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Deng A, Mao Z, Jin X, Lv W, Huang L, Zhong H, Wang S, Shi Y, Zhou T, Zhao J, Huang Q, Luo X, Ma L, Zou H, Fu R, Huang G. ID-CRISPR: A CRISPR/Cas12a platform for label-free and sensitive detection of rare mutant alleles using self-interference DNA hydrogel reporter. Biosens Bioelectron 2025; 278:117309. [PMID: 40020637 DOI: 10.1016/j.bios.2025.117309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Revised: 02/16/2025] [Accepted: 02/23/2025] [Indexed: 03/03/2025]
Abstract
Accurate and sensitive detection of single nucleotide variants (SNVs) is paramount for cancer diagnosis and treatment. The CRISPR/Cas12a system shows promise for SNV detection due to its high sensitivity and single-base specificity. However, most CRISPR/Cas12a-based methods rely on F/Q-labeled single-stranded DNA (ssDNA) reporters, which are susceptible to fluorescence fluctuations, thereby reducing accuracy. To address these limitations, researchers have proposed using DNA hydrogels as signal transducers in CRISPR/Cas12a systems. Yet, the encapsulation of indicators into DNA hydrogels introduces additional instability, which could compromise both detection sensitivity and linearity. In this study, we integrated hyperspectral interferometry into a DNA hydrogel-based CRISPR/Cas12a detection platform (ID-CRISPR) to achieve sensitive label-free SNV detection. Using EGFR L858R SNV as a model target, we demonstrated that ID-CRISPR can detect mutant allele frequencies (MAFs) as low as 0.1% with a limit of detection (LOD) of 5 aM, while also showing its potential for quantifying SNV abundance. Its clinical utility was confirmed through analysis of lung tumor samples, with results consistent with sequencing data. Therefore, ID-CRISPR provides a sensitive, label-free, and user-friendly platform for SNV detection, offering new insights into combining optical sensing with DNA hydrogel technology in CRISPR/Cas assays.
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Affiliation(s)
- Anni Deng
- School of Biomedical Engineering, Tsinghua University, Beijing, 100084, China
| | - Zeyin Mao
- School of Biomedical Engineering, Tsinghua University, Beijing, 100084, China
| | - Xiangyu Jin
- School of Biomedical Engineering, Tsinghua University, Beijing, 100084, China
| | - Wenqi Lv
- School of Biomedical Engineering, Tsinghua University, Beijing, 100084, China
| | - Leyang Huang
- School of Biomedical Engineering, Tsinghua University, Beijing, 100084, China
| | - Hao Zhong
- School of Biomedical Engineering, Tsinghua University, Beijing, 100084, China
| | - Shihong Wang
- School of Biomedical Engineering, Tsinghua University, Beijing, 100084, China
| | - Yixuan Shi
- School of Biomedical Engineering, Tsinghua University, Beijing, 100084, China
| | - Tianqi Zhou
- School of Medical Technology, Beijing Institute of Technology, Beijing, 100081, China
| | - Jianxin Zhao
- School of Biomedical Engineering, Tsinghua University, Beijing, 100084, China
| | - Qin Huang
- School of Biomedical Engineering, Tsinghua University, Beijing, 100084, China
| | - Xianbo Luo
- National Engineering Research Center for Beijing Biochip Technology, Beijing, 102206, China
| | - Li Ma
- National Engineering Research Center for Beijing Biochip Technology, Beijing, 102206, China
| | - Heng Zou
- Department of Respiratory Medicine, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China.
| | - Rongxin Fu
- School of Medical Technology, Beijing Institute of Technology, Beijing, 100081, China; Engineering Research Center of Integrated Acousto-opto-electronic Microsystems (Ministry of Education of China), Beijing Institute of Technology, Beijing, 100081, China.
| | - Guoliang Huang
- School of Biomedical Engineering, Tsinghua University, Beijing, 100084, China; National Engineering Research Center for Beijing Biochip Technology, Beijing, 102206, China
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Turner WM, Tuminello S, Untalan M, Flores R, Taioli E. Incongruence Between Prerequisite Molecular Testing and Treatment with Personalized Therapies for Non-Small Cell Lung Cancer: A Surveillance, Epidemiology and End Results-Medicare Study. Int J Mol Sci 2025; 26:4581. [PMID: 40429725 PMCID: PMC12111554 DOI: 10.3390/ijms26104581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2025] [Revised: 05/02/2025] [Accepted: 05/08/2025] [Indexed: 05/29/2025] Open
Abstract
Personalized medicine, including targeted and immunotherapy, has substantially changed the landscape of non-small cell lung cancer (NSCLC). About 30% of NSCLC tumors have targetable mutations, like EGFR, and 28% of tumors will have a PD-L1 score or tumor mutation burden high enough to warrant immunotherapy; a molecular test prior to therapy assesses eligibility. However, the congruence between testing and treatment, and the effect of treatment without testing on outcomes, is understudied. We extracted a cohort of NSCLC patients from the Surveillance, Epidemiology and End Results (SEER)-Medicare-linked data. The primary outcome was survival. Demographic and clinical characteristics of those receiving vs. not receiving a molecular test were compared, and a Kaplan-Meier curve along with a multivariable Cox proportional hazards regression assessed the association of survival with the receipt of molecular diagnostic testing, adjusting for sex, race, age, income tract, metro/urban/rural region, histology, and stage. There were 911 NSCLC patients treated with personalized therapy, of which 513 (56.3%) had received prior molecular testing. Black patients were less likely than White patients to receive testing (36.4% vs. 59.9%; p < 0.001). Testing was significantly more frequent in patients with fewer comorbidities (p < 0.001), adenocarcinoma (p = 0.004), tumors in the lower lobe (p = 0.037), or diagnosed at a later stage (p = 0.026). Only 39.9% of patients receiving EGFR inhibitors were initially tested for an EGFR mutation. Among NSCLC patients treated with personalized therapy, untested patients were at increased mortality risk compared to tested patients (median survival 8.22 vs. 12.79 months, p = 0.024). After adjustment, treated patients not tested beforehand had a significantly higher mortality risk (HRadj: 1.20; 95% CI: 1.04-1.40). Substantial incongruence between receipt of molecular testing and personalized therapies exists according to nationwide claims data, with only about half of treated patients having had an appropriate molecular diagnostic workup. This could explain, in part, the higher mortality among treated patients who did not undergo testing. Before expanding personalized therapies, further addressing these issues through standardized, reflexive testing protocols and improved clinician education is critical to optimizing the integration of molecular diagnostics into treatment planning.
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Affiliation(s)
- Wiley M. Turner
- Institute for Translational Epidemiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (W.M.T.); (S.T.); (M.U.)
| | - Stephanie Tuminello
- Institute for Translational Epidemiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (W.M.T.); (S.T.); (M.U.)
- Department of Thoracic Surgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
| | - Matthew Untalan
- Institute for Translational Epidemiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (W.M.T.); (S.T.); (M.U.)
| | - Raja Flores
- Department of Thoracic Surgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
| | - Emanuela Taioli
- Institute for Translational Epidemiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (W.M.T.); (S.T.); (M.U.)
- Department of Thoracic Surgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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Othus M, Patel SP, Chae YK, Dietrich E, Streicher H, Sharon E, Kurzrock R. First cycle toxicity and survival in patients with rare cancers treated with checkpoint inhibitors. J Natl Cancer Inst 2025; 117:692-700. [PMID: 39565908 PMCID: PMC11972677 DOI: 10.1093/jnci/djae297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Revised: 10/23/2024] [Accepted: 11/11/2024] [Indexed: 11/22/2024] Open
Abstract
BACKGROUND Associations between immune-related adverse events from checkpoint inhibitor therapy and outcomes have been previously evaluated, with most prior research finding a positive association between toxicity and survival. This prior research has generally reported on more common tumor types. We use a unique data resource of a federally funded basket trial (NCT02834013) for patients with rare cancers (n = 684) to evaluate associations between immune-related adverse events and overall survival and progression-free survival (PFS). METHODS Patients were treated with nivolumab and ipilimumab; the trial was opened at more than 1000 sites. Landmark Cox regression models were used to assess first cycle immune-related adverse event associations with PFS and overall survival. RESULTS We found that grade 1-2 treatment-related immune-related adverse events in the first cycle of therapy were associated with longer overall survival (multivariable hazard ratio [HR] = 0.61, 95% confidence interval [CI] = 0.49 to 0.75; P < .001) compared with no treatment-related immune-related adverse event, while grade 3-4 immune-related adverse events were associated with shorter overall survival (HR = 1.41, 95% CI = 1.04 to 1.90; P = .025). Similar but weaker associations were observed with PFS and grade 1-2 treatment-related immune-related adverse events (HR = 0.83, 95% CI = 0.67 to 1.01; P = .067) and grade 3-4 (HR = 1.35, 95% CI = 1.02 to 1.78; P = .037) compared with no treatment-related immune-related adverse events. Grade 1-2 dermatologic toxicity was associated with improved overall survival compared with other grade 1-2 toxicities (HR = 0.67, 95% CI = 0.52 to 0.85; P = .002). There was no statistically significant overall survival difference between patients with grade 1-2 fatigue, gastrointestinal, metabolic, hepatic, endocrine, and thyroid toxicities vs other grade 1-2 toxicities. CONCLUSION In this large cohort of patients with rare tumors receiving checkpoint inhibitor therapy, grade of immune-related adverse event in the first cycle was predictive for survival.
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Affiliation(s)
- Megan Othus
- SWOG Cancer Research Network Statistical Center, Seattle, WA 98109, United States
- Biostatistics Program, Public Health Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, United States
| | - Sandip P Patel
- Division of Hematology-Oncology, University of California at San Diego Moores Cancer Center, La Jolla, CA 92037, United States
| | - Young Kwang Chae
- Department of Hematology and Oncology, Northwestern University, Chicago, IL 60611, United States
| | - Eliana Dietrich
- Biostatistics Program, Public Health Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, United States
| | - Howard Streicher
- Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States
| | - Elad Sharon
- Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States
- Department of Medicine, Dana-Farber/Harvard Cancer Center, Boston, MA 02215, United States
| | - Razelle Kurzrock
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, United States
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Yu J, Sun W, Zhao X, Chen Y. The therapeutic potential of RNA m(6)A in lung cancer. Cell Commun Signal 2024; 22:617. [PMID: 39736743 DOI: 10.1186/s12964-024-01980-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Accepted: 12/04/2024] [Indexed: 01/01/2025] Open
Abstract
Lung cancer (LC) is a highly malignant and metastatic form of cancer. The global incidence of and mortality from LC is steadily increasing; the mean 5-year overall survival (OS) rate for LC is less than 20%. This frustrating situation may be attributed to the fact that the pathogenesis of LC remains poorly understood and there is still no cure for mid to advanced LC. Methylation at the N6-position of adenosine (N6mA) of RNA (m(6)A) is widely present in human tissues and organs, and has been found to be necessary for cell development and maintenance of homeostasis. However, numerous basic and clinical studies have demonstrated that RNA m(6)A is deregulated in many human malignancies including LC. This can drive LC malignant characteristics such as proliferation, stemness, invasion, epithelial-mesenchymal transition (EMT), metastasis, and therapeutic resistance. Intriguingly, an increasing number of studies have also shown that eliminating RNA m(6)A dysfunction can exert significant anti-cancer effects on LC such as suppression of cell proliferation and viability, induction of cell death, and reversal of treatment insensitivity. The current review comprehensively discusses the therapeutic potential of RNA m(6)A and its underlying molecular mechanisms in LC, providing useful information for the development of novel LC treatment strategies.
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Affiliation(s)
- Jingran Yu
- Department of Pulmonary and Critical Care Medicine, Shengjing Hospital of China Medical University, No. 39 Huaxiang Road, Shenyang , Liaoning, 110022, China
| | - Wei Sun
- Department of Radiology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Shenyang, 110004, China
| | - Xiangxuan Zhao
- Center for Innovative Engineering Technology in Traditional Chinese Medicine, Liaoning University of Traditional Chinese Medicine, No.79 Chongshandong Road, Shenyang, 110847, China.
- Health Sciences Institute, China Medical University, Puhe Road, Shenyang North New Area, Shenyang, 110022, China.
| | - Yingying Chen
- Department of Pulmonary and Critical Care Medicine, Shengjing Hospital of China Medical University, No. 39 Huaxiang Road, Shenyang , Liaoning, 110022, China.
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Helal AA, Kamal IH, Osman A, Youssef M, Ibrahim AK. The prevalence and clinical significance of EGFR mutations in non-small cell lung cancer patients in Egypt: a screening study. J Egypt Natl Canc Inst 2024; 36:39. [PMID: 39710832 DOI: 10.1186/s43046-024-00251-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 11/16/2024] [Indexed: 12/24/2024] Open
Abstract
BACKGROUND Lung cancer is a form of cancer that is responsible for the largest incidence of deaths attributed to cancer worldwide. Non-small cell lung cancer (NSCLC) is the most prevalent of all the subtypes of the disease. Treatment with tyrosine kinase inhibitors (TKI) may help some people who have been diagnosed with non-small cell lung cancer. The presence of actionable mutations in the epidermal growth factor receptor (EGFR) gene is a key predictor of how a patient will respond to a TKI. Thus, the frequency of identification of mutations in EGFR gene in patients with NSCLC can facilitate personalized treatment. OBJECTIVE The objective of this study was to screen for mutations in the EGFR gene and to investigate whether there is a correlation between the screened mutations and various clinical and pathological factors, such as gender, smoking history, and age, in tissue samples from patients with NSCLC. METHODS The study comprised 333 NSCLC tissue samples from 230 males and 103 females with an average age of 50 years. Exons 18-21 of the EGFR gene have been examined using real-time PCR. Using SPSS, correlations between clinical and demographic variables were examined, and EGFR mutation and clinical features associations were studied. RESULTS The study's findings revealed that the incidence rate of EGFR mutation was 24.32% (81/333), with partial deletion of exon 19 (19-Del) and a point mutation of L858R in exon 21 accounting for 66.67% (P < 0.001) and 28.40% (P < 0.001) of the mutant cases, respectively. Patients who had the T790M mutation represent 4.94% (P = 0.004) of total number of patients. Females harbored EGFR mutations (54.32%) with higher frequency than men (45.68%) (P < 0.001), while nonsmokers had EGFR mutations (70.37%) more frequently than current smokers (29.63%) (P < 0.001). CONCLUSION The screening study conducted in Egypt reported that the EGFR mutations prevalence was 24.32% among Egyptians with NSCLC. The study also found a slight gender bias, with females having an incidence rate of these mutations higher than males. Additionally, nonsmokers had higher rates of mutations in EGFR gene compared to smokers. According to the findings, somatic EGFR mutations can be employed as a diagnostic tool for non-small cell lung cancer in Egypt, and they can be implemented in conjunction with clinical criteria to identify which patients are more likely to respond favorably to TKIs.
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Affiliation(s)
- Asmaa A Helal
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, 11566, Egypt.
| | - Ibrahim H Kamal
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, 11566, Egypt
| | - Ahmed Osman
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, 11566, Egypt
- Biotechnology Program, Institute of Basic and Applied Sciences, Egypt-Japan University of Science and Technology, Alexandria, 21934, Egypt
| | | | - Adel K Ibrahim
- Department of Clinical Pathology, Faculty of Veterinary Medicine, Cairo University, Giza, 12211, Egypt
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Yu Y, Fan Y, Dong X, Li J, Yu Y, Zhao J, Tao S, Chen Y, Chen M, Liu Y, Xu J, Zhu Q, Hu X, Lu S. Entrectinib versus crizotinib in Asian patients with ROS1-positive non-small cell lung cancer: A matching-adjusted indirect comparison. Lung Cancer 2024; 198:108018. [PMID: 39549678 DOI: 10.1016/j.lungcan.2024.108018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 11/05/2024] [Indexed: 11/18/2024]
Abstract
OBJECTIVES Entrectinib and crizotinib are the only ROS proto-oncogene 1 receptor (ROS1) tyrosine kinase inhibitors available for most Asian patients. Their efficacy has neither been compared directly in clinical trials in patients with ROS1-positive non-small cell lung cancer (NSCLC), nor indirectly in Asian populations. Thus, we aimed to provide comparative evidence of the efficacy and safety of entrectinib and crizotinib for Asian patients with advanced or metastatic ROS1-positive NSCLC. MATERIALS AND METHODS Efficacy, including overall survival (OS) and progression-free survival (PFS), and safety were evaluated using an unanchored matching-adjusted indirect comparison (MAIC). Individual patient data (IPD) from entrectinib trials (ALKA-372-001/EudraCT 2012-000148-88, STARTRK-1/NCT02097810, and STARTRK-2/NCT02568267; dosage, ≥600 mg once daily; enrollment cutoff, 02 July 2020; data cutoff, 02 August 2021) and aggregate data with simulated pseudo-IPD from a crizotinib trial (OxOnc/NCT01945021; dosage, 250 mg twice daily) were analyzed. Key eligibility criteria from the crizotinib trial were applied to IPD from the entrectinib trials. Baseline characteristics were match-adjusted between arms using propensity score weighting. RESULTS Fifty-two and 127 patients from the entrectinib and crizotinib trials, respectively, were available for evaluation. Median OS was not reached (NR; weighted; 95 % confidence interval [CI] 28.3-NR) in the entrectinib arm and 44.2 months (95 % CI 32.0-NR) in the crizotinib arm (hazard ratio [HR], 0.662; 95 % CI 0.32-1.37). The respective median PFS was 39.4 months (weighted; 95 % CI 10.4-46.8) and 15.9 months (95 % CI 12.9-24.0) (HR, 0.688; 95 % CI 0.37-1.27). Most AEs were Grade 1-2; both drugs were generally well tolerated. Neutropenia was the most common Grade 3 or 4 treatment-related adverse event for both entrectinib and crizotinib. CONCLUSIONS The outcomes in this MAIC study including Asian patients with ROS1-positive NSCLC showed a trend for greater clinical benefit with entrectinib versus crizotinib. These findings may contribute to better-informed treatment decisions.
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Affiliation(s)
- Yongfeng Yu
- Department of Medical Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, No. 241, Huaihai West Road, Shanghai 200030, China
| | - Yun Fan
- Department of Medical Thoracic Oncology, Zhejiang Cancer Hospital, Hangzhou, China
| | - Xiaorong Dong
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Juan Li
- Department of Medical Oncology, Sichuan Cancer Hospital, Chengdu, China
| | - Yan Yu
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Jun Zhao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department I of Thoracic Oncology, Peking University Cancer Hospital and Institute, Beijing, China
| | - Sha Tao
- Medical Affairs, Shanghai Roche Pharmaceutical Ltd., Shanghai, China
| | - Yujun Chen
- Medical Affairs, Shanghai Roche Pharmaceutical Ltd., Shanghai, China
| | - Mo Chen
- Medical Affairs, Shanghai Roche Pharmaceutical Ltd., Shanghai, China
| | - Yueming Liu
- Medical Affairs, Shanghai Roche Pharmaceutical Ltd., Shanghai, China
| | - Jiahui Xu
- Medical Affairs, Shanghai Roche Pharmaceutical Ltd., Shanghai, China
| | - Qiaonan Zhu
- Medical Affairs, Shanghai Roche Pharmaceutical Ltd., Shanghai, China
| | - Xichun Hu
- Department of Medical Oncology, Shanghai Cancer Center, Fudan University, Shanghai, China
| | - Shun Lu
- Department of Medical Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, No. 241, Huaihai West Road, Shanghai 200030, China.
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Shalata W, Abu Jama A, Dudnik Y, Abu Saleh O, Shalata S, Tourkey L, Sheva K, Meirovitz A, Yakobson A. Adverse Events in Osimertinib Treatment for EGFR-Mutated Non-Small-Cell Lung Cancer: Unveiling Rare Life-Threatening Myelosuppression. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:1270. [PMID: 39202551 PMCID: PMC11356521 DOI: 10.3390/medicina60081270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 08/01/2024] [Accepted: 08/05/2024] [Indexed: 09/03/2024]
Abstract
Recent advancements in targeted therapies for non-small-cell lung cancer (NSCLC), specifically focusing on epidermal growth factor receptor (EGFR) mutations, have revolutionized treatment strategies. Osimertinib, an approved therapy for metastatic NSCLC with EGFR mutations, highlights remarkable efficacy but also harbors the potential for severe adverse events, whose rarity or lack of precedence may mask their criticality. This article delves into the exploration of adverse events linked to osimertinib, shedding light on a rare yet life-threatening occurrence: severe myelosuppression. A case study detailing a patient with EGFR-mutated NSCLC exhibiting a robust treatment response but experiencing severe myelosuppression following osimertinib initiation is presented. Immediate discontinuation of osimertinib alongside concurrent blood transfusions facilitated toxicity recovery, prompting a successful reduction in myelosuppression severity upon re-administration at a lowered dosage.
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Affiliation(s)
- Walid Shalata
- The Legacy Heritage Cancer Center and Dr. Larry Norton Institute, Soroka Medical Center, Beer Sheva 84105, Israel
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel
| | - Ashraf Abu Jama
- The Legacy Heritage Cancer Center and Dr. Larry Norton Institute, Soroka Medical Center, Beer Sheva 84105, Israel
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel
| | - Yulia Dudnik
- The Legacy Heritage Cancer Center and Dr. Larry Norton Institute, Soroka Medical Center, Beer Sheva 84105, Israel
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel
| | - Omar Abu Saleh
- Department of Dermatology and Venereology, Emek Medical Centre, Afula 18341, Israel
| | - Sondos Shalata
- Nutrition Unit, Galilee Medical Center, Nahariya 22000, Israel
| | - Lena Tourkey
- The Legacy Heritage Cancer Center and Dr. Larry Norton Institute, Soroka Medical Center, Beer Sheva 84105, Israel
| | - Kim Sheva
- The Legacy Heritage Cancer Center and Dr. Larry Norton Institute, Soroka Medical Center, Beer Sheva 84105, Israel
| | - Amichay Meirovitz
- The Legacy Heritage Cancer Center and Dr. Larry Norton Institute, Soroka Medical Center, Beer Sheva 84105, Israel
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel
| | - Alexander Yakobson
- The Legacy Heritage Cancer Center and Dr. Larry Norton Institute, Soroka Medical Center, Beer Sheva 84105, Israel
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel
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Valcárcel S, Villanueva N, Álvarez C, Esteban E. EGFR exon 18 delE709_T710insD mutated stage IV non-small cell lung cancer treated with osimertinib: a case report. Anticancer Drugs 2024; 35:638-640. [PMID: 38513159 DOI: 10.1097/cad.0000000000001605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/23/2024]
Abstract
Mutations in tyrosine kinase domain of epidermal growth factor receptor (EGFR) are observed in approximately 15% of non-small cell lung cancer adenocarcinoma. Exon 19 deletions or exon 21 L858R mutations are predominant in frequency and show high sensitivity to EGFR tyrosine kinase inhibitors (TKIs). Exon 18 mutations are extremely rare and the delE709_T710insD mutation accounts for only 0.16% of mutations when occurring as a sole mutation. This specific mutation in exon 18 seems to respond to certain EGFR TKIs such as afatinib. However, given the rarity of this mutation, determining the most effective TKI for its treatment remains unclear. We report a 70-year-old woman diagnosed with stage IV-A lung adenocarcinoma harboring EGFR delE709_T710insD mutation treated in first-line with Osimertinib using standard schedule and doses experiencing renal toxicity and disease progression after 9 weeks of treatment.
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Affiliation(s)
- Sena Valcárcel
- Medical Oncology Department, Hospital Universitario Central de Asturias, ISPA, Oviedo, Spain
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Aye PS, Barnes J, Laking G, Cameron L, Anderson M, Luey B, Delany S, Harris D, McLaren B, Brenman E, Wong J, Lawrenson R, Arendse M, Tin Tin S, Elwood M, Hope P, McKeage MJ. Erlotinib or Gefitinib for Treating Advanced Epidermal Growth Factor Receptor Mutation-Positive Lung Cancer in Aotearoa New Zealand: Protocol for a National Whole-of-Patient-Population Retrospective Cohort Study and Results of a Validation Substudy. JMIR Res Protoc 2024; 13:e51381. [PMID: 38954434 PMCID: PMC11252616 DOI: 10.2196/51381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 02/29/2024] [Accepted: 03/04/2024] [Indexed: 07/04/2024] Open
Abstract
BACKGROUND Starting in 2010, the epidermal growth factor receptor (EGFR) kinase inhibitors erlotinib and gefitinib were introduced into routine use in Aotearoa New Zealand (NZ) for treating advanced lung cancer, but their impact in this setting is unknown. OBJECTIVE The study described in this protocol aims to understand the effectiveness and safety of these new personalized lung cancer treatments and the contributions made by concomitant medicines and other factors to adverse outcomes in the general NZ patient population. A substudy aimed to validate national electronic health databases as the data source and the methods for determining patient eligibility and identifying outcomes and variables. METHODS This study will include all NZ patients with advanced EGFR mutation-positive lung cancer who were first dispensed erlotinib or gefitinib before October 1, 2020, and followed until death or for at least 1 year. Routinely collected health administrative and clinical data will be collated from national electronic cancer registration, hospital discharge, mortality registration, and pharmaceutical dispensing databases by deterministic data linkage using National Health Index numbers. The primary effectiveness and safety outcomes will be time to treatment discontinuation and serious adverse events, respectively. The primary variable will be high-risk concomitant medicines use with erlotinib or gefitinib. For the validation substudy (n=100), data from clinical records were compared to those from national electronic health databases and analyzed by agreement analysis for categorical data and by paired 2-tailed t tests for numerical data. RESULTS In the validation substudy, national electronic health databases and clinical records agreed in determining patient eligibility and for identifying serious adverse events, high-risk concomitant medicines use, and other categorical data with overall agreement and κ statistic of >90% and >0.8000, respectively; for example, for the determination of patient eligibility, the comparison of proxy and standard eligibility criteria applied to national electronic health databases and clinical records, respectively, showed overall agreement and κ statistic of 96% and 0.8936, respectively. Dates for estimating time to treatment discontinuation and other numerical variables and outcomes showed small differences, mostly with nonsignificant P values and 95% CIs overlapping with zero difference; for example, for the dates of the first dispensing of erlotinib or gefitinib, national electronic health databases and clinical records differed on average by approximately 4 days with a nonsignificant P value of .33 and 95% CIs overlapping with zero difference. As of May 2024, the main study is ongoing. CONCLUSIONS A protocol is presented for a national whole-of-patient-population retrospective cohort study designed to describe the safety and effectiveness of erlotinib and gefitinib during their first decade of routine use in NZ for treating EGFR mutation-positive lung cancer. The validation substudy demonstrated the feasibility and validity of using national electronic health databases and the methods for determining patient eligibility and identifying the study outcomes and variables proposed in the study protocol. TRIAL REGISTRATION Australian New Zealand Clinical Trials Registry ACTRN12615000998549; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368928. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID) DERR1-10.2196/51381.
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Affiliation(s)
- Phyu Sin Aye
- Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand
| | - Joanne Barnes
- School of Pharmacy, University of Auckland, Auckland, New Zealand
| | - George Laking
- Te Aka Mātauranga Matepukupuku Centre for Cancer Research, University of Auckland, Auckland, New Zealand
| | - Laird Cameron
- Department of Medical Oncology, Te Pūriri o Te Ora Regional Cancer and Blood Service, Te Whatu Ora Health New Zealand, Auckland City Hospital, Auckland, New Zealand
| | - Malcolm Anderson
- Department of Medical Oncology, Te Whatu Ora Health New Zealand Te Pae Hauuora o Ruahine o Tararua, Palmerston North Hospital, Palmerston North, New Zealand
| | - Brendan Luey
- Wellington Blood and Cancer Centre, Te Whatu Ora Health New Zealand Capital, Coast and Hutt Valley, Wellington Hospital, Wellington, New Zealand
| | - Stephen Delany
- Department of Oncology, Te Whatu Ora Health New Zealand Nelson Marlborough, Nelson Hospital, Nelson, New Zealand
| | - Dean Harris
- Oncology Service, Te Whatu Ora - Waitaha Canterbury, Christchurch Hospital, Christchurch, New Zealand
| | - Blair McLaren
- Southern Blood and Cancer Service, Te Whatu Ora Southern, Dunedin Hospital, Dunedin, New Zealand
| | - Elliott Brenman
- Cancer and Haematology Services, Te Whatu Ora Health New Zealand Haora a Toi Bay of Plenty, Tauranga Hospital, Tauranga, New Zealand
| | - Jayden Wong
- Cancer Services, Te Whatu Ora Health New Zealand Waikato, Waikato Hospital, Hamilton, New Zealand
| | - Ross Lawrenson
- Medical Research Centre, University of Waikato, Hamilton, New Zealand
| | - Michael Arendse
- Department of Pathology, Te Whatu Ora Health New Zealand Waikato, Waikato Hospital, Hamilton, New Zealand
| | - Sandar Tin Tin
- Department of Epidemiology and Biostatistics, University of Auckland, Auckland, New Zealand
| | - Mark Elwood
- Department of Epidemiology and Biostatistics, University of Auckland, Auckland, New Zealand
| | - Philip Hope
- Lung Foundation New Zealand, Manukau, Auckland, New Zealand
| | - Mark James McKeage
- Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand
- Department of Medical Oncology, Te Pūriri o Te Ora Regional Cancer and Blood Service, Te Whatu Ora Health New Zealand, Auckland City Hospital, Auckland, New Zealand
- Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand
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10
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Xu Y, Zhao P, Xu X, Zhang S, Xia B, Zhu L. T790M mutation sensitizes non-small cell lung cancer cells to radiation via suppressing SPOCK1. Biochem Biophys Rep 2024; 38:101729. [PMID: 38766382 PMCID: PMC11098717 DOI: 10.1016/j.bbrep.2024.101729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Accepted: 05/01/2024] [Indexed: 05/22/2024] Open
Abstract
Background Approximately 50% of patients harbor the T790M mutation after developing first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance. Evidence has showed the major treatment failure is local relapses and limited metastases. Several studies have demonstrated the value of radiotherapy in metastatic non-small cell lung cancer (NSCLC) with the EGFR T790M mutation after the development of TKI resistance. The aim of this study was to explore the role of radiation in T790M-mutant NSCLC and the value of early radiotherapy for NSCLC with T790M-mediated EGFR-TKI resistance. Methods Gefitinib-resistant NSCLC cell lines were established via stepwise exposure to increasing concentrations of gefitinib (PC-9-GR). Droplet digital PCR was used to determine the relative T790M subclone abundance. In vitro and in vivo models were established using different mixtures of PC-9-GR and PC-9 cells. Differentially expressed genes were identified using RNA sequencing. Two research models were constructed (salvage and prophylactic radiotherapy) to determine the effects of early radiotherapy on gefitinib-resistant cells. Results PC-9-GR cells exhibited higher radiosensitivity than PC-9 cells (sensitivity enhancement ratio = 1.5). Salvage radiation reduced the number of T790M-mutant subclones, and the relative T790M abundance was significantly lower than that without radiation at 90 days (10.94% vs. 21.54%). Prophylactic radiation prevented the development of T790M subclones. These results were also confirmed in vivo. qRT-PCR revealed threefold elevation of miR-1243 in PC-9-GR cells, and the increased radiosensitivity of PC-9-GR cells was inhibited when miR-1243 was knocked down. RNA sequencing revealed that SPOCK1 was downregulated in PC-9-GR cells. Interestingly, bioinformatic analysis showed that SPOCK1 was a target gene of miR-1243. SPOCK1 knockdown markedly increased the radiosensitivity of PC-9 cells. Conclusion Gefitinib-resistant NSCLC with the T790M mutation had higher radiosensitivity than that without the mutation, possibly mediated by SPOCK1. Early radiotherapy can eliminate T790M subclones, providing evidence for the benefit of early local treatment in patients with TKI-resistant NSCLC.
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Affiliation(s)
- Yasi Xu
- Department of Translational Medicine Research Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, 310006, PR China
| | - Pengjun Zhao
- Department of Radiotherapy, Hangzhou Cancer Hospital, Hangzhou, 310002, PR China
| | - Xiao Xu
- Department of Thoracic Oncology, Hangzhou Cancer Hospital, Hangzhou, 310002, PR China
| | - Shirong Zhang
- Department of Translational Medicine Research Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, 310006, PR China
| | - Bing Xia
- Department of Thoracic Oncology, Hangzhou Cancer Hospital, Hangzhou, 310002, PR China
- Department of Oncology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou Cancer Hospital, Zhejiang Chinese Medical University, Hangzhou, 310002, PR China
| | - Lucheng Zhu
- Department of Thoracic Oncology, Hangzhou Cancer Hospital, Hangzhou, 310002, PR China
- Department of Oncology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou Cancer Hospital, Zhejiang Chinese Medical University, Hangzhou, 310002, PR China
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11
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Matsuda R, Hasegawa M, Tamamoto T, Inooka N, Morimoto T, Maeoka R, Nakazawa T, Ochi T, Miyasaka T, Hontsu S, Yamaki K, Miura S, Yamada S, Nishimura F, Nakagawa I, Park YS, Nakase H. Clinical Results and Hematologic Predictors of Linear Accelerator-Based Stereotactic Radiosurgery or Fractionated Stereotactic Radiotherapy for Brain Metastasis in Patients Aged 75 Years or Older: A Retrospective Study. World Neurosurg 2024; 183:e944-e952. [PMID: 38244685 DOI: 10.1016/j.wneu.2024.01.069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 01/11/2024] [Accepted: 01/12/2024] [Indexed: 01/22/2024]
Abstract
OBJECTIVE This study aimed to evaluate prognostic factors including pre-radiosurgical blood count in elderly patients (EPs) with brain metastasis (BM) who were treated using linear accelerator (LINAC)-based stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (fSRT) with a micro-multileaf collimator. METHODS Between January 2011 and November 2021, 101 consecutive EPs with BM were treated by LINAC-based SRS or fSRT using LINAC with a micro-multileaf collimator. EPs were defined as patients aged ≥75 years. RESULTS The tumors originated from the lungs (n = 90; 89.1%), colon (n = 2; 2.0%), and others (n = 9; 8.8%) in these EPs. The median pretreatment Karnofsky Performance Status was 80 (range, 40-100). The median follow-up time was 10 months (range, 0-76), as was the median survival. The 6-month, 1-year, and 2-year survival in the EP group was 58.3%, 43.2%, and 28.5%, respectively. Freedom from local failure at 6 months and 1 and 2 years was 97%, 95%, and 91.5%, respectively. Freedom from distant failure at 6 months and 1 and 2 years in EPs was 70.6%, 59.4%, and 54.2%, respectively. A high neutrophil/lymphocyte ratio >5.33 was an unfavorable predictor of prognosis for EPs with BMs treated with SRS and fSRT (P < 0.001). In the EPs, the prognostic factors associated with prolonged survival in the Cox proportional hazards model were being female and a good pretreatment Karnofsky Performance Status. CONCLUSIONS The findings of our study highlight the efficacy of LINAC-based SRS and fSRT with a micro-multileaf collimator in the treatment of EPs with BMs. Neutrophil/lymphocyte ratio can be an important factor in treatment decisions for EPs with BMs.
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Affiliation(s)
- Ryosuke Matsuda
- Department of Neurosurgery, Nara Medical University, Kashihara, Nara, Japan.
| | - Masatoshi Hasegawa
- Department of Radiation Oncology, Nara Medical University, Kashihara, Nara, Japan
| | - Tetsuro Tamamoto
- Department of Radiation Oncology, Nara Medical University, Kashihara, Nara, Japan; Department of Medical Informatics, Nara Medical University Hospital, Kashihara, Nara, Japan
| | - Nobuyoshi Inooka
- Department of Radiation Oncology, Nara Medical University, Kashihara, Nara, Japan
| | - Takayuki Morimoto
- Department of Neurosurgery, Nara Medical University, Kashihara, Nara, Japan
| | - Ryosuke Maeoka
- Department of Neurosurgery, Nara Medical University, Kashihara, Nara, Japan
| | - Tsutomu Nakazawa
- Department of Neurosurgery, Nara Medical University, Kashihara, Nara, Japan
| | - Tomoko Ochi
- Department of Respiratory Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Toshiteru Miyasaka
- Department of Respiratory Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Shigeto Hontsu
- Department of Respiratory Medicine, Nara Medical University, Kashihara, Nara, Japan
| | - Kaori Yamaki
- Department of Radiation Oncology, Nara Medical University, Kashihara, Nara, Japan
| | - Sachiko Miura
- Department of Radiation Oncology, Nara Medical University, Kashihara, Nara, Japan
| | - Shuichi Yamada
- Department of Neurosurgery, Nara Medical University, Kashihara, Nara, Japan
| | - Fumihiko Nishimura
- Department of Neurosurgery, Nara Medical University, Kashihara, Nara, Japan
| | - Ichiro Nakagawa
- Department of Neurosurgery, Nara Medical University, Kashihara, Nara, Japan
| | - Young-Soo Park
- Department of Neurosurgery, Nara Medical University, Kashihara, Nara, Japan
| | - Hiroyuki Nakase
- Department of Neurosurgery, Nara Medical University, Kashihara, Nara, Japan
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12
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Yang B, Yao L, Yang L, Zhao F, Zhou W. Inhibition of miR-578 through SOCS2-dependent manner reverses gefitinib resistance in NSCLC cells. ENVIRONMENTAL TOXICOLOGY 2024; 39:1283-1293. [PMID: 37948135 DOI: 10.1002/tox.24004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Revised: 08/30/2023] [Accepted: 10/07/2023] [Indexed: 11/12/2023]
Abstract
BACKGROUND Nonsmall-cell lung cancer (NSCLC) has emerged as one of the dreadful lung cancers globally due to its increased mortality rates. Concerning chemotherapy, gefitinib has been employed as an effective first-line treatment drug for NSCLC. Nonetheless, the acquired resistance to gefitinib has remained one of the treatment obstacles of NSCLC, requiring improvement in the therapeutic effect of gefitinib. METHODS Initially, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and Western blotting (WB) analyses were conducted to measure micro-ribose nucleic acid (miRNA, specifically miR-578) and suppressor of cytokine signaling 2 (SOCS2) levels in the clinical samples. Further, NSCLC cell lines resistance to gefitinib, established in vitro, were transfected by miR-578 inhibitor, miR-578 mimic, and si-SOCS2. Similarly, the xenograft mouse model in vivo was constructed to validate the reversing effect of miR-578. RESULTS Our findings indicated the increased miR-578 expression levels in the gefitinib resistance group. Further, inhibiting the miR-578 expression substantially reversed the gefitinib resistance. In addition, the miR-578 effect was modulated via the SOCS2 expression level. The decreased gefitinib resistance effect of miR-578 was weakened by inhibiting the SOCS2 expression. CONCLUSION These findings demonstrated that miR-578 effectively abolished gefitinib resistance by regulating the SOCS2 expression within NSCLC cells in vitro and in vivo. Together, these results will undoubtedly support a reference to provide potential molecular therapeutic targets and clinical treatments for treating NSCLC patients.
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Affiliation(s)
- Bo Yang
- Department of Thoracic Surgery, Cangzhou Central Hospital, Cangzhou, Hebei Province, China
| | - Lei Yao
- Department of Thoracic Surgery, Cangzhou Central Hospital, Cangzhou, Hebei Province, China
| | - Liankai Yang
- Department of Thoracic Surgery, Cangzhou Central Hospital, Cangzhou, Hebei Province, China
| | - Fang Zhao
- Department of Thoracic Surgery, Cangzhou Central Hospital, Cangzhou, Hebei Province, China
| | - Wenyan Zhou
- Department of Thoracic Surgery, Cangzhou Central Hospital, Cangzhou, Hebei Province, China
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13
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Wang TW, Chao HS, Chiu HY, Lu CF, Liao CY, Lee Y, Chen JR, Shiao TH, Chen YM, Wu YT. Radiomics of metastatic brain tumor as a predictive image biomarker of progression-free survival in patients with non-small-cell lung cancer with brain metastasis receiving tyrosine kinase inhibitors. Transl Oncol 2024; 39:101826. [PMID: 37984256 PMCID: PMC10689936 DOI: 10.1016/j.tranon.2023.101826] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Revised: 10/18/2023] [Accepted: 11/07/2023] [Indexed: 11/22/2023] Open
Abstract
BACKGROUND AND OBJECTIVE Epidermal growth factor receptor (EGFR)-targeted tyrosine kinase inhibitors (TKIs) are the first-line therapy for EGFR-mutant non-small-cell lung cancer (NSCLC). Early prediction of treatment failure in patients with brain metastases treated with EGFR-TKIs may help in making decisions for systemic drug therapy or local brain tumor control. This study examined the predictive power of the radiomics of both brain metastasis tumors and primary lung tumors. We propose a deep learning based CoxCC model based on quantitative brain magnetic resonance imaging (MRI), a prognostic index and clinical data; the model can be used to predict progression-free survival (PFS) after EGFR-TKI therapy in advanced EGFR-mutant NSCLC. METHODS This retrospective single-center study included 271 patients receiving first-line EGFR-TKI targeted therapy in 2018-2019. Among them, 72 patients who had brain metastases before receiving first-line EGFR-TKI treatment. Three radiomic features were extracted from pretreatment brain MRI images. A CoxCC model for the progression risk stratification of EGFR-TKI treatment was proposed on the basis of MRI radiomics, clinical features, and a prognostic index. We performed time-dependent PFS predictions to evaluate the performance of the CoxCC model. RESULTS The CoxCC model based on a prognostic index, clinical features, and radiomic features of brain metastasis exhibited higher performance than clinical features combined with indexes previously proposed for determining the prognosis of brain metastasis, including recursive partitioning analysis, diagnostic-specific graded prognostic assessment, graded prognostic assessment for lung cancer using molecular markers (lung-molGPA), and modified lung-molGPA, with c-index values of 0.75, 0.67, 0.66, 0.65, and 0.65, respectively. The model achieved areas under the curve of 0.88, 0.73, 0.92, and 0.90 for predicting PFS at 3, 6, 9 and 12 months, respectively. PFS significantly differed between the high- and low-risk groups (p < 0.001). CONCLUSIONS For patients with advanced-stage NSCLC with brain metastasis, MRI radiomics of brain metastases may predict PFS. The CoxCC model integrating brain metastasis radiomics, clinical features, and a prognostic index provided reliable multi-time-point PFS predictions for patients with advanced NSCLC and brain metastases receiving EGFR-TKI treatment.
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Affiliation(s)
- Ting-Wei Wang
- Institute of Biophotonics, National Yang Ming Chiao Tung University, Taipei, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Heng-Sheng Chao
- Department of Chest Medicine, Taipei Veteran General Hospital, Taipei, Taiwan
| | - Hwa-Yen Chiu
- Institute of Biophotonics, National Yang Ming Chiao Tung University, Taipei, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Department of Chest Medicine, Taipei Veteran General Hospital, Taipei, Taiwan
| | - Chia-Feng Lu
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chien-Yi Liao
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yen Lee
- Institute of Biophotonics, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Jyun-Ru Chen
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Tsu-Hui Shiao
- Department of Chest Medicine, Taipei Veteran General Hospital, Taipei, Taiwan
| | - Yuh-Min Chen
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Department of Chest Medicine, Taipei Veteran General Hospital, Taipei, Taiwan
| | - Yu-Te Wu
- Institute of Biophotonics, National Yang Ming Chiao Tung University, Taipei, Taiwan.
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14
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Liu SV, Elkins IB, Feldman J, Goldberg SB. EGFR Mutations Are Not All the Same: the Importance of Biomarker Testing in Non-small Cell Lung Cancer (NSCLC)-A Podcast Discussion Between Patients and Oncologists. Oncol Ther 2023; 11:419-431. [PMID: 37750968 PMCID: PMC10673799 DOI: 10.1007/s40487-023-00242-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 08/23/2023] [Indexed: 09/27/2023] Open
Abstract
This podcast, for healthcare professionals (HCPs), patients, and patient advocates, is a discussion among a panel of two patients (and co-founders of the patient advocacy group EGFR Resisters, https://egfrcancer.org/ ) and two oncologists. The objective of the podcast is to explain the importance of biomarker testing for patients with EGFR-mutated non-small cell lung cancer. The treatment landscape for EGFR-mutated non-small cell lung cancer is evolving, and biomarker testing has become central to determining the best therapies for individual patients. The panel discusses what biomarkers are, the processes involved in obtaining biomarker testing, how biomarker information is used, and the importance of waiting for biomarker results prior to determining treatment. The panel also discusses patient perspectives on biopsy and biomarker testing and how HCPs can best help guide new patients through this process.
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Affiliation(s)
- Stephen V Liu
- Division of Hematology and Oncology, Department of Medicine, Georgetown University Medical Center, Washington, DC, USA.
| | - Ivy B Elkins
- Patient Advocacy Group EGFR Resisters, Evanston, IL, USA
| | - Jill Feldman
- Patient Advocacy Group EGFR Resisters, Deerfield, IL, USA
| | - Sarah B Goldberg
- Division of Thoracic Oncology, Center for Thoracic Cancers, Yale School of Medicine, New Haven, CT, USA
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15
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Aquilano M, Loi M, Visani L, Livi L, Nuyttens JJ. Is stereotactic body radiotherapy an effective treatment in metastatic lung cancer with oligoprogressive disease? Acta Oncol 2023; 62:298-304. [PMID: 36905644 DOI: 10.1080/0284186x.2023.2186187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/12/2023]
Abstract
BACKGROUND Oligoprogression (OPD) is defined as a condition where limited progression (1-3 metastases) is observed in patients undergoing systemic cancer treatment. In this study we investigated the impact of stereotactic body radiotherapy (SBRT) in patients with OPD from metastatic lung cancer. MATERIAL AND METHODS Data from a cohort of consecutive patients with SBRT treated between June 2015 and August 2021 were collected. All extracranial metastatic sites of OPD from lung cancer were included. Dose regimens consisted of mainly 24 in 2 fractions, 30-51 Gy in 3 fractions, 30-55 Gy in 5 fractions, 52.5 Gy in 7 fractions and 44-56 Gy in 8 fractions. Kaplan-Meier method was used to calculate Overall Survival (OS), Local Control (LC), and Disease-Free Survival (DFS) from the start date of SBRT to the event. RESULTS Sixty-three patients, 34 female and 29 males were included. Median age was 75 years (range 25-83). All patients received concurrent systemic treatment before the start of the SBRT: 19 chemotherapy (CT), 26 CT plus immunotherapy (IT) or Tyrosin kinase inhibitors (TKI) and 18 IT/TKI. SBRT was delivered to the lung (n = 29), mediastinal node (n = 9), bone (n = 7), adrenal gland (n = 19), other visceral metastases (1) and other node metastases (n = 4). After a median follow-up of 17 months, median OS was 23 months. LC was 93% at 1 year and 87% at 2 years. DFS was 7 months. According to our results, there was no statistically significant correlation between prognostic factors and OS after SBRT in OPD patients. CONCLUSIONS Median DFS was 7 months, translating into the continuation of effective systemic treatment as other metastases grow slowly. In patients with oligoprogression disease, SBRT is a valid and efficient treatment that may enable postponing the switch of systemic line.
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Affiliation(s)
| | - Mauro Loi
- Department of Radiation Oncology, University of Florence, Florence, Italy
| | - Luca Visani
- Department of Radiation Oncology, University of Florence, Florence, Italy
| | - Lorenzo Livi
- Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", University of Florence, Florence, Italy
| | - Joost J Nuyttens
- Department of Radiation Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
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16
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Wu H, Lv WH, Zhu YY, Jia YY, Nie F. Ultrasound-mediated mesoporous silica nanoparticles loaded with PDLIM5 siRNA inhibit gefitinib resistance in NSCLC cells by attenuating EMT. Eur J Pharm Sci 2023; 182:106372. [PMID: 36621614 DOI: 10.1016/j.ejps.2023.106372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 12/12/2022] [Accepted: 01/05/2023] [Indexed: 01/09/2023]
Abstract
Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKIs) was one of the main drugs in the treatment of non-small cell lung cancer (NSCLC). Previous studies had demonstrated that PDZ and LIM Domain 5 (PDLIM5) played an important role in EGFR TKIs resistance. However, there was no feasible method to eliminate EGFR TKIs resistance by suppressing this gene. Here, we formulated a novel mesoporous silica-loaded PDLIM5 siRNA (Small interfering RNA) nanoplatforms. The results have shown that PDLIM5 siRNA could be effectively bound to the nanoplatforms and had good biocompatibility. Further exploration suggested that the nano-platform combined with ultrasonic irradiation could be very effective for siRNA delivery and ultrasound imaging. Moreover, Epithelial-mesenchymal transformation (EMT) changes occurred in PC-9 Gefitinib resistance (PC-9/GR) cells during the development of drug resistance. When PDLIM5 siRNA entered PC-9/GR cells, the sensitivity of drug-resistant cells to gefitinib could be restored through the transforming growth factor-β (TGF-β)/EMT pathway. Therefore, PDLIM5 may be an important reason for the resistance of NSCLC cells to gefitinib, and this nanoplatform may become a novel treatment for EGFR TKIs resistance in NSCLC patients.
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Affiliation(s)
- Hao Wu
- Ultrasound Medical Center, Lanzhou University Second Hospital, Cuiyingmen No.82, Chengguan District, Lanzhou 730030, China; Gansu Province Clinical Research Center for Ultrasonography, Lanzhou, China; Gansu Province Medical Engineering Research Center for Intelligence Ultrasound, Lanzhou, China
| | - Wen-Hao Lv
- Ultrasound Medical Center, Lanzhou University Second Hospital, Cuiyingmen No.82, Chengguan District, Lanzhou 730030, China; Gansu Province Clinical Research Center for Ultrasonography, Lanzhou, China; Gansu Province Medical Engineering Research Center for Intelligence Ultrasound, Lanzhou, China
| | - Yang-Yang Zhu
- Ultrasound Medical Center, Lanzhou University Second Hospital, Cuiyingmen No.82, Chengguan District, Lanzhou 730030, China; Gansu Province Clinical Research Center for Ultrasonography, Lanzhou, China; Gansu Province Medical Engineering Research Center for Intelligence Ultrasound, Lanzhou, China
| | - Ying-Ying Jia
- Ultrasound Medical Center, Lanzhou University Second Hospital, Cuiyingmen No.82, Chengguan District, Lanzhou 730030, China; Gansu Province Clinical Research Center for Ultrasonography, Lanzhou, China; Gansu Province Medical Engineering Research Center for Intelligence Ultrasound, Lanzhou, China
| | - Fang Nie
- Ultrasound Medical Center, Lanzhou University Second Hospital, Cuiyingmen No.82, Chengguan District, Lanzhou 730030, China; Gansu Province Clinical Research Center for Ultrasonography, Lanzhou, China; Gansu Province Medical Engineering Research Center for Intelligence Ultrasound, Lanzhou, China.
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Miura K, Koyanagi-Aoi M, Maniwa Y, Aoi T. Chorioallantoic membrane assay revealed the role of TIPARP (2,3,7,8-tetrachlorodibenzo-p-dioxin-inducible poly (ADP-ribose) polymerase) in lung adenocarcinoma-induced angiogenesis. Cancer Cell Int 2023; 23:34. [PMID: 36841751 PMCID: PMC9960622 DOI: 10.1186/s12935-023-02870-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 02/13/2023] [Indexed: 02/27/2023] Open
Abstract
BACKGROUND The chorioallantoic membrane (CAM) assay is a well-established technique to evaluate tumor invasion and angiogenesis and may overcome the shortcoming of the patient-derived xenograft (PDX) mouse model. Currently, few reports have described lung cancer invasion and angiogenesis in the CAM assay. We therefore used the CAM assay in the evaluation of lung cancer. METHOD Lung cancer cell line-derived organoids or lung cancer cell lines were transplanted into the CAM on embryonic development day (EDD) 10, and an analysis was performed on EDD 15. Microscopic and macroscopic images and movies of the grafts on the CAM were captured and analyzed. The relationships between the graft and chick vessels were evaluated using immunohistochemistry. RESULTS We transplanted lung cancer cell lines and cell line-derived organoid into a CAM to investigate angiogenesis and invasion. They engrafted on the CAM at a rate of 50-83%. A549-OKS cells showed enhanced cell invasion and angiogenesis on the CAM in comparison to A549-GFP cells as was reported in vitro. Next, we found that A549-TIPARP cells promoted angiogenesis on the CAM. RNA-seq identified 203 genes that were upregulated more than twofold in comparison to A549-GFP cells. A pathway analysis revealed many upregulated pathways related to degradation and synthesis of the extracellular matrix in A549-TIPARP cells. CONCLUSIONS The CAM assay can be used to evaluate and research invasion and angiogenesis in lung cancer. The elevated expression of TIPARP in lung cancer may induce angiogenesis by remodeling the extracellular matrix.
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Affiliation(s)
- Kenji Miura
- grid.31432.370000 0001 1092 3077Division of Stem Cell Medicine, Graduate School of Medicine, Kobe University, 7-5-1 Kusunoki-cho, Chuo-Ku, Kobe, Hyogo 650-0017 Japan ,grid.31432.370000 0001 1092 3077Division of Advanced Medical Science, Graduate School of Science, Technology and Innovation, Kobe University, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017 Japan ,grid.31432.370000 0001 1092 3077Division of Thoracic Surgery, Graduate School of Medicine, Kobe University, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017 Japan
| | - Michiyo Koyanagi-Aoi
- grid.31432.370000 0001 1092 3077Division of Stem Cell Medicine, Graduate School of Medicine, Kobe University, 7-5-1 Kusunoki-cho, Chuo-Ku, Kobe, Hyogo 650-0017 Japan ,grid.31432.370000 0001 1092 3077Division of Advanced Medical Science, Graduate School of Science, Technology and Innovation, Kobe University, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017 Japan ,grid.411102.70000 0004 0596 6533Center for Human Resource Development for Regenerative Medicine, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017 Japan
| | - Yoshimasa Maniwa
- grid.31432.370000 0001 1092 3077Division of Thoracic Surgery, Graduate School of Medicine, Kobe University, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017 Japan
| | - Takashi Aoi
- Division of Stem Cell Medicine, Graduate School of Medicine, Kobe University, 7-5-1 Kusunoki-cho, Chuo-Ku, Kobe, Hyogo, 650-0017, Japan. .,Division of Advanced Medical Science, Graduate School of Science, Technology and Innovation, Kobe University, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan. .,Center for Human Resource Development for Regenerative Medicine, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan.
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18
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Noguchi R, Yoshimura A, Uchino J, Takeda T, Chihara Y, Ota T, Hiranuma O, Gyotoku H, Takayama K, Kondo T. Comprehensive Kinase Activity Profiling Revealed the Kinase Activity Patterns Associated with the Effects of EGFR Tyrosine Kinase Inhibitor Therapy in Advanced Non-Small-Cell Lung Cancer Patients with Sensitizing EGFR Mutations. Proteomes 2023; 11:proteomes11010006. [PMID: 36810562 PMCID: PMC9944465 DOI: 10.3390/proteomes11010006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 01/11/2023] [Accepted: 01/26/2023] [Indexed: 02/08/2023] Open
Abstract
EGFR mutations are strong predictive markers for EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy in patients with non-small-cell lung cancer (NSCLC). Although NSCLC patients with sensitizing EGFR mutations have better prognoses, some patients exhibit worse prognoses. We hypothesized that various activities of kinases could be potential predictive biomarkers for EGFR-TKI treatment among NSCLC patients with sensitizing EGFR mutations. In 18 patients with stage IV NSCLC, EGFR mutations were detected and comprehensive kinase activity profiling was performed using the peptide array PamStation12 for 100 tyrosine kinases. Prognoses were observed prospectively after the administration of EGFR-TKIs. Finally, the kinase profiles were analyzed in combination with the prognoses of the patients. Comprehensive kinase activity analysis identified specific kinase features, consisting of 102 peptides and 35 kinases, in NSCLC patients with sensitizing EGFR mutations. Network analysis revealed seven highly phosphorylated kinases: CTNNB1, CRK, EGFR, ERBB2, PIK3R1, PLCG1, and PTPN11. Pathway analysis and Reactome analysis revealed that the PI3K-AKT and RAF/ MAPK pathways were significantly enriched in the poor prognosis group, being consistent with the outcome of the network analysis. Patients with poor prognoses exhibited high activation of EGFR, PIK3R1, and ERBB2. Comprehensive kinase activity profiles may provide predictive biomarker candidates for screening patients with advanced NSCLC harboring sensitizing EGFR mutations.
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Affiliation(s)
- Rei Noguchi
- Division of Rare Cancer Research, National Cancer Center Research Institute, Tokyo 104-0045, Japan
| | - Akihiro Yoshimura
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Junji Uchino
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
- Bannan Central Hospital, Shizuoka 438-0814, Japan
| | - Takayuki Takeda
- Department of Respiratory Medicine, Japanese Red Cross Kyoto Daini Hospital, Kyoto 602-8026, Japan
| | - Yusuke Chihara
- Department of Respiratory Medicine, Uji-Tokushukai Medical Center, Kyoto 611-0041, Japan
| | - Takayo Ota
- Department of Medical Oncology, Izumi City General Hospital, Osaka 594-0073, Japan
| | - Osamu Hiranuma
- Department of Respiratory Medicine, Otsu City Hospital, Shiga 520-0804, Japan
| | - Hiroshi Gyotoku
- Department of Respiratory Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8501, Japan
| | - Koichi Takayama
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Tadashi Kondo
- Division of Rare Cancer Research, National Cancer Center Research Institute, Tokyo 104-0045, Japan
- Correspondence: ; Tel.: +81-3-3542-2511 (ext. 3419)
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19
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Woldmar N, Schwendenwein A, Kuras M, Szeitz B, Boettiger K, Tisza A, László V, Reiniger L, Bagó AG, Szállási Z, Moldvay J, Szász AM, Malm J, Horvatovich P, Pizzatti L, Domont GB, Rényi-Vámos F, Hoetzenecker K, Hoda MA, Marko-Varga G, Schelch K, Megyesfalvi Z, Rezeli M, Döme B. Proteomic analysis of brain metastatic lung adenocarcinoma reveals intertumoral heterogeneity and specific alterations associated with the timing of brain metastases. ESMO Open 2023; 8:100741. [PMID: 36527824 PMCID: PMC10024110 DOI: 10.1016/j.esmoop.2022.100741] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 09/07/2022] [Accepted: 11/02/2022] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Brain metastases are associated with considerable negative effects on patients' outcome in lung adenocarcinoma (LADC). Here, we investigated the proteomic landscape of primary LADCs and their corresponding brain metastases. MATERIALS AND METHODS Proteomic profiling was conducted on 20 surgically resected primary and brain metastatic LADC samples via label-free shotgun proteomics. After sample processing, peptides were analyzed using an Ultimate 3000 pump coupled to a QExactive HF-X mass spectrometer. Raw data were searched using PD 2.4. Further data analyses were carried out using Perseus, RStudio and GraphPad Prism. Proteomic data were correlated with clinical and histopathological parameters and the timing of brain metastases. Mass spectrometry-based proteomic data are available via ProteomeXchange with identifier PXD027259. RESULTS Out of the 6821 proteins identified and quantified, 1496 proteins were differentially expressed between primary LADCs and corresponding brain metastases. Pathways associated with the immune system, cell-cell/matrix interactions and migration were predominantly activated in the primary tumors, whereas pathways related to metabolism, translation or vesicle formation were overrepresented in the metastatic tumors. When comparing fast- versus slow-progressing patients, we found 454 and 298 differentially expressed proteins in the primary tumors and brain metastases, respectively. Metabolic reprogramming and ribosomal activity were prominently up-regulated in the fast-progressing patients (versus slow-progressing individuals), whereas expression of cell-cell interaction- and immune system-related pathways was reduced in these patients and in those with multiple brain metastases. CONCLUSIONS This is the first comprehensive proteomic analysis of paired primary tumors and brain metastases of LADC patients. Our data suggest a malfunction of cellular attachment and an increase in ribosomal activity in LADC tissue, promoting brain metastasis. The current study provides insights into the biology of LADC brain metastases and, moreover, might contribute to the development of personalized follow-up strategies in LADC.
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Affiliation(s)
- N Woldmar
- Department of Biomedical Engineering, Lund University, Lund, Sweden; Laboratory of Molecular Biology and Proteomics of Blood/LADETEC, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - A Schwendenwein
- Department of Thoracic Surgery, Medical University Vienna, Vienna, Austria
| | - M Kuras
- Section for Clinical Chemistry, Department of Translational Medicine, Lund University, Skåne University Hospital Malmö, Malmö, Sweden
| | - B Szeitz
- Division of Oncology, Department of Internal Medicine and Oncology, Semmelweis University, Budapest, Hungary
| | - K Boettiger
- Department of Thoracic Surgery, Medical University Vienna, Vienna, Austria
| | - A Tisza
- National Korányi Institute of Pulmonology, Budapest, Hungary; Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - V László
- Department of Thoracic Surgery, Medical University Vienna, Vienna, Austria; National Korányi Institute of Pulmonology, Budapest, Hungary
| | - L Reiniger
- Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary; Department of Pathology, Forensic and Insurance Medicine, MTA-SE NAP, Brain Metastasis Research Group, Hungarian Academy of Sciences, Budapest, Hungary
| | - A G Bagó
- Department of Neurooncology, National Institute of Clinical Neurosciences, Budapest, Hungary
| | - Z Szállási
- Department of Pathology, Forensic and Insurance Medicine, MTA-SE NAP, Brain Metastasis Research Group, Hungarian Academy of Sciences, Budapest, Hungary; Computational Health Informatics Program, Boston Children's Hospital, Harvard Medical School, Boston, USA; Danish Cancer Society Research Center, Copenhagen, Denmark
| | - J Moldvay
- National Korányi Institute of Pulmonology, Budapest, Hungary; Department of Pathology, Forensic and Insurance Medicine, MTA-SE NAP, Brain Metastasis Research Group, Hungarian Academy of Sciences, Budapest, Hungary
| | - A M Szász
- National Korányi Institute of Pulmonology, Budapest, Hungary; Department of Bioinformatics, Semmelweis University, Budapest, Hungary
| | - J Malm
- Section for Clinical Chemistry, Department of Translational Medicine, Lund University, Skåne University Hospital Malmö, Malmö, Sweden
| | - P Horvatovich
- Department of Analytical Biochemistry, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - L Pizzatti
- Laboratory of Molecular Biology and Proteomics of Blood/LADETEC, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - G B Domont
- Department of Biochemistry, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - F Rényi-Vámos
- National Korányi Institute of Pulmonology, Budapest, Hungary; Department of Thoracic Surgery, National Institute of Oncology-Semmelweis University, Budapest, Hungary
| | - K Hoetzenecker
- Department of Thoracic Surgery, Medical University Vienna, Vienna, Austria
| | - M A Hoda
- Department of Thoracic Surgery, Medical University Vienna, Vienna, Austria
| | - G Marko-Varga
- Department of Biomedical Engineering, Lund University, Lund, Sweden
| | - K Schelch
- Department of Thoracic Surgery, Medical University Vienna, Vienna, Austria
| | - Z Megyesfalvi
- Department of Thoracic Surgery, Medical University Vienna, Vienna, Austria; National Korányi Institute of Pulmonology, Budapest, Hungary; Department of Thoracic Surgery, National Institute of Oncology-Semmelweis University, Budapest, Hungary
| | - M Rezeli
- Department of Biomedical Engineering, Lund University, Lund, Sweden.
| | - B Döme
- Department of Thoracic Surgery, Medical University Vienna, Vienna, Austria; Section for Clinical Chemistry, Department of Translational Medicine, Lund University, Skåne University Hospital Malmö, Malmö, Sweden; National Korányi Institute of Pulmonology, Budapest, Hungary; Department of Thoracic Surgery, National Institute of Oncology-Semmelweis University, Budapest, Hungary.
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20
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Allmann V, Dyntar D, Lehnick D, Dressler M, Zeidler K, Niederberger P, Godau J, Diebold J, Gautschi O. Overall survival and role of programmed death ligand 1 expression in patients with metastatic non-small-cell lung cancer and immunotherapy: an observational study from central Switzerland. Swiss Med Wkly 2023; 153:40039. [PMID: 36787492 DOI: 10.57187/smw.2023.40039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2023] Open
Abstract
BACKGROUND In clinical trials, therapy with immune checkpoint inhibitors has improved the survival of patients with metastatic non-small-cell lung cancer (NSCLC). These trials were important for drug approval and for defining new treatment standards but the effect of checkpoint inhibitors in patients treated outside of clinical trials is not well known. The goal of this study was to assess the effect of immunotherapy on the overall survival of patients with metastatic NSCLC in the region of central Switzerland. MATERIALS AND METHODS The study included 274 patients with histologically confirmed metastatic (stage IV) NSCLC in central Switzerland in the years 2015 to 2018. Patients with NSCLC and actionable driver mutations were excluded. Patients with checkpoint inhibitor treatment (immuno-oncology [IO] group, n = 122) were compared with patients without checkpoint inhibitor treatment (no-IO group, n = 152). Baseline demographics, disease characteristics and therapies applied were collected retrospectively. The primary endpoint was median overall survival calculated either from diagnosis or from the start of checkpoint inhibitor therapy to death or data cut-off (21 July 2021). We used the Kaplan-Meier method and an adjusted Cox proportional-hazards regression model. The expression of programmed-death ligand 1 (PD-L1) on tumour cells was used for exploratory analysis. RESULTS Patients had a median age of 68.4 years, most were male (61.7%) and more than half were current or former smokers (65%). A test for PD-L1 expression was available for 55.8% of the tumours. Patients in the IO group were younger than patients in the no-IO group. Among the 122 patients in the IO group, the median overall survival was 15 months (95% confidence interval [CI] 12-20). In the no-IO group, the median overall survival was 4 months (95% CI 3-7) with chemotherapy and 2 months (95% CI 1-2) with best supportive care. Patients with high (≥50%) PD-L1 expression and checkpoint inhibitor therapy had a slightly longer overall survival than patients with low PD-L1 and checkpoint inhibitor therapy. CONCLUSION These results suggest that treatment with checkpoint inhibitors improves overall survival in patients with metastatic NSCLC and that PD-L1 expression could have a predictive value in patients treated outside of clinical trials. Further studies are needed to study the magnitude of the benefit of checkpoint inhibitors according to molecular NSCLC subtype.
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Affiliation(s)
| | - Daniela Dyntar
- Cancer Registry of Central Switzerland, Cantonal Hospital Lucerne, Switzerland
| | - Dirk Lehnick
- Biostatistics and Methodology, Department of Health Sciences and Medicine, University of Lucerne, Switzerland
| | - Marco Dressler
- Department of Medical Oncology, Clinic Hirslanden St Anna, Lucerne, Switzerland
| | - Kristin Zeidler
- Department of Medical Oncology, Cantonal Hospital Nidwalden, Stans, Switzerland
| | | | - Jeanne Godau
- Department of Medical Oncology, Cantonal Hospital Uri, Altdorf, Switzerland
| | - Joachim Diebold
- Institute of Pathology, Cantonal Hospital Lucerne, Switzerland
| | - Oliver Gautschi
- University of Bern and Cantonal Hospital of Lucerne, Switzerland
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21
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Lu CF, Liao CY, Chao HS, Chiu HY, Wang TW, Lee Y, Chen JR, Shiao TH, Chen YM, Wu YT. A radiomics-based deep learning approach to predict progression free-survival after tyrosine kinase inhibitor therapy in non-small cell lung cancer. Cancer Imaging 2023; 23:9. [PMID: 36670497 PMCID: PMC9854198 DOI: 10.1186/s40644-023-00522-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 01/05/2023] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a first-line therapy for non-small cell lung cancer (NSCLC) with EGFR mutations. Approximately half of the patients with EGFR-mutated NSCLC are treated with EGFR-TKIs and develop disease progression within 1 year. Therefore, the early prediction of tumor progression in patients who receive EGFR-TKIs can facilitate patient management and development of treatment strategies. We proposed a deep learning approach based on both quantitative computed tomography (CT) characteristics and clinical data to predict progression-free survival (PFS) in patients with advanced NSCLC after EGFR-TKI treatment. METHODS A total of 593 radiomic features were extracted from pretreatment chest CT images. The DeepSurv models for the progression risk stratification of EGFR-TKI treatment were proposed based on CT radiomic and clinical features from 270 stage IIIB-IV EGFR-mutant NSCLC patients. Time-dependent PFS predictions at 3, 12, 18, and 24 months and estimated personalized PFS curves were calculated using the DeepSurv models. RESULTS The model combining clinical and radiomic features demonstrated better prediction performance than the clinical model. The model achieving areas under the curve of 0.76, 0.77, 0.76, and 0.86 can predict PFS at 3, 12, 18, and 24 months, respectively. The personalized PFS curves showed significant differences (p < 0.003) between groups with good (PFS > median) and poor (PFS < median) tumor control. CONCLUSIONS The DeepSurv models provided reliable multi-time-point PFS predictions for EGFR-TKI treatment. The personalized PFS curves can help make accurate and individualized predictions of tumor progression. The proposed deep learning approach holds promise for improving the pre-TKI personalized management of patients with EGFR-mutated NSCLC.
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Affiliation(s)
- Chia-Feng Lu
- grid.260539.b0000 0001 2059 7017Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chien-Yi Liao
- grid.260539.b0000 0001 2059 7017Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Heng-Sheng Chao
- grid.278247.c0000 0004 0604 5314Department of Chest Medicine, Taipei Veteran General Hospital, Taipei, Taiwan
| | - Hwa-Yen Chiu
- grid.278247.c0000 0004 0604 5314Department of Chest Medicine, Taipei Veteran General Hospital, Taipei, Taiwan ,grid.260539.b0000 0001 2059 7017Institute of Biophotonics, National Yang Ming Chiao Tung University, Taipei, Taiwan ,grid.260539.b0000 0001 2059 7017School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Ting-Wei Wang
- grid.260539.b0000 0001 2059 7017Institute of Biophotonics, National Yang Ming Chiao Tung University, Taipei, Taiwan ,grid.260539.b0000 0001 2059 7017School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yen Lee
- grid.260539.b0000 0001 2059 7017Institute of Biophotonics, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Jyun-Ru Chen
- grid.260539.b0000 0001 2059 7017Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Tsu-Hui Shiao
- grid.278247.c0000 0004 0604 5314Department of Chest Medicine, Taipei Veteran General Hospital, Taipei, Taiwan
| | - Yuh-Min Chen
- grid.278247.c0000 0004 0604 5314Department of Chest Medicine, Taipei Veteran General Hospital, Taipei, Taiwan ,grid.260539.b0000 0001 2059 7017School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yu-Te Wu
- grid.260539.b0000 0001 2059 7017Institute of Biophotonics, National Yang Ming Chiao Tung University, Taipei, Taiwan ,grid.260539.b0000 0001 2059 7017Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
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22
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Wang F, Yang W, Liu H, Zhou B. Identification of the structural features of quinazoline derivatives as EGFR inhibitors using 3D-QSAR modeling, molecular docking, molecular dynamics simulations and free energy calculations. J Biomol Struct Dyn 2022; 40:11125-11140. [PMID: 34338597 DOI: 10.1080/07391102.2021.1956591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Epidermal growth factor receptor (EGFR) is a promising target for the treatment of different types of malignant tumors. Therefore, a combined molecular modeling study was performed on a series of quinazoline derivatives as EGFR inhibitors. The optimum ligand-based CoMFA and CoMSIA models showed reliable and satisfactory predictability (with R2cv=0.681, R2ncv=0.844, R2pred=0.8702 and R2cv=0.643, R2ncv=0.874, R2pred=0.6423). The derived contour maps provide structural features to improve inhibitory activity. Furthermore, the contour maps, molecular docking, and molecular dynamics (MD) simulations have good consistency, illustrating that the derived models are reliable. In addition, MD simulations and binding free energy calculations were also carried out to understand the conformational fluctuations at the binding pocket of the receptor. The results indicate that hydrogen bond, hydrophobic and electrostatic interactions play significant roles on activity and selectivity. Furthermore, amino acids Val31, Lys50, Thr95, Leu149 and Asp160 are considered as essential residues to participate in the ligand-receptor interactions. Overall, this work would offer reliable theoretical basis for future structural modification, design and synthesis of novel EGFR inhibitors with good potency.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Fangfang Wang
- School of Life Science, Linyi University, Linyi, China
| | - Wei Yang
- Warshel Institute for Computational Biology, School of Science and Engineering, The Chinese University of Hong Kong, Shenzhen, China.,School of Biotechnology, University of Science and Technology of China, Hefei, China.,Biomedicine Discovery Institute, Monash University, Melbourne, Australia
| | - Hongping Liu
- School of Life Science, Linyi University, Linyi, China
| | - Bo Zhou
- State Key Laboratory of Functions and Applications of Medicinal Plants, College of Basic Medical, Guizhou Medical University, Guizhou, China
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23
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Wen Y, Liu W, David B, Ren W, Irudayaraj J. Multifunctional Oxygenated Particles for Targeted Cancer Drug Delivery and Evaluation with Darkfield Hyperspectral Imaging. ACS OMEGA 2022; 7:41275-41283. [PMID: 36406533 PMCID: PMC9670270 DOI: 10.1021/acsomega.2c04953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 10/20/2022] [Indexed: 06/16/2023]
Abstract
We propose a novel multifunctional nanocarrier system for targeted drug delivery for lung cancer theranostics. Oxygenated particles (OPs) synthesized with an oxygen-encapsulating carboxymethyl cellulose shell were used as a platform to deliver oxygen to the hypoxic tumor microenvironment. The OPs synthesized could also be conjugated with ligands (e.g., antibodies) to target cancer cells expressing the corresponding antigens to deliver a drug, doxorubicin. In vitro testing of functionalized OPs showed increased efficacy of doxorubicin against the proliferation of lung cancer cells. Both confocal fluorescence imaging and darkfield microscopy hyperspectral imaging validated the OP complex and its efficient targeting of specific cells to deliver the therapeutic. The nanocarrier platform developed can also serve as a diagnostic imaging reagent as demonstrated by darkfield microscopy. Results show that the theranostic OPs developed with multifunctional modalities enabled targeted drug delivery with improved efficacy and tracking of drug delivery vehicles by imaging.
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Affiliation(s)
- Yi Wen
- Department
of Bioengineering, College of Engineering, University of Illinois Urbana-Champaign, Urbana, Illinois 61801, United States
- Biomedical
Research Center, Mills Breast Cancer Institute, Carle Foundation Hospital, Urbana, Illinois 61801, United States
- Department
of Comparative Biosciences, College of Veterinary Medicine, University of Illinois Urbana-Champaign, Urbana, Illinois 61801, United States
| | - Wenjie Liu
- Department
of Bioengineering, College of Engineering, University of Illinois Urbana-Champaign, Urbana, Illinois 61801, United States
- Biomedical
Research Center, Mills Breast Cancer Institute, Carle Foundation Hospital, Urbana, Illinois 61801, United States
| | - Benjamin David
- Department
of Bioengineering, College of Engineering, University of Illinois Urbana-Champaign, Urbana, Illinois 61801, United States
| | - Wen Ren
- Department
of Bioengineering, College of Engineering, University of Illinois Urbana-Champaign, Urbana, Illinois 61801, United States
- Biomedical
Research Center, Mills Breast Cancer Institute, Carle Foundation Hospital, Urbana, Illinois 61801, United States
| | - Joseph Irudayaraj
- Department
of Bioengineering, College of Engineering, University of Illinois Urbana-Champaign, Urbana, Illinois 61801, United States
- Biomedical
Research Center, Mills Breast Cancer Institute, Carle Foundation Hospital, Urbana, Illinois 61801, United States
- Department
of Comparative Biosciences, College of Veterinary Medicine, University of Illinois Urbana-Champaign, Urbana, Illinois 61801, United States
- Cancer
Center at Illinois; Carl R. Woese Institute for Genomic Biology; Beckman
Institute; Micro and Nanotechnology Laboratory, University of Illinois Urbana-Champaign, Urbana, Illinois 61801, United States
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24
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Zhang Q, Zheng J, Wang W, Cornett EM, Kaye AD, Urits I, Viswanath O, Wei FL. The Anticancer Effect of Metformin Combined with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-small Cell Lung Cancer Patients with or Without Type 2 Diabetes Mellitus: A Systematic Review and Meta-analysis. Oncol Ther 2022; 10:363-375. [DOI: 10.1007/s40487-022-00209-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 08/31/2022] [Indexed: 11/30/2022] Open
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25
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Which Scoring System Is the Most Accurate for Assessing Survival Prognosis in Patients Undergoing Surgery for Spinal Metastases from Lung Cancer? A Single-Center Experience. World Neurosurg 2022; 168:e408-e417. [DOI: 10.1016/j.wneu.2022.10.061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 10/17/2022] [Indexed: 11/07/2022]
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Altaf R, Jadoon SS, Muhammad SA, Ilyas U, Duan Y. Recent advances in immune checkpoint inhibitors for non-small lung cancer treatment. Front Oncol 2022; 12:1014156. [PMID: 36237320 PMCID: PMC9552217 DOI: 10.3389/fonc.2022.1014156] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 09/12/2022] [Indexed: 11/13/2022] Open
Abstract
Lung cancer is one of the deadliest types of cancer responsible for thousands of cancer-related deaths. Its treatment has remained a challenge for researchers, but an increase in the knowledge of molecular pathways and biology of lung cancer has dramatically changed its management in recent decades. Immunotherapies and immunomodulation of lung cancer have previously failed for a long time but thanks to continuous research work and enthusiasm, now, this field is emerging as a novel effective therapy. Now, it is hope with potential benefits and promising results in the treatment of lung cancer. This review article focuses on immune checkpoints inhibitors: CTLA-4 inhibitors (ipilimumab and tremelimumab) and PDL-1 inhibitors (durvalumab and atezolizumab) that can be blocked to treat lung carcinoma. It is also focused on critically analyzing different studies and clinical trials to determine the potential benefits, risks, and adverse events associated with immunotherapeutic treatment.
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Affiliation(s)
- Reem Altaf
- Henan Provincial Key Laboratory of Children’s Genetics and Metabolic Diseases, Children’s Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Department of Pharmacy, Iqra University Islamabad Campus, Islamabad, Pakistan
| | - Sarmad Sheraz Jadoon
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Syed Aun Muhammad
- Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan, Pakistan
- *Correspondence: Syed Aun Muhammad, ; Umair Ilyas, ; Yongtao Duan,
| | - Umair Ilyas
- Department of Pharmaceutics, Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan
- *Correspondence: Syed Aun Muhammad, ; Umair Ilyas, ; Yongtao Duan,
| | - Yongtao Duan
- Henan Provincial Key Laboratory of Children’s Genetics and Metabolic Diseases, Children’s Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou, China
- *Correspondence: Syed Aun Muhammad, ; Umair Ilyas, ; Yongtao Duan,
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Hintzen G, Dulat HJ, Rajkovic E. Engaging innate immunity for targeting the epidermal growth factor receptor: Therapeutic options leveraging innate immunity versus adaptive immunity versus inhibition of signaling. Front Oncol 2022; 12:892212. [PMID: 36185288 PMCID: PMC9518002 DOI: 10.3389/fonc.2022.892212] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 07/28/2022] [Indexed: 12/15/2022] Open
Abstract
The epidermal growth factor receptor (EGFR) is a key player in the normal tissue physiology and the pathology of cancer. Therapeutic approaches have now been developed to target oncogenic genetic aberrations of EGFR, found in a subset of tumors, and to take advantage of overexpression of EGFR in tumors. The development of small-molecule inhibitors and anti-EGFR antibodies targeting EGFR activation have resulted in effective but limited treatment options for patients with mutated or wild-type EGFR-expressing cancers, while therapeutic approaches that deploy effectors of the adaptive or innate immune system are still undergoing development. This review discusses EGFR-targeting therapies acting through distinct molecular mechanisms to destroy EGFR-expressing cancer cells. The focus is on the successes and limitations of therapies targeting the activation of EGFR versus those that exploit the cytotoxic T cells and innate immune cells to target EGFR-expressing cancer cells. Moreover, we discuss alternative approaches that may have the potential to overcome limitations of current therapies; in particular the innate cell engagers are discussed. Furthermore, this review highlights the potential to combine innate cell engagers with immunotherapies, to maximize their effectiveness, or with unspecific cell therapies, to convert them into tumor-specific agents.
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Ding H, Chen Y, Zhao Y, Zhu L, Huang H, Liu C, Zhang F, Zhang C, Jin C. The clinical significance and function of EGFR mutation in TKI treatments of NSCLC patients. Cancer Biomark 2022; 35:119-125. [PMID: 35912729 DOI: 10.3233/cbm-210281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND: EGFR mutations widely exists in NSCLC patients, which are involved in cancer development. OBJECTIVE: The function of EGFR mutations in the resistance to TKI treatments of NSCLC was evaluated to provide theoretical support for the clinical management of NSCLC patients. METHODS: A total of 150 NSCLC patients including 118 patients with EGFR mutation and 32 without, were included in this study. The EGFR mutation status and subtypes were analyzed in recruited patients. The distribution of EGFR mutation subtypes and their association with clinicopathological features were also assessed. The prognostic value of EGFR mutation was evaluated by the overall survival of recruited patients. The function of EGFR mutation was estimated, in vitro, in the TKI resistant NSCLC cells with different subtypes of EGFR mutation. RESULTS: The exon 19 deletion was the most common subtype of EGFR mutation in the enrolled patients followed by the exon 21 L858R point mutation. The EGFR mutations were closely associated with the differentiation degree and the histological types of NSCLC cases. EGFR mutation was an independent prognostic factor of NSCLC with a close relationship with the overall survival of patients. The exon 20 T790M mutation results in the erlotinib resistance through EGFR/PI3K/Akt signaling pathway. CONCLUSIONS: The EGFR mutation is a critical factor in the prognosis and for the resistance to TKI treatment in NSCLC. The exon 20 T790M mutation was involved in the erlotinib resistance through PI3K/Akt signaling pathway.
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Affiliation(s)
- Hao Ding
- Division of Respiratory Disease, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Yuxing Chen
- Division of Respiratory Disease, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Yuanyang Zhao
- Division of Respiratory Disease, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Li Zhu
- Division of Nephrology, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Huaying Huang
- Division of Respiratory Disease, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Chenyang Liu
- Division of Respiratory Disease, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Feng Zhang
- Division of Respiratory Disease, Zhenjiang First People’s Hospital Branch, Zhenjiang, Jiangsu, China
| | - Cunxi Zhang
- Division of Thoracic Surgery, Zhenjiang First People’s Hospital Branch, Zhenjiang, Jiangsu, China
| | - Cheng Jin
- Department of Geriatrics, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
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Overall Survival Benefits of First-Line Treatments for Asian Patients with Advanced Epidermal Growth Factor Receptor-Mutated NSCLC Harboring Exon 19 Deletion: A Systematic Review and Network Meta-Analysis. Cancers (Basel) 2022; 14:cancers14143362. [PMID: 35884423 PMCID: PMC9316403 DOI: 10.3390/cancers14143362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 07/07/2022] [Accepted: 07/08/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary Survival benefits and clinical responsiveness have been exhibited by various generations of EGFR-tyrosine kinase inhibitors (TKIs) in numerous randomized-controlled trials for EGFR-mutated advanced non-small-cell lung cancer (NSCLC) over the past two decades. However, the efficacy, especially long-term overall survival (OS) for Asians harboring an exon 19 deletion (19del) in their NSCLC, remains uncertain. This systematic review and network meta-analysis evaluate the efficacy of all first-line treatments in Asian patients with advanced EGFR-mutated NSCLC harboring 19del. EGFR-TKIs and combination treatments demonstrated no OS benefits in comparison with standard chemotherapy treatments, although progression-free survival (PFS) benefits were revealed. Erlotinib plus bevacizumab, ramucirumab plus erlotinib, and osimertinib are the optimal regimens to prolong PFS for Asians with 19del. Further studies are warranted to investigate the resistance mechanisms and possible strategies for individuals harboring this common mutation. Abstract (1) Background: Randomized controlled trials (RCTs) have explored various primary treatments for individuals diagnosed as having later-stage epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer. Nevertheless, the extent to which such treatments are efficacious, particularly with regard to overall survival (OS) rates of patients from Asia with exon 19 deletion (19del), has yet to be clarified. (2) Methods: A systematic review and frequentist network meta-analysis were conducted by obtaining pertinent studies from PubMed/MEDLINE Ovid, Embase, Cochrane Library, and trial registries, as well as various other sources. RCTs in which two or multiple treatments in the primary setting for patients from Asia with EGFR 19del were compared were included. This research has been recorded in the Prospective Register of Systematic Reviews (CRD 42022320833). (3) Results: A total of 2715 patients from Asia participated in 18 trials in which 12 different treatments were administered, which included: EGFR tyrosine kinase inhibitors (TKIs) (osimertinib, dacomitinib, afatinib, erlotinib, gefitinib, and icotinib), pemetrexed-based chemotherapy, pemetrexed-free chemotherapy, and combination treatments (gefitinib plus apatinib, erlotinib plus ramucirumab, erlotinib plus bevacizumab, and gefitinib plus pemetrexed-based chemotherapy). Such treatments were not significantly beneficial in terms of OS for patients from Asia who had 19del. It was demonstrated that erlotinib plus bevacizumab, ramucirumab plus erlotinib, and osimertinib consistently yielded the greatest benefits regarding progression-free survival benefit (P-scores = 94%, 84%, and 80%, respectively). Combination treatments resulted in increased toxicity, particularly gefitinib plus apatinib and erlotinib plus bevacizumab, causing the highest prevalence of grade ≥ 3 adverse events. Icotinib and osimertinib had the fewest grade ≥ 3 adverse events. Specific treatments were associated with a wide range of toxicity levels. (4) Conclusions: In patients from Asia with 19del, both EGFR-TKIs and treatments in which therapies were combined exhibited no OS benefits in comparison with standard chemotherapy treatments. Additional research is required to study TKIs’ resistance mechanisms and possible combined approaches for individuals harboring this common mutation.
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Predicting EGFR mutation, ALK rearrangement, and uncommon EGFR mutation in NSCLC patients by driverless artificial intelligence: a cohort study. Respir Res 2022; 23:132. [PMID: 35624472 PMCID: PMC9145462 DOI: 10.1186/s12931-022-02053-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 05/11/2022] [Indexed: 11/16/2022] Open
Abstract
Background Timely identification of epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement status in patients with non-small cell lung cancer (NSCLC) is essential for tyrosine kinase inhibitors (TKIs) administration. We aimed to use artificial intelligence (AI) models to predict EGFR mutations and ALK rearrangement status using common demographic features, pathology and serum tumor markers (STMs). Methods In this single-center study, demographic features, pathology, EGFR mutation status, ALK rearrangement, and levels of STMs were collected from Wuhan Union Hospital. One retrospective set (N = 1089) was used to train diagnostic performance using one deep learning model and five machine learning models, as well as the stacked ensemble model for predicting EGFR mutations, uncommon EGFR mutations, and ALK rearrangement status. A consecutive testing cohort (n = 1464) was used to validate the predictive models. Results The final AI model using the stacked ensemble yielded optimal diagnostic performance with areas under the curve (AUC) of 0.897 and 0.883 for predicting EGFR mutation status and 0.995 and 0.921 for predicting ALK rearrangement in the training and testing cohorts, respectively. Furthermore, an overall accuracy of 0.93 and 0.83 in the training and testing cohorts, respectively, were achieved in distinguishing common and uncommon EGFR mutations, which were key evidence in guiding TKI selection. Conclusions In this study, driverless AI based on robust variables could help clinicians identify EGFR mutations and ALK rearrangement status and provide vital guidance in TKI selection for targeted therapy in NSCLC patients. Supplementary Information The online version contains supplementary material available at 10.1186/s12931-022-02053-2.
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Chan SK, Choi HCW, Lee VHF. Overall Survival Benefits of First-Line Treatments for Asian Patients With Advanced EGFR-Mutated NSCLC Harboring L858R Mutation: A Systematic Review and Network Meta-Analysis. JTO Clin Res Rep 2022; 3:100322. [PMID: 35516725 PMCID: PMC9065903 DOI: 10.1016/j.jtocrr.2022.100322] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 03/26/2022] [Accepted: 04/01/2022] [Indexed: 12/09/2022] Open
Abstract
Introduction Randomized controlled trials have investigated different first-line treatments for patients with advanced EGFR-mutated NSCLC. Nevertheless, their efficacy, in particular, the long-term overall survival (OS) benefit in Asian patients with L858R mutation, remains unclear. Methods We performed a systematic review and frequentist network meta-analysis by retrieving relevant literature from PubMed/MEDLINE, Ovid, EMBASE, Cochrane Library, trial registries, and other sources. We included randomized controlled trials comparing two or more treatments in the first-line setting for Asian patients with L858R mutation. This study was registered in the Prospective Register of Systematic Reviews (CRD 42022295897). Results There were a total of 18 trials that involved 1852 Asian patients and 12 treatments, including the following: EGFR tyrosine kinase inhibitors (TKIs) (osimertinib, dacomitinib, afatinib, erlotinib, gefitinib, and icotinib), pemetrexed-based chemotherapy, pemetrexed-free chemotherapy, and combination treatments (gefitinib plus apatinib, erlotinib plus ramucirumab, erlotinib plus bevacizumab and gefitinib plus pemetrexed-based chemotherapy). Asian patients with L858R mutation had no significant OS benefits from all these treatments. Gefitinib plus pemetrexed-based chemotherapy, dacomitinib, osimertinib, and erlotinib plus bevacizumab were found to be consistent in yielding the best progression-free survival benefit (p scores = 93%, 79%, 77%, and 70%). Combination treatments caused more toxicity, especially erlotinib plus bevacizumab and gefitinib plus pemetrexed-based chemotherapy, resulting in the greatest incidence of grade greater than or equal to 3 adverse events. Conclusions In Asian patients harboring L858R mutation, EGFR TKIs and combination treatments had no OS benefit when compared with conventional chemotherapies. Further studies are warranted to investigate the resistance mechanism with TKIs and potential combination strategies in patients with this common but less favorable mutation.
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Affiliation(s)
- Sik-Kwan Chan
- Department of Clinical Oncology, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Horace Cheuk-Wai Choi
- School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Victor Ho-Fun Lee
- Department of Clinical Oncology, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
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Role of Image-Guided Percutaneous Needle Biopsy in the Age of Precision Medicine. Curr Oncol Rep 2022; 24:1035-1044. [PMID: 35362826 DOI: 10.1007/s11912-022-01271-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/27/2022] [Indexed: 11/03/2022]
Abstract
PURPOSE OF REVIEW With the remarkable progress in cancer precision medicine, the demand for biopsy has been increasing, and the role of biopsy has been changing. In this review, we discuss the current state and recent advances in the role of image-guided percutaneous needle biopsy (PNB) in facilitating precision medicine. RECENT FINDINGS Biopsies are useful not only in the diagnosis of cancer and histological sub-type but also in the analysis of its molecular characteristics for targeted treatments. PNB specimens have been shown to provide high DNA yields for genomic analysis. Liquid biopsy is an emerging technology but is under development; therefore, PNB is the current standard of practice and is performed complimentarily with liquid biopsy. In the age of precision medicine, interventional oncologists play a key role in optimal tissue collection for adequate genomic analysis. Effective PNB may improve its diagnostic utility and help optimize precision medicine.
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Delgado Sillero I, Lopetegui Lia N, Sánchez Cousido LF, Rojas Piedra M, Távara Silva B, Garrido Onecha ML, Medina Valdivieso S, Alonso Horcajo N, Díez Tascón C, López González A, Castañón López C, Pedraza Lorenzo M, García Palomo A, Martín V, Diz Tain P. EGFR-mutated advanced lung cancer. Data from a single institution, the Hospital of Leon, in Spain. J Oncol Pharm Pract 2022:10781552221085253. [PMID: 35306915 DOI: 10.1177/10781552221085253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
INTRODUCTION 10-16% of non-small cell lung cancer (NSCLC) cases have the epidermal growth factor receptor (EGFR) amplified and/or mutated. Studies show that EGFR tyrosine kinase inhibitors (TKIs) significantly prolong progression-free survival (PFS) in patients with advanced NSCLC compared to those treated with platinum-based chemotherapy (CT) doublets. Our aim is to perform a real-world survival analysis of patients treated with TKI as first-line therapy at the Hospital of Leon (CAULE) in Spain. The impact on global survival rates and responses to clinical and histopathological factors were also analyzed. MATERIAL AND METHODS We retrospectively reviewed patients diagnosed with EGFR-mutated NSCLC who received treatment with EGFR-TKI in the Department of Oncology at the University of Leon Health Center complex between March 2011 and June 2018. Data was analyzed with Kaplan-Meier and Cox regression models to show overall survival (OS), progression-free survival (PFS), and the associated variables. RESULTS 53 patients were included in the study, 50% (n = 27) were treated with gefitinib, 32% (n = 18) with erlotinib and 10% (n = 6) with afatinib. The median OS and PFS were 27.7 months (95% CI: 21-33.8 months) and 18 months (95% CI 14.25-21.89 months), respectively. The variables associated with OS and with PFS were exon19 deletion as a protective factor and presence of extrathoracic metastasis as a risk factor. The most frequent adverse effects were rash, diarrhea, asthenia, and conjunctivitis. CONCLUSIONS Real-world analysis of this data confirms that treatment with TKI is beneficial for patients diagnosed with EGFR-mutated NSCLC. Our OS outcomes were similar to those reported in clinical trials.
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Affiliation(s)
- Irene Delgado Sillero
- Department of Medical Oncology, University of Leon Health Center complex, Leon, Spain
| | - Nerea Lopetegui Lia
- Department of Hematology/Oncology, Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland OH, USA
| | | | - Mariam Rojas Piedra
- Department of Medical Oncology, University of Leon Health Center complex, Leon, Spain
| | - Blanca Távara Silva
- Department of Medical Oncology, University of Leon Health Center complex, Leon, Spain
| | | | | | - Nieves Alonso Horcajo
- Department of Anatomic Pathology, 21654University of Leon Health Center complex, Leon, Spain
| | - Cristina Díez Tascón
- Department of Anatomic Pathology, 21654University of Leon Health Center complex, Leon, Spain
| | - Ana López González
- Department of Medical Oncology, University of Leon Health Center complex, Leon, Spain
| | - Carmen Castañón López
- Department of Medical Oncology, University of Leon Health Center complex, Leon, Spain
| | | | - Andrés García Palomo
- Department of Medical Oncology, University of Leon Health Center complex, Leon, Spain
| | | | - Pilar Diz Tain
- Department of Medical Oncology, University of Leon Health Center complex, Leon, Spain
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Puliafito I, Esposito F, Raciti G, Giuffrida P, Caltavuturo C, Colarossi C, Munao S, Sciacca D, Giuffrida D. Metabolic complete tumor response in a patient with epidermal growth factor receptor mutant non-small cell lung cancer treated with a reduced dose of afatinib. J Int Med Res 2022; 50:3000605211058864. [PMID: 35291829 PMCID: PMC8943310 DOI: 10.1177/03000605211058864] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) are the first-line treatment for EGFR-mutant non-small cell lung cancer. Toxicities related to EGFR-TKIs include skin rash, paronychia, and diarrhea, which in some cases can lead to dose reductions or treatment interruptions. Herein, we report the case of a 51-year-old woman affected by advanced adenocarcinoma harboring an exon 19 deletion in the EGFR gene, who was treated with second-generation EGFR-TKI following a scheduled gradual dose reduction to better manage toxicities. Following prescription labeling, treatment was initiated at a dose of 40 mg daily. After a few months, the dose was reduced to 30 mg daily owing to grade 3 skin toxicity. A metabolic complete tumor response was observed after 1 year of treatment, then therapy was continued at 20 mg daily, enabling disease stabilization. In conclusion, low dose afatinib was effective in an EGFR-mutant non-small cell lung cancer patient who required dose reductions to better manage toxicities.
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Affiliation(s)
- Ivana Puliafito
- Medical Oncology, Istituto Oncologico del Mediterraneo, Viagrande, Catania, Italy
| | | | | | - Paolo Giuffrida
- Medical Oncology, Istituto Oncologico del Mediterraneo, Viagrande, Catania, Italy
| | | | - Cristina Colarossi
- Pathology, Istituto Oncologico del Mediterraneo, Viagrande, Catania, Italy
| | - Stefania Munao
- Medical Oncology, Istituto Oncologico del Mediterraneo, Viagrande, Catania, Italy
| | - Dorotea Sciacca
- Medical Oncology, Istituto Oncologico del Mediterraneo, Viagrande, Catania, Italy
| | - Dario Giuffrida
- Medical Oncology, Istituto Oncologico del Mediterraneo, Viagrande, Catania, Italy
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Kaewjanthong P, Sooksai S, Sasano H, Hutvagner G, Bajan S, McGowan E, Boonyaratanakornkit V. Cell-penetrating peptides containing the progesterone receptor polyproline domain inhibits EGF signaling and cell proliferation in lung cancer cells. PLoS One 2022; 17:e0264717. [PMID: 35235599 PMCID: PMC8890653 DOI: 10.1371/journal.pone.0264717] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 02/15/2022] [Indexed: 01/10/2023] Open
Abstract
Non-small cell lung cancer (NSCLC) accounts for the majority (80-85%) of all lung cancers. All current available treatments have limited efficacy. The epidermal growth factor receptor (EGFR) plays a critical role in the development and progression of NSCLC, with high EGFR expression associated with increased cell proliferation and poor prognosis. Thus, interfering with EGFR signaling has been shown to effectively reduce cell proliferation and help in the treatment of NSCLC. We previously demonstrated that the progesterone receptor (PR) contains a polyproline domain (PPD) that directly interacts with Src homology 3 (SH3) domain-containing molecules and expression of PR-PPD peptides inhibits NSCLC cell proliferation. In this study, we investigated whether the introduction of PR-PPD by cell-penetrating peptides (CPPs) could inhibit EGF-induced cell proliferation in NSCLC cells. PR-PPD was attached to a cancer-specific CPP, Buforin2 (BR2), to help deliver the PR-PPD into NSCLC cells. Interestingly, addition of BR2-2xPPD peptides containing two PR-PPD repeats was more effective in inhibiting NSCLC proliferation and significantly reduced EGF-induced phosphorylation of Erk1/2. BR2-2xPPD treatment induced cell cycle arrest by inhibiting the expression of cyclin D1 and CDK2 genes in EGFR-wild type A549 cells. Furthermore, the combination treatment of EGFR-tyrosine kinase inhibitors (TKIs), including Gefitinib or Erlotinib, with BR2-2xPPD peptides further suppressed the growth of NSCLC PC9 cells harboring EGFR mutations as compared to EGFR-TKIs treatment alone. Importantly, BR2-2xPPD peptides mediated growth inhibition in acquired Gefitinib- and Erlotinib- resistant lung adenocarcinoma cells. Our data suggests that PR-PPD is the minimal protein domain sufficient to inhibit NSCLC cell growth and has the potential to be developed as a novel NSCLC therapeutic agent.
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Affiliation(s)
- Panthita Kaewjanthong
- Department of Clinical Chemistry and Graduate Program in Clinical Biochemistry and Molecular Medicine, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand
| | - Sarintip Sooksai
- The Institute of Biotechnology and Genetic Engineering, Chulalongkorn University, Bangkok, Thailand
| | - Hironobu Sasano
- Department of Anatomic Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Gyorgy Hutvagner
- School of Biomedical Engineering, Faculty of Engineering and IT, University of Technology Sydney, Australia
| | - Sarah Bajan
- School of Biomedical Engineering, Faculty of Engineering and IT, University of Technology Sydney, Australia
- School of Health and Behavioural Sciences, University of the Sunshine Coast, Australia
- Sunshine Coast Health Institute, Birtinya, Australia
| | - Eileen McGowan
- School of Life Sciences, University of Technology Sydney, Sydney, Australia
| | - Viroj Boonyaratanakornkit
- Department of Clinical Chemistry and Graduate Program in Clinical Biochemistry and Molecular Medicine, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand
- Age-related Inflammation and Degeneration Research Unit, Chulalongkorn University, Bangkok, Thailand
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Minchom A, Viteri S, Bazhenova L, Gadgeel SM, Ignatius Ou SH, Trigo J, Bauml JM, Backenroth D, Bhattacharya A, Li T, Mahadevia P, Girard N. Amivantamab compared with real-world therapies in patients with advanced non-small cell lung cancer harboring EGFR exon 20 insertion mutations who progressed after platinum-based chemotherapy. Lung Cancer 2022; 168:74-82. [DOI: 10.1016/j.lungcan.2022.03.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 02/28/2022] [Accepted: 03/03/2022] [Indexed: 12/19/2022]
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Okuma Y, Shimokawa M, Hashimoto K, Mizutani H, Wakui H, Murakami S, Atagi S, Minato K, Seike M, Ohe Y, Kubota K. Uncommon EGFR mutations conducted with osimertinib in patients with NSCLC: a study protocol of phase 2 study (UNICORN/TCOG1901). Future Oncol 2022; 18:523-531. [PMID: 35034503 DOI: 10.2217/fon-2021-0892] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Patients with uncommon EGFR-mutated non-small-cell lung cancer (NSCLC) demonstrated lower clinical efficacy of first-generation EGFR-tyrosine kinase inhibitors compared with patients harboring common EGFR-mutated NSCLC. The US FDA has approved afatinib for uncommon EGFR mutation positive NSCLC based on the pooled analysis in the first- or second-line setting. Osimertinib has limited evidence in the small sample sizes of phase 2 studies in any-line settings. The aim of the present single-arm, multicenter, phase 2 study is to evaluate the efficacy of osimertinib for previously untreated NSCLC. The primary end point is to assess the overall response to osimertinib. The secondary end points include disease control rate, progression-free survival, duration of time-to-treatment failure, overall survival and safety. Clinical trial registration: jRCTs071200002.
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Affiliation(s)
- Yusuke Okuma
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan
| | - Mototsugu Shimokawa
- Department of Biostatistics, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
| | - Kana Hashimoto
- Department of Thoracic Oncology & Respiratory Medicine, Tokyo Metropolitan Komagome Hospital, Tokyo 113-8677, Japan
| | - Hideaki Mizutani
- Department of Thoracic Oncology, Saitama Cancer Center, Saitama 362-0806, Japan
| | - Hiroshi Wakui
- Department of Internal Medicine, Division of Respiratory Diseases, The Jikei University School of Medicine, Tokyo 105-8461, Japan
| | - Shuji Murakami
- Deparmtment of Thoracic Oncology, Kanagawa Cancer Center, Kanagawa 241-8515, Japan
| | - Shinji Atagi
- Department of Thoracic Oncology, Kinki-Chuo Chest Medical Center, Osaka 591-8555, Japan
| | - Koichi Minato
- Division of Respiratory Medicine, Gunma Prefectural Cancer Center, Gunma 373-0828, Japan
| | - Masahiro Seike
- Department of Pulmonary Medicine & Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8602, Japan
| | - Yuichiro Ohe
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan
| | - Kaoru Kubota
- Department of Pulmonary Medicine & Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8602, Japan
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A Multicenter, Randomized Phase III Study Comparing Platinum Combination Chemotherapy Plus Pembrolizumab With Platinum Combination Chemotherapy Plus Nivolumab and Ipilimumab for Treatment-Naive Advanced Non-Small Cell Lung Cancer Without Driver Gene Alterations: JCOG2007 (NIPPON Study). Clin Lung Cancer 2021; 23:e285-e288. [PMID: 34802879 DOI: 10.1016/j.cllc.2021.10.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Accepted: 10/11/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND First-line treatment of non-small cell lung cancer (NSCLC) has undergone a paradigm shift to platinum combination chemotherapy together with an immune checkpoint inhibitor, regardless of the expression level of the programmed cell death-1 (PD-1) ligand PD-L1 on tumor cells. Moreover, such chemotherapy plus nivolumab (antibody to PD-1) and ipilimumab (antibody to cytotoxic T lymphocyte-associated protein-4) prolonged survival in advanced NSCLC patients compared with chemotherapy alone. We have now designed a randomized, controlled phase III trial (NIPPON, JCOG2007) to confirm that platinum combination chemotherapy plus nivolumab and ipilimumab is superior to such chemotherapy plus pembrolizumab (antibody to PD-1) for treatment-naive patients with advanced NSCLC. PATIENTS AND METHODS Chemotherapy-naïve patients aged 20 years or older with a performance status of 0 or 1 are randomly assigned in a 1:1 ratio to receive platinum combination chemotherapy and either pembrolizumab or nivolumab plus ipilimumab. Patients with known genetic driver alterations such as those affecting EGFR or ALK are excluded. Enrollment of 422 patients over 3 years at 55 oncology facilities throughout Japan is planned. The primary endpoint is overall survival. In addition, as ancillary research, metagenomic analysis of the gut microbiota will be performed with fecal samples collected before treatment onset, and the results will be examined for their association to therapeutic effect and adverse events. CONCLUSION If the primary endpoint is met, platinum combination chemotherapy together with nivolumab plus ipilimumab will be established as a new, more effective standard treatment for advanced NSCLC.
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Perdrizet K, Sutradhar R, Li Q, Liu N, Earle CC, Leighl NB. Second and later-line erlotinib use in non-small cell lung cancer: real world outcomes and practice patterns overtime in Canada. J Thorac Dis 2021; 13:5419-5429. [PMID: 34659808 PMCID: PMC8482335 DOI: 10.21037/jtd-21-804] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Accepted: 08/06/2021] [Indexed: 12/25/2022]
Abstract
Background In Canada, epidermal growth factor receptor (EGFR) inhibitor therapies in advanced non-small cell lung cancer (NSCLC) were initially approved regardless of EGFR status. The purpose of this study is to characterise the use of second or later-line erlotinib therapy in Ontario, Canada from 2007–2016, as well as evaluate the impact of erlotinib therapy on survival and emergency department (ED) visits in a real-world population. Methods This is a retrospective cohort study derived at ICES (formerly known as the Institute for Clinical and Evaluative Sciences) of advanced NSCLC patients diagnosed from 2007–2016 in Ontario, Canada, over the age of 65, who received at least one dose of first-line chemotherapy. The exposure of interest was receipt of second or later-line erlotinib. The primary outcome was the hazard ratio for mortality evaluated using a Cox proportional hazards model, and the secondary outcome, ED visits, was evaluated using a Poisson model. Results First-line chemotherapy was administered in 30.4% of stage IV NSCLC patients. Of these patients, 19.7% received second or later-line erlotinib. The proportion of patients prescribed second or later-line erlotinib decreased over the course of the study (P<0.0001). Unadjusted median overall survival in the entire cohort was 325 days (95% CI: 314–337 days), 513 days (95% CI: 485–539 days) in the erlotinib cohort, and 282 days (95% CI: 270–291 days) in the non-erlotinib cohort. Despite this, the adjusted hazard ratio for death was 1.89 (95% CI: 1.73–2.07, P<0.0001) for patients on erlotinib. Patients receiving erlotinib also had a marginally higher relative rates of ED visits with an adjusted relative risk of 1.10 (95% CI: 1.02–1.19, P=0.013). Conclusions This study highlights the importance of using EGFR targeted treatments in NSCLC patients with a predictive biomarker, and suggests that treatment with erlotinib therapy is unlikely to benefit unselected patients with advanced NSCLC.
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Affiliation(s)
- Kirstin Perdrizet
- Department of Oncology and Hematology, Princess Margaret Cancer Centre/University Health Network, Toronto, Canada.,Division of Oncology, William Osler Health System, Brampton, Canada.,Department of Medicine, University of Toronto, Toronto, ON, Canada.,Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada
| | - Rinku Sutradhar
- Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada.,ICES (formerly the Institute for Clinical and Evaluates Sciences), Toronto, Canada.,Department of Biostatistics, Dalla Lana School of Public Health at the University of Toronto, Toronto, Canada
| | - Qing Li
- ICES (formerly the Institute for Clinical and Evaluates Sciences), Toronto, Canada
| | - Ning Liu
- ICES (formerly the Institute for Clinical and Evaluates Sciences), Toronto, Canada
| | - Craig C Earle
- Department of Medicine, University of Toronto, Toronto, ON, Canada.,ICES (formerly the Institute for Clinical and Evaluates Sciences), Toronto, Canada.,Department of Oncology and Hematology, Sunnybrook Health Sciences Centre, Toronto, Canada
| | - Natasha B Leighl
- Department of Oncology and Hematology, Princess Margaret Cancer Centre/University Health Network, Toronto, Canada.,Department of Medicine, University of Toronto, Toronto, ON, Canada.,Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada
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Chien YN, Lin YC, Chang CL, Lin WC, Wu SY. Thoracic surgery improved overall survival in patients with stage IIIB-IV epidermal growth factor receptor-mutant lung adenocarcinoma who received and responded to tyrosine kinase inhibitor treatment. Lung Cancer 2021; 162:29-35. [PMID: 34662782 DOI: 10.1016/j.lungcan.2021.10.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 09/20/2021] [Accepted: 10/07/2021] [Indexed: 12/25/2022]
Abstract
PURPOSE No large-scale, prospective, randomized study has evaluated the effect of thoracic surgery on patients with unresectable stage IIIB-IV epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma who received and responded to EGFR tyrosine kinase inhibitor (TKI) treatment. Therefore, we designed a propensity-score-matched, nationwide, population-based, cohort study to investigate the effects of thoracic surgery on patients with EGFR-mutant lung adenocarcinoma. PATIENTS AND METHODS We included patients with unresectable stage IIIB-IV EGFR-mutant lung adenocarcinoma and categorized them into two groups according to their treatment modalities and compared their outcomes: the case group consisted of patients who underwent thoracic surgery for lung tumors after receiving and responding to EGFR-TKI treatment and the comparison group consisted of patients who received EGFR-TKI treatment alone until tumor progression. Patients in both groups were matched at a ratio of 1:4. RESULTS The matching process yielded a final cohort of 1395 patients (279 and 1,116 in the case and comparison groups, respectively) who were eligible for further analysis. According to multivariable Cox regression analyses, the adjusted hazard ratio (aHR; 95% confidence interval [CI]) for thoracic surgery for lung tumors after EGFR-TKI use and tumor response (group 2) compared with EGFR-TKI treatment alone (group 1) was 0.445 (0.351-0.564). CONCLUSIONS Thoracic surgery prolonged overall survival in patients with unresectable stage IIIB-IV EGFR-mutant lung adenocarcinoma who received and responded to EGFR-TKI treatment.
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Affiliation(s)
- Yu-Ning Chien
- Master Program of Big Data Analysis in Biomedicine, College of Medicine, Fu Jen Catholic University, Taipei, Taiwan
| | - Yi-Chun Lin
- School of Public Health, College of Public Health, Taipei Medical University, Taipei, Taiwan
| | - Chia-Lun Chang
- Department of Hemato-Oncology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Wei-Chun Lin
- Division of Chest Medicine, Department of Internal Medicine, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan.
| | - Szu-Yuan Wu
- Department of Food Nutrition and Health Biotechnology, College of Medical and Health Science, Asia University, Taichung, Taiwan; Big Data Center, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan; Division of Radiation Oncology, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan; Department of Healthcare Administration, College of Medical and Health Science, Asia University, Taichung, Taiwan; Cancer Center, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan; Graduate Institute of Business Administration, College of Management, Fu Jen Catholic University, Taipei, Taiwan; Centers for Regional Anesthesia and Pain Medicine, Taipei Municipal Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
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Poudel B, Desman J, Aihara G, Weidman DI, Tsang A, Kovrizhkin K, Pereira T, Arun S, Pradeep T, Matin S, Liddell RP. Adequacy of samples obtained via percutaneous core-needle rebiopsy for EGFR T790M molecular analysis in patients with non-small cell lung cancer following acquired resistance to first-line therapy: A systematic review and meta-analysis. Cancer Treat Res Commun 2021; 29:100470. [PMID: 34628209 DOI: 10.1016/j.ctarc.2021.100470] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 09/23/2021] [Accepted: 09/26/2021] [Indexed: 12/23/2022]
Abstract
MICRO ABSTRACT Rebiopsies characterizing resistance mutations in patients with non-small cell lung cancer (NSCLC) can guide personalized medicine and improve overall survival rates. In this systematic review, we examine the suitability of percutaneous core-needle biopsy (PT-CNB) to obtain adequate samples for molecular characterization of the acquired resistance mutation T790M. This review provides evidence that PT-CNB can obtain samples with high adequacy, with a mutation detection rate that is in accordance with prior literature. BACKGROUND Non-small cell lung cancer (NSCLC) comprises 85% of all lung cancers and has seen improved survival rates with the rise of personalized medicine. Resistance mutations to first-line therapies, such as T790M, however, render first-line therapies ineffective. Rebiopsies characterizing resistance mutations inform therapeutic decisions, which result in prolonged survival. Given the high efficacy of percutaneous core-needle biopsy (PT-CNB), we conducted the first systematic review to analyze the ability of PT-CNB to obtain samples of high adequacy in order to characterize the acquired resistance mutation T790M in patients with NSCLC. METHODS We performed a comprehensive literature search across PubMed, Embase, and CENTRAL. Search terms related to "NSCLC," "rebiopsy," and "PT-CNB" were used to obtain results. We included all prospective and retrospective studies that satisfied our inclusion and exclusion criteria. A random effects model was utilized to pool adequacy and detection rates of the chosen articles. We performed a systematic review, meta-analysis, and meta-regression to investigate the adequacy and T790M detection rates of samples obtained via PT-CNB. RESULTS Out of the 173 studies initially identified, 5 studies met the inclusion and exclusion criteria and were chosen for our final cohort of 436 patients for meta-analysis. The pooled adequacy rate of samples obtained via PT-CNB was 86.92% (95% CI: [79.31%, 92.0%]) and the pooled T790M detection rate was 46.0% (95% CI: [26.6%, 66.7%]). There was considerable heterogeneity among studies (I2 > 50%) in both adequacy and T790M detection rates. CONCLUSION PT-CNB can obtain adequate samples for T790M molecular characterization in NSCLC lung cancer patients. Additional prospective studies are needed to corroborate the results in this review.
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Affiliation(s)
- Bibhav Poudel
- Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America
| | - Jacob Desman
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, United States of America
| | - Gohta Aihara
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, United States of America
| | - Deborah I Weidman
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, United States of America
| | - Ashley Tsang
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, United States of America
| | - Katherine Kovrizhkin
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, United States of America
| | - Tatiana Pereira
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, United States of America
| | - Siddharth Arun
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, United States of America
| | - Tejus Pradeep
- Department of Ophthalmology, Hospital of the University of Pennsylvania, Philadelphia, PA, United States of America
| | - Shababa Matin
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, United States of America
| | - Robert P Liddell
- Department of Radiology and Radiological Science, Johns Hopkins Hospital, Baltimore, MD, United States of America.
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Chen D, Jin Z, Zhang J, Xu C, Zhu K, Ruan Y, Zhang B, Chen B, Shen J. Efficacy and Safety of Neoadjuvant Targeted Therapy vs. Neoadjuvant Chemotherapy for Stage IIIA EGFR-Mutant Non-small Cell Lung Cancer: A Systematic Review and Meta-Analysis. Front Surg 2021; 8:715318. [PMID: 34490338 PMCID: PMC8417411 DOI: 10.3389/fsurg.2021.715318] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 07/26/2021] [Indexed: 12/25/2022] Open
Abstract
Purpose: The role of targeted therapy in the neoadjuvant field of stage IIIA epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) is still controversial. We sought to evaluate the efficacy and safety of neoadjuvant targeted therapy (NTT) with neoadjuvant chemotherapy (NCT) used as a benchmark comparator. Methods: A systematic search was conducted in four databases (Pubmed, Cochrane Library, Embase, CNKI) for eligible studies on NTT published before October 2020. The primary endpoints were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and grade 3/4 adverse events (AEs). Statistical analysis and bias assessment were performed by RevMan 5.3. Results: A total of 319 patients, including 3 randomized controlled trials and 2 non-randomized controlled trials, were included in the meta-analysis. Perform the second subgroup analysis after excluding 2 non-randomized controlled trials. The meta-analysis reveals that, for EGFR mutation-positive stage IIIA NSCLC patients, compared with NCT, NTT can significantly increase ORR (relative risk [RR]:1.70, 95% confidence interval [CI]:1.35–2.15; subgroup-RR:1.56, 95% CI 1.23–2.0) and significantly reduce grade 3/4 AEs (RR:0.5, 95% CI 0.34–0.75; subgroup-RR: 0.53, 95% CI 0.26–1.08). The OS of the NTT arm is slightly higher, but the difference is not significant (hazards ratio [HR]: 0.74, 95% CI: 0.43–1.27; subgroup-HR: 0.64 95% CI 0.40–1.03). No difference in PFS was found (HR: 0.81, 95% CI 0.27–2.44). Conclusion: In neoadjuvant setting, targeted therapy has a definitive effect on patients with EGFR mutation-positive stage IIIA NSCLC and is even better than chemotherapy in terms of toxicity and tumor response rate. Systematic Review Registration: PROSPERO, identifier CRD42021221136.
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Affiliation(s)
- Dong Chen
- Department of Thoracic Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Zixian Jin
- Department of Thoracic Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Jian Zhang
- Department of Thoracic Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Congcong Xu
- Department of Thoracic Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Kanghao Zhu
- Department of Thoracic Surgery, Taizhou Hospital, Zhejiang University, Linhai, China
| | - Yuhang Ruan
- Department of Thoracic Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Bo Zhang
- Department of Thoracic Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Baofu Chen
- Department of Thoracic Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Jianfei Shen
- Department of Thoracic Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
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Jiang H, Xu A, Xia W, Xia X, Li P, Zhang B, Zhu K, Zhou S, Wang R. Nivolumab monotherapy or combination therapy with ipilimumab for lung cancer: a systemic review and meta-analysis. Cancer Cell Int 2021; 21:426. [PMID: 34391428 PMCID: PMC8364020 DOI: 10.1186/s12935-021-02100-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 07/17/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The high incidence and mortality of lung cancer have seriously affected human life and health. Nivolumab is a monoclonal antibody that can inhibit programmed death 1 (PD-1) and Ipilimumab is a monoclonal antibody against CTLA-4(cytotoxic T lymphocyte-associated antigen 4), both of which can prevent the immune escape of tumor cells. Our goal was to synthesize evidence from published randomized controlled trials involving the safety and efficacy of either Nivolumab alone or in combination for the treatment of unresectable lung cancer. METHODS We searched the following electronic databases: PubMed, Embase, and Cochrane libraries, and screened the retrieved records for eligibility. We used the Stata16 software for the analyses. The results of the analysis are expressed as hazard ratios (HRs) or risk ratios (RRs) and their corresponding 95% confidence intervals (CI). RESULTS The final analysis included seven trials involving 3817 patients. Among patients with advanced lung cancer, patients using immunotherapy had better overall survival (OS), progression-free survival (PFS), and an objective response rate (ORR) than patients receiving chemotherapy. The HR of Nivolumab monotherapy or combination therapy with OS was compared with that of chemotherapy (HR: 0.73, 95% CI 0.64-0.83; HR: 0.67, 95% CI 0.55-0.81), and the HR of PFS was (HR: 0.81, 95% CI 0.69-0.94; HR: 0.67, 95% CI 0.55-0.82). CONCLUSIONS Immunotherapy has been shown to have more clinically meaningful survival benefits for patients with lung cancer, whether monotherapy or combination immunotherapy. CRD42020213440.
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Affiliation(s)
- Huihui Jiang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Aiqun Xu
- Department of General Medicine, Hefei Second People's Hospital, Hefei, 230001, China
| | - Wanli Xia
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Xingyuan Xia
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Pulin Li
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Binbin Zhang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Ke Zhu
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Sijing Zhou
- Hefei Third Clinical College of Anhui Medical University, Hefei, 230022, China. .,Hefei Prevention and Treatment Center for Occupational Diseases, Hefei, 230022, China.
| | - Ran Wang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
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Feng X, Ding W, Ma J, Liu B, Yuan H. Targeted Therapies in Lung Cancers: Current Landscape and Future Prospects. Recent Pat Anticancer Drug Discov 2021; 16:540-551. [PMID: 34132185 DOI: 10.2174/1574892816666210615161501] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 03/09/2021] [Accepted: 03/31/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Lung cancer is the most common and malignant cancer worldwide. Targeted therapies have emerged as a promising treatment strategy for lung cancers. OBJECTIVE The objective of this study is to evaluate the current landscape of targets and finding promising targets for future new drug discovery for lung cancers by identifying the science-technology-clinical development pattern and mapping the interaction network of targets. METHODS Targets for cancers were classified into 3 groups based on a paper published in Nature. We search for scientific literature, patent documents and clinical trials of targets in Group 1 and Group 2 for lung cancers. Then, a target-target interaction network of Group 1 was constructed, and the science-technology-clinical(S-T-C) development patterns of targets in Group 1 were identified. Finally, based on the cluster distribution and the development pattern of targets in Group 1, interactions between the targets were employed to predict potential targets in Group 2 on drug development. RESULTS The target-target interaction(TTI)network of group 1 resulted in 3 clusters with different developmental stages. The potential targets in Group 2 are divided into 3 ranks. Level-1 is the first priority and level-3 is the last. Level-1 includes 16 targets, such as STAT3, CRKL, and PTPN11, that are mostly involved in signaling transduction pathways. Level-2 and level-3 contain 8 and 6 targets related to various biological functions. CONCLUSION This study will provide references for drug development in lung cancers, emphasizing that priorities should be given to targets in Level-1, whose mechanisms are worth further exploration.
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Affiliation(s)
- Xin Feng
- School of Business Administration, Shenyang Pharmaceutical University, Shenyang, China
| | - Wenqing Ding
- School of Business Administration, Shenyang Pharmaceutical University, Shenyang, China
| | - Junhong Ma
- School of Business Administration, Shenyang Pharmaceutical University, Shenyang, China
| | - Baijun Liu
- School of Business Administration, Shenyang Pharmaceutical University, Shenyang, China
| | - Hongmei Yuan
- School of Business Administration, Shenyang Pharmaceutical University, Shenyang, China
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Fanjat Y, Barazzutti H, Di Mauro I, Tabary-Martin L, Duranton-Tanneur V, Gimet S, Bérard H, Pedeutour F. Molecular follow-up of first-line treatment by osimertinib in lung cancer: Importance of using appropriate tools for detecting EGFR resistance mutation C797S. Cancer Genet 2021; 256-257:158-161. [PMID: 34157597 DOI: 10.1016/j.cancergen.2021.06.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 04/26/2021] [Accepted: 06/06/2021] [Indexed: 12/22/2022]
Abstract
The C797S mutation encoded by EGFR exon 20 is classically observed as a tertiary event in EGFR-mutant non-small-cell lung carcinoma (NSCLC) primarily treated by first generation tyrosine kinase inhibitors (TKI) and secondarily treated by third-generation TKI, such as osimertinib, if the EGFR-T790M resistance mutation is detected. Recently, significant prolonged progression free survival has been observed following first-line osimertinib, in EGFR-mutant NSLC. While mechanisms of molecular resistance to first-generation TKI have been well studied, little is known about resistance induced by primary third-generation TKI treatments. We report the case of a 65 year-old female treated by first-line osimertinib for a multimetastatic exon 19-EGFR-mutant NSCLC. EGFR-C797S resistance mutation and PIK3CA mutation were detected together with the remaining EGFR-exon 19 deletion. This observation provides insights of acquired resistance to first line-osimertinib. It also highlights the importance of making molecular platforms which perform routine EGFR testing in lung cancer aware of the kind of therapeutic protocols given to the patient. Indeed, for rapid results or low-costs procedures, some targeted methods specifically targeting T790M may be used at relapse and may overlook alterations such as C797S or PIK3CA mutations. Targeted next generation sequencing is therefore a recommended option.
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Affiliation(s)
- Y Fanjat
- Laboratory of Solid Tumor Genetics, University Hospital of Nice-Côte d'Azur University, Nice, France.
| | - H Barazzutti
- Hôpital d'Instruction des Armées Sainte-Anne, Toulon, France
| | - I Di Mauro
- Laboratory of Solid Tumor Genetics, University Hospital of Nice-Côte d'Azur University, Nice, France; Laboratory of Solid Tumor Genetics, Institute for Research on Cancer and Aging of Nice (IRCAN), CNRS UMR 7284/INSERM U1081, Nice, France.
| | | | - V Duranton-Tanneur
- Laboratory of Solid Tumor Genetics, University Hospital of Nice-Côte d'Azur University, Nice, France; Laboratory of Solid Tumor Genetics, Institute for Research on Cancer and Aging of Nice (IRCAN), CNRS UMR 7284/INSERM U1081, Nice, France.
| | - S Gimet
- Laboratory of Solid Tumor Genetics, University Hospital of Nice-Côte d'Azur University, Nice, France; Laboratory of Solid Tumor Genetics, Institute for Research on Cancer and Aging of Nice (IRCAN), CNRS UMR 7284/INSERM U1081, Nice, France.
| | - H Bérard
- Hôpital d'Instruction des Armées Sainte-Anne, Toulon, France.
| | - F Pedeutour
- Laboratory of Solid Tumor Genetics, University Hospital of Nice-Côte d'Azur University, Nice, France; Laboratory of Solid Tumor Genetics, Institute for Research on Cancer and Aging of Nice (IRCAN), CNRS UMR 7284/INSERM U1081, Nice, France.
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Liu R, Ota K, Iwama E, Yoneshima Y, Tanaka K, Inoue H, Tagawa T, Oda Y, Mori M, Nakanishi Y, Okamoto I. Quantification of HER family dimers by proximity ligation assay and its clinical evaluation in non-small cell lung cancer patients treated with osimertinib. Lung Cancer 2021; 158:156-161. [PMID: 34059353 DOI: 10.1016/j.lungcan.2021.05.023] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 05/12/2021] [Accepted: 05/20/2021] [Indexed: 11/17/2022]
Abstract
OBJECTIVES The epidermal growth factor receptor (EGFR, also known as Her1) is a member of the human epidermal growth factor receptor (HER) family of proteins and a target of tyrosine kinase inhibitors (TKIs) in the treatment of non-small cell lung cancer (NSCLC) positive for activating mutations ofEGFR. Signal transduction by HER family proteins is dependent on their homo- or heterodimerization, but little is known of the relation between the relative proportions of such dimers of Her1 and sensitivity to EGFR-TKIs. We here investigated the feasibility of assessing this relation with the in situ proximity ligation assay (PLA) technique, which is able to detect the interaction of two proteins of interest when they are in close proximity. MATERIALS AND METHODS In situ PLA was applied to detect Her1 homodimers and Her1 heterodimers in NSCLC cell lines and tissue specimens positive for EGFR activating mutations. RESULTS In situ PLA allowed visualization and quantitative assessment of Her1 homodimers as well as of Her1 heterodimers with Her2, Her3, or Her4 not only in NSCLC cell lines but also in NSCLC tissue specimens obtained from various anatomic sites and by different collection methods. Treatment of NSCLC cell lines with EGFR-TKIs resulted in a decrease in the number of Her1 dimers, with the effect on homodimers being greater than that on heterodimers. A high ratio of Her1 heterodimers to homodimers was associated with poor progression-free survival in NSCLC patients treated with osimertinib. CONCLUSION In situ PLA allows the detection of HER family dimers in NSCLC tissue, and quantitative assessment of Her1 homo- and heterodimers may prove informative for prediction of the response of NSCLC patients to EGFR-TKI treatment.
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Affiliation(s)
- Renpeng Liu
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Keiichi Ota
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan; Department of Comprehensive Clinical Oncology, Faculty of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
| | - Eiji Iwama
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Yasuto Yoneshima
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Kentaro Tanaka
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Hiroyuki Inoue
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan; Department of Respiratory Medicine, Fukuoka University Hospital, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan
| | - Tetsuzo Tagawa
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Masaki Mori
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Yoichi Nakanishi
- Kitakyushu City Hospital Organization, 2-1-1 Bashaku, Kokurakita-ku, Kitakyushu, 802-8561, Japan
| | - Isamu Okamoto
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
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El Ayachy R, Giraud N, Giraud P, Durdux C, Giraud P, Burgun A, Bibault JE. The Role of Radiomics in Lung Cancer: From Screening to Treatment and Follow-Up. Front Oncol 2021; 11:603595. [PMID: 34026602 PMCID: PMC8131863 DOI: 10.3389/fonc.2021.603595] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 04/06/2021] [Indexed: 12/12/2022] Open
Abstract
PURPOSE Lung cancer represents the first cause of cancer-related death in the world. Radiomics studies arise rapidly in this late decade. The aim of this review is to identify important recent publications to be synthesized into a comprehensive review of the current status of radiomics in lung cancer at each step of the patients' care. METHODS A literature review was conducted using PubMed/Medline for search of relevant peer-reviewed publications from January 2012 to June 2020. RESULTS We identified several studies at each point of patient's care: detection and classification of lung nodules (n=16), determination of histology and genomic (n=10) and finally treatment outcomes predictions (=23). We reported the methodology of those studies and their results and discuss the limitations and the progress to be made for clinical routine applications. CONCLUSION Promising perspectives arise from machine learning applications and radiomics based models in lung cancers, yet further data are necessary for their implementation in daily care. Multicentric collaboration and attention to quality and reproductivity of radiomics studies should be further consider.
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Affiliation(s)
- Radouane El Ayachy
- Radiation Oncology Department, Georges Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France
- Cancer Research and Personalized Medicine-Integrated Cancer Research Center (SIRIC), Georges Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France
- INSERM UMR 1138 Team 22: Information Sciences to support Personalized Medicine, Cordeliers Research Centre, Paris Descartes University, Paris, France
| | - Nicolas Giraud
- INSERM UMR 1138 Team 22: Information Sciences to support Personalized Medicine, Cordeliers Research Centre, Paris Descartes University, Paris, France
- Radiation Oncology Department, Haut-Lévêque Hospital, CHU de Bordeaux, Pessac, France
| | - Paul Giraud
- Radiation Oncology Department, Georges Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France
- Cancer Research and Personalized Medicine-Integrated Cancer Research Center (SIRIC), Georges Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France
- INSERM UMR 1138 Team 22: Information Sciences to support Personalized Medicine, Cordeliers Research Centre, Paris Descartes University, Paris, France
| | - Catherine Durdux
- Radiation Oncology Department, Georges Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France
- Cancer Research and Personalized Medicine-Integrated Cancer Research Center (SIRIC), Georges Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France
| | - Philippe Giraud
- Radiation Oncology Department, Georges Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France
- Cancer Research and Personalized Medicine-Integrated Cancer Research Center (SIRIC), Georges Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France
| | - Anita Burgun
- Cancer Research and Personalized Medicine-Integrated Cancer Research Center (SIRIC), Georges Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France
- INSERM UMR 1138 Team 22: Information Sciences to support Personalized Medicine, Cordeliers Research Centre, Paris Descartes University, Paris, France
| | - Jean Emmanuel Bibault
- Radiation Oncology Department, Georges Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France
- Cancer Research and Personalized Medicine-Integrated Cancer Research Center (SIRIC), Georges Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France
- INSERM UMR 1138 Team 22: Information Sciences to support Personalized Medicine, Cordeliers Research Centre, Paris Descartes University, Paris, France
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Yoneshima Y, Morita S, Ando M, Nakamura A, Iwasawa S, Yoshioka H, Goto Y, Takeshita M, Harada T, Hirano K, Oguri T, Kondo M, Miura S, Hosomi Y, Kato T, Kubo T, Kishimoto J, Yamamoto N, Nakanishi Y, Okamoto I. Phase 3 Trial Comparing Nanoparticle Albumin-Bound Paclitaxel With Docetaxel for Previously Treated Advanced NSCLC. J Thorac Oncol 2021; 16:1523-1532. [PMID: 33915251 DOI: 10.1016/j.jtho.2021.03.027] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 02/12/2021] [Accepted: 03/30/2021] [Indexed: 11/26/2022]
Abstract
INTRODUCTION We aimed to evaluate the efficacy and safety of nanoparticle albumin-bound (nab-) paclitaxel for previously treated patients with advanced NSCLC. METHODS In this randomized, open-label, noninferiority phase 3 trial, we enrolled patients with advanced NSCLC previously treated with cytotoxic chemotherapy. Patients were randomly allocated (1:1) to receive docetaxel (60 mg/m2) on day 1 or nab-paclitaxel (100 mg/m2) on days 1, 8, and 15 of a 21-day cycle. The primary end point was overall survival (OS) analyzed on an intention-to-treat basis. RESULTS Between May 22, 2015, and March 12, 2018, a total of 503 patients were randomly allocated to the treatment. Median OS was 16.2 months (95% confidence interval [CI]: 14.4-19.0) for the 252 patients allocated to nab-paclitaxel and 13.6 months (95% CI: 10.9-16.5) for the 251 patients allocated to docetaxel (hazard ratio = 0.85, 95.2% CI: 0.68-1.07). Median progression-free survival was 4.2 months (95% CI: 3.9-5.0) for the nab-paclitaxel group versus 3.4 months (95% CI: 2.9-4.1) for the docetaxel group (hazard ratio = 0.76, 95% CI: 0.63-0.92, p = 0.0042). The objective response rate was 29.9% (95% CI: 24.0-36.2) for the nab-paclitaxel group and 15.4% (95% CI: 10.9-20.7) for the docetaxel group (p = 0.0002). Adverse events of grade greater than or equal to 3 included febrile neutropenia (5 of 245 patients [2%] in the nab-paclitaxel group versus 55 of 249 patients [22%] in the docetaxel group) and peripheral sensory neuropathy (24 [10%] versus 2 [1%], respectively). CONCLUSIONS Nab-paclitaxel was noninferior to docetaxel in terms of OS. It should, thus, be considered a standard treatment option for previously treated patients with advanced NSCLC.
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Affiliation(s)
- Yasuto Yoneshima
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Satoshi Morita
- Department of Biomedical Statistics and Bioinformatics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Masahiko Ando
- Department of Advanced Medicine, Nagoya University Hospital, Nagoya, Japan
| | - Atsushi Nakamura
- Department of Pulmonary Medicine, Sendai Kousei Hospital, Sendai, Japan
| | | | - Hiroshige Yoshioka
- Department of Thoracic Oncology, Kansai Medical University Hospital, Hirakata, Japan
| | - Yasuhiro Goto
- Department of Respiratory Medicine, Fujita Health University School of Medicine, Toyoake, Japan
| | - Masafumi Takeshita
- Department of Respiratory Medicine, Kitakyushu Municipal Medical Center, Kitakyushu, Japan
| | - Toshiyuki Harada
- Center for Respiratory Diseases, JCHO Hokkaido Hospital, Sapporo, Japan
| | - Katsuya Hirano
- Department of Respiratory Medicine, Hyogo Prefectural Amagasaki General Medical Center, Amagasaki, Japan
| | - Tetsuya Oguri
- Department of Education and Research Center for Community Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Masashi Kondo
- Department of Respiratory Medicine, Fujita Health University School of Medicine, Toyoake, Japan
| | - Satoru Miura
- Department of Internal Medicine, Niigata Cancer Center Hospital, Niigata, Japan
| | - Yukio Hosomi
- Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Terufumi Kato
- Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama, Japan
| | - Toshio Kubo
- Center for Clinical Oncology, Okayama University Hospital, Okayama, Japan
| | - Junji Kishimoto
- Center for Clinical and Translational Research, Kyushu University Hospital, Fukuoka, Japan
| | | | - Yoichi Nakanishi
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Center for Clinical and Translational Research, Kyushu University Hospital, Fukuoka, Japan
| | - Isamu Okamoto
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
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Hu J, Chen Y, Zhu X, Ma Q, Zhang J, Jiang G, Zhang P. Surgical choice of non-small cell lung cancer with unexpected pleural dissemination intraoperatively. BMC Cancer 2021; 21:445. [PMID: 33888088 PMCID: PMC8061008 DOI: 10.1186/s12885-021-08180-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 04/08/2021] [Indexed: 12/09/2022] Open
Abstract
BACKGROUND Whether patients with non-small cell lung cancer (NSCLC) with unexpected pleural dissemination (UPD) could get survival benefit from tumor resection remained controversial. METHODS Totally, 169 patients with NSCLC with UPD were included between 2012 and 2016. Patients were divided into the tumor resection and open-close group. Progression-free survival (PFS) and overall survival (OS) were compared with a log-rank test. The multivariable Cox analysis was applied to identify prognostic factors. RESULTS Sixty-five patients received open-close surgery and 104 patients underwent main tumor and visible pleural nodule resection. Tumor resection significantly prolonged OS (hazard ratio [HR]: 0.408, P < 0.001), local PFS (HR: 0.283, P < 0.001), regional PFS (HR: 0.506, P = 0.005), and distant metastasis (HR: 0.595, P = 0.032). Multivariable Cox analysis confirmed that surgical method was an independent prognostic factor for OS, local PFS and regional PFS, except distant metastasis. Subgroup analyses indicated that tumor resection could not improve OS in the patients who received targeted therapy (HR: 0.649, P = 0.382), however, tumor resection was beneficial for the patients who received adjuvant chemotherapy alone (HR: 0.322, P < 0.001). In the tumor resection group, lobectomy (HR: 0.960, P = 0.917) and systematic lymphadenectomy (HR: 1.512, P = 0.259) did not show survival benefit for OS. CONCLUSIONS Main tumor and visible pleural nodule resection could improve prognosis in patients with UPD who could not receive adjuvant targeted therapy. Sublobar resection without systematic lymphadenectomy may be the optimal procedure.
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Affiliation(s)
- Junjie Hu
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, No. 507 Zhengmin Road, Yangpu District, Shanghai, 200433, P.R. China
| | - Yan Chen
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, No. 507 Zhengmin Road, Yangpu District, Shanghai, 200433, P.R. China
| | - Xinsheng Zhu
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, No. 507 Zhengmin Road, Yangpu District, Shanghai, 200433, P.R. China
| | - Qiang Ma
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, No. 507 Zhengmin Road, Yangpu District, Shanghai, 200433, P.R. China
| | - Jing Zhang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, No. 507 Zhengmin Road, Yangpu District, Shanghai, 200433, P.R. China
| | - Gening Jiang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, No. 507 Zhengmin Road, Yangpu District, Shanghai, 200433, P.R. China
| | - Peng Zhang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, No. 507 Zhengmin Road, Yangpu District, Shanghai, 200433, P.R. China.
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Zhao D, Fan J, Peng L, Huang B, Zhu Y, Shi H, Dai X, Nie X. Two different patterns of lung adenocarcinoma with concomitant EGFR mutation and ALK rearrangement. TUMORI JOURNAL 2021; 108:12-18. [PMID: 33818198 DOI: 10.1177/03008916211005546] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements are considered mutually exclusive in non-small cell lung cancer (NSCLC), especially in lung adenocarcinoma (LUAC). However, sporadic cases harboring concomitant EGFR and ALK alterations have been increasingly reported. There is no consensus opinion regarding the treatment of patients positive for both molecular alterations. NSCLC with EGFR/ALK coalterations should be separated into two subtypes: unifocal and multifocal LUAC. Here, we present an overview of the available literature regarding this rare group of patients to provide useful suggestions for therapeutic strategies.
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Affiliation(s)
- Dashi Zhao
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jun Fan
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Li Peng
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bo Huang
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yili Zhu
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Heshui Shi
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaofang Dai
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiu Nie
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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