58 results on '"Hua-Jun CHEN"'
Search Results
2. A potential treatment option for transformed small-cell lung cancer on PD-L1 inhibitor-based combination therapy improved survival
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Chan-Yuan, Zhang, Hao, Sun, Jun-Wei, Su, Yu-Qing, Chen, Shi-Ling, Zhang, Ming-Ying, Zheng, Yu-Fa, Li, Jie, Huang, Chao, Zhang, Zai-Xian, Tai, Miao, Cai, Xu-Chao, Zhang, Jian, Su, Chong-Rui, Xu, Hong-Hong, Yan, Hua-Jun, Chen, Yi-Long, Wu, and Jin-Ji, Yang
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Pulmonary and Respiratory Medicine ,Cancer Research ,Oncology - Abstract
Transformed small-cell lung cancer (T-SCLC) has an extremely poor prognosis, and no remedies based on immunotherapy have been evaluated among T-SCLC patients. We retrospectively analysed the efficacy and safety of combining atezolizumab with chemotherapy for T-SCLC.Forty-seven patients harbouring EGFR mutations who developed T-SCLC were enrolled. Eleven patients who used immunotherapy were defined as the I/O group, and the remaining 36 were defined as the Non-I/O group. Clinical characteristics, pathological data, and survival outcomes were collected. RNA sequencing and whole-exome sequencing (WES) were performed for in-depth analysis.All patients received at least one line of EGFR-TKI before rebiopsy to confirm T-SCLC. Nine patients received atezolizumab-bevacizumab-carboplatin-paclitaxel (albumin-bound) (ABCP), and the remaining 2 received atezolizumab-etoposide-carboplatin (ECT) in the I/O group. The objective response rate was 73 % (8/11). The median progression-free survival (mPFS) of T-SCLC on post-transformation therapy with I/O group and Non-I/O group was 5.1 m and 4.1 m, respectively. The median post-T-SCLC overall survival of the I/O group was significantly longer than that Non-I/O group (20.2 m vs 7.9 m, P < 0.01). T-SCLC harbouring EGFR L858R tended to be longer than EGFR 19del (mPFS: not reached vs 3.7 m, P = 0.11). Positive PD-L1 status was also associated with PFS benefits (mPFS: 6.0 m vs 3.7 m, P = 0.20). Furthermore, RNA sequencing revealed that expression of SFTPA1 is significantly higher in the durable clinical benefit group. WES showed that STC2 mutation is more frequently observed at the time-point immunotherapy acquired resistance. Combination therapy based on a PD-L1 inhibitor was well tolerated, and the safety profile was consistent with previously reported studies.Our study first demonstrated that a PD-L1 inhibitor combined with chemotherapy ± bevacizumab could be a potential safe option for specific SCLC-transformed patients. Subsequent studies with more patients are essential to verify the efficacy and potential biomarkers.
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- 2023
3. Clinicopathological features and resistance mechanisms in <scp> HIP1‐ALK </scp> ‐rearranged lung cancer: A multicenter study
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Bao Ting Zhu, Qiu-Mei Deng, Hua-Jun Chen, Wen-Zhao Zhong, Wenxian Wang, Jin Kang, Chuang-Zhou Rao, Kai-Cheng Peng, Jin-Ji Yang, Chunwei Xu, Peng Li, Xiang-Peng Chu, Pan Wang, and Hua-Fei Chen
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Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,Oncogene Proteins, Fusion ,Brigatinib ,Activin Receptors, Type II ,Recombinant Fusion Proteins ,Biology ,Crizotinib ,Carcinoma, Non-Small-Cell Lung ,hemic and lymphatic diseases ,Internal medicine ,Biopsy ,Genetics ,medicine ,Humans ,Anaplastic lymphoma kinase ,Anaplastic Lymphoma Kinase ,Lung cancer ,Protein Kinase Inhibitors ,Aged ,Retrospective Studies ,Genetic testing ,Gene Rearrangement ,medicine.diagnostic_test ,Retrospective cohort study ,Middle Aged ,medicine.disease ,Survival Analysis ,Lorlatinib ,Immunoglobulin Fc Fragments ,respiratory tract diseases ,DNA-Binding Proteins ,Drug Resistance, Neoplasm ,Female ,medicine.drug - Abstract
Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) respond well to ALK tyrosine kinase inhibitors (TKIs), and echinoderm microtubule-associated protein-like 4 (EML4)-ALK-rearranged NSCLC accounts for the majority of those patients. However, few studies have evaluated ALK-TKIs treatment for patients with huntingtin-interacting protein 1 (HIP1)-ALK fusions. This retrospective study evaluated the clinicopathological characteristics, genomic features, response to ALK-TKIs, and resistance mechanisms in 11 cases with HIP1-ALK fusions from five Chinese centers. Patients who received crizotinib at the Chinese centers had an objective response rate of 90% [9/10 cases, 95% confident index (CI): 54.1%-99.5%], median progression-free survival of 17.9 months (95% CI: 5.8-NA months), and median overall survival of 58.8 months (95% CI: 24.7-NA months). One patient who received first-line lorlatinib treatment achieved partial response for > 26.5 months. Despite the small sample size, HIP1-ALK (H21:A20) variant was the most common variant (four of 11 cases, 36.4%) and associated with better outcomes. Among the 11 cases, there were eight patients having available specimens for genetic testing before ALK-TKIs treatment and four patients undergoing biopsy after ALK-TKIs failure. The most common coexisting gene was TP53 among 11 patients and two of four patients after crizotinib failure harbored acquired ALK mutations (e.g., L1152V/Q1146K and L1196M). Brigatinib treatment appeared to be effective for a patient who failed crizotinib treatment because of the L1152V/Q1146K mutations, which might be related to increased binding affinity to these mutants. Although HIP1-ALK-rearranged NSCLC appears to initially respond well to ALK-TKIs, crizotinib resistance may be correlated with the AKAP9-BRAF fusion, ALK compound mutations (L1152V/Q1146K), and the ALK L1196M mutation. Larger studies are needed to evaluate the significance of HIP1-ALK-rearranged NSCLC.
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- 2021
4. Design and Rationale for a Phase II, Randomized, Open-Label, Two-Cohort Multicenter Interventional Study of Osimertinib with or Without Savolitinib in De Novo MET Aberrant, EGFR-Mutant Patients with Advanced Non-Small-Cell Lung Cancer: The FLOWERS Trial
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Anna Li, Hua-Jun Chen, and Jin-Ji Yang
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Pulmonary and Respiratory Medicine ,Cancer Research ,Oncology - Abstract
Epidermal growth factor receptor (EGFR) mutations are well-known genetic alterations in advanced non-small cell lung cancer (NSCLC) which are associated with remarkable survival benefits from first-line treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, around 30% of patients exhibit primary resistance to EGFR-TKIs therapy. Co-existing MET amplification/over-expression has showed shorter time to progression on EGFR-TKI monotherapy. Osimertinib (TAGRISSO, AZD9291) has been recommended in EGFR-mutant advanced NSCLC patients as first-line treatment. Savolitinib (AZD6094, HMPL-504) is a highly selective MET-TKI which has demonstrated anti-tumor activity in various cancers with MET alterations.This FLOWERS study, a phase II, randomized, open-label, 2-cohort multicenter trial aimed to evaluate the efficacy and safety of osimertinib with or without savolitinib as first-line therapy in patients with de novo MET amplified/over-expressed, EGFR-mutant positive, locally advanced or metastatic NSCLC. Approximately 44 patients will be randomized to receive osimertinib (80 mg once daily) monotherapy or osimertinib (80 mg once daily) and savolitinib (300 mg twice daily) combination therapy; patients in osimertinib monotherapy cohort confirmed as MET positive (MET-amplified/over-expressed) after disease progression will have the opportunity to receive the cross-over combination therapy as second-line treatment. Primary endpoint will be objective response rate. Key secondary endpoints will be progression-free survival, duration of response, disease control rate, overall survival, safety and tolerability.The results of the study will provide better perspectives on the efficacy and safety of EGFR-TKI plus MET-TKI combination therapy (osimertinib plus savolitinib) in patients with de novo MET-amplified/over-expressed, EGFR-mutant positive, treatment naïve, advanced NSCLC and offer a meaningful guidance in clinical practice (NCT05163249).
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- 2022
5. Intrathecal Pemetrexed: Another Potential Treatment Modality for Tyrosine Kinase Inhibitor–Failed Leptomeningeal Metastases?
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Yang-Si Li, Hao Sun, Yi-Long Wu, Mei-Mei Zheng, and Hua-Jun Chen
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Pulmonary and Respiratory Medicine ,Lung Neoplasms ,medicine.drug_class ,business.industry ,Pemetrexed ,Intrathecal ,Tyrosine-kinase inhibitor ,Oncology ,Treatment modality ,Carcinoma, Non-Small-Cell Lung ,medicine ,Cancer research ,Humans ,business ,Meningeal Carcinomatosis ,Protein Kinase Inhibitors ,medicine.drug - Published
- 2021
6. Integrated histological and molecular analyses of rebiopsy samples at osimertinib progression improve post-progression survivals: A single-center retrospective study
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Jian Su, Yu-Er Gao, Jianxing Xiang, Zhi Xie, Hong-Hong Yan, Zhen Wang, Yi-Long Wu, Xuan Lin, Yi-Hui Yao, Jin-Ji Yang, Shi-Ling Zhang, Xu-Chao Zhang, Qing Zhou, Hai-Yan Tu, Analyn Lizaso, Jiang-Tao Cheng, Shuyin Chen, and Hua-Jun Chen
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0301 basic medicine ,Pulmonary and Respiratory Medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,medicine.medical_treatment ,Single Center ,Targeted therapy ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Overall survival ,Clinical endpoint ,Humans ,Medicine ,Osimertinib ,Protein Kinase Inhibitors ,Retrospective Studies ,Acrylamides ,Chemotherapy ,Aniline Compounds ,business.industry ,Retrospective cohort study ,ErbB Receptors ,030104 developmental biology ,030220 oncology & carcinogenesis ,Mutation ,business ,Cohort study - Abstract
Background This single-center retrospective cohort study sought to investigate the impact of rebiopsy analysis after osimertinib progression in improving the survival outcomes. Methods Eighty-nine patients with EGFR T790M-positive advanced NSCLC who received second- or further-line osimertinib between January 2017 and July 2019 were included in this study. The co-primary study endpoints were post-progression progression-free survival (pPFS), defined as the time from osimertinib progression until progression from further-line treatment, and post-progression overall survival (pOS), defined as the time from osimertinib progression until death or the last follow-up date. Results Pairwise analysis revealed that receiving targeted therapy as further-line treatment after osimertinib progression did not statistically improve the pPFS (P = 0.285) or the pOS (P = 0.903) compared to chemotherapy. However, patients who submitted rebiopsy samples at osimertinib progression for histological and molecular analyses, particularly those who had actionable markers and received highly matched therapy, had significantly longer pPFS and pOS as compared to those who received low-level matched therapy (pPFS = 10.0 m vs. 4.1 m, P = 0.005; pOS = 19.4 m vs. 10.0 m, P = 0.023), unmatched therapy (pPFS = 10.0 m vs. 4.7 m, P = 0.009; pOS = 19.4 m vs. 7.0 m, P = 0.001), and those without rebiopsy data (Rebiopsy vs Non-rebiopsy; pPFS = 6.1 m vs. 3.3 m, P = 0.014; pOS = 11.7 m vs. 6.8 m, P = 0.011). Conclusion Our real-world cohort study demonstrates that integrated histological and molecular analyses of rebiopsy specimens after osimertinib progression could provide more opportunities for individualized treatments to improve the post-progression survival of patients with advanced NSCLC. Our findings provide clinical evidence that supports the inclusion of NGS-based analysis of rebiopsy specimens as standard-of-care after osimertinib progression and warrants further prospective evaluation.
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- 2020
7. Association of genetic and immuno-characteristics with clinical outcomes in patients with RET-rearranged non-small cell lung cancer: a retrospective multicenter study
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Bo Zhu, Rongrong Chen, Xu-Chao Zhang, Jun Bai, Yina Wang, Jun Zhao, Jin-Ji Yang, Jin-Lu Shan, Gai-Li An, Hua-Jun Chen, Yi-Long Wu, Huamin Xu, Wu Zhuang, Hui-Ta Wu, Xiang Liu, Xiao-Feng Chen, Xiao-Rong Dong, Xinghao Ai, Chang Lu, Hai-Yan Tu, Qing Zhou, Dejian Gu, Xuefeng Xia, and Shuanying Yang
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0301 basic medicine ,Oncology ,Male ,Cancer Research ,Lung Neoplasms ,medicine.medical_treatment ,Cell ,Immune checkpoint inhibitor ,medicine.disease_cause ,B7-H1 Antigen ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,TP53 ,Immune Checkpoint Inhibitors ,Aged, 80 and over ,Gene Rearrangement ,Mutation ,Hematology ,lcsh:Diseases of the blood and blood-forming organs ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.anatomical_structure ,Advanced NSCLC ,030220 oncology & carcinogenesis ,Female ,Adult ,medicine.medical_specialty ,RET rearrangement ,Next-generationsequencing ,lcsh:RC254-282 ,03 medical and health sciences ,Young Adult ,Internal medicine ,medicine ,Humans ,Lung cancer ,Molecular Biology ,Aged ,Retrospective Studies ,Chemotherapy ,Lung ,business.industry ,lcsh:RC633-647.5 ,Research ,T-cell receptor ,Proto-Oncogene Proteins c-ret ,medicine.disease ,Survival Analysis ,030104 developmental biology ,Concomitant ,Tumor Suppressor Protein p53 ,business - Abstract
Background Rearranged during transfection (RET) has been proven to be a tumorigenic target in non-small cell lung cancers (NSCLCs). In RET-rearranged NSCLCs, molecular features and their impact on prognosis were not well illustrated, and the activity of mainstay therapeutics has not currently been well compared. Methods Patients diagnosed with NSCLCs with RET rearrangements were analyzed for concomitant mutations, tumor mutation burden (TMB), PD-L1 expression, T cell receptor repertoire and clinical outcomes with chemotherapy, immune checkpoint inhibitors (ICIs), and multikinase inhibitors (MKIs). Results Among 129 patients with RET-rearranged NSCLC who were analyzed, 41.1% (53/129) had co-occurring genetic alterations by next-generation sequencing, and concomitant TP53 mutation appeared most frequently (20/53, 37.7%). Patients with concurrent TP53 mutation (n = 15) had shorter overall survival than those without (n = 30; median, 18.4 months [95% CI, 8.6–39.1] vs 24.8 months [95% CI, 11.7–52.8]; P < 0.05). Patients with lower peripheral blood TCR diversity (n = 5) had superior overall survival compared with those with higher diversity (n = 6; median, 18.4 months [95% CI, 16.9–19.9] vs 4.8 months [95% CI, 4.5–5.3]; P = 0.035). An association with overall survival was not observed for PD-L1 expression nor for tumor mutation burden level. Median progression-free survival was not significantly different across chemotherapy, ICIs, and MKIs (median, 3.5 vs 2.5 vs 3.8 months). For patients treated with ICIs, the disease control rate was 60% (6/10) and the objective response rate was 20% (2/10). Conclusions RET-rearranged lung cancers can be heterogeneous in terms of concomitant genetic alterations. Patients with concurrent TP53 mutation or high peripheral blood TCR repertoire diversity have relatively inferior overall survival in this series. Outcomes with traditional systemic therapies in general are suboptimal.
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- 2020
8. Pathological characteristics and tumour immune microenvironment of lung malignancies with RET rearrangement
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Qing-Yun Gao, Fa-Man Xiao, Xiao-Cheng Lin, Yu-Qing Chen, Yu-Fa Li, Chang Lu, Jun-Wei Su, Quan-Quan Tan, Chan-Yuan Zhang, Jiao Yang, Yi-Long Wu, Hua-Jun Chen, and Jin-Ji Yang
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Cancer Research ,Oncology - Published
- 2023
9. The predictive value of YAP-1 and POU2F3 for the efficacy of immuno-chemotherapy in extensive-stage SCLC patients
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Yu-Qing Chen, Ling-Ling Gao, Ling-Cong Kong, Xu-Hui Guan, Huan Yang, Yu-Fa Li, Zhi-Yi Lv, Xu-Chao Zhang, Hui-Ying Liang, Hua-Jun Chen, Yi-Long Wu, Jie Huang, and Jin-Ji Yang
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Cancer Research ,Oncology - Published
- 2023
10. Response to Icotinib Plus Chemotherapy in Pulmonary Atypical Carcinoid Harboring the EGFR L858R Mutation: A Brief Report
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Chan-Yuan Zhang, Xu-Chao Zhang, Yi-Long Wu, Zhi-Yi Lv, Hua-Jun Chen, Shi-Ling Zhang, Song Dong, Yu-Qing Chen, Jin-Ji Yang, and Yu-Fa Li
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Pulmonary and Respiratory Medicine ,medicine.medical_treatment ,H&E stain ,Icotinib ,medicine.disease_cause ,EGFR L858R ,Neuroendocrine tumor ,Medicine ,Chemotherapy ,RC254-282 ,Cisplatin ,business.industry ,Brief Report ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Histology ,respiratory tract diseases ,Pulmonary atypical carcinoid ,Irinotecan ,Oncology ,Cancer research ,Immunohistochemistry ,KRAS ,business ,medicine.drug - Abstract
Introduction: Pulmonary atypical carcinoid (PAC) is a rare subtype of pulmonary neuroendocrine neoplasm. Although EML4-ALK fusion has been detected in PAC, EGFR mutations have not been reported before. Methods: We performed hematoxylin and eosin staining, immunohistochemistry, and next-generation sequencing on tissues at baseline and after surgery. Results: The patient was diagnosed with having advanced PAC harboring the EGFR L858R mutation and then received a combination of icotinib and irinotecan plus cisplatin chemotherapy, achieving a partial response before the operation. Postoperative histology results revealed SCLC harboring the EGFR L858R mutation. Surprisingly, both the KRAS amplification and the RB1 deletion disappeared. Conclusions: EGFR tyrosine inhibitors plus irinotecan plus cisplatin chemotherapy might be a potential treatment option for advanced pulmonary neuroendocrine neoplasms harboring EGFR mutations.
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- 2021
11. Genetic Profiling of Cell-Free DNA From Pleural Effusion in Advanced Lung Cancer as a Surrogate for Tumor Tissue and Revealed Additional Clinical Actionable Targets
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Jia-Xin Lin, Yi-Long Wu, Jie Huang, Xiao-Yan Bai, Ri-Qiang Liao, Dongqin Zhu, Xu-Chao Zhang, Yang-Si Li, Yue-Li Sun, Ben-Yuan Jiang, E-E Ke, Xue Wu, Hua-Jun Chen, Ruoying Yu, Bin-Chao Wang, Bing-Fei Xu, Xiaoling Tong, Qing Zhou, Jin-Ji Yang, Hai-Yan Tu, and Ming-Ying Zheng
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Pulmonary and Respiratory Medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,Pleural effusion ,medicine.medical_treatment ,Concordance ,DNA Mutational Analysis ,medicine.disease_cause ,Targeted therapy ,Circulating Tumor DNA ,Internal medicine ,Carcinoma, Non-Small-Cell Lung ,medicine ,Biomarkers, Tumor ,Humans ,Liquid biopsy ,Lung cancer ,Mutation ,business.industry ,Liquid Biopsy ,medicine.disease ,Pleural Effusion ,Cell-free fetal DNA ,Case-Control Studies ,SMARCA4 ,business ,Cell-Free Nucleic Acids - Abstract
Background Pleural effusion (PE) has been one of the promising sources of liquid biopsy in advanced lung cancer patients. However, its clinical utility is not widely accepted due to the lack of full estimation of its potential versus routine clinical samples. Method A total of 164 advanced lung cancer patients were enrolled with 164 matched tumor tissue and PE-cfDNA, 153 accompanied plasma and 63 1 PE-sDNA. Result PE-cfDNA displayed significantly higher median mutant allele frequency and an overall mutation concordance rate of 65% to tissue, which was higher than PE-sDNA (43%) and plasma-cfDNA (43%). The discrepancies between PE-cfDNA and tumor tissue were high in several genes, including SMARCA4, PIK3CA, ERBB2, KM T2A, ALK and NF1. For clinically actionable mutations, the concordance rate between PE-cfDNA and tumor tissue is 87%. Eleven patients were identified with actionable mutations in PE-cfDNA and four patients benefited from PE-cfDNA-guided targeted. Meanwhile, PE-cfDNA recapitulated mutations of diverse tissue origins and provided more mutational information under the circumstance that tumor tissue or tumor tissue of different origins were unavailable. The combination of tumor tissue and PE-cfDNA profiling increased positive detection rates of patients compared to tumor tissue alone. Our finding highlighted the importance of PE-cfDNA in the optimal selection of patients for targeted therapy. Conclusion The PE-cfDNA-based liquid biopsy displays better performance in the characterization of gene alterations than PE-sDNA and plasma-cfDNA. PE-cfDNA together with tumor tissue profiling optimizes comprehensively genomic profiling of lung cancer patients, which might be important for selecting patients for better treatment management.
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- 2021
12. Clinical Characteristics and Molecular Patterns of RET-Rearranged Lung Cancer in Chinese Patients
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Bing Li, Tengfei Zhang, Ye Wang, Kai Zhang, Jianxing Xiang, Chengzhi Zhou, Hua-Jun Chen, Lin Yang, Xinru Mao, Weiqiang Yin, Shihong Fei, and Guangsuo Wang
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Cabozantinib ,business.industry ,Retrospective cohort study ,General Medicine ,medicine.disease ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,chemistry ,030220 oncology & carcinogenesis ,Internal medicine ,Concomitant ,Cohort ,medicine ,Adenocarcinoma ,Osimertinib ,Lung cancer ,business ,Cohort study - Abstract
RET rearrangement has been proven as an oncogenic driver in patients with lung cancer. However, the prevalence, clinical characteristics, molecular features, and therapeutic options in RET-rearranged patients remain unclear, especially in Chinese lung cancer patients. We retrospectively collected 6,125 Chinese lung cancer patients who have been profiled using next-generation sequencing (NGS). The clinical demographics and molecular features of RET rearrangement-positive patients were analyzed. RET rearrangements were identified in 84 patients with a proportion of 1.4% in our cohort. The median age at diagnosis was 58 years, and it mainly occurred in females with adenocarcinoma histology. KIF5B-RET was the most frequent fusion type and accounted for 53.8% (57/106) of all RET fusions identified, with K15-R12 as the most frequent variant (71.9%). Among 47 RET+ patients profiled with larger panels, 72.3% (34/47) harbored concurrent alterations. TP53 ranked as the most common concurrent alteration, and concomitant EGFR oncogenic alterations were identified in seven patients. Moreover, an adenocarcinoma patient harboring concurrent RET fusion and EGFR L858R responded to combinatorial treatment of cabozantinib and osimertinib, with a progression-free survival of 5 months. Our study improved knowledge of clinical characteristics and molecular features of RET-rearranged lung cancers in China. It might be helpful to guide clinicians for more effective personalized diagnostic and therapeutic approaches.
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- 2019
13. Clinical Utility of Cerebrospinal Fluid Cell-Free DNA as Liquid Biopsy for Leptomeningeal Metastases in ALK-Rearranged NSCLC
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Xu-Chao Zhang, Chao Liu, Junyi Ye, Yang-Si Li, Wen-Zhao Zhong, Zhou Zhang, Hong-Hong Yan, Xue-Ning Yang, Wei-Bang Guo, Shannon Chuai, Ben-Yuan Jiang, Yi-Long Wu, Qing Zhou, Hai-Yan Tu, Mei-Mei Zheng, Jin-Ji Yang, Jian Su, Wen-Fang Tang, Zhen Wang, and Hua-Jun Chen
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Adult ,Male ,0301 basic medicine ,Pulmonary and Respiratory Medicine ,Alectinib ,Lung Neoplasms ,Brigatinib ,03 medical and health sciences ,0302 clinical medicine ,Cyclin D1 ,Cerebrospinal fluid ,CDKN2A ,Carcinoma, Non-Small-Cell Lung ,FGF4 ,Meningeal Neoplasms ,Humans ,Medicine ,Neoplasm Metastasis ,Liquid biopsy ,Lung cancer ,business.industry ,Liquid Biopsy ,Middle Aged ,medicine.disease ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Female ,business ,Cell-Free Nucleic Acids - Abstract
Introduction Leptomeningeal metastases (LMs) indicated a poor prognosis in NSCLC. LMs were more frequent in driver gene–mutated patients, and cerebrospinal fluid (CSF) cell-free DNA has shown unique genetic profiles of LM in EGFR-mutated LM. However, studies in patients with ALK receptor tyrosine kinase gene (ALK)-rearranged NSCLC with LMs are scarce. Methods Patients with lung cancer with ALK rearrangement were screened from September 2011 to February 2018 at our institute. CSF and paired plasma were tested by next-generation sequencing. Results LMs were diagnosed in 30 (10.3%) of 291 patients with ALK-rearranged lung cancer. A total of 11 paired CSF and plasma samples tested by next-generation sequencing were analyzed. Driver genes were detected in 81.8% of the CSF samples (9 of 11) and 45.5% of the plasma samples (5 of 11) (p = 0.183). The maximum allelic fractions were all higher in CSF than in plasma (p = 0.009). ALK and tumor protein p53 gene (TP53) were the two most frequently mutated genes in CSF. Gatekeeper gene ALK G1202R and C1156F mutations were identified in CSF after resistance to alectinib. Multiple copy number variants were mainly found in CSF, including in EGFR, cyclin D1 gene (CCND1), fibroblast growth factor 3 gene (FGF3), and fibroblast growth factor 4 gene (FGF4). Also found were v-myc avian myelocytomatosis viral oncogene homolog gene (MYC) copy number gains and TP53 and cyclin dependent kinase inhibitor 2A gene (CDKN2A) copy number deletions. Brigatinib seemed to be effective in controlling LM. One case showed that CSF could be used to monitor disease development of LM and longitudinally monitor tumor response. Conclusion Liquid biopsy of CSF is more sensitive than liquid biopsy of plasma to detect targetable alterations, characterizing resistance mechanisms on progression and monitoring tumor response in patients with ALK-rearranged NSCLC with LM. Thus, CSF might be promising as a medium of liquid biopsy in LM.
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- 2019
14. A molecular graded prognostic assessment (molGPA) model specific for estimating survival in lung cancer patients with leptomeningeal metastases
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Xu-Chao Zhang, Ben-Yuan Jiang, Lin-Lin Li, Kai Yin, Mei-Mei Zheng, Yang-Si Li, Xue-Ning Yang, Qing Zhou, Hong-Hong Yan, Wen-Zhao Zhong, Wen-Feng Li, Yi-Long Wu, Jin-Ji Yang, Hai-Yan Tu, and Hua-Jun Chen
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Adult ,Male ,0301 basic medicine ,Pulmonary and Respiratory Medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,Karnofsky performance score ,Gene mutation ,Survival outcome ,Age and gender ,03 medical and health sciences ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,Meningeal Neoplasms ,medicine ,Humans ,Karnofsky Performance Status ,Lung cancer ,Aged ,Retrospective Studies ,Extracranial metastasis ,Models, Statistical ,Training set ,business.industry ,Middle Aged ,Prognosis ,medicine.disease ,Survival Analysis ,030104 developmental biology ,030220 oncology & carcinogenesis ,Mutation ,Female ,business ,Outcome prediction - Abstract
Leptomeningeal metastases (LM) had increased in advanced non-small-cell lung cancer (NSCLC) over the last 10 years. The survival outcome remained overall poor, heterogeneous and was reported in association with genotypes in lung cancer patients with LM. Graded prognostic assessment model integrated with molecular alterations (molGPA) might be accurate for outcome prediction of LM patients, but needs to be established.We retrospectively screened 8921 consecutive lung cancer patients from January 2011 to March 2018. A total of 301 patients diagnosed as LM were enrolled, and randomly divided into training and validation sets after stratified by gender and age. A molGPA score for each patient was calculated based on the weighted significant parameters including gene mutations.The median OS for the 301 patients was 9.2 months (95%CI: 7.9-10.5). In the training set, EGFR/ALK positivity, Karnofsky performance score (KPS) score≥60 and absence of extracranial metastasis (ECM) independently predicted better OS. We developed a molGPA model based on above significant prognostic factors. This molGPA model classified LM patients into three prognosis groups of high, intermediate and low risk (molGPA score of 0, 0.5-1.0 and 1.5-2.0, respectively. The median OS of high, intermediate and low risk LM patients in the training set was 0.3, 3.5 and 15.9 months, respectively (p 0.001). In the validation set, the median OS was 0.9, 5.8 and 17.7 months in the three molGPA subgroups, accordingly (p 0.001). The C-index of this model in training and validation sets was 0.70 (95%CI: 0.66-0.73) and 0.64 (95%CI: 0.58-0.70) respectively.The LM molGPA model with integration of gene status, KPS and ECM can accurately classify lung cancer patients with LM into diverse prognosis.
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- 2019
15. Patient-derived organoids to predict the drug response in locally advanced or metastatic lung cancer: A real-world study
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Chan-Yuan Zhang, Han-Min Wang, Kai-Cheng Peng, Ze-Xin Chen, Jun-wei Su, Yuqing Chen, Qing-Yun Gao, Shi-Ling Zhang, Chongrui Xu, Jian Su, Hong-Hong Yan, Xuchao Zhang, Hua-Jun Chen, and Jin-Ji Yang
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Cancer Research ,Oncology - Abstract
9136 Background: Lung cancer organoids (LCOs) were expected to be the potential precision medicine approach for clinical response prediction. However, the clinical applications of both tissue and malignant serous effusions (MSE) derived LCOs were rarely reported. Our previous work demonstrated that MSE-derived LCOs maintain the genomic signature of the original tumor. In this study, we aimed to create LCOs using tissue or MSE, then validate the reliability of the model by comparing LCOs and their origin from the pathological and molecular levels. Furthermore, drug sensitivity tests of LCOs were also performed to evaluate the feasibility of LCO drug test as an approach for personalized medicine. Methods: Primary or metastatic tumor tissues were obtained from advanced lung cancer patients through core biopsy or surgically resected biopsy at the Guangdong Provincial People’s Hospital. MSEs were also collected. LCOs were generated from the obtained tissue and MSE, and the pathological features and genomic profiles were verified by analyzing the consistency with their origin. Then, the drug sensitivity scheme was formulated to follow the principles of clinical medication. In addition, proteomics analysis by 4D LC-MS/MS was also performed to analysis the molecular details of combinational therapy. Results: In our study, we generated 213 LCOs from 106 patients, mainly from MSE. The success rate to generate LCOs derived from MSE was 81.4% (131/161). The concordance rate of pathological phenotypes of LCOs samples verified by immunohistochemistry with clinical samples was 75% (63/84). In our cohort, LCO based drug sensitivity tests (LCO-DST) of targeted therapies were performed to predict the tumor response, and the AUC value of ROC analysis of osimertinib in EGFR-mutant adenocarcinoma reached 0.94(LCOs samples = 15, p= 0.0047). There were 2 patients with advanced lung adenocarcinoma, one with de novo EGFR mutation /MET amplification and the other with EGFR mutation combined with acquired RET fusion. The results of LCO based drug tests of 2 patients showed that combined targeted therapy (osimertinib plus savolitinib/cabozantinib) showed high tumor inhibition rate validated in clinical treatment and made differences. Then, 4D label-free high through-put proteomic analysis was performed in the patient with EGFR mutation and acquired RET fusion, demonstrating caspase 3 increased dramatically in combination of osimertinib and BLU-667 and the downstream proteins of EGFR and RET were down-regulated. Conclusions: LCOs derived from MSE faithfully reflected the pathological and genomic features of their original patients. The LCOs based drug test results are remarkably consistent with the tumor response. These results suggested the important prospects of LCO as an in vitro model for lung cancer precision medicine.
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- 2022
16. Complex ALK Fusions Are Associated With Better Prognosis in Advanced Non-Small Cell Lung Cancer
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Jin Kang, Xu-Chao Zhang, Hua-Jun Chen, Wen-Zhao Zhong, Yang Xu, Jian Su, Qing Zhou, Hai-Yan Tu, Zhen Wang, Chong-Rui Xu, Xue-Ning Yang, Zhi-Hong Chen, Xue Wu, Xian Zhang, Yang Shao, Yi-Long Wu, and Jin-Ji Yang
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Cancer Research ,complex ALK fusions ,Crizotinib ,business.industry ,Treatment outcome ,EML4-ALK ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,lcsh:RC254-282 ,Oncology ,hemic and lymphatic diseases ,non-canonical ALK fusion ,tyrosine kinase inhibitors ,medicine ,Cancer research ,Anaplastic lymphoma kinase ,In patient ,Non small cell ,Lung cancer ,business ,Tyrosine kinase ,Objective response ,non-small cell lung cancer ,medicine.drug ,Original Research - Abstract
BackgroundEchinoderm microtubule-associated protein-like 4 (EML4) is the canonical anaplastic lymphoma kinase (ALK) fusion partner in non-small cell lung cancer (NSCLC), and ALK-positive patients showed promising responses to ALK tyrosine kinase inhibitors (TKIs). However, studies that comprehensively investigate ALK TKI treatment in patients with different ALK fusion patterns are still lacking.MethodsNinety-eight ALK-positive patients with advanced NSCLC were retrospectively studied for their response to crizotinib and subsequent treatments. Comprehensive genomic profiling (CGP) was conducted to divide patients into different groups based on their ALK fusion patterns. Non-canonical ALK fusions were validated using RNA-sequencing.Results54.1% of patients had pure canonical EML4-ALK fusions, 19.4% carried only non-canonical ALK fusions, and 26.5% harbored complex ALK fusions with coexisting canonical and non-canonical ALK fusions. The objective response rate and median progression-free survival to crizotinib treatment tended to be better in the complex ALK fusion group. Notably, patients with complex ALK fusions had significantly improved overall survival after crizotinib treatment (p = 0.012), especially when compared with the pure canonical EML4-ALK fusion group (p = 0.010). The complex ALK fusion group also tended to respond better to next-generation ALK TKIs, which were used as later-line therapies. Most identified non-canonical ALK fusions were likely to be expressed in tumors, and some of them formed canonical EML4-ALK transcripts during mRNA maturation.ConclusionOur results suggest NSCLC patients with complex ALK fusions could potentially have better treatment outcomes to ALK TKIs therapy. Also, diagnosis using CGP is of great value to identify novel ALK fusions and predict prognosis.
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- 2020
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17. Heterogeneous responses and resistant mechanisms to crizotinib in ALK -positive advanced non-small cell lung cancer
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Bin-Chao Wang, Zhen Wang, Xue Wu, Xue-Ning Yang, Jin Kang, Zhenfan Yang, Xu-Chao Zhang, Mei Wang, Jian-Gang Fu, Yi-Long Wu, Xian Zhang, Jian Su, Zhi-Hong Chen, Qing Zhou, Jin-Ji Yang, Wen-Zhao Zhong, Hai-Yan Tu, Hua-Jun Chen, Yan Ding, and Yang W. Shao
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0301 basic medicine ,Pulmonary and Respiratory Medicine ,Crizotinib ,medicine.diagnostic_test ,business.industry ,General Medicine ,medicine.disease ,medicine.disease_cause ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Dynamic mutation ,Cancer research ,Medicine ,Immunohistochemistry ,DNA mismatch repair ,KRAS ,business ,Lung cancer ,Gene ,medicine.drug ,Fluorescence in situ hybridization - Abstract
Background ALK-tyrosine kinase inhibitors (TKIs) have been proven effective for treating ALK-positive non-small cell lung cancer (NSCLC), although patients present with variable responses and disease progression courses. The detailed underlying molecular mechanisms require further investigation to yield a better prognosis. Methods Targeted next-generation sequencing (NGS) mutation profiling was performed on samples from 42 NSCLC patients confirmed positive for ALK rearrangements by fluorescence in situ hybridization or immunohistochemistry who experienced disease progression after crizotinib treatment. Results ALK rearrangements were not confirmed in six patients (14%) with other potential oncogenic drivers identified by NGS, who therefore did not respond to crizotinib and had significantly shorter overall survival (OS) compared to NGS ALK -positive patients. Fifteen ALK activating mutations were detected in 8 out of 26 post-treatment samples (31%), among which ALK L1196M and G1269A were the most common acquired mutations detected in half of the patients with ALK activating mutations. Dynamic monitoring of the genetic evolution in one patient revealed both spatial and temporal heterogeneity of resistant mechanisms during different ALK-TKI treatment courses. Activation of ALK downstream or bypass pathways was detected in patients without ALK activating mutations, such as genetic alterations in PIK3CA, MET, and KRAS. Interestingly, we identified two patients with acquired mutations in the DNA mismatch repair gene POLE, which resulted in a dramatically increased tumor mutation burden, and might contribute to the poor response to crizotinib. Conclusions Heterogeneous resistant mechanisms have been identified and correlate to diverse responses to crizotinib. Comprehensive and dynamic mutation profiling is required to better predict clinical outcomes.
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- 2018
18. Osimertinib and Cabozantinib Combinatorial Therapy in an EGFR -Mutant Lung Adenocarcinoma Patient with Multiple MET Secondary-Site Mutations after Resistance to Crizotinib
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Jing Liu, Yi-Long Wu, Bing Li, Tengfei Zhang, Zheng Wang, Jin-Ji Yang, Zhenfan Yang, Jin Kang, and Hua-Jun Chen
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Adult ,0301 basic medicine ,Pulmonary and Respiratory Medicine ,Lung Neoplasms ,Cabozantinib ,Pyridines ,Mutant ,Adenocarcinoma of Lung ,Drug resistance ,medicine.disease_cause ,Piperazines ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Crizotinib ,medicine ,Humans ,Neoplasm ,Anilides ,Osimertinib ,Acrylamides ,Mutation ,Aniline Compounds ,business.industry ,medicine.disease ,ErbB Receptors ,030104 developmental biology ,Oncology ,chemistry ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer research ,Adenocarcinoma ,Female ,business ,medicine.drug - Published
- 2018
19. Adverse events in non-small cell lung cancer patients receiving immune checkpoint inhibitors: A single center, real-world study in China
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Yi-Long Wu, Yang-Si Li, Qing Zhou, Zhen Wang, Yueli Sun, Bin-Chao Wang, Qi Yang, Chongrui Xu, Hua-Jun Chen, Bing-Fei Xu, Hai-Yan Tu, and Jin-Ji Yang
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Immune checkpoint inhibitors ,Single Center ,medicine.disease ,Internal medicine ,Medicine ,Non small cell ,business ,Lung cancer ,Adverse effect - Abstract
e21081 Background: Immune checkpoint inhibitors (ICIs) have improved clinical outcomes in non-small cell lung cancer (NSCLC), whereas they also can cause various adverse events (AEs). We reported the incidences, spectrum and severity of AEs in real-life practice after the approval of ICIs in Chinese NSCLC patients. Methods: In this single center, retrospective study, anonymized electronic medical record data were collected from the dedicated lung cancer immunotherapy outpatient clinic of Guangdong Provincial People’s Hospital through the LinkDoc database. The patients (≥18 years old) with pathologically diagnosed metastatic NSCLC who receiving ICIs between 1 June 2019 and 31 December 2020 were included. The immune-related adverse events (irAEs) were diagnosed and assessed by oncologists. All AEs were classified and graded according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE V5.0). Results: A total of 203 patients with a median age of 60.5 years were included in this study. Most patients were male (81.8%), smokers (49.8%), non-squamous histological type (51.7%). 61.1% of patients visited the outpatient clinic more than once. Pembrolizumab and Nivolumab were given to the majority of patients (80.8%). 114 patients (56.2%) received single-agent and 89 patients (43.8%) received combination therapy. The median duration of ICIs therapy was 271.2 days. In our study, 68.0% of patients experienced any-grade AEs, and 19.7% experienced grade≥3 AEs. The most commonly AEs were abnormal laboratory findings (57.1%), blood and lymphatic system disorders (25.1%), and respiratory disorders (19.7%). All of 93 patients (45.8%) experienced irAEs and 6 patients (8.4%) developed grade≥3 irAEs. The most frequent irAEs included blood and lymphatic system disorders (25.1%), hepatobiliary disorders (17.7%), and cardiac disorders (9.9%). Cough (3.4%), sputum (2.5%), and pain (2.0%) were the most frequent AEs which received treatment. Conclusions: Our results showed 68.0% and 45.8% patients experienced AEs and irAEs, respectively. The AEs and irAEs were primarily low grade. This study also demonstrated the information of AEs could be well collected and managed through our dedicated lung cancer immunotherapy outpatient clinic. [Table: see text]
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- 2021
20. Detection of Driver and Resistance Mutations in Leptomeningeal Metastases of NSCLC by Next-Generation Sequencing of Cerebrospinal Fluid Circulating Tumor Cells
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Wen-Zhao Zhong, Zhi-Hong Chen, Biao Huang, Wei-Bang Guo, Jin-Ji Yang, Zhen Wang, Hua-Jun Chen, Bin-Chao Wang, Chong-Rui Xu, Cun-yi Gao, Xu-Chao Zhang, Yan-hui Liu, Yang W. Shao, Xian Zhang, Hai-Yan Tu, Qing Zhou, Jian Su, Yi-Long Wu, Ben-Yuan Jiang, Yang-Si Li, Xue-Ning Yang, and Shuyu Wu
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Adult ,Male ,0301 basic medicine ,Cancer Research ,Pathology ,medicine.medical_specialty ,Lung Neoplasms ,Drug resistance ,Sensitivity and Specificity ,03 medical and health sciences ,0302 clinical medicine ,Cerebrospinal fluid ,Circulating tumor cell ,Carcinoma, Non-Small-Cell Lung ,Meningeal Neoplasms ,medicine ,Carcinoma ,Humans ,Liquid biopsy ,Aged ,Neoplasm Staging ,medicine.diagnostic_test ,business.industry ,Gene Expression Profiling ,Cancer ,Magnetic resonance imaging ,Middle Aged ,Neoplastic Cells, Circulating ,medicine.disease ,Magnetic Resonance Imaging ,Primary tumor ,030104 developmental biology ,Oncology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Mutation ,Tomography, X-Ray Computed ,business ,Cell-Free Nucleic Acids - Abstract
Purpose: Leptomeningeal metastases are more common in non–small cell lung cancer (NSCLC) with EGFR mutations. The diagnosis is difficult by traditional imaging only, and leads to poor understanding of resistance mechanisms of leptomeningeal metastases. Experimental Design: We compared the CellSearch Assay, the Thinprep cytologic test (TCT), and brain magnetic resonance imaging (MRI) in 21 NSCLC patients with suspected leptomeningeal metastases. Next-generation sequencing that included 416 cancer-associated genes was also performed on cerebrospinal fluid circulating tumor cells (CSFCTC) of 19 patients. Results: Twenty-one patients were diagnosed with leptomeningeal metastases, and CSFCTCs were captured by CellSearch in 20 patients (median, 969 CSFCTCs/7.5 mL; range, 27–14,888). CellSearch had a sensitivity of 95.2% for leptomeningeal metastases diagnosis, which was higher than that of TCT (12/21, 57.1%), MRI (10/21, 47.6%), and MRI plus TCT (19/21, 90.5%), respectively. CTCs were found only in 5 of 14 patients (median, 2 CTCs/7.5 mL; range, 2–4), which was a much lower ratio than CSFCTCs. Genetic profiles of CSFCTCs were highly concordant with molecular mutations identified in the primary tumor (17/19, 89.5%). The resistance gene EGFR T790M was detected in 7 of 9 patients with extracranial lesions, but was detected in only 1 of 14 CSFCTC samples. Other potential resistant mutations, such as MET amplification and ERBB2 mutation, were also identified in CSFCTCs. Conclusions: CSFCTCs captured by CellSearch may be a more sensitive and effective way to diagnose leptomeningeal metastases, and may serve as a liquid biopsy medium for gene profiles in NSCLC patients with leptomeningeal metastases. Clin Cancer Res; 23(18); 5480–8. ©2017 AACR.
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- 2017
21. Acquired MET Y1248H and D1246N Mutations Mediate Resistance to MET Inhibitors in Non–Small Cell Lung Cancer
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Si-Yang Liu, Qing Zhou, Lan-Ying Gou, A. Li, Zhi-Hong Chen, Bin Gan, Hua-Jun Chen, Bin-Chao Wang, Jian Su, Chong-Rui Xu, Qi Zhang, Jin-Ji Yang, Zheng Wang, Xue-Ning Yang, Zhenfan Yang, Shannon Chuai, Han Han-Zhang, Zhen Wang, Zhi Xie, Wen-Zhao Zhong, Zhou Zhang, Yu Bai, Xu-Chao Zhang, Si-Pei Wu, Ben-Yuan Jiang, Hong-Fei Gao, and Yi-Long Wu
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0301 basic medicine ,Cancer Research ,Mutation ,Cancer ,Drug resistance ,Biology ,Bioinformatics ,medicine.disease_cause ,medicine.disease ,In vitro ,respiratory tract diseases ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Gefitinib ,Oncology ,In vivo ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,Carcinoma ,Lung cancer ,medicine.drug - Abstract
Purpose: MET amplification, responsible for 20% of acquired resistance to EGFR tyrosine kinase inhibitor (TKI) in patients with advanced non–small cell lung cancer (NSCLC), presents an attractive target. Numerous studies have conferred susceptibility of MET mutations and focal amplification to targeted MET-TKIs. However, the mechanism underlying MET-TKIs–induced resistance remains elusive. Experimental Design: We conducted a cohort of 12 patients with advanced NSCLC who developed resistance to a combinatorial therapy consisting of gefitinib and a type I MET-TKI. We performed capture-based targeted ultra-deep sequencing on serial tumor biopsies and plasmas ctDNA samples to detect and quantify genetic alterations. Results: We identified 2 newly acquired MET mutations, Y1248H and D1246N, in 2 patients and further confirmed their resistance against type I MET-TKIs in silco, in vitro, and in vivo. Interestingly, NIH3T3 cells harboring either mutation exhibited responses to type II MET-TKIs, suggesting sequential use of MET-TKIs may offer a more durable response. In addition, we also discovered that EGFR amplification may act as an alternative MET-TKI resistance mechanism. Conclusions: Our study provides insight into the diversity of mechanisms underlying MET-TKI–induced resistance and highlights the potential of sequential use of MET-TKIs. Clin Cancer Res; 23(16); 4929–37. ©2017 AACR.
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- 2017
22. Potential Predictive Value of TP53 and KRAS Mutation Status for Response to PD-1 Blockade Immunotherapy in Lung Adenocarcinoma
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Jin-Ji Yang, Yi-Long Wu, Hua-Jun Chen, Wen-Zhao Zhong, Hong-Hong Yan, Xu-Chao Zhang, Li-Xu Yan, Zhong-Yi Dong, Yue-Li Sun, Zhi Xie, Jia-Xin Lin, Ri-Qiang Liao, Si-Yang Liu, Qing Zhou, Si-Pei Wu, Xue-Ning Yang, Hai-Yan Tu, Jian Su, and Hao-Ran Zhai
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0301 basic medicine ,Cancer Research ,Mutation ,medicine.medical_treatment ,Cancer ,Immunotherapy ,Biology ,medicine.disease ,medicine.disease_cause ,Blockade ,Clinical trial ,Transcriptome ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,Adenocarcinoma ,KRAS ,neoplasms - Abstract
Purpose: Although clinical studies have shown promise for targeting programmed cell death protein-1 (PD-1) and ligand (PD-L1) signaling in non–small cell lung cancer (NSCLC), the factors that predict which subtype patients will be responsive to checkpoint blockade are not fully understood. Experimental Design: We performed an integrated analysis on the multiple-dimensional data types including genomic, transcriptomic, proteomic, and clinical data from cohorts of lung adenocarcinoma public (discovery set) and internal (validation set) database and immunotherapeutic patients. Gene set enrichment analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups. Results: We observed that TP53 mutation significantly increased expression of immune checkpoints and activated T-effector and interferon-γ signature. More importantly, the TP53/KRAS comutated subgroup manifested exclusive increased expression of PD-L1 and a highest proportion of PD-L1+/CD8A+. Meanwhile, TP53- or KRAS-mutated tumors showed prominently increased mutation burden and specifically enriched in the transversion-high (TH) cohort. Further analysis focused on the potential molecular mechanism revealed that TP53 or KRAS mutation altered a group of genes involved in cell-cycle regulating, DNA replication and damage repair. Finally, immunotherapeutic analysis from public clinical trial and prospective observation in our center were further confirmed that TP53 or KRAS mutation patients, especially those with co-occurring TP53/KRAS mutations, showed remarkable clinical benefit to PD-1 inhibitors. Conclusions: This work provides evidence that TP53 and KRAS mutation in lung adenocarcinoma may be served as a pair of potential predictive factors in guiding anti–PD-1/PD-L1 immunotherapy. Clin Cancer Res; 23(12); 3012–24. ©2016 AACR.
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- 2017
23. Predictive and Prognostic Potential of TP53 in Patients With Advanced Non–Small-Cell Lung Cancer Treated With EGFR-TKI: Analysis of a Phase III Randomized Clinical Trial (CTONG 0901)
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Bin-Chao Wang, Hai-Yan Tu, Xu-Chao Zhang, Rui-Lian Chen, Xiang-Meng Li, Hong-Hong Yan, Jun-Tao Lin, Wen-Feng Li, Jin-Ji Yang, Yi-Long Wu, Jian Su, Hua-Jun Chen, Qing Zhou, and Zhen Wang
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Male ,0301 basic medicine ,Pulmonary and Respiratory Medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,medicine.drug_class ,Tyrosine-kinase inhibitor ,law.invention ,03 medical and health sciences ,Exon ,0302 clinical medicine ,Randomized controlled trial ,law ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,medicine ,Humans ,Epidermal growth factor receptor ,Lung cancer ,Protein Kinase Inhibitors ,Gene ,biology ,Proportional hazards model ,business.industry ,High-Throughput Nucleotide Sequencing ,Exons ,Middle Aged ,Prognosis ,medicine.disease ,Survival Analysis ,ErbB Receptors ,030104 developmental biology ,030220 oncology & carcinogenesis ,Concomitant ,Mutation ,biology.protein ,Female ,Tumor Suppressor Protein p53 ,business - Abstract
Background Mutations in TP53 are commonly found in patients with epidermal growth factor receptor (EGFR) mutant advanced non–small-cell lung cancer (NSCLC). In this study, we determined the predictive and prognostic potential of different subtypes of TP53 using data from a phase III randomized trial (CTONG 0901). Patients and Methods The trial enrolled 195 patients who had undergone next-generation sequencing of 168 genes before treatment with EGFR tyrosine kinase inhibitors. Mutations in TP53 (exon 4 or 7, other mutations, and wild-type) were analyzed based on the therapeutic response and survival. A Cox proportional hazards model was used to determine the potential of the predictive and prognostic factors. Results All 195 patients harbored activating EGFR mutations: the most common concomitant mutations were TP53 (134/195, 68.7%), CTNNB1 (20/195, 10.3%), and RB1 (16/195, 8.2%). The genetic profiles between patient subgroups administered first-line (132, 67.7%) or later-line (63, 32.3%) treatments did not significantly differ. The median progression-free survival in patients with mutations in exon 4 or 7 of TP53, other TP53 mutations, and wild-type TP53 were 9.4, 11.0, and 14.5 months (P = .009), respectively. Overall survival times were 15.8, 20.0, and 26.1 months (P = .004), respectively. Mutations in exon 4 or 7 of TP53 served as independent prognostic factors for progression-free (P = .001) and overall survival (P = .004) in patients. Conclusion Mutations in exon 4 and/or 7 in TP53 are promising predictive and prognostic indicators in EGFR-mutated NSCLC.
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- 2021
24. Clinical outcomes of advanced non-small-cell lung cancer patients with EGFR mutation, ALK rearrangement and EGFR/ALK co-alterations
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Zhen Wang, Hua-Jun Chen, Ben-Yuan Jiang, Chong-Rui Xu, Bin-Chao Wang, Zhi-Hong Chen, Yi-Long Wu, Jin-Ji Yang, Hong-Hong Yan, Na-Na Lou, Xu-Chao Zhang, Jian Su, Zhi Xie, Xiao-Yan Bai, Wen-Zhao Zhong, Qing Zhou, Hai-Yan Tu, and Li-Xu Yan
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Male ,0301 basic medicine ,Pathology ,Lung Neoplasms ,non-small cell lung cancer (NSCLC) ,Kaplan-Meier Estimate ,Cohort Studies ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,hemic and lymphatic diseases ,Medicine ,Anaplastic lymphoma kinase ,Anaplastic Lymphoma Kinase ,Epidermal growth factor receptor ,Aged, 80 and over ,Gene Rearrangement ,biology ,Hazard ratio ,Middle Aged ,epidermal growth factor receptor (EGFR) ,ErbB Receptors ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Female ,Tyrosine kinase ,Research Paper ,medicine.drug ,Adult ,medicine.medical_specialty ,overall survival ,non-small-cell lung cancer (NSCLC) ,Antineoplastic Agents ,Disease-Free Survival ,03 medical and health sciences ,cohort study ,Humans ,Lung cancer ,Protein Kinase Inhibitors ,Aged ,Retrospective Studies ,Crizotinib ,business.industry ,Receptor Protein-Tyrosine Kinases ,Gene rearrangement ,medicine.disease ,030104 developmental biology ,anaplastic lymphoma kinase (ALK) ,Mutation ,Cancer research ,biology.protein ,business - Abstract
The co-occurrence of epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements constitutes a rare molecular subtype of non-small-cell lung cancer (NSCLC). Herein, we assessed the clinical outcomes and incidence of acquired resistance to tyrosine kinase inhibitors (TKIs) in this subtype. So we enrolled 118 advanced NSCLC treated with TKIs. EGFR mutations and ALK rearrangements were detected by DNA sequencing or Scorpion amplification refractory mutation system and fluorescence in situ hybridization respectively. Immunohistochemistry was used to evaluate the activation of associated proteins. We found that nine in ten patients with EGFR/ALK co-alterations had good response with first-line EGFR TKI, and the objective response rate (ORR) of EGFR TKIs was 80% (8/10) for EGFR/ALK co-altered and 65.5% (55/84) for EGFR-mutant (P = 0.57), with a median progression-free survival (PFS) of 11.2 and 13.2 months, (hazard ratio [HR]=0.95, 95% [CI], 0.49-1.84, P= 0.87). ORR of crizotinib was 40% (2/5) for EGFR/ALK co-altered and 73.9% (17/23) for ALK-rearranged (P= 0.29), with a median PFS of 1.9 and 6.9 months (hazard ratio [HR], 0.40; 95% [CI] 0.15-1.10, P = 0.08). The median overall survival (OS) was 21.3, 23.7, and 18.5 months in EGFR-mutant, ALK-rearranged, and EGFR/ALK co-altered (P= 0.06), and there existed a statistically significant difference in OS between ALK-rearranged and EGFR/ALK co-altered (P=0.03). Taken together, the first-line EGFR-TKI might be the reasonable care for advanced NSCLC harbouring EGFR/ALK co-alterations, whether or nor to use sequential crizotinib should be guided by the status of ALK rearrangement and the relative level of phospho-EGFR and phospho-ALK.
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- 2016
25. Abstract CT127: A phase I study of cMET inhibitor bozitinib in patients with advanced NSCLC harboring cMET alterations
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Weizhe Xue, Hua-Jun Chen, Renhua Guo, Hao Liu, Qing Zhou, Bin Gan, Yi-Long Wu, Lu Zhang, Lin Wu, Shuyin Chen, Han-Zhang Han, Jin-Ji Yang, Xinru Mao, Yun Fan, Hepeng Shi, Xuan Lin, Peilong Zhang, and Jun Zhao
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Bilirubin ,Peripheral edema ,Cancer ,medicine.disease ,Exon ,chemistry.chemical_compound ,chemistry ,Tolerability ,Pharmacokinetics ,In vivo ,Internal medicine ,Medicine ,medicine.symptom ,business ,Lung cancer - Abstract
Introduction: Cellular mesenchymal-epithelial transition (cMET) dysregulation has been described in non-small-cell lung cancer (NSCLC) and implicated as a negative prognostic factor. It can occur as amplification, overexpression or mutations leading to exon 14 skipping. Bozitinib (PLB-1001, CBT-101) is a potent highly selective cMET inhibitor, which has demonstrated superior activity in both in vitro and in vivo NSCLC models. Methods: This was a phase I, open-label multicenter study conducted in locally advanced or metastatic NSCLC patients that included a dose-escalation (19 patients) and a dose-expansion phase (18 patients) (NCT02896231). A traditional 3+3 design was adopted for dose escalation. The primary objective was to characterize the safety and tolerability of single agent Bozitinib. The secondary objectives included pharmacokinetics (PK) analysis and antitumor activity assessed by RECIST v1.1. cMET dysregulation was defined by: IHC 3+ expression in >50% of tumor cells or gain of copy numbers (GCN) ≥5 or cMET/centromere ≥2.2 by FISH or MET copy number ≥2.25 or with exon 14 skipping by next-generation sequencing (NGS). Only central laboratory testing was acceptable. Patients≥18 years with locally advanced or metastatic NSCLC with an ECOG performance status ≤2 were enrolled. Those previously treated with cMET inhibitor or HGF targeting therapy were excluded. Patients were orally administrated with Bozitinib capsules in a total of 6 dose cohorts: 5 BID dose cohorts (50 mg BID, 100 mg BID, 150 mg BID, 200 mg BID and 275 mg BID), and 1 QD dose cohort (300 mg QD). The enrollment had been completed by October 31 2019 with 37 enrolled patients. Results: Of the 37 enrolled patients, with a median age of 61: 8 had overexpression; 11 had exon 14 skipping; 8 had amplification and 10 patients had more than 1 type of MET alterations. Bozitinib was generally well-tolerated in all cohorts. Treatment-related AEs of any grade were observed in 35 patients and those of ≥ grade 3 were observed in 10 patients (in 200mg BID, 275mg BID and 300mg QD groups), including ALT increase, AST increase, bilirubin increase and peripheral edema. Common AEs occurring in more than 20% of patients included: ALT increase (40.5%), AST increase (40.5%), bilirubin increase (40.5%), peripheral edema (32.4%) and QTc interval prolongation (18.9%). Bozitinib showed good linear PK characteristics, with dose-dependent increases in exposure and a half-life around 13.8-44.6h. 36 were included in the BOR analysis. One patient was excluded due to the development of brain metastases after first dose. This cohort presented an ORR of 30.6% (11/36) and a DCR of 94.4% (34/36). Sub-analysis of ORR for patients with overexpression, amplification and exon 14 skipping were 35.7%, 41.2% and 66.7%, respectively. ORR for patients with overexpression and amplification (N=6) was 50%. ORR for patients harboring both exon 14 skipping and amplification (N=4) was 100%. Conclusions: Based on safety profiles, PK and efficacy analyses, 200mg BID was determined to be RP2D. Bozitinib was well-tolerated with manageable safety profiles when administered at RP2D. Preliminary antitumor activity was observed in patients with exon 14 skipping and/or amplification, particularly in those with NGS-identified exon 14 skipping. Citation Format: Jinji Yang, Qing Zhou, Huajun Chen, Lin Wu, Jun Zhao, Renhua Guo, Yun Fan, Hepeng Shi, Weizhe Xue, Peilong Zhang, Han-Zhang Han, Xuan Lin, Shuyin Chen, Lu Zhang, Hao Liu, Xinru Mao, Bin Gan, Yilong Wu. A phase I study of cMET inhibitor bozitinib in patients with advanced NSCLC harboring cMET alterations [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT127.
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- 2020
26. Safety of nivolumab/pembrolizumab in hepatitis B surface antigen-positive non-small cell lung cancer (NSCLC) patients
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Zhen Wang, Hai-Yan Tu, Chongrui Xu, Bin-Chao Wang, Yi-Long Wu, Yang-Si Li, Yueli Sun, Jin-Ji Yang, Qing Zhou, Bing-Fei Xu, and Hua-Jun Chen
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Cell ,non-small cell lung cancer (NSCLC) ,Hepatitis B surface antigen positive ,Pembrolizumab ,medicine.disease ,Virus ,Clinical trial ,medicine.anatomical_structure ,Chronic hepatitis ,Internal medicine ,medicine ,Nivolumab ,business - Abstract
e21670 Background: Chronic hepatitis B virus infection patients are noted about 7% in Chinese population who are excluded from the clinical trials of the nivolumab or pembrolizumab in non-small cell lung cancer (NSCLC). However, in clinical practice these patients received checkpoint inhibitors as well. Limited evidence exist on the safety of the checkpoint inhibitors in hepatitis B surface antigen positive NSCLC patients. Methods: From January 1, 2018 to September 30, 2019, clinical information of advanced non-small cell lung cancer patients who received nivolumab or pembrolizumab ± chemotherapy as routine clinical practice in Guangdong Lung Cancer Institute were collected according to a standardized procedure. Gender, histology, treatment regimens, experimental test, respose rate, and adverse events were recorded. Status of hepatitis B surface antigen (HBsAg) were tested for every patient before the treatment and data of the positive patients were accessed for this research. Adverse events were assessed according to Common Terminology Criteria for Adverse Events v5.0. Results: Among 232 eligible patients, HBsAg were found positive in 17 patients(7.3%). Clinical characteristics were list in the table. The median age was 55.2 years (range 39-72) and transaminase and bilirubin of all the patients were normal before treatment. The median treatment cycle was 7 (95%CI 4.6-10.3) and the median time to discontinuation was 4.4 months (95%CI 2.8-7.1). 8 patients received anti-virus therapy including entecavir and adefovir during the treatment. Grade 1 transaminase or bilirubin elevation were noted in 6 patients during the treatment. Grade 3 transaminase and grade 4 bilirubin elevation were found in 1 patient without evidence of viral reactivation. Conclusions: Nivolumab or pembrolizumab are safety treatment options for HBsAg positive NSCLC patients. [Table: see text]
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- 2020
27. Next-generation sequencing of tissue and liquid rebiopsy favors post-progression outcomes of EGFR T790M-positive NSCLC patients treated with osimertinib
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Shi-Ling Zhang, Hong-Hong Yan, Xu-Chao Zhang, Hai-Yan Tu, Hua-Jun Chen, Yi-Long Wu, Jian Su, Qing Zhou, Yi-Hui Yao, Yu-Er Gao, Jiangtao Cheng, Zhen Wang, Jin-Ji Yang, and Zhi Xie
- Subjects
Cancer Research ,Standard of care ,biology ,business.industry ,EGFR T790M ,medicine.disease ,DNA sequencing ,T790M ,Oncology ,Mutation (genetic algorithm) ,Cancer research ,biology.protein ,medicine ,Osimertinib ,Epidermal growth factor receptor ,Lung cancer ,business - Abstract
e21563 Background: Osimertinib is standard of care for patients with advanced non–small-cell lung cancer (NSCLC) carrying acquired epidermal growth factor receptor ( EGFR) T790M mutation. However, few studies have been conducted to investigate the impact of rebiopsy on clinical outcomes after resistance to osimertinib. We evaluated whether next-generation sequencing (NGS) of tissue and liquid rebiopsy could favor post-progression outcomes of T790M-positive advanced NSCLC patients treated with osimertinib. Methods: Immediately just after resistance to second- or further-line osimertinib, advanced NSCLC patients with acquired EGFR T790M mutation were retrospectively divided into the NGS and non-NGS groups according to whether they underwent NGS of tissue or liquid rebiopsy. The co-primary endpoints were post-progression survival (PPS) defined as the time from osimertinib resistance to subsequent-line treatment resistance, and post-progression overall survival (pOS) defined as from osimertinib resistance to death or end of the last follow-up. Multivariable analyses were done using Cox proportional hazards regression model and log-rank test. Results: Between January 2017 and July 2019, 89 patients (62 vs. 27 for the NGS and non-NGS groups respectively) were eligible for final analyses. In the NGS group, 3.2% (2/62) underwent tissue rebiopsy only, 29.0% (18/62)only had liquid rebiopsy, and 66.8% (42/62)with both tissue and liquid rebiopsy.The NGS group received more targeted or combined therapy after resistance to osimertinib (62.9% vs. 40.8%, P= 0.053). The NGS group was significantly superior to the non-NGS group in the co-primary endpoints. The median PPS was 6.1 vs. 2.7 months (hazard ratio [HR], 0.49; 95%CI, 0.30 to 0.80; 2-sided log-rank P= 0.004). Meanwhile, the median pOS was 11.7 vs. 6.8 months (HR, 0.50; 95%CI, 0.29 to 0.85, 2-sided log-rank P= 0.009). Conclusions: Providing more opportunities for individualized treatment, NGS of tissue and liquid rebiopsy favors post-progression outcomes of EGFR T790M-positive advanced NSCLC patients treated with osimertinib.
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- 2020
28. A dedicated lung cancer immunotherapy outpatient clinic: The first experience in China
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Bing-Fei Xu, Jin-Ji Yang, Yang-Si Li, Hua-Jun Chen, Yi-Long Wu, Chanchan Li, Yueli Sun, Hai-Yan Tu, Bin-Chao Wang, Chongrui Xu, Qing Zhou, and Zhen Wang
- Subjects
Cancer Research ,medicine.medical_specialty ,business.industry ,General surgery ,medicine.medical_treatment ,Cancer ,Immunotherapy ,medicine.disease ,Oncology ,Medicine ,Outpatient clinic ,business ,China ,Lung cancer - Abstract
e14022 Background: Immunotherapy (IO) has become the fourth pillar of clinical cancer care. There is an increasing need to the treatment of more patients for a longer period with acceptable cost and risk. We here described the development and operationalization of the first dedicated lung cancer IO outpatient clinic in China using an iterative process. Methods: The clinic is staffed by one attending physician, one medical oncologist, several nurses, and medical assistants along with a dedicated care coordinator. Patients (pts) were scheduled to visit every Thursday morning for the treatment and then visit every 2-4 weeks as per IO regimen. Written informed consent were obtained after well-informing about the IO and possible side-effects, and administration of self-purchased drugs. The minimum workup including routine general physical examinations or tests along with tests specific for IO, and toxicities was undertaken during the clinic visits. Treatments response, adverse events (AE), quality of life (QOL), and patient reported outcomes were measured/reviewed by the oncologist accordingly (CTCAE 5.0, RECIST 1.1, and iRECIST criteria). Pts can report their symptoms and be noticed/alerted during the clinic visits or between visits via electronic interfaces. All these data were integrated into the EMR database (LinkDoc) and valued as continuous documentation to support clinical decisions making, so as to improve clinical symptom management and overall QOL. Also, the pts were coached about possible symptoms and corresponding self-monitoring and management strategies. A standardized workflow was established, as well as staff education and training programs. Results: During May to December 2019, 99 pts presented at our IO clinic, and 79 received IO therapy (46 pembrolizumab, 32 nivolumab, and 1 camrelizumab). Pts on average received 3 cycles (Total: 280; range 1-11 cycles). AE were noted in 57 (72.2%) pts. All pts were well. Conclusions: This study demonstrates that our dedicated lung cancer IO clinic worked well. Therapeutic alliance of IO clinics has already been established with primarily 15 hospitals participated in. The design process and standardized workflow components will be further expanded to other cancers or conditions.
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- 2020
29. A phase I clinical trial to assess the safety, pharmacokinetics, and antitumor activity of glumetinib (SCC244) in patients with advanced non-small cell lung cancers (NSCLCs)
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Yi-Long Wu, Minghui Sun, Xue-Ning Yang, Yue Li, Hua-Jun Chen, Qing Zhou, Jin-Ji Yang, and Ziyong Xiang
- Subjects
Antitumor activity ,Oncology ,Cancer Research ,Poor prognosis ,medicine.medical_specialty ,Lung ,business.industry ,Phases of clinical research ,Cancer ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Pharmacokinetics ,030220 oncology & carcinogenesis ,Internal medicine ,Medicine ,In patient ,Non small cell ,business ,030215 immunology - Abstract
e21702 Background: Aberrant activation of the MET pathway is associated poor prognosis and poor response to standard therapies in cancer patients. Glumetinib (SCC224) is an oral potent and highly selective MET inhibitor. This is an open label, dose-escalation, phase I clinical study to determine the safety, pharmacokinetics and anti-tumor activity in patients with advanced NSCLC regardless of MET status. Methods: Patients with advanced NSCLC failed standard treatments received glumetinib orally according to one of four dose escalation regimens on a 28-day cycle: 100 mg, 200 mg, 300mg and 400 mg once daily, in a Pharmacologically Guided Dose Escalation (PGDE) design (a variation of the standard 3+3 design). The primary endpoints are the incidence of dose limit toxicity (DLT), maximally tolerated dose (MTD), biologically effective dose (BED). The secondary endpoints are treatment-emergent adverse events (TEAE), safety and tolerability, anti-tumor efficacy, pharmacokinetics, and its metabolites. Results: As of Feb 7, 2020, a total of eighteen eligible (18) patients were enrolled into this study: 3 at 100 mg, 3 at 200 mg, 6 at 300 mg and 6 at 400 mg. Only one patient among 6 evaluable patients at 400mg cohort reported one DLT of grade 3 vomiting. Treatment-related adverse events mostly were grade 1 or 2 nausea, vomiting, elevated alkaline phosphatase, elevated conjugated bilirubin, edema, headache, asthenia and decreased appetite. Non-DLT treatment related G3/4 adverse events were peripheral edema (n = 1, 5.5%), hypothyroidism (n = 1, 5.5%). Absorption was rapid after dosing and the median time to reach maximum plasma drug concentration ( Tmax) was 2.0‐6.0 hours. The mean value of half-life(t1/2) in each dose group ranged from 20.43h to 35.36 h. In response to glumetinib, one patient with MET overexpression at 200mg dose level had a best of response of partial response and completed 44 weeks glumetinib treatment, 4 patients (3 with MET amplification) had a best of response of stable disease. Conclusions: Glumetinib was well tolerated at doses up to 400 mg once daily and demonstrated clinical activity in advanced NSCLC with MET alterations. Glumetinib is used in ongoing clinical trials to further explore safety and efficacy in NSCLC. Clinical trial information: NCT03466268.
- Published
- 2020
30. Single Nucleotide Polymorphisms in VTI1A Gene Contribute to the Susceptibility of Chinese Population to Non-Small Cell Lung cancer
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Hong-Hong Yan, Xu-Chao Zhang, Zhi-Hong Chen, Wen-Mei Su, Jin-Ji Yang, Yi-Long Wu, Zhi Xie, Hua-Jun Chen, Jian Su, Shiliang Chen, Wen-Zhao Zhong, Wei-Bang Guo, and Qing Zhou
- Subjects
Male ,Risk ,China ,Cancer Research ,Lung Neoplasms ,Genotype ,Clinical Biochemistry ,Single-nucleotide polymorphism ,Genome-wide association study ,Biology ,Polymorphism, Single Nucleotide ,Pathology and Forensic Medicine ,Asian People ,Polymorphism (computer science) ,Carcinoma, Non-Small-Cell Lung ,medicine ,Humans ,SNP ,Genetic Predisposition to Disease ,Neoplasm Metastasis ,Lung cancer ,Alleles ,Aged ,Genetic association ,Genetics ,Smoking ,DNA, Neoplasm ,Middle Aged ,Qb-SNARE Proteins ,medicine.disease ,Lung cancer susceptibility ,Oncology ,Case-Control Studies ,Female ,Genome-Wide Association Study - Abstract
Background Genome-wide association studies (GWAS) have determined a new single nucleotide polymorphism (SNP) called VTI1A (rs7086803) that induces lung cancer susceptibility in nonsmoking women in Asia. This study aimed to evaluate the association between the VTI1A gene and the susceptibility of Chinese patients to lung cancer; it was also conducted to investigate the relationship between VTI1A SNP and adiponectin receptor 1 expression. Methods A total of 887 subjects were enrolled in this study. VTI1A (rs7086803) genotypes were determined by genotyping. Overall survival (OS) was evaluated using Kaplan-Meier analysis with a log-rank test. Results Multivariate regression analysis results indicated that the AA genotype of VTI1A (rs7086803) polymorphism was associated with an increased risk of developing non-small cell lung carcinoma (NSCLC) compared with the GG genotype (AA vs. GG: odds ratio [OR] = 2.020; 95% confidence interval [95% CI], 1.033-3.949, p = 0.037). The AA genotype of VTI1A (rs7086803) in smokers predicted significantly shorter OS (median survival time [MST]: AA 9.8 months, AG 19.3 months, GG 12.2 months, p = 0.017). Adiponectin receptor 1 expression in tumor tissues with the AA genotype was significantly lower than that for other genotypes (mean rank: AA 18.55, AG 25, GG 45.76, p = 0.001). Conclusions The presence of the allele A of VTI1A (rs7086803) may be the allele contributing to the risk of lung cancer susceptibility in Chinese population. Smoking lung cancer patients with the AA genotype of VTI1A gene (rs7086803) had a poor survival rate. Adiponectin receptor 1 expression may be correlated with the susceptibility of the allele A of VTI1A.
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- 2015
31. A comprehensive review of uncommon EGFR mutations in patients with non-small cell lung cancer
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Yue-Li Sun, Jin-Ji Yang, Jian Su, Zhi-Hong Chen, Dong-Lan Luo, Qing Zhou, Ming-Ying Zheng, Hua-Jun Chen, Ben-Yuan Jiang, Zhen Wang, Chong-Rui Xu, Ping Mei, Xue-Ning Yang, Yi-Long Wu, Xiao-Yan Bai, Bin-Chao Wang, Hai-Yan Tu, Wen-Zhao Zhong, E-E Ke, Si-Pei Wu, Zhong-Yi Dong, Xu-Chao Zhang, and Hong-Hong Yan
- Subjects
0301 basic medicine ,Oncology ,Male ,Cancer Research ,Lung Neoplasms ,medicine.disease_cause ,T790M ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,Epidermal growth factor receptor ,EGFR inhibitors ,Aged, 80 and over ,Mutation ,biology ,Smoking ,Gefitinib ,Exons ,Middle Aged ,ErbB Receptors ,030220 oncology & carcinogenesis ,Female ,Erlotinib ,medicine.drug ,Pulmonary and Respiratory Medicine ,Adult ,medicine.medical_specialty ,Genotype ,Disease-Free Survival ,03 medical and health sciences ,Erlotinib Hydrochloride ,Asian People ,Predictive Value of Tests ,Internal medicine ,medicine ,Humans ,Lung cancer ,Protein Kinase Inhibitors ,Aged ,Retrospective Studies ,business.industry ,Retrospective cohort study ,medicine.disease ,respiratory tract diseases ,030104 developmental biology ,biology.protein ,Quinazolines ,business - Abstract
Introduction Patients with non-small cell lung cancer (NSCLC) harboring uncommon epidermal growth factor receptor (EGFR) mutations are a heterogeneous group exhibiting differential responses to EGFR inhibitors. This retrospective study reviews the prevalence of uncommon EGFR mutations in a Chinese NSCLC cohort and the clinical characteristics and efficacy of EGFR tyrosine kinase inhibitors (TKIs) associated with these patients. Materials andmethods A total of 5363 lung cancer patients were screened and underwent EGFR genotyping at the Guangdong Lung Cancer Institute. Of those with uncommon EGFR mutations, the clinical characteristics and responses to EGFR-TKIs were reviewed retrospectively. Results Uncommon EGFR mutations were observed in 218 patients, comprising 11.9% of all patients with documented EGFR mutations. More smokers (30.7% vs. 24.3%, P=0.039) and males (54.1% vs. 44.4%, P=0.007) were among the patients with uncommon mutations compared with common mutations. The most frequent uncommon mutations were exon 20 insertions (30.7%, n=67), followed by G719X mutations (21.1%, n=46) and compound L858R mutations (17.0%, n=37). Favorable efficacy was observed in patients harboring compound L858R or G719X mutations, with a median progression-free survival (PFS) of 15.2 (95% CI: 8.7-21.7) or 11.6 (95% CI: 3.6-19.6) months, respectively. The median PFS of those with the T790M mutation or an exon 20 insertion was 1.0 (95% CI: 0.0-2.2) and 3.0 (95% CI: 1.3-4.7) months, respectively. Conclusion This study reviewed the prevalence of uncommon EGFR mutations and their sensitivity to EGFR-TKIs. Favorable responses were observed in patients with G719X and compound L858R mutations, indicating that they may benefit from EGFR-TKIs as a first-line therapy.
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- 2017
32. Lung Cancer Treatment Disparities in China: A Question in Need of an Answer
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Yi-Long Wu, She-Juan An, Lu-Lu Yang, Xu-Chao Zhang, Zhen Wang, Yan-yan He, Jin-Ji Yang, Hua-Jun Chen, Xue-Ning Yang, Chong-Rui Xu, Wen-Zhao Zhong, Ji-lin Guan, and Hong-Hong Yan
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Cancer Research ,Pathology ,medicine.medical_specialty ,biology ,business.industry ,Hazard ratio ,Retrospective cohort study ,Guideline ,Treatment of lung cancer ,medicine.disease ,Oncology ,Internal medicine ,medicine ,biology.protein ,Epidermal growth factor receptor ,business ,China ,Lung cancer ,Chemoradiotherapy - Abstract
Background. Substantial progress has been made in the treatment of malignancies in the People's Republic of China in recent years. The goal of this study was to identify the extent to which national treatment guidelines are being used to customize patient care in lung cancer and to analyze the reasons for treatment disparities. Methods. Patient characteristics and treatments were investigated retrospectively for the period from October 2004 to January 2013 using the outpatient database of the Guangdong Lung Cancer Institute (GLCI) in China. Results. A total of 2,535 outpatients with lung cancer were studied in this retrospective analysis. The treatment disparity was 45.3%. Overall, 20.6% of patients with stage I non-small cell lung cancer (NSCLC) were overtreated, and 20.1% of stage II patients were undertreated. Only 19.6% of stage IIIA patients and 30.7% of stage IIIB patients underwent the recommended combination of chemotherapy and radiotherapy, respectively. For advanced NSCLC, the greatest treatment disparity appeared in the second-line setting and beyond. Patients who were positive for epidermal growth factor receptor (EGFR) and receiving EGFR tyrosine kinase inhibitors experienced significant prolongation of survival compared with patients who were EGFR negative or whose EGFR mutation status was unknown (hazard ratio: 0.79; p = .037). The treatment disparities were significantly larger among patients aged younger than 65 years and in patients from developing regions compared with patients aged 65 years and older and from developed regions, respectively (p < .001, p = .046). The difference in treatment disparity was statistically significant between GLCI and other hospitals (p < .001). Conclusion. This retrospective study of a large number of patients from an outpatient oncology database demonstrated large disparities in the treatment of lung cancer in China. It is important to develop a new guideline for recommendations that are based on resource classification.
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- 2014
33. The continued osimertinib plus chemotherapy overcoming resistance after histologic transformation in EGFR-mutant lung adenocarcinoma treated with osimertinib
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Jin Kang, Jia-Tao Cheng, Xu-Chao Zhang, Yi-Long Wu, Hai-Yan Tu, Hua-Jun Chen, Qing Zhou, Xiang-Meng Li, and Jin-Ji Yang
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Cancer Research ,Chemotherapy ,Lung ,biology ,medicine.drug_class ,business.industry ,medicine.medical_treatment ,Mutant ,medicine.disease ,Tyrosine-kinase inhibitor ,respiratory tract diseases ,Transformation (genetics) ,medicine.anatomical_structure ,Oncology ,medicine ,Cancer research ,biology.protein ,Adenocarcinoma ,Osimertinib ,Epidermal growth factor receptor ,business - Abstract
e20615 Background: Although the third-generation Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib is more potent, histologic transformation from lung adenocarcinoma to other histological types is still a mechanism of resistance in EGFR-mutant adenocarcinoma. Those with histologic transformation usually have poor prognosis. Hence, we focused on the unique molecular mechanism of histologic transformation after osimertinib and explore the strategy of treatment. Methods: Pathology was confirmed in 55 EGFR-mutant patients treated with osimertinib at baseline and disease progression. They were all lung adenocarcinoma at baseline. We established the patient-derived xenograft (PDX) mouse model from an EGFR-mutant adenocarcinoma transforming to neuroendocrine carcinoma. Preclinical efficacy of erlotinib versus osimertinib was evaluated in vivo. All the clinical data of these patients were analyzed. Results: The frequency of histologic transformation after resistance to osimertinib was 14.5% (8/55). Three of them were transformed to small-cell lung cancer totally, two transformed to complex small-cell lung cancer, two transformed to adenosquamous cell carcinoma and one transformed to neuroendocrine carcinoma without T790M mutation in which an PDX mouse model was successfully established. The genetic profiles of those transformed to small-cell lung cancer were characterized by Rb1, TP53 mutations, and PI3K/AKT/MTOR aberrances. Those transformed to adenosquamous carcinoma were characterized by KRAS amplification and EGFR amplification. The median progression-free survival (PFS) was not significantly different between the patients with histologic transformation and those without during the treatment of osimertinib (7.7 VS. 5.7 months, P = 0.763). One went on first-line osimertinib, added etoposide/ cisplatin (EP) chemotherapy meanwhile after progressive disease, and achieved minor response after 2 cycles. The other one received the treatment of EP + osimertinib + erlotinib, and acheived partial response with a PFS of 7 months without obvious toxicities. The PDX model showed more sensitivity to erlotinib than osimertinib. Conclusions: Continued osimertinib plus chemotherapy might be effective in overcoming the resistance. Particularly, the first-generation EGFR-TKI seems to be efficacious in histologically-transformed EGFR-mutant patients without T790M mutation. Further investigations of these patients and PDXs are warranted.
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- 2019
34. Disease Flare After EGFR Tyrosine Kinase Inhibitor Cessation Predicts Poor Survival in Patients with Non-small Cell Lung Cancer
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Xu-Chao Zhang, Yi-Long Wu, Hong-Hong Yan, Jian Su, Jin-Ji Yang, Hua-Jun Chen, and Zhi-Hong Chen
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Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,medicine.drug_class ,medicine.medical_treatment ,Population ,Antineoplastic Agents ,Gene mutation ,Disease-Free Survival ,Tyrosine-kinase inhibitor ,Pathology and Forensic Medicine ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,Prevalence ,medicine ,Carcinoma ,Humans ,Lung cancer ,education ,Protein Kinase Inhibitors ,Retrospective Studies ,Chemotherapy ,education.field_of_study ,business.industry ,Retrospective cohort study ,General Medicine ,Middle Aged ,Prognosis ,medicine.disease ,Substance Withdrawal Syndrome ,respiratory tract diseases ,Surgery ,ErbB Receptors ,Mutation ,Cohort ,Disease Progression ,Female ,business - Abstract
Available study revealed non-small cell lung cancer (NSCLC) patients faced a risk of disease flare after cessation of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment. There was no data concerning the prognostic value of disease flare. This study aimed to investigate the prevalence of disease flare in a Chinese cohort, and analyzed its prediction to survival. A cohort of 227 NSCLC patients with acquired resistance to EGFR TKI was retrospectively analyzed. Prevalence and clinical features of disease flare after TKI cessation were reviewed. Survival data were analyzed between patients with flare and those without flare. EGFR gene mutations in tumors were detected. Twenty of 227 (8.8 %) patients were determined with disease flare after TKI cessation. The median interval from TKI cessation to disease flare was 7 days (range 3-18). Forty percent of patients complained of deteriorated dyspnea attributable to malignant effusion. Thirty percent of patients had progressive lesions in the brain. After TKI cessation 35 % of flare patients died before challenge of subsequent treatment. No response was observed in 30 % of flare patients undergoing subsequent chemotherapy. When compared with the non-flare group, patients with disease flare demonstrated comparable progression-free survival (10.1 vs. 9.9 months; P = 0.973), shorter post-TKI survival (4.1 vs. 6.1 months; P < 0.001), and a significantly poor overall survival (16.6 vs. 21.6 months; P = 0.002). Disease flare after cessation of EGFR TKI occurred in Chinese NSCLC population and predicted a poor survival.
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- 2013
35. Clinical modes of EGFR tyrosine kinase inhibitor failure and subsequent management in advanced non-small cell lung cancer
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Zhen Wang, Song Dong, Ben-Yuan Jiang, Ri-Qiang Liao, Hua-Jun Chen, Yi-Long Wu, Xu-Chao Zhang, Jian Su, Jin-Ji Yang, Chong-Rui Xu, Qiang Nie, Qing Zhou, Yi-Sheng Huang, Xue-Ning Yang, Wen-Zhao Zhong, Bin-Chao Wang, and Hong-Hong Yan
- Subjects
Adult ,Male ,Pulmonary and Respiratory Medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,medicine.drug_class ,Tyrosine-kinase inhibitor ,Erlotinib Hydrochloride ,Gefitinib ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Carcinoma ,Humans ,Treatment Failure ,Lung cancer ,Survival analysis ,Aged ,Neoplasm Staging ,Retrospective Studies ,business.industry ,Retrospective cohort study ,Middle Aged ,Proto-Oncogene Proteins c-met ,medicine.disease ,Survival Analysis ,Tumor Burden ,Surgery ,ErbB Receptors ,Clinical trial ,Mutation ,Cohort ,Quinazolines ,Female ,business ,Follow-Up Studies ,medicine.drug - Abstract
There is no published overview of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) failure modes in advanced non-small-cell lung cancer (NSCLC). This study aimed to classify the diversity of EGFR-TKI failure, and to investigate the usefulness of clinical modes in subsequent management and prognosis.One-hundred and twenty consecutive clinical trial patients with EGFR-TKI failure were enrolled as the training set to establish a clinical model based on clinical factors. Another 107 routine patients were enrolled as the validating set according to a Bayes discriminant analysis. EGFR mutations and c-MET amplification were analyzed. Kaplan-Meier survival analysis was used to test the differences among three clinical modes and subsequent management.The duration of disease control, evolution of tumor burden, and clinical symptom were verified as feasible grouping variables. A correct grouping rate achieved 87.9%. The cohort was classified into three groups, as follows: 130 patients with dramatic progression, 42 with gradual progression, and 55 with local progression. Progression-free survivals (PFSs) for the dramatic progression, gradual progression, and local progression groups were 9.3, 12.9, and 9.2 months, respectively (P = 0.007). Overall survivals for the groups (OSs) were 17.1, 39.4, and 23.1 months, respectively (P0.001). TKI continuation was superior to switching chemotherapy in a subsequent setting for gradual progression (39.4 months vs. 17.8 months; P = 0.02). The difference of EGFR or c-MET among the three groups was not significant.Clinical modes of EGFR-TKI failure could favor strategies for subsequent treatment and predicting a survival benefit in advanced NSCLC.
- Published
- 2013
36. Serial cfDNA assessment of response and resistance to EGFR-TKI for patients with EGFR-L858R mutant lung cancer from a prospective clinical trial
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Jian Su, Xue-Ning Yang, Hua-Jun Chen, Chong-Rui Xu, Hai-Yan Tu, Qing Zhou, Xu-Chao Zhang, Zhi-Hong Chen, Wen-Zhao Zhong, Jin-Ji Yang, Hong-Hong Yan, and Yi-Long Wu
- Subjects
0301 basic medicine ,Oncology ,Male ,Cancer Research ,Lung Neoplasms ,Quantitative change ,medicine.disease_cause ,Plasma EGFR mutation ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,Cluster Analysis ,Epidermal growth factor receptor ,Erlotinib Hydrochloride ,Circulating free DNA ,Aged, 80 and over ,Mutation ,Hematology ,biology ,Kinase ,Gefitinib ,lcsh:Diseases of the blood and blood-forming organs ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,ErbB Receptors ,Survival Rate ,030220 oncology & carcinogenesis ,Female ,Lung cancer ,Adult ,medicine.medical_specialty ,lcsh:RC254-282 ,Disease-Free Survival ,03 medical and health sciences ,Internal medicine ,EGFR-TKI ,medicine ,Humans ,Survival rate ,Molecular Biology ,Protein Kinase Inhibitors ,Aged ,business.industry ,lcsh:RC633-647.5 ,Research ,DNA ,medicine.disease ,respiratory tract diseases ,Clinical trial ,030104 developmental biology ,Drug Resistance, Neoplasm ,biology.protein ,Quinazolines ,business - Abstract
Background Detecting epidermal growth factor receptor (EGFR) activating mutations in plasma could guide EGFR-tyrosine kinase inhibitor (EGFR-TKI) treatment for advanced non-small cell lung cancer (NSCLC). However, dynamic quantitative changes of plasma EGFR mutations during the whole course of EGFR-TKI treatment and its correlation with clinical outcomes were not determined. The aim of this study was to measure changes of plasma EGFR L858R mutation during EGFR-TKI treatment and to determine its correlation with the response and resistance to EGFR-TKI. Methods This study was a pre-planned exploratory analysis of a randomized phase III trial conducted from 2009 to 2014 comparing erlotinib with gefitinib in advanced NSCLC harboring EGFR mutations in tumor (CTONG0901). Totally, 256 patients were enrolled in CTONG0901 and randomized to receive erlotinib or gefitinib. One hundred and eight patients harbored L858R mutation in their tumors and 80 patients provided serial blood samples as pre-planned scheduled. Serial plasma L858R was detected using quantitative polymerase chain reaction. Dynamic types of plasma L858R were analyzed using Ward’s hierarchical clustering method. Progression-free survival (PFS) and overall survival (OS) were compared between different types. Results As a whole, the quantity of L858R decreased and reached the lowest level at the time of best response to EGFR-TKI. After the analysis of Ward’s hierarchical clustering method, two dynamic types were found. In 61 patients, L858R increased to its highest level when disease progressed (ascend type), while in 19 patients, L858R maintained a stable level when disease progressed (stable type). Median PFS was 11.1 months (95 % CI, 6.6–15.6) and 7.5 months (95 % CI, 1.4–13.6) in patients with ascend and stable types, respectively (P = 0.023). Median OS was 19.7 months (95 % CI, 16.5–22.9) and 16.0 months (95 % CI, 13.4–18.5), respectively (P = 0.050). Conclusions This is the first report finding two different dynamic types of plasma L858R mutation during EGFR-TKI treatment based on a prospective randomized study. Different dynamic types were correlated with benefits from EGFR-TKI. The impact of plasma L858R levels at disease progression on subsequent treatment strategy needs further exploration. Trial registration ClinicalTrials.gov, NCT01024413 Electronic supplementary material The online version of this article (doi:10.1186/s13045-016-0316-8) contains supplementary material, which is available to authorized users.
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- 2016
37. Endothelial Progenitor Cells Combined with Cytosine Deaminase-Endostatin for Suppression of Liver Carcinoma
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Yan-Li An, Hui Yu, Rong Chen, Gao-Jun Teng, Hua-Jun Chen (陈华俊), and Zhen-Yu Jia
- Subjects
0301 basic medicine ,Carcinoma, Hepatocellular ,Biomedical Engineering ,Pharmaceutical Science ,Medicine (miscellaneous) ,Bioengineering ,Antineoplastic Agents ,Biology ,Cytosine Deaminase ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Liver Neoplasms, Experimental ,Cell Movement ,Carcinoma ,medicine ,Animals ,General Materials Science ,Progenitor cell ,Magnetite Nanoparticles ,Endothelial Progenitor Cells ,Cytosine deaminase ,Transfection ,medicine.disease ,In vitro ,Endostatins ,Transplantation ,Mice, Inbred C57BL ,030104 developmental biology ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,embryonic structures ,Immunology ,cardiovascular system ,Cancer research ,Endostatin ,circulatory and respiratory physiology - Abstract
Transplantation of gene transfected endothelial progenitor cells (EPCs) provides a novel method for treatment of human tumors. To study treatment of hepatocellular carcinoma using cytosine deaminase (CD)- and endostatin (ES)-transfected endothelial progenitor cells (EPCs), mouse bone marrow-derived EPCs were cultured and transfected with Lenti6.3-CD-EGFP and Lenti6.3-ES-Monomer-DsRed labeled with superparamagnetic iron oxide (SPIO) nanoparticles. DiD (lipophilic fluorescent dye)-labeled EPCs were injected into normal mice and mice with liver carcinoma. The EPCs loaded with CD-ES were infused into the mice through caudal veins and tumor volumes were measured. The tumor volumes in the EPC + SPIO + CD/5-Fc + ES group were found to be smaller as a result and grew more slowly than those from the EPC + SPIO + LV (lentivirus, empty vector control) group. Survival times were also measured after infusion of the cells into the mice. The median survival time was found to be longer in the EPC + SPIO + CD/5-Fc + ES group than in the others. In conclusion, the EPCs transfected with CD-ES suppressed the liver carcinoma cells in vitro, migrated primarily to the carcinoma, inhibited tumor growth, and also extended the median survival time for the mice with liver carcinoma.
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- 2016
38. Distribution and prognosis of uncommon metastases from non-small cell lung cancer
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Xu-Chao Zhang, Zhu Zeng, Ning Zhao, Yi-Long Wu, Wen-Zhao Zhong, Hui-Wen Sun, Jin-Ji Yang, Hua-Jun Chen, Qiuyi Zhang, Na Zhang, Zhi-Hong Chen, Yan-yan He, E-E Ke, Qing Zhou, Zhi Xie, Wei Deng, and Fei-Yu Niu
- Subjects
0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Pathology ,Cancer Research ,Lung Neoplasms ,NSCLC ,Metastasis ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Surgical oncology ,Carcinoma, Non-Small-Cell Lung ,Carcinoma ,Genetics ,Medicine ,Humans ,Neoplasm Metastasis ,Lung cancer ,Survival rate ,Aged ,Proportional Hazards Models ,Aged, 80 and over ,business.industry ,Hazard ratio ,Thyroid ,Uncommon metastases ,Local treatment ,Middle Aged ,medicine.disease ,Prognosis ,Survival Rate ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Tonsil ,Female ,Radiology ,business ,Research Article - Abstract
Background According to the literature and our experience, the most common sites of non-small cell lung cancer (NSCLC) metastases include the brain, bone, liver, adrenal glands, contralateral lung and distant lymph nodes. Metastases to other organs are relatively rare. There have been numerous case reports and a few small case series of uncommon metastases derived from NSCLC. Methods We defined all organs except the common metastatic sites mentioned above as uncommon sites of metastasis. Patients with uncommon metastases among 2,872 consecutive NSCLC patients with stage IV disease at the Guangdong Lung Cancer Institute (GLCI) from 2006 to 2012 were included in this study. The diagnosis of uncommon metastases was based on pathology or imaging studies. Results Uncommon metastases were diagnosed in 193 cases at anatomical sites such as the soft tissue, kidney, pancreas, spleen, peritoneum, intestine, bone marrow, eye, ovary, thyroid, heart, breast, tonsil and nasal cavity. Uncommon metastases were identified as independent poor prognostic factors through a multivariate analysis with a HR (hazard ratio) of 1.29 [95 % confidence interval (CI) 1.09–1.52, P
- Published
- 2016
39. Nedaplatin/gemcitabine versus carboplatin/gemcitabine in treatment of advanced non-small cell lung cancer: A randomized clinical trial
- Author
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Bin-Chao Wang, Yi-Long Wu, Jin-Ji Yang, Qing Zhou, Ri-Qiang Liao, Zhen Wang, Hua-Jun Chen, Yi-Sheng Huang, and Chong-Rui Xu
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,law.invention ,Carboplatin/Gemcitabine ,chemistry.chemical_compound ,Randomized controlled trial ,law ,Internal medicine ,medicine ,Nedaplatin ,Lung cancer ,neoplasms ,Chemotherapy ,business.industry ,medicine.disease ,Gemcitabine ,Carboplatin ,respiratory tract diseases ,chemistry ,Original Article ,Non small cell ,business ,medicine.drug - Abstract
To evaluate the efficacy and safety of nedaplatin/gemcitabine (NG) and carboplatin/gemcitabine (CG) in the management of untreated advanced non-small cell lung cancer (NSCLC).Sixty-two patients with previously untreated advanced NSCLC were recruited between June 2006 and November 2007. Subjects were randomly assigned to the NG arm (n=30) and the CG arm (n=32). Only patients (24 and 25 in the NG and CG arms, respectively) who completed ≥2 chemotherapy cycles were included in the data analysis. The primary outcome measure was the objective response rate (ORR). The secondary outcome measures included progression-free survival (PFS), overall survival (OS) and adverse events.There were no statistically significant differences in the efficacy measures (ORR, P=0.305; median PFS, P=0.198; median OS, P=0.961) or in the major adverse events (grade 3/4 neutropenia, P=0.666; grade 3/4 anemia, P=0.263; grade 3/4 thrombocytopenia, P=0.212) between the two treatment arms. However, there was a trend towards higher ORR (37.5% vs. 24.0%), longer PFS (6.0 vs. 5.0 months), and less adverse events in the NG arm.NG regimen seems to be superior over CG regimen for advance NSCLS, but further investigation is needed to validate this superiority.
- Published
- 2012
40. Involvement of epidermal growth factor receptor overexpression in the promotion of breast cancer brain metastasis
- Author
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Zhen Zhao, Jie Ding, Yan Li An, Fang Nie, Xin Gui Peng, Hua Jun Chen, Hong Zhao, Sheng Hong Ju, Stephen T. C. Wong, Song Wen, Jian Yang, and Gao Jun Teng
- Subjects
Cancer Research ,biology ,Cell growth ,Growth factor ,medicine.medical_treatment ,Cancer ,Cell migration ,medicine.disease ,Cell biology ,Oncology ,Gentamicin protection assay ,medicine ,biology.protein ,Erlotinib ,Epidermal growth factor receptor ,Protein kinase B ,medicine.drug - Abstract
BACKGROUND: Brain-metastatic breast cancer (BMBC) is increasing and poses a severe clinical problem because of the lack of effective treatments and because the underlying molecular mechanisms are largely unknown. Recent work has demonstrated that deregulation of epidermal growth factor receptor (EGFR) may correlate with BMBC progression. However, the exact contribution that EGFR makes to BMBC remains unclear. METHODS: The role of EGFR in BMBC was explored by serial analyses in a brain-trophic clone of human MDA-MB-231 breast carcinoma cells (231-BR cells). EGFR expression was inhibited by stable short-hairpin RNA transfection or by the kinase inhibitor erlotinib, and it was activated by heparin-binding epidermal growth factor-like growth factor (HB-EGF). Cell growth and invasion activities also were analyzed in vitro and in vivo. RESULTS: EGFR inhibition or activation strongly affected 231-BR cell migration/invasion activities as assessed by an adhesion assay, a wound-healing assay, a Boyden chamber invasion assay, and cytoskeleton staining. Also, EGFR inhibition significantly decreased brain metastases of 231-BR cells in vivo. Surprisingly, changes to EGFR expression affected cell proliferation activities less significantly as determined by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, an anchorage-independent growth assay, and cell cycle analysis. Immunoblot analysis suggested that EGFR drives cells' invasiveness capability mainly through phosphoinositide 3-kinase/protein kinase B and phospholipase C γ downstream pathways. In addition, EGFR was involved less in proliferation because of the insensitivity of the downstream mitogen-activated protein kinase pathway. CONCLUSIONS: The current results indicated that EGFR plays more important roles in cell migration and invasion to the brain than in cell proliferation progression on 231-BR cells, providing new evidence of the potential value of EGFR inhibition in treating BMBC. Cancer 2012. © 2012 American Cancer Society.
- Published
- 2012
41. Development of genetic profiles-based nomograms for predicting survival among EGFR-mutant lung cancer
- Author
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Wen-Zhao Zhong, Zhou Zhang, Jian Wu, Hong-Hong Yan, Hua-Jun Chen, Rui-lian Chen, Xu-Chao Zhang, Jin-Ji Yang, Yi-Long Wu, Hai-Yan Tu, Qing Zhou, and Junyi Ye
- Subjects
Cancer Research ,integumentary system ,business.industry ,medicine.drug_class ,Mutant ,Nomogram ,medicine.disease ,Tyrosine-kinase inhibitor ,respiratory tract diseases ,Oncology ,Cancer research ,Medicine ,business ,Lung cancer - Abstract
e21219Background: Not all advanced non-small-cell lung cancer (NSCLC) patients respond equally to tyrosine kinase inhibitor (TKI) treatments, despite the presence of sensitizing epidermal growth fa...
- Published
- 2018
42. Uncommon ALK fusion partners in advanced ALK-positive non-small-cell lung cancer
- Author
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Hua-Jun Chen, Jin-Ji Yang, Qing Zhou, Yi-Long Wu, W.-. Li, Hai-Yan Tu, Xu-Chao Zhang, and Jin Kang
- Subjects
0301 basic medicine ,Cancer Research ,Lung ,Crizotinib ,business.industry ,ALK-Positive ,medicine.disease ,respiratory tract diseases ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Oncology ,Microtubule ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,Anaplastic lymphoma kinase ,Non small cell ,Lung cancer ,business ,medicine.drug - Abstract
8561Background: The variants affect the efficacy of crizotinib in echinoderm microtubule protein-like-4 (EML4)- anaplastic lymphoma kinase (ALK) fusion-positive non–small-cell lung cancers (NSCLCs)...
- Published
- 2018
43. Anaplastic Lymphoma Kinase Variants and the Percentage of ALK-Positive Tumor Cells and the Efficacy of Crizotinib in Advanced NSCLC
- Author
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Wei-Bang Guo, Jian Su, Jie-Fei Han, Zhi Xie, Wen-Zhao Zhong, Lu-Lu Yang, Yi-Long Wu, Yuan-Yuan Lei, Jin-Ji Yang, Qing Zhou, Hong-Hong Yan, Xu-Chao Zhang, Hai-Yan Tu, Hong-Xia Tian, and Hua-Jun Chen
- Subjects
0301 basic medicine ,Pulmonary and Respiratory Medicine ,Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Pathology ,Lung Neoplasms ,Pyridines ,Tumor cells ,Antineoplastic Agents ,Biomarkers, Pharmacological ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Crizotinib ,hemic and lymphatic diseases ,Internal medicine ,Carcinoma, Non-Small-Cell Lung ,medicine ,Anaplastic lymphoma kinase ,Humans ,Anaplastic Lymphoma Kinase ,Progression-free survival ,Young adult ,Lung cancer ,Survival analysis ,Aged ,Neoplasm Staging ,Polymorphism, Genetic ,business.industry ,Receptor Protein-Tyrosine Kinases ,Middle Aged ,medicine.disease ,Survival Analysis ,Confidence interval ,030104 developmental biology ,Treatment Outcome ,030220 oncology & carcinogenesis ,Pyrazoles ,Female ,business ,medicine.drug ,Follow-Up Studies - Abstract
Background Anaplastic lymphoma kinase ( ALK )-positive non–small-cell lung cancer patients exhibited heterogeneous magnitude of response and duration time to criztotinib treatment. This study explored ALK variants and the percentage of ALK -positive cells using fluorescent in situ hybridization (FISH) on clinical efficacy of crizotinib. Patients and Methods A total of 120 patients with ALK rearrangement who were treated with criztotinib were enrolled. ALK variants were clarified in 61 patients, and ALK percentages were evaluated using FISH in 114 ALK -positive patients. Retrospectively, objective response rate, and progression-free survival (PFS) were evaluated. Results A total of 61 patients with specific ALK variants were divided into 3 subgroups, echinoderm microtubule-associated protein like 4 ( EML4)-ALK variant 1 (n = 22), EML4-ALK variant 3a/b (n = 18), and other ALK variants (n = 21). Median PFS in the 3 subgroups was 11.0 months (95% confidence interval [CI], 5.5-16.5), 10.9 months (95% CI, 5.9-15.8), 7.4 months (95% CI, 3.2-11.6), respectively, and no significant difference ( P = .795) existed among them. The percentage of ALK -positive cells in FISH analysis was weakly correlated with PFS ( r s = 0.235; P = .015). Additionally, it was also weakly correlated with best response to crizotinib ( r s = 0.288; P = .003). Overall, there were 45, 49, and 26 patients receiving first, second, and third or further-line crizotinib, respectively. Median PFS in the first-line setting (10.5 months; 95% CI, 8.6-12.4) was significantly longer than that in the second-line setting (8.3 months; 95% CI, 4.7-12.0; P = .020). Conclusion Anaplastic lymphoma kinase variants might have no correlation with clinical response to crizotinib. The percentage of ALK -positive cells might correlate with the extent of benefit from crizotinib treatment.
- Published
- 2015
44. Coexistence of MET exon 14 mutations with EGFR mutations in non-small cell lung cancer
- Author
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W.-. Li, Xu-Chao Zhang, Hai-Yan Tu, Su Jian, Zhen Wang, Qing Zhou, Bin-Chao Wang, Hua-Jun Chen, Yi-Long Wu, Jin-Ji Yang, and Jin Kang
- Subjects
0301 basic medicine ,Cancer Research ,business.industry ,medicine.disease ,03 medical and health sciences ,Exon ,030104 developmental biology ,0302 clinical medicine ,Oncology ,Egfr mutation ,030220 oncology & carcinogenesis ,Molecular targets ,Cancer research ,Medicine ,Non small cell ,MET oncogene ,business ,Lung cancer - Abstract
e20636 Background: Activation of MET oncogene as the result of amplification or activation MET exon 14 mutations represents an emerging molecular target for non-small cell lung cancer (NSCLC) treatment. MET exon 14 mutations account for 1.0% in Chinese NSCLC patients. However, few data have been reported on the coexisting of MET exon 14 mutations and EGFR mutations in NSCLC. Moreover, the clinicopathological characteristics and targeted therapy of these MET/ EGFR-coexisting patients remain elusive. Methods: Next-generation sequencing was performed on the DNA of 969 patients and Sanger sequencing was conducted on cDNA of 621 patients for MET exon 14 mutations in NSCLCs. EGFR mutations were determined by direct DNA sequencing. Results: Fifteen patients harbored positive MET exon 14 mutations. Frequency of concomitant EGFR and MET exon 14 mutations was 0.2%(3/1590). 3 patients with concomitant MET exon 14 mutation and EGFR activating mutation were all female, never smokers and adenocarcinoma. Their stagings were stageⅠB (n = 1) and stage Ⅳ(n = 2). The stage ⅠB patient harboring concomitant MET exon 14 skipping and EGFR L858R mutation did not relapse 2 years after operation. The other two stage Ⅳ patients received first-line gefitinib. Case one harbored concomitant MET exon 14 point mutations (IVS13-36G > A) and EGFR exon 19 deletion, and showed resistance to gefitinib with progression free survival(PFS) of 2 weeks and overall survival(OS) of 1 month. Case two had concomitant MET exon 14 point mutations (IVS13-36G > A) and EGFR L858R mutation. Meanwhile, she also had both METamplification and c-Met overexpression at the baseline. She showed partial response (PR) to gefitinib with 3.8 months PFS. Then she was enrolled in a clinical trial (NCT02374645) to receive volitinib plus gefitinib on December 20, 2016. Initial response was good PR on January 24, 2017. Only grade 1 rash was observed. Conclusions: Coexisting MET exon 14 /EGFR mutation is an uncommon molecular event in NSCLC patients. Such coexisted patients might show relative resistance to EGFR inhibitor. However, combination of MET and EGFR inhibitors will be potentially a good strategy to overcome such a relative resistance for MET exon 14 /EGFR co-mutant patients.
- Published
- 2017
45. Sensitivity to epidermal growth factor receptor tyrosine kinase inhibitors in males, smokers, and non-adenocarcinoma lung cancer in patients with EGFR mutations
- Author
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Zhu Zeng, Hua-Jun Chen, Yi-Long Wu, Xu-Chao Zhang, Jin-Ji Yang, and Hong-Hong Yan
- Subjects
0301 basic medicine ,Adult ,Male ,Cancer Research ,Lung Neoplasms ,Clinical Biochemistry ,medicine.disease_cause ,Pathology and Forensic Medicine ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,medicine ,Carcinoma ,Humans ,In patient ,Survival rate ,Protein Kinase Inhibitors ,Aged ,Retrospective Studies ,Aged, 80 and over ,Mutation ,business.industry ,Smoking ,Histology ,Middle Aged ,medicine.disease ,Prognosis ,respiratory tract diseases ,ErbB Receptors ,Survival Rate ,030104 developmental biology ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Adenocarcinoma ,Female ,business ,Tyrosine kinase ,Epidermal growth factor receptor tyrosine kinase - Abstract
Introduction The demographical/clinical characteristics of being Asian, having an adenocarcinoma, being female, and being a “never-smoker” are regarded as favorable predictors for epidermal growth factor receptor ( EGFR) tyrosine kinase inhibitor (TKI) efficacy in non-small cell lung cancer (NSCLC) with unknown EGFR gene status. In this study, we examined the effects of the supposedly unfavorable clinical variables in EGFR-mutant patients. Method In total, 159 EGFR-mutant NSCLC patients' clinical features were correlated with progression-free survival (PFS), response rate (RR), and overall survival (OS). Multivariate analysis of clinical characteristics was performed using the Cox and logistic regression methods. Result There were 90 females (56.6%), 112 never-smokers (70.4%), and 153 patients with adenocarcinomas (96.2%). All patients were treated with EGFR-TKI, and 52.8% received TKI in a first-line setting. The median PFS of patients receiving first-line TKI was similar, regardless of gender (males vs females: 9.1 vs 9.7 months, p=0.793), smoking status (never-smokers vs smokers: 9.9 vs 9.1 months, p=0.570), or histology (adenocarcinoma vs non-adenocarcinoma: 9.7 vs 9.2 months, p=0.644). OS curves of first-line TKI-treated patients were also not associated with gender (p=0.722), smoking status (p=0.579), or histology (p=0.480). Similar results of PFS and OS were obtained for patients who received TKI beyond first-line. Multivariate analysis indicated that none of these clinical factors was an independent predictor of survival. Conclusions The supposedly ‘favorable’ clinical factors of female gender, non-smoking status, and adenocarcinoma were not independent predictive factors for PFS or OS in this population of EGFR-mutant NSCLC patients.
- Published
- 2013
46. Response to tyrosine kinase inhibitors in advanced non-small-cell lung cancer with concomitant c-MET overexpression and EGFR mutation
- Author
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Bin-Chao Wang, Xu-Chao Zhang, Qing Zhou, Yi-Long Wu, Xiao-Yan Bai, Jin-Ji Yang, Na Na Lou, Jian Su, Zhen Wang, and Hua-Jun Chen
- Subjects
Cancer Research ,C-Met ,business.industry ,medicine.disease ,medicine.disease_cause ,respiratory tract diseases ,chemistry.chemical_compound ,Oncology ,chemistry ,Egfr mutation ,hemic and lymphatic diseases ,Concomitant ,Cancer research ,Medicine ,Non small cell ,KRAS ,business ,Lung cancer ,neoplasms ,Gene ,Tyrosine kinase - Abstract
9054Background: The common driver genes in non-small-cell lung cancer (NSCLC) include EGFR, ALK, KRAS and so on. MET amplification coexisting with EGFR mutation is recognized as intrinsic resistanc...
- Published
- 2016
47. Molecular mechanism of transformation from adenocarcinoma to small-cell lung cancer after EGFR-TKI
- Author
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Hua-Jun Chen, Jin-Ji Yang, Bin-Chao Wang, Jie-Fei Han, Fei-Yu Niu, Zhi Xie, Jian Su, Zhen Wang, Qiuyi Zhang, Yi-Long Wu, Hai-Yan Tu, Li-Xu Yan, and Qing Zhou
- Subjects
Cancer Research ,integumentary system ,biology ,business.industry ,Kinase ,medicine.disease ,respiratory tract diseases ,Transformation (genetics) ,Egfr tki ,Oncology ,Molecular mechanism ,Cancer research ,biology.protein ,Medicine ,Adenocarcinoma ,Non small cell ,Epidermal growth factor receptor ,business ,Lung cancer - Abstract
e20601Background: In patients with advanced non–small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) activating mutations, EGFR-tyrosine kinase inhibitors (TKIs) are oft...
- Published
- 2016
48. Relative abundance of EGFR mutations predicts benefit from gefitinib treatment for advanced non-small-cell lung cancer
- Author
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Wen-Zhao Zhong, Bin-Chao Wang, Xue-Ning Yang, Jin-Ji Yang, Zhen Wang, Yi-Sheng Huang, Xu-Chao Zhang, Jian Su, Hong-Hong Yan, She-Juan An, Yi-Long Wu, Zhi-Hong Chen, Hua-Jun Chen, Chong-Rui Xu, Qing Zhou, and Xiao-Lu Yin
- Subjects
Adult ,Male ,Cancer Research ,Lung Neoplasms ,Antineoplastic Agents ,Bioinformatics ,medicine.disease_cause ,DNA sequencing ,Disease-Free Survival ,Gefitinib ,Carcinoma, Non-Small-Cell Lung ,medicine ,Carcinoma ,Humans ,Epidermal growth factor receptor ,Lung cancer ,Relative species abundance ,Protein Kinase Inhibitors ,Aged ,Aged, 80 and over ,Mutation ,biology ,Kinase ,business.industry ,Middle Aged ,medicine.disease ,ErbB Receptors ,Oncology ,Cancer research ,biology.protein ,Quinazolines ,Female ,business ,medicine.drug - Abstract
Purpose Our aim was to determine whether abundance of epidermal growth factor receptor (EGFR) mutations in tumors predicts benefit from treatment with EGFR–tyrosine kinase inhibitors (TKIs) for advanced non–small-cell lung cancer (NSCLC). Patients and Methods We detected EGFR mutations in 100 lung cancer samples using direct DNA sequencing and amplification refractory mutation system (ARMS). Mutation-positive tumors by both methods carried high abundance of EGFR mutations. Tumors that were mutation positive by ARMS but mutation negative by direct DNA sequencing harbored low abundance of EGFR mutations. Mutation-negative tumors by both methods carried wild-type EGFR. All patients received gefitinib treatment. The correlation between EGFR mutation abundance and clinical benefit from gefitinib treatment was analyzed. Results Of 100 samples, 51 and 18 harbored high and low abundances of EGFR mutations, respectively; 31 carried wild-type EGFR. Median progression-free survival (PFS) was 11.3 (95% CI, 7.4 to 15.2) and 6.9 months (95% CI, 5.5 to 8.4) in patients with high and low abundances of EGFR mutations, respectively (P = .014). Median PFS of patients with low abundance of EGFR mutations was significantly longer than that of those with wild-type tumors (2.1 months; 95% CI, 1.0 to 3.2; P = .010). Objective response rates (ORRs) were 62.7%, 44.4%, and 16.1%, and overall survival (OS) rates were 15.9 (95% CI, 13.4 to 18.3), 10.9 (95% CI, 2.7 to 19.1), and 8.7 months (95% CI, 4.6 to 12.7) for patients with high abundance of EGFR mutations, low abundance of EGFR mutations, and wild-type EGFR, respectively. The difference between patients with high and low abundances of EGFR mutations was not significant regarding ORR and OS. Conclusion The relative EGFR mutation abundance could predict benefit from EGFR-TKI treatment for advanced NSCLC.
- Published
- 2011
49. In vitro sequence-dependent synergism between paclitaxel and gefitinib in human lung cancer cell lines
- Author
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Qiu-Xiong Lin, Hua Cheng, Zhi-Hong Chen, Ailin Guo, Xu-Chao Zhang, She-Juan An, Hua-Jun Chen, Yi-Long Wu, Song Dong, and Yi-Fang Zhang
- Subjects
Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,Paclitaxel ,medicine.drug_class ,Toxicology ,Tyrosine-kinase inhibitor ,Drug Administration Schedule ,chemistry.chemical_compound ,Gefitinib ,Internal medicine ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Humans ,Pharmacology (medical) ,Epidermal growth factor receptor ,Phosphorylation ,Lung cancer ,neoplasms ,Pharmacology ,biology ,business.industry ,Cell growth ,Cell Cycle ,Cancer ,Drug Synergism ,Cell cycle ,medicine.disease ,respiratory tract diseases ,ErbB Receptors ,Endocrinology ,Oncology ,chemistry ,Cancer research ,biology.protein ,Quinazolines ,business ,medicine.drug ,Signal Transduction - Abstract
In clinical trials, the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) administered concomitantly with first-line cytotoxicity chemotherapy failed to confer a survival benefit to patients with non-small-cell lung cancer (NSCLC). The aim of this study was to test whether paclitaxel followed by gefitinib is superior to other treatment schedules of NSCLC cell lines and to clarify the underlying mechanisms. Human lung cancer cell lines with wild-type and mutant-type EGFR genes were used as in vitro models to define the differential effects of various schedules of paclitaxel with gefitinib treatment on cell growth, signaling pathway, and cell cycle distribution. Sequence-dependent antiproliferative effects differed between EGFR-TKI-resistant and EGFR-TKI-sensitive lung cancer cell lines. Exposure to paclitaxel resulted in an increased pEGFR level. This increase in phosphorylation was inhibited by subsequent exposure to gefitinib, whereas during the reverse sequence, the inhibition effect was reduced. After paclitaxel exposure, a higher level of pEGFR was observed in mitotic than in interphase cells. The sequence of paclitaxel followed by gefitinib resulted in greater anti-VEGF activity than did the reverse sequence. We confirmed that gefitinib arrested cells in G1, and paclitaxel arrested them in S phase. The sequence of paclitaxel followed by gefitinib arrested cells in G1, whereas the reverse sequence arrested cells in S and G2 phases. These findings suggest that the sequence of paclitaxel followed by gefitinib may be superior to other sequences in treating NSCLC cell lines. Our results also provide molecular evidence to support clinical treatment strategies for patients with lung cancer.
- Published
- 2010
50. The -271 G>A polymorphism of kinase insert domain-containing receptor gene regulates its transcription level in patients with non-small cell lung cancer
- Author
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Zhi-Hong Chen, Jiaying Lin, She-Juan An, Jian Su, Yi-Long Wu, Hua-Jun Chen, and Qiu-Xiong Lin
- Subjects
Adult ,Male ,Cancer Research ,Lung Neoplasms ,Genotype ,Transcription, Genetic ,Biology ,lcsh:RC254-282 ,Young Adult ,Asian People ,Carcinoma, Non-Small-Cell Lung ,parasitic diseases ,Gene duplication ,Gene expression ,Genetics ,medicine ,Humans ,Point Mutation ,Lung cancer ,neoplasms ,Gene ,Aged ,Aged, 80 and over ,Polymorphism, Genetic ,Kinase insert domain receptor ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Vascular Endothelial Growth Factor Receptor-2 ,Molecular biology ,Real-time polymerase chain reaction ,Oncology ,Case-Control Studies ,cardiovascular system ,Cancer research ,Female ,Gene polymorphism ,Research Article - Abstract
BackgroundKinase insert domain-containing receptor (KDR) plays a critical role in the metastasis of cancer and is used as a molecular target in cancer therapy. We investigated the characteristics of the -271 G>A polymorphism of the KDR gene to gain information that may benefit the development of individualized therapies for patients with non-small cell lung cancer (NSCLC).MethodsThe -271 G>A polymorphism of the KDR gene in 106 lung cancer patients and 203 healthy control individuals was analyzed by polymerase chain reaction (PCR) and DNA sequencing methods. Real-time quantitative PCR and immunohistochemical methods were used to evaluate KDR mRNA and protein expression levels, respectively, in frozen tumor specimens.ResultsThe -271 G>A polymorphism was associated with the mRNA expression level of the KDR gene in tumor tissues (t = 2.178, P = 0.032, independent samplest-test). Compared with the AG/GG genotype, the AA genotype was associated with higher KDR mRNA expression in tumor tissues. We found no relationship between the genotype and the KDR protein expression level and no significant difference in the distribution of the KDR gene polymorphism genotypes between lung cancer patients and the control group (χ2= 1.269, P = 0.264, Fisher's exact test).ConclusionThis study is the first to show that the -271 G>A polymorphism of the KDR gene may be a functional polymorphism related to the regulation of gene transcription. These findings may have important implications for therapies targeting KDR in patients with NSCLC.
- Published
- 2009
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