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Khadela A, Postwala H, Rana D, Dave H, Ranch K, Boddu SHS. A review of recent advances in the novel therapeutic targets and immunotherapy for lung cancer. Med Oncol 2023; 40:152. [PMID: 37071269 DOI: 10.1007/s12032-023-02005-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 03/22/2023] [Indexed: 04/19/2023]
Abstract
Lung cancer is amongst the most pervasive malignancies having high mortality rates. It is broadly grouped into non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). The concept of personalized medicine has overshadowed the conventional chemotherapy given to all patients with lung cancer. The targeted therapy is given to a particular population having specific mutations to help in the better management of lung cancer. The targeting pathways for NSCLC include the epidermal growth factor receptor, vascular endothelial growth factor receptor, MET (Mesenchymal epithelial transition factor) oncogene, Kirsten rat sarcoma viral oncogene (KRAS), and anaplastic lymphoma kinase (ALK). SCLC targeting pathway includes Poly (ADP-ribose) polymerases (PARP) inhibitors, checkpoint kinase 1 (CHK 1) pathway, WEE1 pathway, Ataxia Telangiectasia and Rad3-related (ATR)/Ataxia telangiectasia mutated (ATM), and Delta-like canonical Notch ligand 3 (DLL-Immune checkpoint inhibitors like programmed cell death protein 1 (PD-1)/ programmed death-ligand 1 (PD-L1) inhibitors and Cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) blockade are also utilized in the management of lung cancer. Many of the targeted therapies are still under development and require clinical trials to establish their safety and efficacy. This review summarizes the mechanism of molecular targets and immune-mediated targets, recently approved drugs, and their clinical trials for lung cancer.
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Affiliation(s)
- Avinash Khadela
- Department of Pharmacology, L. M. College of Pharmacy, Navrangpura, Ahmedabad, Gujarat, 380009, India.
| | - Humzah Postwala
- Pharm.D Section, L. M. College of Pharmacy, Navrangpura, Ahmedabad, Gujarat, 380009, India
| | - Deval Rana
- Pharm.D Section, L. M. College of Pharmacy, Navrangpura, Ahmedabad, Gujarat, 380009, India
| | - Hetvi Dave
- Pharm.D Section, L. M. College of Pharmacy, Navrangpura, Ahmedabad, Gujarat, 380009, India
| | - Ketan Ranch
- Department of Pharmaceutics and Pharm. Technology, L. M. College of Pharmacy, Navrangpura, Ahmedabad, Gujarat, 380009, India
| | - Sai H S Boddu
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Ajman University, P.O. Box 346, Ajman, United Arab Emirates
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Cai L, Duan J, Qian L, Wang Z, Wang S, Li S, Wang C, Zhao J, Zhang X, Bai H, Wang J. ROS1 Fusion Mediates Immunogenicity by Upregulation of PD-L1 After the Activation of ROS1-SHP2 Signaling Pathway in Non-Small Cell Lung Cancer. Front Immunol 2020; 11:527750. [PMID: 33324391 PMCID: PMC7723923 DOI: 10.3389/fimmu.2020.527750] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Accepted: 10/26/2020] [Indexed: 12/19/2022] Open
Abstract
The drug resistance of first-line crizotinib therapy for ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) fusion non-small cell lung cancer (NSCLC) is inevitable. Whether the administration of immune checkpoint inhibitor (ICI) therapy is suitable for ROS 1 fusion NSCLCs or after the development of crizotinib resistance is still unknown. In this study, five different crizotinib resistant concentration cell lines (HCC78CR1-5) from primary sensitive HCC78 cells were cultured. Ba/F3 cells expressing crizotinib sensitive ROS1 fusion and crizotinib resistant ROS1-G2032R mutation were used to explore the relationship between ROS1 fusion, ROS1-G2032R mutation and programmed death-ligand 1 (PD-L1) expression and the clinical potential of anti-PD-L1 ICI therapy. The signaling pathway net was compared between HCC78 and HCC78CR1-5 cells using RNA sequencing. Anti- PD-L1 ICI therapy was performed on mouse xenograft models with Ba/F3 ROS1 fusion or ROS1-G2032R mutation. HCC78CR1-5 showed more immunogenicity than HCC78 in immune-related pathways. The PD-L1 expression level was remarkably higher in HCC78CR1-5 with ROS1 fusion upregulation than HCC78 primary cell. Furthermore, the expression of PD-L1 was down-regulated by RNA interference with ROS1 siRNAs and up-regulated lower in Ba/F3 ROS1-G2032R resistant mutation than ROS1 fusion. Western blotting analysis showed the ROS1–SHP2 signaling pathway activation in HCC78CR1-5 cells, Ba/F3 ROS1 fusion and ROS1-G2032R resistant mutation. Mouse xenograft models with Ba/F3 ROS1 fusion showed more CD3+PD-1+ T cells both in blood and tissue, and more sensitivity than the cells with Ba/F3 ROS1-G2032R resistant mutation after anti-PD-L1 therapy. Our findings indicate that PD-L1 upregulation depends on ROS1 fusion more than ROS1-G2032R mutation. We share our insights of NSCLCs treatment management into the use of anti-PD-L1 ICI therapy in ROS1 fusion and not in ROS1-G2032R resistant mutation.
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Affiliation(s)
- Liangliang Cai
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, China.,Jiangsu Key Laboratory of Experimental & Translational Non-coding RNA Research, Yangzhou, China.,National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jianchun Duan
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Li Qian
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, China.,Jiangsu Key Laboratory of Experimental & Translational Non-coding RNA Research, Yangzhou, China
| | - Zhijie Wang
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shuhang Wang
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Sini Li
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chao Wang
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jie Zhao
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xue Zhang
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hua Bai
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jie Wang
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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S100A4 drives non-small cell lung cancer invasion, associates with poor prognosis, and is effectively targeted by the FDA-approved anti-helminthic agent niclosamide. Oncotarget 2017; 7:34630-42. [PMID: 27127879 PMCID: PMC5085181 DOI: 10.18632/oncotarget.8969] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Accepted: 04/10/2016] [Indexed: 01/11/2023] Open
Abstract
S100A4 (metastasin-1), a metastasis-associated protein and marker of the epithelial to mesenchymal transition, contributes to several hallmarks of cancer and has been implicated in the progression of several types of cancer. However, the impacts of S100A4 signaling in lung cancer progression and its potential use as a target for therapy in lung cancer have not been properly explored. Using established lung cancer cell lines, we demonstrate that S100A4 knockdown reduces cell proliferation, invasion and three-dimensional invasive growth, while overexpression of S100A4 increases invasive potential. In patient-derived tissues, S100A4 is preferentially elevated in lung adenocarcinoma. This elevation is associated with lymphovascular invasion and decreased overall survival. In addition, depletion of S100A4 by shRNA inhibits NF-κB activity and decreases TNFα-induced MMP9 expression. Furthermore, inhibition of the NF-κB/MMP9 axis decreases lung carcinoma invasive potential. Niclosamide, a reported inhibitor of S100A4, blocks expression and function of S100A4 with a reduction in proliferation, invasion and NF-κB-mediated MMP9 expression. Collectively, this study highlights the importance of the S100A4/NF-κB/MMP9 axis in lung cancer invasion and provides a rationale for targeting S100A4 to combat lung cancer.
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Chen Y, Guo W, Fan J, Chen Y, Zhang X, Chen X, Luo P. The applications of liquid biopsy in resistance surveillance of anaplastic lymphoma kinase inhibitor. Cancer Manag Res 2017; 9:801-811. [PMID: 29263703 PMCID: PMC5724713 DOI: 10.2147/cmar.s151235] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
With the clinical promotion of precision medicine and individualized medical care, molecular targeted medicine has been used to treat non-small cell lung cancer (NSCLC) patients and proved to be significantly effective. Anaplastic lymphoma kinase (ALK) inhibitor is one of the most important specific therapeutic agents for patients with ALK-positive NSCLC. It can extend the survival of patients. However, resistance to the ALK inhibitor inevitably develops in the application process. So, the real-time resistance surveillance is particularly important, and liquid biopsy is one of the most potential inspection methods. Circulating tumor cells, circulating free tumor DNA and exosome in body fluid are used as the main detection biomarkers to reflect the occurrence of resistance in real time through sequencing or counting and then to guide the follow-up treatment.
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Affiliation(s)
- Yating Chen
- Department of Respiratory, Zhujiang Hospital of Southern Medical University, Guangzhou, China
| | - Wenjie Guo
- Department of Respiratory, Zhujiang Hospital of Southern Medical University, Guangzhou, China
| | - Junsheng Fan
- Department of Respiratory, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - Yuqing Chen
- Department of Respiratory, Zhujiang Hospital of Southern Medical University, Guangzhou, China
| | - Xiaoli Zhang
- Department of Respiratory, Zhujiang Hospital of Southern Medical University, Guangzhou, China
| | - Xin Chen
- Department of Respiratory, Zhujiang Hospital of Southern Medical University, Guangzhou, China
| | - Peng Luo
- Department of Respiratory, Zhujiang Hospital of Southern Medical University, Guangzhou, China
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Saito S, Espinoza-Mercado F, Liu H, Sata N, Cui X, Soukiasian HJ. Current status of research and treatment for non-small cell lung cancer in never-smoking females. Cancer Biol Ther 2017; 18:359-368. [PMID: 28494184 DOI: 10.1080/15384047.2017.1323580] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide with over 1 million deaths each year. The overall prognosis of lung cancer patients remains unsatisfactory, with a 5-year overall survival rate of less than 15%. Although most lung cancers are a result of smoking, approximately 25% of lung cancer cases worldwide are not attributable to tobacco use. Notably, more than half of the lung cancer cases in women occur in non-smokers. Among non-small-cell lung cancer (NSCLC) cases, cigarette-smokers have a greater association with squamous cell carcinoma than adenocarcinoma, which is more common in non-smokers. These findings imply that specific molecular and pathological features may associate with lung adenocarcinoma arising in non-smoker female patients. Over the past decade, whole genome sequencing and other '-omics' technologies led to the discovery of pathogenic mutations that drive tumor cell formation. These technological developments may enable tailored patient treatments throughout the course of their disease, potentially leading to improved patient outcomes. Some clinical and laboratory studies have shown success outcomes using epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI) in patients with EGFR mutations and ALK rearrangements, respectively. In fact, these 2 mutations are predominantly present in female non-smokers with adenocarcinoma. Immunotherapy has also recently emerged as a major therapeutic modality in NSCLC. In this review, we summarize the current understanding of NSCLC biology and new therapeutic molecular targets, focusing on the pathogenesis of non-smoker female NSCLC patients.
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Affiliation(s)
- Shin Saito
- a Department of Surgery , Jichi Medical University , Yakushiji, Shimotsuke-City , Tochigi , Japan
| | - Fernando Espinoza-Mercado
- b Department of Surgery, Division of Thoracic Surgery , Cedars-Sinai Medical Center , Los Angeles , CA , USA
| | - Hui Liu
- c College of Medical Laboratory Techniques, Tianjin Medical University , Tianjin , China
| | - Naohiro Sata
- a Department of Surgery , Jichi Medical University , Yakushiji, Shimotsuke-City , Tochigi , Japan
| | - Xiaojiang Cui
- d Department of Surgery , Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center , Los Angeles , CA , USA
| | - Harmik J Soukiasian
- b Department of Surgery, Division of Thoracic Surgery , Cedars-Sinai Medical Center , Los Angeles , CA , USA
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Lee DH, Lee JS, Wang J, Hsia TC, Wang X, Kim J, Orlando M. Pemetrexed-Erlotinib, Pemetrexed Alone, or Erlotinib Alone as Second-Line Treatment for East Asian and Non-East Asian Never-Smokers with Locally Advanced or Metastatic Nonsquamous Non-small Cell Lung Cancer: Exploratory Subgroup Analysis of a Phase II Trial. Cancer Res Treat 2014; 47:616-29. [PMID: 25672577 PMCID: PMC4614205 DOI: 10.4143/crt.2014.051] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2014] [Accepted: 05/25/2014] [Indexed: 12/18/2022] Open
Abstract
PURPOSE This subgroup analysis of a phase II trial was conducted to assess possible ethnicity-based trends in efficacy and safety in East Asian (EA) and non-EA populations with nonsquamous non-small cell lung cancer (NSCLC). MATERIALS AND METHODS Never-smoker patients (n=240) with locally advanced or metastatic nonsquamous NSCLC included 133 EA patients randomized to pemetrexed supplemented with dexamethasone, folic acid, and vitamin B12 plus erlotinib (pemetrexed-erlotinib) (n=41), erlotinib (n=49), or pemetrexed (n=43), and 107 non-EA patients randomized to pemetrexed-erlotinib (n=37), erlotinib (n=33), or pemetrexed (n=37). The primary endpoint, progression-free survival (PFS), was analyzed using a multivariate Cox model. RESULTS Consistent with the results of the overall study, a statistically significant difference in PFS among the three arms was noted in the EA population favoring pemetrexed-erlotinib (overall p=0.003) as compared with either single-agent arm (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.29 to 0.79; p=0.004 vs. erlotinib; HR, 0.40; 95% CI, 0.23 to 0.70; p=0.001 vs. pemetrexed). The EA patients treated with pemetrexed-erlotinib achieved a longer median PFS (7.4 months) compared with erlotinib (4.5 months) and pemetrexed (4.0 months). The PFS results also numerically favored pemetrexed-erlotinib in the non-EA population (overall p=0.210) (HR, 0.62; 95% CI, 0.37 to 1.05; p=0.078 vs. erlotinib; HR, 0.75; 95% CI, 0.42 to 1.32; p=0.320 vs. pemetrexed) (median PFS: pemetrexed-erlotinib, 6.7 months; erlotinib, 3.0 months; pemetrexed, 4.4 months). CONCLUSION The PFS results from this subset analysis in both EA and non-EA populations are consistent with the results in the overall population. The PFS advantage for pemetrexed-erlotinib is significant compared with the single agents in EA patients.
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Affiliation(s)
- Dae Ho Lee
- Department of Oncology, Asan Medical Center, Seoul, Korea
| | - Jung Shin Lee
- Department of Oncology, Asan Medical Center, Seoul, Korea
| | - Jie Wang
- Department of Thoracic Medical Oncology, Beijing Tumor Hospital and Institute, Beijing, China
| | - Te-Chun Hsia
- Department of Respiratory Therapy, China Medical University and China Medical University Hospital, Taichung, Taiwan
| | - Xin Wang
- Asia Pacific Statistical Sciences, Lilly China Drug Development and Medical Affairs Centre, Shanghai, China
| | - Jongseok Kim
- Medical Department, Lilly Korea Ltd., Seoul, Korea
| | - Mauro Orlando
- Medical Department, Eli-Lilly Interamerica Inc., Buenos Aires, Argentina
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Chia PL, Mitchell P, Dobrovic A, John T. Prevalence and natural history of ALK positive non-small-cell lung cancer and the clinical impact of targeted therapy with ALK inhibitors. Clin Epidemiol 2014; 6:423-32. [PMID: 25429239 PMCID: PMC4242069 DOI: 10.2147/clep.s69718] [Citation(s) in RCA: 130] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Improved understanding of molecular drivers of carcinogenesis has led to significant progress in the management of lung cancer. Patients with non-small-cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) gene rearrangements constitute about 4%-5% of all NSCLC patients. ALK+ NSCLC cells respond well to small molecule ALK inhibitors such as crizotinib; however, resistance invariably develops after several months of treatment. There are now several newer ALK inhibitors, with the next generation of agents targeting resistance mutations. In this review, we will discuss the prevalence and clinical characteristics of ALK+ lung cancer, current treatment options, and future directions in the management of this subset of NSCLC patients.
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Affiliation(s)
- Puey Ling Chia
- Department of Medical Oncology, Olivia-Newton John Cancer and Wellness Centre, Victoria, Australia
| | - Paul Mitchell
- Department of Medical Oncology, Olivia-Newton John Cancer and Wellness Centre, Victoria, Australia
| | - Alexander Dobrovic
- Ludwig Institute for Cancer Research, Austin Health, Victoria, Australia
- Department of Pathology, University of Melbourne, Victoria, Australia
- School of Cancer Medicine, La Trobe University, Victoria, Australia
| | - Thomas John
- Department of Medical Oncology, Olivia-Newton John Cancer and Wellness Centre, Victoria, Australia
- Ludwig Institute for Cancer Research, Austin Health, Victoria, Australia
- School of Cancer Medicine, La Trobe University, Victoria, Australia
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Revannasiddaiah S, Thakur P, Bhardwaj B, Susheela SP, Madabhavi I. Pulmonary adenocarcinoma: implications of the recent advances in molecular biology, treatment and the IASLC/ATS/ERS classification. J Thorac Dis 2014; 6:S502-25. [PMID: 25349702 DOI: 10.3978/j.issn.2072-1439.2014.05.19] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2014] [Accepted: 05/16/2014] [Indexed: 12/13/2022]
Abstract
A decade ago, lung cancer could conveniently be classified into two broad categories-either the small cell lung carcinoma (SCLC), or the non-small cell lung carcinoma (NSCLC), mainly to assist in further treatment related decision making. However, the understanding regarding the eligibility of adenocarcinoma histology for treatments with agents such as pemetrexed and bevacizumab made it a necessity for NSCLC to be classified into more specific sub-groups. Then, the availability of molecular targeted therapy with oral tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib not only further emphasized the need for accurate sub-classification of lung cancer, but also heralded the important role of molecular profiling of lung adenocarcinomas. Given the remarkable advances in molecular biology, oncology and radiology, a need for felt for a revised classification for lung adenocarcinoma, since the existing World Health Organization (WHO) classification of lung cancer, published in the year 2004 was mainly a pathological system of classification. Thus, there was a combined effort by the International Association for the Study of Lung Cancer (IASLC), the American Thoracic Society (ATS) and the European Respiratory Society (ERS) with an effort to inculcate newly established perspectives from clinical, molecular and radiological aspects in evolving a modern classification for lung adenocarcinomas. This review provides a summary of the recent advances in molecular biology and molecular targeted therapy with respect to lung adenocarcinoma. Also, a brief summation of the salient recommendations provided in the IASLC/ATS/ERS classification of lung adenocarcinomas is provided. Lastly, a discussion regarding the future prospects with lung adenocarcinoma is included.
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Affiliation(s)
- Swaroop Revannasiddaiah
- 1 Department of Radiation Oncology, Swami Rama Cancer, Hospital & Research Institute, Government Medical College-Haldwani, Nainital, Uttarakhand, India ; 2 Department of Radiotherapy, Regional Cancer Centre, Shimla, India, 3 Department of Pulmonary Medicine, Indira Gandhi Medical College, Shimla, India ; 4 Department of Radiation Oncology, HealthCare Global-Bangalore Institute of Oncology, Bengaluru, Karnataka, India ; 5 Department of Medical, Oncology, Gujarat Cancer Research Institute, Ahmedabad, Gujarat, India
| | - Priyanka Thakur
- 1 Department of Radiation Oncology, Swami Rama Cancer, Hospital & Research Institute, Government Medical College-Haldwani, Nainital, Uttarakhand, India ; 2 Department of Radiotherapy, Regional Cancer Centre, Shimla, India, 3 Department of Pulmonary Medicine, Indira Gandhi Medical College, Shimla, India ; 4 Department of Radiation Oncology, HealthCare Global-Bangalore Institute of Oncology, Bengaluru, Karnataka, India ; 5 Department of Medical, Oncology, Gujarat Cancer Research Institute, Ahmedabad, Gujarat, India
| | - Bhaskar Bhardwaj
- 1 Department of Radiation Oncology, Swami Rama Cancer, Hospital & Research Institute, Government Medical College-Haldwani, Nainital, Uttarakhand, India ; 2 Department of Radiotherapy, Regional Cancer Centre, Shimla, India, 3 Department of Pulmonary Medicine, Indira Gandhi Medical College, Shimla, India ; 4 Department of Radiation Oncology, HealthCare Global-Bangalore Institute of Oncology, Bengaluru, Karnataka, India ; 5 Department of Medical, Oncology, Gujarat Cancer Research Institute, Ahmedabad, Gujarat, India
| | - Sridhar Papaiah Susheela
- 1 Department of Radiation Oncology, Swami Rama Cancer, Hospital & Research Institute, Government Medical College-Haldwani, Nainital, Uttarakhand, India ; 2 Department of Radiotherapy, Regional Cancer Centre, Shimla, India, 3 Department of Pulmonary Medicine, Indira Gandhi Medical College, Shimla, India ; 4 Department of Radiation Oncology, HealthCare Global-Bangalore Institute of Oncology, Bengaluru, Karnataka, India ; 5 Department of Medical, Oncology, Gujarat Cancer Research Institute, Ahmedabad, Gujarat, India
| | - Irappa Madabhavi
- 1 Department of Radiation Oncology, Swami Rama Cancer, Hospital & Research Institute, Government Medical College-Haldwani, Nainital, Uttarakhand, India ; 2 Department of Radiotherapy, Regional Cancer Centre, Shimla, India, 3 Department of Pulmonary Medicine, Indira Gandhi Medical College, Shimla, India ; 4 Department of Radiation Oncology, HealthCare Global-Bangalore Institute of Oncology, Bengaluru, Karnataka, India ; 5 Department of Medical, Oncology, Gujarat Cancer Research Institute, Ahmedabad, Gujarat, India
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Jacobsen B, Kriegbaum MC, Santoni-Rugiu E, Ploug M. C4.4A as a biomarker in pulmonary adenocarcinoma and squamous cell carcinoma. World J Clin Oncol 2014; 5:621-632. [PMID: 25302166 PMCID: PMC4129527 DOI: 10.5306/wjco.v5.i4.621] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2014] [Revised: 03/10/2014] [Accepted: 06/16/2014] [Indexed: 02/06/2023] Open
Abstract
The high prevalence and mortality of lung cancer, together with a poor 5-year survival of only approximately 15%, emphasize the need for prognostic and predictive factors to improve patient treatment. C4.4A, a member of the Ly6/uPAR family of membrane proteins, qualifies as such a potential informative biomarker in non-small cell lung cancer. Under normal physiological conditions, it is primarily expressed in suprabasal layers of stratified squamous epithelia. Consequently, it is absent from healthy bronchial and alveolar tissue, but nevertheless appears at early stages in the progression to invasive carcinomas of the lung, i.e., in bronchial hyperplasia/metaplasia and atypical adenomatous hyperplasia. In the stages leading to pulmonary squamous cell carcinoma, expression is sustained in dysplasia, carcinoma in situ and invasive carcinomas, and this pertains to the normal presence of C4.4A in squamous epithelium. In pulmonary adenocarcinomas, a fraction of cases is positive for C4.4A, which is surprising, given the origin of these carcinomas from mucin-producing and not squamous epithelium. Interestingly, this correlates with a highly compromised patient survival and a predominant solid tumor growth pattern. Circumstantial evidence suggests an inverse relationship between C4.4A and the tumor suppressor LKB1. This might provide a link to the prognostic impact of C4.4A in patients with adenocarcinomas of the lung and could potentially be exploited for predicting the efficacy of treatment targeting components of the LKB1 pathway.
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Sun Q, Wu JY, Jiao SC. Heterogeneity of epidermal growth factor receptor mutations in lung adenocarcinoma harboring anaplastic lymphoma kinase rearrangements: A case report. Oncol Lett 2014; 8:2093-2095. [PMID: 25295096 PMCID: PMC4186595 DOI: 10.3892/ol.2014.2468] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2014] [Accepted: 06/19/2014] [Indexed: 02/05/2023] Open
Abstract
Lung cancer is a heterogeneous and complex disease that remains the leading cause of cancer-related mortality worldwide. The identification of epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangements has changed the treatment of non-small cell lung cancer, creating a personalized treatment era that is based on the appropriate molecular selection of patients. In spite of the efficacy of tyrosine kinase inhibitors (TKIs), acquired resistance remains inevitable due to various mechanisms. The present study reports the case of a 30-year-old patient with stage IV lung adenocarcinoma initially harboring an EGFR mutation. However, following disease progression and a series of treatments, the wild-type EGFR gene was observed and the ALK rearrangements were revealed. Erlotinib administration resulted in a good response in the patient initially, but crizotinib did not. This indicated an association between the secondary mutations in kinases and the drug resistance to TKIs. This case should also highlight the clinical significance of repeat biopsies for the subsequent therapeutic choices at the onset of clinical progression.
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Affiliation(s)
- Qiong Sun
- Department of Oncology, Chinese People's Liberation Army General Hospital, Beijing 100853, P.R. China
| | - Jian-Yu Wu
- Department of Oncology, Chinese People's Liberation Army General Hospital, Beijing 100853, P.R. China
| | - Shun-Chang Jiao
- Department of Oncology, Chinese People's Liberation Army General Hospital, Beijing 100853, P.R. China
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Factors affecting the association between overall survival and progression-free survival in clinical trials of first-line treatment for patients with advanced non-small cell lung cancer. J Cancer Res Clin Oncol 2014; 140:839-48. [PMID: 24562618 PMCID: PMC3983956 DOI: 10.1007/s00432-014-1617-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2014] [Accepted: 02/08/2014] [Indexed: 12/17/2022]
Abstract
PURPOSE New treatment strategies, particularly the introduction of molecular-targeted agents and appropriate patient selection based on histology and/or genotyping, have progressed markedly in recent years, and the overall survival (OS) in advanced non-small cell lung cancer (NSCLC) patients has improved. The aim of the study was to identify factors affecting longer OS than that estimated from progression-free survival (PFS) in first-line treatment for advanced NSCLC. METHODS Sixty-five controlled trials for first-line treatment of advanced NSCLC were extracted for the study. Factors influencing higher than predicted OS were examined by logistic regression analysis between the OS-extended group and the OS-association group. RESULTS PFS was moderately associated with OS. Twenty arms of 14 trials were categorized as an OS-extended group, in which the ratio of observed OS to estimated OS was found to be over 1.2. On multivariate logistic regression analysis, number of patients lower than 150, average age younger than 63 years, and percentage of squamous carcinoma <30 % were found to significantly affect this relationship. CONCLUSION We identified number of patients and well-known prognostic factors including age and histological cancer type as factors influencing longer OS. These factors should be considered for patient eligibility, when PFS is used as a surrogate primary endpoint for OS in randomized clinical trials of first-line treatment for patients with advanced NSCLC.
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