana Oncology Center, Curitiba 80030-200, Brazil;
| | - Maria Inez Dacoregio
- Department of Medicine, University of Centro Oeste, Guarapuava 85040-167, Brazil;
| | - Manglio Rizzo
- Cancer Immunobiology Laboratory, Instituto de Investigaciones en Medicina Traslacional, Universidad Austral-Consejo Nacional de Investigaciones Cientificas y Tecnologicas (CONICET), Buenos Aires 1428, Argentina;
- Clinical Oncology Unit, Hospital Universitario Austral, Av. Presidente Perón 1500, (B1629ODT) Derqui-Pilar, Buenos Aires 1428, Argentina
| | | | - Ludimila Cavalcante
- Department of Hematology and Medical Oncology, University of Virginia Comprehensive Cancer Center, Charlottesville, VA 22903, USA;
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Morimoto K, Yamada T, Takeda T, Shiotsu S, Date K, Tamiya N, Goto Y, Kanda H, Chihara Y, Kunimatsu Y, Katayama Y, Iwasaku M, Tokuda S, Takayama K. Clinical Efficacy and Safety of First- or Second-Generation EGFR-TKIs after Osimertinib Resistance for EGFR Mutated Lung Cancer: A Prospective Exploratory Study. Target Oncol 2023; 18:657-665. [PMID: 37610516 DOI: 10.1007/s11523-023-00991-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/10/2023] [Indexed: 08/24/2023]
Abstract
BACKGROUND Osimertinib monotherapy is a common treatment for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC); however, standard treatment strategies for acquired resistance to this drug have not been established. In addition, the clinical significance of first-generation (1G) or second-generation (2G) EGFR-tyrosine kinase inhibitors (TKI) in patients with EGFR-mutant NSCLC and osimertinib resistance has not yet been fully evaluated. OBJECTIVE We aimed to conduct a prospective multicenter observational study to evaluate the efficacy and safety of 1G and 2G EGFR-TKIs after the development of osimertinib resistance. METHODS Patients with EGFR-mutant NSCLC who received 1G or 2G EGFR-TKIs after developing resistance to osimertinib monotherapy were prospectively assessed at eight institutions in Japan. The primary endpoint was progression-free survival (PFS). RESULTS A total of 29 patients with advanced or recurrent EGFR-mutant NSCLC were analyzed. The objective response and disease control rates were 6.9% (2/29) and 58.6% (17/29), respectively. The median PFS was 1.9 months [95% confidence interval (CI): 1.3-5.3]. There was no significant difference in PFS between the 1G and 2G EGFR-TKI groups (3.7 versus 1.5 months, log-rank test p = 0.20). However, patients with normal cytokeratin 19 fragment (CYFRA 21-1) and pro-gastrin-releasing peptide (ProGRP) levels experienced longer PFS than those with elevated CYFRA 21-1 and/or ProGRP (5.5 versus 1.3 months, log-rank test p < 0.001). CONCLUSION Administration of 1G or 2G EGFR-TKIs after the development of osimertinib resistance has limited efficacy in patients with EGFR-mutant NSCLC. Moreover, normal CYFRA 21-1 and ProGRP levels could be promising indicators for 1G and 2G EGFR-TKI administration after osimertinib resistance development. TRIAL REGISTRATION NUMBER UMIN000044049.
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Affiliation(s)
- Kenji Morimoto
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kajii-cho, Kamigyo-ku, Kyoto, Japan
| | - Tadaaki Yamada
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kajii-cho, Kamigyo-ku, Kyoto, Japan.
| | - Takayuki Takeda
- Department of Respiratory Medicine, Japanese Red Cross Kyoto Daini Hospital, Kyoto, Japan
| | - Shinsuke Shiotsu
- Department of Respiratory Medicine, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan
| | - Koji Date
- Department of Pulmonary Medicine, Kyoto Chubu Medical Center, Kyoto, Japan
| | - Nobuyo Tamiya
- Department of Pulmonary Medicine, Rakuwakai Otowa Hospital, Kyoto, Japan
| | - Yasuhiro Goto
- Department of Respiratory Medicine, Fujita Health University School of Medicine, Aichi, Japan
| | - Hibiki Kanda
- Department of Respiratory Medicine, Omi Medical Center, Shiga, Japan
| | - Yusuke Chihara
- Department of Respiratory Medicine, Uji-Tokushukai Medical Center, Kyoto, Japan
| | - Yusuke Kunimatsu
- Department of Respiratory Medicine, Japanese Red Cross Kyoto Daini Hospital, Kyoto, Japan
| | - Yuki Katayama
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kajii-cho, Kamigyo-ku, Kyoto, Japan
| | - Masahiro Iwasaku
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kajii-cho, Kamigyo-ku, Kyoto, Japan
| | - Shinsaku Tokuda
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kajii-cho, Kamigyo-ku, Kyoto, Japan
| | - Koichi Takayama
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kajii-cho, Kamigyo-ku, Kyoto, Japan
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Luo YH, Liang KH, Huang HC, Shen CI, Chiang CL, Wang ML, Chiou SH, Chen YM. State-of-the-Art Molecular Oncology of Lung Cancer in Taiwan. Int J Mol Sci 2022; 23:ijms23137037. [PMID: 35806042 PMCID: PMC9266727 DOI: 10.3390/ijms23137037] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 06/14/2022] [Accepted: 06/22/2022] [Indexed: 02/05/2023] Open
Abstract
Lung cancers are life-threatening malignancies that cause great healthcare burdens in Taiwan and worldwide. The 5-year survival rate for Taiwanese patients with lung cancer is approximately 29%, an unsatisfactorily low number that remains to be improved. We first reviewed the molecular epidemiology derived from a deep proteogenomic resource in Taiwan. The nuclear factor erythroid 2-related factor 2 (NRF2)antioxidant mechanism was discovered to mediate the oncogenesis and tumor progression of lung adenocarcinoma. Additionally, DNA replication, glycolysis and stress response are positively associated with tumor stages, while cell-to-cell communication, signaling, integrin, G protein coupled receptors, ion channels and adaptive immunity are negatively associated with tumor stages. Three patient subgroups were discovered based on the clustering analysis of protein abundance in tumors. The first subgroup is associated with more advanced cancer stages and visceral pleural invasion, as well as higher mutation burdens. The second subgroup is associated with EGFR L858R mutations. The third subgroup is associated with PI3K/AKT pathways and cell cycles. Both EGFR and PI3K/AKT signaling pathways have been shown to induce NRF2 activation and tumor cell proliferation. We also reviewed the clinical evidence of patient outcomes in Taiwan given various approved targeted therapies, such as EGFR-tyrosine kinase inhibitors and anaplastic lymphoma kinase (ALK)inhibitors, in accordance with the patients’ characteristics. Somatic mutations occurred in EGFR, KRAS, HER2 and BRAF genes, and these mutations have been detected in 55.7%, 5.2%, 2.0% and 0.7% patients, respectively. The EGFR mutation is the most prevalent targetable mutation in Taiwan. EML4-ALK translocations have been found in 9.8% of patients with wild-type EGFR. The molecular profiling of advanced NSCLC is critical to optimal therapeutic decision-making. The patient characteristics, such as mutation profiles, protein expression profiles, drug-resistance profiles, molecular oncogenic mechanisms and patient subgroup systems together offer new strategies for personalized treatments and patient care.
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Affiliation(s)
- Yung-Hung Luo
- Department of Chest Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; (Y.-H.L.); (H.-C.H.); (C.-I.S.); (C.-L.C.)
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan;
| | - Kung-Hao Liang
- Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan;
- Institute of Food Safety and Health Risk Assessment, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
- Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
| | - Hsu-Ching Huang
- Department of Chest Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; (Y.-H.L.); (H.-C.H.); (C.-I.S.); (C.-L.C.)
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan;
| | - Chia-I Shen
- Department of Chest Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; (Y.-H.L.); (H.-C.H.); (C.-I.S.); (C.-L.C.)
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan;
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
| | - Chi-Lu Chiang
- Department of Chest Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; (Y.-H.L.); (H.-C.H.); (C.-I.S.); (C.-L.C.)
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan;
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
| | - Mong-Lien Wang
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan;
- Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan;
- Institute of Food Safety and Health Risk Assessment, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
- Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
| | - Shih-Hwa Chiou
- Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan;
- Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
- Correspondence: (S.-H.C.); (Y.-M.C.); Tel.: +886-2-28757865 (Y.-M.C.)
| | - Yuh-Min Chen
- Department of Chest Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; (Y.-H.L.); (H.-C.H.); (C.-I.S.); (C.-L.C.)
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan;
- Correspondence: (S.-H.C.); (Y.-M.C.); Tel.: +886-2-28757865 (Y.-M.C.)
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Effectiveness and Safety of EGFR-TKI Rechallenge Treatment in Elderly Patients with Advanced Non-Small-Cell Lung Cancer Harboring Drug-Sensitive EGFR Mutations. ACTA ACUST UNITED AC 2021; 57:medicina57090929. [PMID: 34577852 PMCID: PMC8466413 DOI: 10.3390/medicina57090929] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 08/30/2021] [Accepted: 09/01/2021] [Indexed: 11/30/2022]
Abstract
Background and Objectives: Epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKIs) are effective first-line chemotherapeutic agents for patients with advanced non-small-cell lung cancer (NSCLC) harboring drug-sensitive EGFR mutations. However, the effectiveness of EGFR-TKI rechallenge after first-line EGFR-TKI treatment is not sufficient in elderly patients (over 75 years of age) harboring drug-sensitive EGFR mutations. Therefore, we investigated the effectiveness and safety of EGFR-TKI rechallenge after first-line EGFR-TKI treatment in elderly patients with advanced NSCLC harboring drug-sensitive EGFR mutations. Materials and Methods: Between April 2008 and December 2015, we analyzed 78 elderly patients with advanced NSCLC harboring drug-sensitive EGFR mutations with first-line EGFR-TKI treatment at four Japanese institutions. We retrospectively evaluated the clinical effectiveness and safety profiles of EGFR-TKI rechallenge after first-line EGFR-TKI treatment in elderly patients with advanced NSCLC harboring drug-sensitive EGFR mutations (exon 19 deletion/exon 21 L858R mutation). Results: Twenty-two patients in the cohort were rechallenged with EGFR-TKI. The median age was 79.5 years (range 75–87 years). Despite the fact that it was a retrospective analysis, even with EGFR-TKI rechallenge treatment the response rate was 23%, progression-free survival was 5.3 months, and overall survival was 14.4 months. Common adverse events included rash acneiform, paronychia, diarrhea, and anorexia. There were no treatment-related deaths. Due to the occurrence of adverse events of grade 2 or more, dose reduction was performed in 15 (68.2%) of 22 cases. Conclusions: EGFR-TKI rechallenge treatment after first-line EGFR-TKI treatment in elderly patients with advanced NSCLC harboring drug-sensitive EGFR mutations was one of the limited, safe and effective treatment options for elderly EGFR-positive lung cancer patients.
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Haga Y, Marrocco I, Noronha A, Uribe ML, Nataraj NB, Sekar A, Drago-Garcia D, Borgoni S, Lindzen M, Giri S, Wiemann S, Tsutsumi Y, Yarden Y. Host-Dependent Phenotypic Resistance to EGFR Tyrosine Kinase Inhibitors. Cancer Res 2021; 81:3862-3875. [PMID: 33941614 DOI: 10.1158/0008-5472.can-20-3555] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 03/01/2021] [Accepted: 04/28/2021] [Indexed: 11/16/2022]
Abstract
Lung cancers driven by mutant forms of EGFR invariably develop resistance to kinase inhibitors, often due to secondary mutations. Here we describe an unconventional mechanism of resistance to dacomitinib, a newly approved covalent EGFR kinase inhibitor, and uncover a previously unknown step of resistance acquisition. Dacomitinib-resistant (DR) derivatives of lung cancer cells were established by means of gradually increasing dacomitinib concentrations. These DR cells acquired no secondary mutations in the kinase or other domains of EGFR. Along with resistance to other EGFR inhibitors, DR cells acquired features characteristic to epithelial-mesenchymal transition, including an expanded population of aldehyde dehydrogenase-positive cells and upregulation of AXL, a receptor previously implicated in drug resistance. Unexpectedly, when implanted in animals, DR cells reverted to a dacomitinib-sensitive state. Nevertheless, cell lines derived from regressing tumors displayed renewed resistance when cultured in vitro. Three-dimensional and cocultures along with additional analyses indicated lack of involvement of hypoxia, fibroblasts, and immune cells in phenotype reversal, implying that other host-dependent mechanisms might nullify nonmutational modes of resistance. Thus, similar to the phenotypic resistance of bacteria treated with antibiotics, the reversible resisters described here likely evolve from drug-tolerant persisters and give rise to the irreversible, secondary mutation-driven nonreversible resister state. SIGNIFICANCE: This study reports that stepwise acquisition of kinase inhibitor resistance in lung cancers driven by mutant EGFR comprises a nonmutational, reversible resister state. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/14/3862/F1.large.jpg.
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Affiliation(s)
- Yuya Haga
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.,Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
| | - Ilaria Marrocco
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
| | - Ashish Noronha
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
| | - Mary Luz Uribe
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
| | | | - Arunachalam Sekar
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
| | - Diana Drago-Garcia
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
| | - Simone Borgoni
- Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Moshit Lindzen
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
| | - Suvendu Giri
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
| | - Stefan Wiemann
- Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Yasuo Tsutsumi
- Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.,Global Center for Medical Engineering and Informatics, Osaka University, Osaka, Japan
| | - Yosef Yarden
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
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Hu XY, Fei YC, Zhou WC, Zhu JM, Lv DL. Triple administration of osimertinib followed by chemotherapy for advanced lung adenocarcinoma: A case report. World J Clin Cases 2021; 9:2627-2633. [PMID: 33889629 PMCID: PMC8040179 DOI: 10.12998/wjcc.v9.i11.2627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 01/10/2021] [Accepted: 01/28/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Osimertinib is the recommended first-line treatment for adult patients with epidermal growth factor receptor (EGFR) mutation positive advanced or metastatic non-small cell lung cancer (NSCLC). However, primary or acquired resistance to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) seems inevitable, and when drug-resistance occurs during treatment with osimertinib, the standard of care is to discontinue the TKI.
CASE SUMMARY A 57-year-old female patient with lung adenocarcinoma presented with an irritating cough accompanied by chest distress of one month duration. An enhanced head magnetic resonance imaging scan showed brain metastases. An EGFR mutation (exon 21 L858R) was detected in pleural fluid. The patient was treated with oral osimertinib (80 mg once daily) from January 2018 but developed progressive disease on December 2018. She was then successfully treated with re-challenge and tri-challenge with osimertinib (80 mg once daily) by resensitization chemotherapy twice after the occurrence of drug-resistance to osimertinib, and to date has survived for 31 mo.
CONCLUSION This case may provide some selective therapeutic options for NSCLC patients with acquired drug-resistance who were previously controlled on osimertinib treatment.
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Affiliation(s)
- Xu-Yan Hu
- Department of Clinical Medicine, Bengbu Medical College, Bengbu 233030, Anhui Province, China
| | - Yu-Cheng Fei
- Department of Clinical Oncology, 901 Hospital of Joint Logistics Support Force of People Liberation Army, Hefei 230031, Anhui Province, China
| | - Wen-Chao Zhou
- Intelligent Pathology Institute, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230036, Anhui Province, China
| | - Jin-Miao Zhu
- Department of Pharmaceutical Engineering, Hefei Normal University, Hefei 230601, Anhui Province, China
| | - Dong-Lai Lv
- Department of Clinical Oncology, 901 Hospital of Joint Logistics Support Force of People Liberation Army, Hefei 230031, Anhui Province, China
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Hexiao T, Yuquan B, Lecai X, Yanhong W, Li S, Weidong H, Ming X, Xuefeng Z, Gaofeng P, Li Z, Minglin Z, Zheng T, Zetian Y, Xiao Z, Yi C, Lanuti M, Jinping Z. Knockdown of CENPF inhibits the progression of lung adenocarcinoma mediated by ERβ2/5 pathway. Aging (Albany NY) 2021; 13:2604-2625. [PMID: 33428600 PMCID: PMC7880349 DOI: 10.18632/aging.202303] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Accepted: 09/05/2020] [Indexed: 01/21/2023]
Abstract
Many studies have reported that estrogen (E2) promotes lung cancer by binding to nuclear estrogen receptors (ER), and altering ER related nuclear protein expressions. With the GEO database analysis, Human centromere protein F (CENPF) is highly expressed in lung adenocarcinoma (LUAD), and the co-expression of CENPF and ERβ was found in the nucleus of LUAD cells through immunofluorescence. We identified the nuclear protein CENPF and explored its relationship with the ER pathway. CENPF and ERβ2/5 were related with T stage and poor prognosis (P<0.05). CENPF knockout significantly inhibited LUAD cell growth, the tumor growth of mice and the expression of ERβ2/5 (P<0.05). The protein expression of CENPF and ERβ2/5 in the CENPF-Knockdown+Fulvestrant group was lower than CENPF- Negative Control +Fulvestrant group (P=0.002, 0.004, 0.001) in A549 cells. The tumor size and weight of the CENPF-Knockdown+Fulvestrant group were significantly lower than CENPF- Negative Control +Fulvestrant group (P=0.001, 0.039) in nude mice. All the results indicated that both CENPF and ERβ2/5 play important roles in the progression of LUAD, and knockdown CENPF can inhibit the progression of LUAD by inhibiting the expression of ER2/5. Thus, the development of inhibitors against ERβ2/5 and CENPF remained more effective in improving the therapeutic effect of LUAD.
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Affiliation(s)
- Tang Hexiao
- Department of Thoracic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Bai Yuquan
- Department of Thoracic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Xiong Lecai
- Department of Thoracic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Wei Yanhong
- Department of Geriatrics, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Shen Li
- Division of Thoracic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Hu Weidong
- Department of Thoracic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Xu Ming
- Department of Thoracic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Zhou Xuefeng
- Department of Thoracic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Pan Gaofeng
- Department of Thoracic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Zhang Li
- Department of Thoracic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Zhu Minglin
- Department of Thoracic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Tang Zheng
- Department of Thoracic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yang Zetian
- Department of Thoracic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Zhou Xiao
- Department of Thoracic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Cai Yi
- Department of Thoracic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Michael Lanuti
- Division of Thoracic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Zhao Jinping
- Department of Thoracic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
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Ilan Y, Spigelman Z. Establishing patient-tailored variability-based paradigms for anti-cancer therapy: Using the inherent trajectories which underlie cancer for overcoming drug resistance. Cancer Treat Res Commun 2020; 25:100240. [PMID: 33246316 DOI: 10.1016/j.ctarc.2020.100240] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 10/30/2020] [Accepted: 11/16/2020] [Indexed: 06/11/2023]
Abstract
Drug resistance is a major obstacle for successful therapy of many malignancies and is affecting the loss of response to chemotherapy and immunotherapy. Tumor-related compensatory adaptation mechanisms contribute to the development of drug resistance. Variability is inherent to biological systems and altered patterns of variability are associated with disease conditions. The marked intra and inter patient tumor heterogeneity, and the diverse mechanism contributing to drug resistance in different subjects, which may change over time even in the same patient, necessitate the development of personalized dynamic approaches for overcoming drug resistance. Altered dosing regimens, the potential role of chronotherapy, and drug holidays are effective in cancer therapy and immunotherapy. In the present review we describe the difficulty of overcoming drug resistance in a dynamic system and present the use of the inherent trajectories which underlie cancer development for building therapeutic regimens which can overcome resistance. The establishment of a platform wherein patient-tailored variability signatures are used for overcoming resistance for ensuing long term sustainable improved responses is presented.
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Affiliation(s)
- Yaron Ilan
- Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
| | - Zachary Spigelman
- Department of Hematology and Oncology, Lahey Hospital and Beth Israel Medical Center, MA, USA
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Establishment and validation of a novel droplet digital PCR assay for ultrasensitive detection and dynamic monitoring of EGFR mutations in peripheral blood samples of non-small-cell lung cancer patients. Clin Chim Acta 2020; 510:88-96. [PMID: 32645388 DOI: 10.1016/j.cca.2020.07.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 06/03/2020] [Accepted: 07/02/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND Droplet digital PCR (ddPCR)-based blood detection of EGFR mutations plays significant roles in the individualized therapy of non-small-cell lung cancer (NSCLC) patients. However, a standard assay that is approved by health authorities is still lacking. Additionally, the proper application of this method in clinical settings also needs further investigation. METHODS The performance of a newly established ddPCR assay was first evaluated using reference samples and then validated by comparing this method with the amplification refractory mutation system (ARMS) using cell-free DNA (cfDNA) in patients' peripheral blood. Further, the correlation between dynamic quantification of EGFR mutation in the patients and their clinical outcome of tyrosine kinase inhibitors (TKIs) therapy was investigated. RESULTS A total of 77 patients were included, with 50 in the test group and 27 in the validation group. According to the results of the reference samples and the blood samples in the test group, the cut-off value for patient detection was proposed as mutation rate ≥ 0.1% (total copy number of cfDNA ≥ 1000) or at least one copy of mutation DNA was detected (total copy number of cfDNA < 1000). With this criterion, superior sensitivity of our assay to that of ARMS was observed (P = 0.002 for Ex19Del & L858R and P < 0.001 for T790M). The dynamic quantification of EGFR mutations during TKI therapy indicated that an increase in mutation abundance was correlated with resistance, while a decline was associated with response. Notably, a rebound in mutation abundance during chemotherapy may indicate a desirable chance for TKI re-treatment. CONCLUSION The novel ddPCR assay showed superior sensitivity in the detection of EGFR mutation in blood. The dynamic quantification of EGFR mutations by this assay would greatly facilitate the administration of TKI therapy, including the monitoring of resistance and response, as well as cohort screening for retreatment.
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Bedard PL, Hyman DM, Davids MS, Siu LL. Small molecules, big impact: 20 years of targeted therapy in oncology. Lancet 2020; 395:1078-1088. [PMID: 32222192 DOI: 10.1016/s0140-6736(20)30164-1] [Citation(s) in RCA: 370] [Impact Index Per Article: 74.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 01/16/2020] [Accepted: 01/20/2020] [Indexed: 12/13/2022]
Abstract
The identification of molecular targets and the growing knowledge of their cellular functions have led to the development of small molecule inhibitors as a major therapeutic class for cancer treatment. Both multitargeted and highly selective kinase inhibitors are used for the treatment of advanced treatment-resistant cancers, and many have also achieved regulatory approval for early clinical settings as adjuvant therapies or as first-line options for recurrent or metastatic disease. Lessons learned from the development of these agents can accelerate the development of next-generation inhibitors to optimise the therapeutic index, overcome drug resistance, and establish combination therapies. The future of small molecule inhibitors is promising as there is the potential to investigate novel difficult-to-drug targets, to apply predictive non-clinical models to select promising drug candidates for human evaluation, and to use dynamic clinical trial interventions with liquid biopsies to deliver precision medicine.
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Affiliation(s)
- Philippe L Bedard
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Department of Medicine, University of Toronto, Toronto, ON, Canada
| | - David M Hyman
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA
| | - Matthew S Davids
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA
| | - Lillian L Siu
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Department of Medicine, University of Toronto, Toronto, ON, Canada.
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11
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Liu L, Fan Y, Chen Z, Zhang Y, Yu J. CaSR Induces Osteoclast Differentiation and Promotes Bone Metastasis in Lung Adenocarcinoma. Front Oncol 2020; 10:305. [PMID: 32269963 PMCID: PMC7109411 DOI: 10.3389/fonc.2020.00305] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Accepted: 02/20/2020] [Indexed: 12/29/2022] Open
Abstract
Objective: Explore the mechanism of CaSR's involvement in bone metastasis in lung adenocarcinoma. Methods: Immunohistochemistry (IHC) was used to detect the expression of calcium-sensing receptor (CaSR) in 120 cases of lung adenocarcinoma with bone metastasis. Stably transfected cell lines with CaSR overexpression and knockdown based on A549 cells were constructed. The expression of CaSR was verified by western blot and qPCR. The proliferation and migration abilities of A549 cells were tested using cholecystokinin-8 (CCK-8) and Transwell assays, respectively. Western blotting was used to detect the expression of matrix metalloproteinases MMP2, MMP9, CaSR, and NF-κB. The supernatant from each cell culture group was collected as a conditional co-culture solution to study the induction of osteoclast precursor cells and osteoblasts. Western blot and qPCR were used to validate the expression of bone matrix degradation-related enzymes cathepsin K and hormone calcitonin receptor (CTR) and osteoblast-induced osteoclast maturation and differentiation enzyme receptor activator of nuclear factor-κB ligand (RANKL), macrophage colony-stimulating factor (M-CSF), osteoprotegerin (OPG), and PTHrP. Immunofluorescent staining was used to detect F-actin ring formation and osteocalcin expression. Western blot results for NF-κB expression identified a regulatory relationship between NF-κB and CaSR. Results: CaSR expression in lung cancer tissues was significantly higher than that in adjacent and normal lung tissues. The expression of CaSR in lung cancer tissues with bone metastasis was higher than that in non-metastatic lung cancer tissues. The proliferation and migration ability of A549 cells increased significantly with overexpressed CaSR. The co-culture solution directly induced osteoclast precursor cells and the expression of bone matrix degradation-related enzymes significantly increased. Osteoblasts were significantly inhibited and osteoblast-induced osteoclast maturation and differentiation enzymes were significantly downregulated. It was found that the expression of NF-κB and PTHrP increased when CaSR was overexpressed. Osteoclast differentiation factor expression was also significantly increased, which directly induces osteoclast differentiation and maturation. These results were reversed when CaSR was knocked down. Conclusions: CaSR can positively regulate NF-κB and PTHrP expression in A549 cells with a high metastatic potential, thereby promoting osteoclast differentiation and maturation, and facilitating the occurrence and development of bone metastasis in lung adenocarcinoma.
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Affiliation(s)
- Lian Liu
- Cancer Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yichang Fan
- Cancer Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Zhaoxin Chen
- Cancer Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yujian Zhang
- Cancer Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Jing Yu
- Cancer Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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12
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Tanaka H, Taima K, Itoga M, Ishioka Y, Baba K, Shiratori T, Sakamoto H, Tsuchiya J, Nakagawa H, Hasegawa Y, Yasugahira H, Okudera K, Takanashi S, Tasaka S. Real-world study of afatinib in first-line or re-challenge settings for patients with EGFR mutant non-small cell lung cancer. Med Oncol 2019; 36:57. [PMID: 31089973 DOI: 10.1007/s12032-019-1278-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Accepted: 04/26/2019] [Indexed: 11/24/2022]
Abstract
Afatinib, a second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) for mutant non-small cell lung cancer (NSCLC), was approved in Japan in 2014. This study evaluated clinical outcomes of afatinib in real-world practice. Medical records of patients who received afatinib for advanced EGFR-mutant NSCLC were retrospectively reviewed. In total, 128 patients were analyzed. Seventy-six patients received afatinib as the first-line setting and 52 as the re-challenge setting (i.e., after failure of prior first-generation TKI). There was no difference in patient characteristics, such as age, sex, and PS, between the first-line and the re-challenge settings. In the first-line setting, the median progression-free survival (PFS) was 17.8 months (95% confidence interval [CI] 13.7-21.5 months). The overall survival (OS) was 39.5 months (95% CI 34.4- not reached). The response rate (RR) was 64.4%. Subset analysis indicated that patients with dose reduction showed longer PFS than those without dose reduction (18.5 months versus 7.9 months) (P = 0.016). In the re-challenge setting, the median PFS was 8.0 months (95% CI 4.9-9.5 months). The RR was 25%. Most common adverse events leading to dose modification or treatment discontinuation included diarrhea, paronychia, and oral mucositis in both settings. Interstitial lung disease occurred in 5.4% (7/128). In the real-world practice in Japan, afatinib showed comparable or better efficacy compared with that shown in previous clinical trials in both the first-line and the re-challenge settings.
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Affiliation(s)
- Hisashi Tanaka
- Department of Respiratory Medicine, Hirosaki University Graduate School of Medicine, 5, Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan.
| | - Kageaki Taima
- Department of Respiratory Medicine, Hirosaki University Graduate School of Medicine, 5, Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan
| | - Masamichi Itoga
- Department of Respiratory Medicine, Hirosaki University Graduate School of Medicine, 5, Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan
| | - Yoshiko Ishioka
- Department of Respiratory Medicine, Hirosaki University Graduate School of Medicine, 5, Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan
| | - Keisuke Baba
- Department of Respiratory Medicine, Hirosaki University Graduate School of Medicine, 5, Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan
| | - Toshihiro Shiratori
- Department of Respiratory Medicine, Hirosaki University Graduate School of Medicine, 5, Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan
| | - Hiroaki Sakamoto
- Department of Respiratory Medicine, Hirosaki University Graduate School of Medicine, 5, Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan
| | - Junichiro Tsuchiya
- Department of Respiratory Medicine, Hirosaki University Graduate School of Medicine, 5, Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan
| | - Hideyuki Nakagawa
- Department of Respiratory Medicine, Hirosaki National Hospital, Aomori, Japan
| | - Yukihiro Hasegawa
- Department of Respiratory Medicine, Aomori Prefectural Central Hospital, Aomori, Japan
| | - Hideo Yasugahira
- Department of Respiratory Medicine, Hachinohe City Hospital, Aomori, Japan
| | - Koichi Okudera
- Department of Respiratory Medicine, Hirosaki Central Hospital, Aomori, Japan
| | - Shingo Takanashi
- Hirosaki University, Health Administration Center, Aomori, Japan
| | - Sadatomo Tasaka
- Department of Respiratory Medicine, Hirosaki University Graduate School of Medicine, 5, Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan
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13
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Lu J, Zhong H, Chu T, Zhang X, Li R, Sun J, Zhong R, Yang Y, Alam MS, Lou Y, Xu J, Zhang Y, Wu J, Li X, Zhao X, Li K, Lu L, Han B. Role of anlotinib-induced CCL2 decrease in anti-angiogenesis and response prediction for nonsmall cell lung cancer therapy. Eur Respir J 2019; 53:13993003.01562-2018. [PMID: 30578392 DOI: 10.1183/13993003.01562-2018] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Accepted: 11/29/2018] [Indexed: 01/21/2023]
Abstract
BACKGROUND Anlotinib has been demonstrated in clinical trials to be effective in prolonging the progression-free survival (PFS) and overall survival (OS) of refractory advanced nonsmall cell lung cancer (NSCLC) patients. However, the underlying molecular mechanisms and predictive biomarkers of anlotinib are still unclear. METHODS A retrospective analysis of anlotinib administered to 294 NSCLC patients was performed to screen for underlying biomarkers of anlotinib-responsive patients. Transcriptome and functional assays were performed to understand the antitumour molecular mechanisms of anlotinib. Changes in serum CCL2 levels were analysed to examine the correlation of the anlotinib response between responders and nonresponders. RESULTS Anlotinib therapy was beneficial for prolonging OS in NSCLC patients harbouring positive driver gene mutations, especially patients harbouring the epithelial growth factor receptor (EGFR)T790M mutation. Moreover, anlotinib inhibited angiogenesis in an NCI-H1975-derived xenograft model via inhibiting CCL2. Finally, anlotinib-induced serum CCL2 level decreases were associated with the benefits of PFS and OS in refractory advanced NSCLC patients. CONCLUSIONS Our study reports a novel anti-angiogenesis mechanism of anlotinib via inhibiting CCL2 in an NCI-H1975-derived xenograft model and suggests that changes in serum CCL2 levels may be used to monitor and predict clinical outcomes in anlotinib-administered refractory advanced NSCLC patients using third-line therapy or beyond.
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Affiliation(s)
- Jun Lu
- Dept of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.,Central laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Institute of Immunology, Shanghai Jiao Ton University School of Medicine, Shanghai, China
| | - Hua Zhong
- Dept of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Institute of Immunology, Shanghai Jiao Ton University School of Medicine, Shanghai, China
| | - Tianqing Chu
- Dept of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Xueyan Zhang
- Dept of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Rong Li
- Dept of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Jiayuan Sun
- Dept of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Runbo Zhong
- Dept of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Yuqin Yang
- Central laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Mohammad Shah Alam
- Bio-ID Center, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Yuqing Lou
- Dept of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Jianlin Xu
- Dept of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Yanwei Zhang
- Dept of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Jun Wu
- School of Life Science, East China Normal University, Shanghai, China
| | - Xiaowei Li
- Bio-ID Center, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaodong Zhao
- Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.,These authors contributed equally: Jun Lu and Hua Zhong
| | - Kai Li
- Dept of Thoracic Oncology, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.,These authors contributed equally: Jun Lu and Hua Zhong
| | - Liming Lu
- Central laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Institute of Immunology, Shanghai Jiao Ton University School of Medicine, Shanghai, China.,These authors contributed equally: Xiaodong Zhao, Kai Li, Liming Lu and Baohui Han
| | - Baohui Han
- Dept of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.,These authors contributed equally: Jun Lu and Hua Zhong
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14
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Hata A, Katakami N, Kaji R, Yokoyama T, Kaneda T, Tamiya M, Inoue T, Kimura H, Yano Y, Tamura D, Morita S, Negoro S, the HANSHIN Oncology Group F. Afatinib plus bevacizumab combination after acquired resistance to EGFR tyrosine kinase inhibitors in EGFR
-mutant non-small cell lung cancer: Multicenter, single-arm, phase 2 trial (ABC Study). Cancer 2018; 124:3830-3838. [DOI: 10.1002/cncr.31678] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 05/26/2018] [Accepted: 06/01/2018] [Indexed: 12/28/2022]
Affiliation(s)
- Akito Hata
- Department of Medical Oncology; Kobe City Medical Center General Hospital; Kobe Japan
| | - Nobuyuki Katakami
- Department of Medical Oncology; Kobe City Medical Center General Hospital; Kobe Japan
| | - Reiko Kaji
- Department of Medical Oncology; Kobe City Medical Center General Hospital; Kobe Japan
| | - Toshihide Yokoyama
- Department of Respiratory Medicine; Kurashiki Central Hospital; Kurashiki Japan
| | - Toshihiko Kaneda
- Department of Respiratory Medicine; Kurashiki Central Hospital; Kurashiki Japan
| | - Motohiro Tamiya
- Department of Thoracic Oncology; Osaka International Cancer Institute; Osaka Japan
| | - Takako Inoue
- Department of Thoracic Oncology; Osaka International Cancer Institute; Osaka Japan
| | - Hiromi Kimura
- Department of Thoracic Oncology; Toneyama National Hospital, National Hospital Organization; Toyonaka Japan
| | - Yukihiro Yano
- Department of Thoracic Oncology; Toneyama National Hospital, National Hospital Organization; Toyonaka Japan
| | - Daisuke Tamura
- Department of Respiratory Medicine; Kobe University Graduate School of Medicine; Kobe Japan
| | - Satoshi Morita
- Department of Biomedical Statistics and Bioinformatics; Kyoto University Graduate School of Medicine; Kyoto Japan
| | - Shunichi Negoro
- Department of Medical Oncology; Takarazuka City Hospital; Takarazuka Japan
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15
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Piotrowska Z, Hazar-Rethinam M, Rizzo C, Nadres B, Van Seventer EE, Shahzade HA, Lennes IT, Iafrate AJ, Dias-Santagata D, Leshchiner I, Jessop NA, Hu H, Digumarthy SR, Nagy RJ, Lanman RB, Moody S, Niederst MJ, Engelman JA, Hata AN, Corcoran RB, Sequist LV. Heterogeneity and Coexistence of T790M and T790 Wild-Type Resistant Subclones Drive Mixed Response to Third-Generation Epidermal Growth Factor Receptor Inhibitors in Lung Cancer. JCO Precis Oncol 2018; 2018. [PMID: 30123863 DOI: 10.1200/po.17.00263] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Purpose Third-generation epidermal growth factor receptor (EGFR) inhibitors like nazartinib are active against EGFR mutation-positive lung cancers with T790M-mediated acquired resistance to initial anti-EGFR treatment, but some patients have mixed responses. Methods Multiple serial tumor and liquid biopsies were obtained from two patients before, during, and after treatment with nazartinib. Next-generation sequencing and droplet digital polymerase chain reaction were performed to assess heterogeneity and clonal dynamics. Results We observed the simultaneous emergence of T790M-dependent and -independent clones in both patients. Serial plasma droplet digital polymerase chain reaction illustrated shifts in relative clonal abundance in response to various systemic therapies, confirming a molecular basis for the clinical mixed radiographic responses observed. Conclusion Heterogeneous responses to treatment targeting a solitary resistance mechanism can be explained by coexistent tumor subclones harboring distinct genetic signatures. Serial liquid biopsies offer an opportunity to monitor clonal dynamics and the emergence of resistance and may represent a useful tool to guide therapeutic strategies.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Susan Moody
- Novartis Institutes for Biomedical Research, Cambridge, MA
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16
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Tang D, Zhao D, Wu Y, Yao R, Zhou L, Lu L, Gao W, Sun Y. The miR-3127-5p/p-STAT3 axis up-regulates PD-L1 inducing chemoresistance in non-small-cell lung cancer. J Cell Mol Med 2018; 22:3847-3856. [PMID: 29726585 PMCID: PMC6050495 DOI: 10.1111/jcmm.13657] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Accepted: 03/27/2018] [Indexed: 01/15/2023] Open
Abstract
It is less known about miRNA3127‐5p induced up‐regulation of PD‐L1, immune escape and drug resistance caused by increased PD‐L1 in lung cancer. In this study, lentivirus was transduced into lung cancer cells, and quantitative PCR and Western blot were used to detect the expression of PD‐L1. Then immunofluorescence assay was applied to detect autophagy, finally we explored the relationship between PD‐L1 expressions and chemoresistance in patients. As a result, we found that microRNA‐3127‐5p promotes pSTAT3 to induce the expression of PD‐L1; microRNA‐3127‐5p promotes STAT3 phosphorylation through suppressing autophagy, and autophagy could retaine pSTAT3 into the nucleus in miRNA‐3127‐5p knocked cells, and immune escape induced by elevated level of PD‐L1 results in chemoresistance of lung cancer. In conclusion, microRNA‐3127‐5p induces PD‐L1 elevation through regulating pSTAT3 expression. We also demonstrate that immune escape induced by PD‐L1 can be dismissed by corresponding monoclonal antibody.
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Affiliation(s)
- Dongfang Tang
- Department of Thoracic Surgery, Shanghai Key Laboratory of Clinical Geriatric Medicine, HuaDong Hospital Affiliated with FuDan University, Shanghai, China
| | - Dandan Zhao
- Central Laboratory of Shanghai Chest Hospital Affiliated with Shanghai Jiaotong University, Shanghai, China
| | - Yun Wu
- Department of Thoracic Surgery, Shanghai Key Laboratory of Clinical Geriatric Medicine, HuaDong Hospital Affiliated with FuDan University, Shanghai, China
| | - Ruyong Yao
- Central laboratory of the Affiliated Hospital of Qingdao University, Shanghai, China
| | - Lin Zhou
- Central Laboratory of Shanghai Chest Hospital Affiliated with Shanghai Jiaotong University, Shanghai, China
| | - Liming Lu
- Central Laboratory of Shanghai Chest Hospital Affiliated with Shanghai Jiaotong University, Shanghai, China
| | - Wen Gao
- Department of Thoracic Surgery, Shanghai Key Laboratory of Clinical Geriatric Medicine, HuaDong Hospital Affiliated with FuDan University, Shanghai, China
| | - Yifeng Sun
- Department of Thoracic Surgery, Shanghai Chest Hospital Affiliated with Shanghai Jiaotong University, Shanghai, China
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17
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Choi MK, Ahn JS, Kim YC, Cho BC, Oh IJ, Kim SW, Lee JS, Kim JH, Ahn MJ, Park K. Afatinib in heavily pretreated advanced NSCLC patients who progressed following prior gefitinib or erlotinib: Compassionate use program in Korea. Lung Cancer 2018; 119:36-41. [PMID: 29656750 DOI: 10.1016/j.lungcan.2018.02.020] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Revised: 02/20/2018] [Accepted: 02/27/2018] [Indexed: 01/26/2023]
Abstract
INTRODUCTION Afatinib, an irreversible ErbB family blocker, approved for first-line treatment of epidermal growth factor receptor (EGFR) mutated advanced non-small cell lung cancer (NSCLC). This study investigated experience of afatinib within a compassionate use program (CUP). METHODS The afatinib CUP was an open-label, multicenter, single-arm program in Korea. We enrolled patients with stage IV NSCLC and who had received at least one line of previous cytotoxic chemotherapy and previous EGFR TKI treatment with either an EGFR mutation or documented clinical benefit. The starting dose of afatinib was 50 mg once daily. RESULTS From August 2011 to September 2014, 332 patients received at least one dose of afatinib. Most patients were registered in the CUP for fourth- or fifth-line treatment with afatinib. Adverse events (AEs) occurred in 98.1% of patients, including 29.8% with serious AEs. The most common AEs (all grades) were diarrhea (90.1%) and skin rash (62.0%). Dose reductions occurred in 60.5% of patients and discontinuations due to AEs were reported in 11.1% of patients. The response rate and median time to treatment failure (TTF) were 27.4% and 3.3 months (CI 95%, 2.8-3.8 months), respectively, in this highly pretreated population. In subgroup analysis, ECOG PS 0 or 1 and immediate pretreatment with pemetrexed monotherapy or a platinum doublet were associated with a longer TTF for afatinib. CONCLUSIONS No additional or unexpected safety concerns were observed, and afatinib demonstrated moderate antitumor activity in advanced NSCLC patients with acquired resistance to gefitinib or erlotinib in a real-world setting.
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Affiliation(s)
- Moon Ki Choi
- Center for Colorectal Cancer, National Cancer Center, Goyang, Republic of Korea
| | - Jin Seok Ahn
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Young-Chul Kim
- Department of Internal Medicine, Chonnam National University Hwasun Hospital, Jeonnam, Republic of Korea
| | - Byoung Chul Cho
- Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - In-Jae Oh
- Department of Internal Medicine, Chonnam National University Hwasun Hospital, Jeonnam, Republic of Korea
| | - Sang-We Kim
- Department of Oncology, Asan Medical Cancer, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jong Seok Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea
| | - Joo-Hang Kim
- Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Myung-Ju Ahn
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Keunchil Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
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18
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Tseng JS, Yang TY, Chen KC, Hsu KH, Huang YH, Su KY, Yu SL, Chang GC. Intercalated Treatment Following Rebiopsy Is Associated with a Shorter Progression-Free Survival of Osimertinib Treatment. Cancer Res Treat 2017; 50:1164-1174. [PMID: 29228521 PMCID: PMC6192904 DOI: 10.4143/crt.2017.460] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Accepted: 12/08/2017] [Indexed: 12/18/2022] Open
Abstract
Purpose Epidermal growth factor receptor (EGFR) T790M mutation serves as an important predictor of osimertinib efficacy. However, little is known about how it works among patients with various timings of T790M emergence and treatment. Materials and Methods Advanced EGFR-mutant lung adenocarcinoma patients with positive T790M mutation in tumor were retrospectively enrolled and observed to determine the outcomes of osimertinib treatment. We evaluated the association between patients’ characteristics and the efficacy of osimertinib treatment, particularly with respect to the timing of T790M emergence and osimertinib prescription. Results A total of 91 patients were enrolled, including 14 (15.4%) with primary and 77 (84.6%) with acquired T790M mutation. The objective response rate and disease controlratewere 60.9% and 85.1%, respectively. The median progression-free survival (PFS) and overall survival were 11.5 months (95% confidence interval [CI], 9.0 to 14.0) and 30.4 months (95% CI, 11.3 to 49.5), respectively. There was no significant difference in response rate and PFS between primary and acquired T790M populations. In the acquired T790M subgroup, patientswho received osimertinib after T790M had been confirmed by rebiopsy had a longer PFS than those with intercalated treatments between rebiopsy and osimertinib prescription (14.0 months [95% CI, 9.0 to 18.9] vs. 7.2 months [95% CI, 3.7 to 10.8]; adjusted hazard ratio, 0.48 [95% CI, 0.24 to 0.98; p=0.043]). Rebiopsy timing did not influence the outcome. Conclusion Osimertinib prescription with intercalated treatment following rebiopsy but not the timing of T790M emergence influenced the treatment outcome. We suggest that it is better to start osimertinib treatment once T790M mutation has been confirmed by biopsy.
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Affiliation(s)
- Jeng-Sen Tseng
- Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.,Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Tsung-Ying Yang
- Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.,Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Kun-Chieh Chen
- Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Kuo-Hsuan Hsu
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.,Division of Critical Care and Respiratory Therapy, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Yen-Hsiang Huang
- Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Kang-Yi Su
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.,Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Sung-Liang Yu
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.,Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Center of Genomic Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Pathology and Graduate Institute of Pathology, National Taiwan University College of Medicine, Taipei, Taiwan.,Center for Optoelectronic Biomedicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Gee-Chen Chang
- Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.,Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Comprehensive Cancer Center, Taichung Veterans General Hospital, Taichung, Taiwan
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19
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Lee AF, Chen MC, Chen CJ, Yang CJ, Huang MS, Liu YP. Reverse epithelial-mesenchymal transition contributes to the regain of drug sensitivity in tyrosine kinase inhibitor-resistant non-small cell lung cancer cells. PLoS One 2017; 12:e0180383. [PMID: 28683123 PMCID: PMC5500319 DOI: 10.1371/journal.pone.0180383] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Accepted: 06/14/2017] [Indexed: 01/06/2023] Open
Abstract
Tyrosine kinase inhibitors (TKIs) are currently the first-line treatment for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. These patients receive platinum-based chemotherapy as the second-line treatment after they develop resistance to TKIs. Many patients regain sensitivity to the TKIs used in the first-line treatment after the failure of chemotherapy. However, the molecular mechanism for the regain of TKI sensitivity is largely unknown. In this study, we established gefitinib-resistant PC9 and HCC827 cell lines, which did not harbor the EGFR T790M mutation and MET amplification but exhibited the epithelial-mesenchymal transition (EMT) phenotype. Overexpression of EMT inducers, Snail or Slug, in the parental lines promoted their resistance to gefitinib. The gefitinib-resistant cell lines regained their sensitivity to gefitinib and displayed reverse EMT phenotypes after long-term culture in gefitinib-free culture medium. Blockage of reverse EMT by stable expression of Snail or Slug prevented the regain of TKI sensitivity. In conclusion, reverse EMT is one of the major mechanisms for the regain of TKI sensitivity in TKI-resistant NSCLC cells, suggesting that the development of small molecules targeting the EMT process may prolong the efficacy of TKIs in NSCLC patients with EGFR mutations.
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Affiliation(s)
- An-Fu Lee
- School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Man-Chin Chen
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chao-Ju Chen
- Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Laboratory Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chih-Jen Yang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- * E-mail: (YPL); (MSH); (CJY)
| | - Ming-Shyang Huang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- Division of Geriatrics and Gerontology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- * E-mail: (YPL); (MSH); (CJY)
| | - Yu-Peng Liu
- Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
- * E-mail: (YPL); (MSH); (CJY)
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A novel EGFR-TKI inhibitor (cAMP-H 3BO 3complex) combined with thermal therapy is a promising strategy to improve lung cancer treatment outcomes. Oncotarget 2017; 8:56327-56337. [PMID: 28915593 PMCID: PMC5593564 DOI: 10.18632/oncotarget.17628] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Accepted: 04/21/2017] [Indexed: 12/20/2022] Open
Abstract
Purpose Although EGFR-TKIs (epidermal growth factor receptor tyrosine kinase inhibitors) induce favorable responses as first-line non-small cell lung cancer treatments, drug resistance remains a serious problem. Meanwhile, thermal therapy also shows promise as a cancer therapy strategy. Here we combine a novel EGFR-TKI treatment with thermal therapy to improve lung cancer treatment outcomes. Results The results suggest that the cAMP-H3BO3 complex effectively inhibits EGFR auto-phosphorylation, while inducing apoptosis and cell cycle arrest in vitro. Compared to the negative control, tumor growth was significantly suppressed in mice treated with oxidative phosphorylation uncoupler thyroxine sodium and either cAMP-H3BO3 complex or cAMP-H3BO3 complex (P < 0.05). Moreover, the body temperature increase induced by treatment with thyroxine sodium inhibited tumor growth. Immunohistochemical analyses showed that A549 cell apoptosis was significantly higher in the cAMP-H3BO3 complex plus thyroxine sodium treatment group than in the other groups. Moreover,Ca2+ content analysis showed that the Ca2+ content of tumor tissue was significantly higher in the cAMP-H3BO3 complex plus thyroxine sodium treatment group than in other groups. Materials and Methods Inhibition of EGFR auto-phosphorylation by cAMP and cAMP-H3BO3 complex was studied using autoradiography and western blot. The antitumor activity of the novel EGFR inhibitor (cAMP-H3BO3 complex) with or without an oxidative phosphorylation uncoupler (thyroxine sodium) was investigated in vitro and in a nude mouse xenograft lung cancer model incorporating human A549 cells. Conclusions cAMP-H3BO3 complex is a novel EGFR-TKI. Combination therapy using cAMP-H3BO3 with thyroxine sodium-induced thermal therapy may improve lung cancer treatment outcomes.
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Yang M, Topaloglu U, Petty WJ, Pagni M, Foley KL, Grant SC, Robinson M, Bitting RL, Thomas A, Alistar AT, Desnoyers RJ, Goodman M, Albright C, Porosnicu M, Vatca M, Qasem SA, DeYoung B, Kytola V, Nykter M, Chen K, Levine EA, Staren ED, D’Agostino RB, Petro RM, Blackstock W, Powell BL, Abraham E, Pasche B, Zhang W. Circulating mutational portrait of cancer: manifestation of aggressive clonal events in both early and late stages. J Hematol Oncol 2017; 10:100. [PMID: 28472989 PMCID: PMC5418716 DOI: 10.1186/s13045-017-0468-1] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Accepted: 04/20/2017] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Solid tumors residing in tissues and organs leave footprints in circulation through circulating tumor cells (CTCs) and circulating tumor DNAs (ctDNA). Characterization of the ctDNA portraits and comparison with tumor DNA mutational portraits may reveal clinically actionable information on solid tumors that is traditionally achieved through more invasive approaches. METHODS We isolated ctDNAs from plasma of patients of 103 lung cancer and 74 other solid tumors of different tissue origins. Deep sequencing using the Guardant360 test was performed to identify mutations in 73 clinically actionable genes, and the results were associated with clinical characteristics of the patient. The mutation profiles of 37 lung cancer cases with paired ctDNA and tumor genomic DNA sequencing were used to evaluate clonal representation of tumor in circulation. Five lung cancer cases with longitudinal ctDNA sampling were monitored for cancer progression or response to treatments. RESULTS Mutations in TP53, EGFR, and KRAS genes are most prevalent in our cohort. Mutation rates of ctDNA are similar in early (I and II) and late stage (III and IV) cancers. Mutation in DNA repair genes BRCA1, BRCA2, and ATM are found in 18.1% (32/177) of cases. Patients with higher mutation rates had significantly higher mortality rates. Lung cancer of never smokers exhibited significantly higher ctDNA mutation rates as well as higher EGFR and ERBB2 mutations than ever smokers. Comparative analysis of ctDNA and tumor DNA mutation data from the same patients showed that key driver mutations could be detected in plasma even when they were present at a minor clonal population in the tumor. Mutations of key genes found in the tumor tissue could remain in circulation even after frontline radiotherapy and chemotherapy suggesting these mutations represented resistance mechanisms. Longitudinal sampling of five lung cancer cases showed distinct changes in ctDNA mutation portraits that are consistent with cancer progression or response to EGFR drug treatment. CONCLUSIONS This study demonstrates that ctDNA mutation rates in the key tumor-associated genes are clinical parameters relevant to smoking status and mortality. Mutations in ctDNA may serve as an early detection tool for cancer. This study quantitatively confirms the hypothesis that ctDNAs in circulation is the result of dissemination of aggressive tumor clones and survival of resistant clones. This study supports the use of ctDNA profiling as a less-invasive approach to monitor cancer progression and selection of appropriate drugs during cancer evolution.
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Affiliation(s)
- Meng Yang
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Medical Center Blvd., Winston-Salem, NC 27157 USA
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
- Department of Epidemiology and Biostatistics, Tianjin Medical University Cancer Institute and Hospital, 300060 Tianjin, China
- Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
| | - Umit Topaloglu
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Medical Center Blvd., Winston-Salem, NC 27157 USA
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
- Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
| | - W. Jeffrey Petty
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Medical Center Blvd., Winston-Salem, NC 27157 USA
- Department of Internal Medicine-Section of Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
- Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
| | - Matthew Pagni
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Medical Center Blvd., Winston-Salem, NC 27157 USA
- Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
- Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
| | - Kristie L. Foley
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Medical Center Blvd., Winston-Salem, NC 27157 USA
- Department of Social Sciences and Health Policy, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
- Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
| | - Stefan C. Grant
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Medical Center Blvd., Winston-Salem, NC 27157 USA
- Department of Internal Medicine-Section of Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
- Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
| | - Mac Robinson
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Medical Center Blvd., Winston-Salem, NC 27157 USA
- Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
| | - Rhonda L. Bitting
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Medical Center Blvd., Winston-Salem, NC 27157 USA
- Department of Internal Medicine-Section of Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
- Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
| | - Alexandra Thomas
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Medical Center Blvd., Winston-Salem, NC 27157 USA
- Department of Internal Medicine-Section of Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
- Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
| | - Angela T. Alistar
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Medical Center Blvd., Winston-Salem, NC 27157 USA
- Department of Internal Medicine-Section of Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
- Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
| | - Rodwige J. Desnoyers
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Medical Center Blvd., Winston-Salem, NC 27157 USA
- Department of Internal Medicine-Section of Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
- Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
| | - Michael Goodman
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Medical Center Blvd., Winston-Salem, NC 27157 USA
- Department of Internal Medicine-Section of Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
- Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
| | - Carol Albright
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Medical Center Blvd., Winston-Salem, NC 27157 USA
- Department of Internal Medicine-Section of Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
- Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
| | - Mercedes Porosnicu
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Medical Center Blvd., Winston-Salem, NC 27157 USA
- Department of Internal Medicine-Section of Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
- Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
| | - Mihaela Vatca
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Medical Center Blvd., Winston-Salem, NC 27157 USA
- Department of Internal Medicine-Section of Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
- Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
| | - Shadi A. Qasem
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Medical Center Blvd., Winston-Salem, NC 27157 USA
- Department of Laboratory Medicine and Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
- Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
| | - Barry DeYoung
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Medical Center Blvd., Winston-Salem, NC 27157 USA
- Department of Laboratory Medicine and Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
- Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
| | - Ville Kytola
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Medical Center Blvd., Winston-Salem, NC 27157 USA
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
- Institute for Biosciences and Medical Technology, University of Tampere, 33520 Tampere, Finland
- Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
| | - Matti Nykter
- Institute for Biosciences and Medical Technology, University of Tampere, 33520 Tampere, Finland
| | - Kexin Chen
- Department of Epidemiology and Biostatistics, Tianjin Medical University Cancer Institute and Hospital, 300060 Tianjin, China
| | - Edward A. Levine
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Medical Center Blvd., Winston-Salem, NC 27157 USA
- Department of General Surgery-Section of Surgical Oncology, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
- Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
| | - Edgar D. Staren
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Medical Center Blvd., Winston-Salem, NC 27157 USA
- Department of General Surgery-Section of Surgical Oncology, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
- Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
| | - Ralph B. D’Agostino
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Medical Center Blvd., Winston-Salem, NC 27157 USA
- Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
- Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
| | - Robin M. Petro
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Medical Center Blvd., Winston-Salem, NC 27157 USA
- Department of Internal Medicine-Section of Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
- Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
| | - William Blackstock
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Medical Center Blvd., Winston-Salem, NC 27157 USA
- Department of Radiation Oncology, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
- Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
| | - Bayard L. Powell
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Medical Center Blvd., Winston-Salem, NC 27157 USA
- Department of Internal Medicine-Section of Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
- Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
| | - Edward Abraham
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Medical Center Blvd., Winston-Salem, NC 27157 USA
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
- Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
| | - Boris Pasche
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Medical Center Blvd., Winston-Salem, NC 27157 USA
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
- Department of Internal Medicine-Section of Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
- Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
| | - Wei Zhang
- Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Medical Center Blvd., Winston-Salem, NC 27157 USA
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
- Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
- Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC 27157 USA
- Cancer Genomics and Precision Medicine, Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC 27157 USA
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