Pub Date : 2024-05-01DOI: 10.1016/j.jtocrr.2024.100672
Duo Xu MD, PhD , Yanyun Gao PhD , Haitang Yang MD, PhD , Marc Spils MD , Thomas M. Marti PhD , Tereza Losmanová MD , Min Su PhD , Wenxiang Wang MD , Qinghua Zhou MD , Patrick Dorn MD , Yongqian Shu MD, PhD , Ren-Wang Peng PhD
Introduction
Malignant pleural mesothelioma (MPM) is a rare and universally lethal malignancy with limited treatment options. Immunotherapy with immune checkpoint inhibitors (ICIs) has recently been approved for unresectable MPM, but response to ICIs is heterogeneous, and reliable biomarkers for prospective selection of appropriate subpopulations likely to benefit from ICIs remain elusive.
Methods
We performed multiscale integrative analyses of published primary tumor data set from The Cancer Genome Atlas (TCGA) and the French cohort E-MTAB-1719 to unravel the tumor immune microenvironment of MPM deficient in BAP1, one of the most frequently mutated tumor suppressor genes (TSGs) in the disease. The molecular profiling results were validated in independent cohorts of patients with MPM using immunohistochemistry and multiplex immunohistochemistry.
Results
We revealed that BAP1 deficiency enriches immune-associated pathways in MPM, leading to increased mRNA signatures of interferon alfa/gamma response, activating dendritic cells, immune checkpoint receptors, and T-cell inflammation. This finding was confirmed in independent patient cohorts, where MPM tumors with low BAP1 levels are associated with an inflammatory tumor immune microenvironment characterized by increased exhausted precursor T-cells and macrophages but decreased myeloid-derived suppressor cells (MDSCs). In addition, BAP1low MPM cells are in close proximity to T cells and therefore can potentially be targeted with ICIs. Finally, we revealed that BAP1-proficient MPM is associated with a hyperactive mitogen-activated protein kinase (MAPK) pathway and may benefit from treatment with MEK inhibitors (MEKis).
Conclusion
Our results suggest that BAP1 plays an immunomodulatory role in MPM and that BAP1-deficient MPM may benefit from immunotherapy, which merits further clinical investigation.
导言恶性胸膜间皮瘤（MPM）是一种罕见的致死性恶性肿瘤，治疗方案有限。使用免疫检查点抑制剂（ICIs）的免疫疗法最近被批准用于不可切除的间皮瘤，但对ICIs的反应是异质性的，而用于前瞻性地选择可能从ICIs中获益的适当亚群的可靠生物标志物仍然难以获得。方法我们对癌症基因组图谱（TCGA）和法国队列E-MTAB-1719中已发表的原发肿瘤数据集进行了多尺度综合分析，以揭示BAP1（该疾病中最常突变的肿瘤抑制基因（TSG）之一）缺失的MPM的肿瘤免疫微环境。结果我们发现，BAP1缺失会丰富骨髓瘤的免疫相关通路，导致干扰素α/γ反应、活化树突状细胞、免疫检查点受体和T细胞炎症的mRNA特征增加。这一发现在独立的患者队列中得到了证实，BAP1 水平低的 MPM 肿瘤与炎症性肿瘤免疫微环境有关，其特征是衰竭的前体 T 细胞和巨噬细胞增多，但髓源性抑制细胞（MDSCs）减少。此外，BAP1 低的 MPM 细胞靠近 T 细胞，因此有可能成为 ICIs 的靶点。最后，我们发现 BAP1 缺乏的 MPM 与丝裂原活化蛋白激酶（MAPK）通路过度活跃有关，可能会从 MEK 抑制剂（MEKis）的治疗中获益。
{"title":"BAP1 Deficiency Inflames the Tumor Immune Microenvironment and Is a Candidate Biomarker for Immunotherapy Response in Malignant Pleural Mesothelioma","authors":"Duo Xu MD, PhD , Yanyun Gao PhD , Haitang Yang MD, PhD , Marc Spils MD , Thomas M. Marti PhD , Tereza Losmanová MD , Min Su PhD , Wenxiang Wang MD , Qinghua Zhou MD , Patrick Dorn MD , Yongqian Shu MD, PhD , Ren-Wang Peng PhD","doi":"10.1016/j.jtocrr.2024.100672","DOIUrl":"10.1016/j.jtocrr.2024.100672","url":null,"abstract":"<div><h3>Introduction</h3><p>Malignant pleural mesothelioma (MPM) is a rare and universally lethal malignancy with limited treatment options. Immunotherapy with immune checkpoint inhibitors (ICIs) has recently been approved for unresectable MPM, but response to ICIs is heterogeneous, and reliable biomarkers for prospective selection of appropriate subpopulations likely to benefit from ICIs remain elusive.</p></div><div><h3>Methods</h3><p>We performed multiscale integrative analyses of published primary tumor data set from The Cancer Genome Atlas (TCGA) and the French cohort E-MTAB-1719 to unravel the tumor immune microenvironment of MPM deficient in <em>BAP1</em>, one of the most frequently mutated tumor suppressor genes (TSGs) in the disease. The molecular profiling results were validated in independent cohorts of patients with MPM using immunohistochemistry and multiplex immunohistochemistry.</p></div><div><h3>Results</h3><p>We revealed that <em>BAP1</em> deficiency enriches immune-associated pathways in MPM, leading to increased mRNA signatures of interferon alfa/gamma response, activating dendritic cells, immune checkpoint receptors, and T-cell inflammation. This finding was confirmed in independent patient cohorts, where MPM tumors with low BAP1 levels are associated with an inflammatory tumor immune microenvironment characterized by increased exhausted precursor T-cells and macrophages but decreased myeloid-derived suppressor cells (MDSCs). In addition, BAP1<sup>low</sup> MPM cells are in close proximity to T cells and therefore can potentially be targeted with ICIs. Finally, we revealed that <em>BAP1</em>-proficient MPM is associated with a hyperactive mitogen-activated protein kinase (MAPK) pathway and may benefit from treatment with MEK inhibitors (MEKis).</p></div><div><h3>Conclusion</h3><p>Our results suggest that BAP1 plays an immunomodulatory role in MPM and that <em>BAP1</em>-deficient MPM may benefit from immunotherapy, which merits further clinical investigation.</p></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666364324000420/pdfft?md5=0474ae2ad9f1cfb0a39f806553857fa3&pid=1-s2.0-S2666364324000420-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140398962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-01DOI: 10.1016/j.jtocrr.2024.100642
{"title":"Acknowledgment of Reviewers","authors":"","doi":"10.1016/j.jtocrr.2024.100642","DOIUrl":"https://doi.org/10.1016/j.jtocrr.2024.100642","url":null,"abstract":"","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666364324000122/pdfft?md5=24fa93b0c8f77c535159560161ec8932&pid=1-s2.0-S2666364324000122-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141084650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-01DOI: 10.1016/j.jtocrr.2024.100692
Kaushal Parikh, Faye Harris, G. Karagouga, Amy Schrandt, Jay Mandrekar, Sarah Johnson, A. Mccune, Dorsay Sadeghian, Roy Debarshi, Katarzyna Polonis, Athanasios Gaitatzes, A. Bungum, Eric S. Edell, Janet L. Schaefer Klein, M. Borad, Tobias Peikert, F. Kosari, John C. Cheville, G. Vasmatzis, A. S. Mansfield
{"title":"Individualized cell-free DNA monitoring with chromosomal junctions for mesothelioma","authors":"Kaushal Parikh, Faye Harris, G. Karagouga, Amy Schrandt, Jay Mandrekar, Sarah Johnson, A. Mccune, Dorsay Sadeghian, Roy Debarshi, Katarzyna Polonis, Athanasios Gaitatzes, A. Bungum, Eric S. Edell, Janet L. Schaefer Klein, M. Borad, Tobias Peikert, F. Kosari, John C. Cheville, G. Vasmatzis, A. S. Mansfield","doi":"10.1016/j.jtocrr.2024.100692","DOIUrl":"https://doi.org/10.1016/j.jtocrr.2024.100692","url":null,"abstract":"","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141131670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
NSCLC is a leading cause of cancer-related mortality worldwide. Specific genetic alterations, such as MET exon 14 (METex14) skipping, have been identified in NSCLC, allowing targeted therapy. Tepotinib, a highly selective MET inhibitor, has displayed promise in patients with advanced NSCLC. Nevertheless, challenges arise when identifying treatment strategies for patients with discordant results regarding METex14 skipping detection between diagnostic tests.
Methods
We investigated patients with NSCLC and discordant results for METex14 skipping between the Oncomine Dx Target Test (ODxTT) and ArcherMET. Clinical response, adverse events, and the duration of tepotinib treatment were assessed, and statistical analysis was performed.
Results
Among the 19 patients deemed METex14 skipping positive by ODxTT, only 10 had concordant results with ArcherMET. The number of METex14 skipping reads detected by ODxTT was significantly lower in discordant cases. Of the 19 patients, 14 received tepotinib, and comparable response and disease control rates were observed in both concordant and discordant cases. The duration of treatment did not significantly differ between the two groups.
Conclusions
Our findings suggest that tepotinib has comparable therapeutic effects in patients with METex14 skipping-positive NSCLC irrespective of the concordance of results between ODxTT and ArcherMET. Tepotinib is a possible treatment option for patients with METex14 skipping, even in patients with discordant test results.
{"title":"Brief Report: Tepotinib as a Treatment Option in MET Exon 14 Skipping-Positive Lung Cancers—Investigating Discordance Between ArcherMET and the Oncomine Dx Target Test","authors":"Yoshihiro Miyashita MD , Yosuke Hirotsu PhD , Yuki Nagakubo MS , Hiroaki Kobayashi MD , Makoto Kawaguchi MD , Koki Hata MD , Ryota Saito MD , Yumiko Kakizaki MD , Toshiharu Tsutsui PhD , Toshio Oyama MD , Masao Omata MD","doi":"10.1016/j.jtocrr.2024.100679","DOIUrl":"https://doi.org/10.1016/j.jtocrr.2024.100679","url":null,"abstract":"<div><h3>Introduction</h3><p>NSCLC is a leading cause of cancer-related mortality worldwide. Specific genetic alterations, such as <em>MET</em> exon 14 (<em>MET</em>ex14) skipping, have been identified in NSCLC, allowing targeted therapy. Tepotinib, a highly selective MET inhibitor, has displayed promise in patients with advanced NSCLC. Nevertheless, challenges arise when identifying treatment strategies for patients with discordant results regarding <em>MET</em>ex14 skipping detection between diagnostic tests.</p></div><div><h3>Methods</h3><p>We investigated patients with NSCLC and discordant results for <em>MET</em>ex14 skipping between the Oncomine Dx Target Test (ODxTT) and ArcherMET. Clinical response, adverse events, and the duration of tepotinib treatment were assessed, and statistical analysis was performed.</p></div><div><h3>Results</h3><p>Among the 19 patients deemed <em>MET</em>ex14 skipping positive by ODxTT, only 10 had concordant results with ArcherMET. The number of <em>MET</em>ex14 skipping reads detected by ODxTT was significantly lower in discordant cases. Of the 19 patients, 14 received tepotinib, and comparable response and disease control rates were observed in both concordant and discordant cases. The duration of treatment did not significantly differ between the two groups.</p></div><div><h3>Conclusions</h3><p>Our findings suggest that tepotinib has comparable therapeutic effects in patients with <em>MET</em>ex14 skipping-positive NSCLC irrespective of the concordance of results between ODxTT and ArcherMET. Tepotinib is a possible treatment option for patients with <em>MET</em>ex14 skipping, even in patients with discordant test results.</p></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666364324000493/pdfft?md5=536c840b02b0e446a642a151aad3d799&pid=1-s2.0-S2666364324000493-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141156387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-06DOI: 10.1016/j.jtocrr.2024.100674
Kavita Sivabalah MB BCh BAO, MRCP (UK) , David Crane PhD , Samantha Neville , Mandy Hancock MSc , Anthony Ryan , Bincy Ajay , Jane Coyne BA , Elizabeth Benbow , Andrea Crossfield MSc , Sebastian Bate MMath , Matthew Evison MD
Introduction
Treating tobacco dependency in National Health Service (NHS) workers delivers substantial benefits at an individual, population, and health care system level. We report the outcomes from the Greater Manchester Integrated Care Partnership’s tobacco dependency treatment program for NHS workers which includes 6-months’ access to behavioral support and 12 weeks of treatment through a digital application.
Methods
Aggregate results for all participants across the program from January 1, 2022, to September 1, 2023, are reported including a deep-dive evaluation of 300 participants recruited to provide chemically validated outcomes.
Results
A total of 1567 NHS workers participated in the program within the evaluation period, completing 24,048 sessions with specialist advisors within the application, ordering 18,710 nicotine vape liquids, 6927 nicotine patches, and 297 short-acting nicotine products. Users reported achieving 89,464 smoke-free days, 1,258,069 less cigarettes smoked, and a financial saving of £622,231. The deep-dive evaluation revealed a CO-verified 12-week abstinence rate of 37% (111 of 300).
Conclusion
This evaluation provides assurance of clinical effectiveness within a bespoke digital tobacco dependency treatment program for NHS workers across an Integrated Care Partnership.
{"title":"Treating Tobacco Dependency in National Health Service Workers in Greater Manchester: An Evaluation of a Bespoke Digital Service","authors":"Kavita Sivabalah MB BCh BAO, MRCP (UK) , David Crane PhD , Samantha Neville , Mandy Hancock MSc , Anthony Ryan , Bincy Ajay , Jane Coyne BA , Elizabeth Benbow , Andrea Crossfield MSc , Sebastian Bate MMath , Matthew Evison MD","doi":"10.1016/j.jtocrr.2024.100674","DOIUrl":"10.1016/j.jtocrr.2024.100674","url":null,"abstract":"<div><h3>Introduction</h3><p>Treating tobacco dependency in National Health Service (NHS) workers delivers substantial benefits at an individual, population, and health care system level. We report the outcomes from the Greater Manchester Integrated Care Partnership’s tobacco dependency treatment program for NHS workers which includes 6-months’ access to behavioral support and 12 weeks of treatment through a digital application.</p></div><div><h3>Methods</h3><p>Aggregate results for all participants across the program from January 1, 2022, to September 1, 2023, are reported including a deep-dive evaluation of 300 participants recruited to provide chemically validated outcomes.</p></div><div><h3>Results</h3><p>A total of 1567 NHS workers participated in the program within the evaluation period, completing 24,048 sessions with specialist advisors within the application, ordering 18,710 nicotine vape liquids, 6927 nicotine patches, and 297 short-acting nicotine products. Users reported achieving 89,464 smoke-free days, 1,258,069 less cigarettes smoked, and a financial saving of £622,231. The deep-dive evaluation revealed a CO-verified 12-week abstinence rate of 37% (111 of 300).</p></div><div><h3>Conclusion</h3><p>This evaluation provides assurance of clinical effectiveness within a bespoke digital tobacco dependency treatment program for NHS workers across an Integrated Care Partnership.</p></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666364324000444/pdfft?md5=7c3c7a54d194921b994c0771480aff7a&pid=1-s2.0-S2666364324000444-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140764914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
It is an ongoing debate how much lung and heart irradiation impact overall survival (OS) after definitive radiotherapy for lung cancer. This study uses a large national cohort of patients with locally advanced NSCLC to investigate the association between OS and irradiation of lung and heart.
Methods
Treatment plans were acquired from six Danish radiotherapy centers, and patient characteristics were obtained from national registries. A hybrid segmentation tool automatically delineated the heart and substructures. Dose-volume histograms for all structures were extracted and analyzed using principal component analyses (PCAs). Parameter selection for a multivariable Cox model for OS prediction was performed using cross-validation based on bootstrapping.
Results
The population consisted of 644 patients with a median survival of 26 months (95% confidence interval [CI]: 24–29). The cross-validation selected two PCA variables to be included in the multivariable model. PCA1 represented irradiation of the heart and affected OS negatively (hazard ratio, 1.14; 95% CI: 1.04–1.26). PCA2 characterized the left-right balance (right atrium and left ventricle) irradiation, showing better survival for tumors near the right side (hazard ratio, 0.92; 95% CI: 0.84–1.00). Besides the two PCA variables, the multivariable model included age, sex, body-mass index, performance status, tumor dose, and tumor volume.
Conclusions
Besides the classic noncardiac risk factors, lung and heart doses had a negative impact on survival, while it is suggested that the left side of the heart is a more radiation dose–sensitive region. The data indicate that overall heart irradiation should be reduced to improve the OS if possible.
{"title":"Heart and Lung Dose as Predictors of Overall Survival in Patients With Locally Advanced Lung Cancer. A National Multicenter Study","authors":"Agon Olloni MD, PhD , Carsten Brink PhD , Ebbe Laugaard Lorenzen PhD , Stefan Starup Jeppesen PhD , Lone Hofmann PhD , Charlotte Kristiansen MD , Marianne Marquard Knap MD , Ditte Sloth Møller PhD , Lotte Nygård MD, PhD , Gitte Fredberg Persson MD, PhD , Rune Slot Thing PhD , Hella Maria Brøgger Sand MD , Axel Diederichsen MD, PhD , Tine Schytte MD, PhD","doi":"10.1016/j.jtocrr.2024.100663","DOIUrl":"10.1016/j.jtocrr.2024.100663","url":null,"abstract":"<div><h3>Introduction</h3><p>It is an ongoing debate how much lung and heart irradiation impact overall survival (OS) after definitive radiotherapy for lung cancer. This study uses a large national cohort of patients with locally advanced NSCLC to investigate the association between OS and irradiation of lung and heart.</p></div><div><h3>Methods</h3><p>Treatment plans were acquired from six Danish radiotherapy centers, and patient characteristics were obtained from national registries. A hybrid segmentation tool automatically delineated the heart and substructures. Dose-volume histograms for all structures were extracted and analyzed using principal component analyses (PCAs). Parameter selection for a multivariable Cox model for OS prediction was performed using cross-validation based on bootstrapping.</p></div><div><h3>Results</h3><p>The population consisted of 644 patients with a median survival of 26 months (95% confidence interval [CI]: 24–29). The cross-validation selected two PCA variables to be included in the multivariable model. PCA1 represented irradiation of the heart and affected OS negatively (hazard ratio, 1.14; 95% CI: 1.04–1.26). PCA2 characterized the left-right balance (right atrium and left ventricle) irradiation, showing better survival for tumors near the right side (hazard ratio, 0.92; 95% CI: 0.84–1.00). Besides the two PCA variables, the multivariable model included age, sex, body-mass index, performance status, tumor dose, and tumor volume.</p></div><div><h3>Conclusions</h3><p>Besides the classic noncardiac risk factors, lung and heart doses had a negative impact on survival, while it is suggested that the left side of the heart is a more radiation dose–sensitive region. The data indicate that overall heart irradiation should be reduced to improve the OS if possible.</p></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S266636432400033X/pdfft?md5=e293483a3ddac4c0c51545322e9a2609&pid=1-s2.0-S266636432400033X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140280135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Osimertinib is a standard treatment for patients with EGFR-mutant NSCLC. Although some osimertinib resistance mechanisms have been identified, nearly 50% of the mechanisms remain to be elucidated. This study was aimed at identifying non-genetic mechanisms underlying osimertinib resistance.
Methods
We established two osimertinib-resistant cell lines from EGFR mutation-positive PC-9 and HCC827 NSCLC cell lines (PC-9OR and HCC827OR, respectively) using a stepwise method. We compared the phosphoproteomic profiles of the osimertinib-resistant and parental cells using mass spectrometry. Upstream kinases were identified using the application Kinase Enrichment Analysis version 3.
Results
Phosphoproteomic analysis revealed 80 phosphorylation sites that were mutually up-regulated in PC-9OR and HCC827OR cells. The Kinase Enrichment Analysis version 3 analysis identified focal adhesion kinase (FAK) and proto-oncogene tyrosine-protein kinase Src (Src) as upstream kinases of these up-regulated phosphoproteins. The small-interfering RNA–mediated knockdown of FAK reduced Src phosphorylation and that of Src reduced FAK phosphorylation in both cell lines. Furthermore, FAK- or Src-specific small-interfering RNA treatments restored EGFR phosphorylation in PC-9OR and HCC827OR cells. The combination of FAK and Src inhibitors inhibited PC-9OR and HCC827OR cell proliferation in vitro and suppressed tumor growth in a xenograft mouse model. Immunohistochemistry of tumors from patients with EGFR-mutant NSCLC suggested that phosphorylated FAK and Src are involved in initial and acquired resistance to osimertinib.
Conclusions
Phosphoproteomic analysis may help elucidate the mechanisms of resistance to molecular-targeted therapies in lung cancer. Mutual phosphorylation of FAK and Src is involved in osimertinib resistance. Thus, FAK and Src inhibition may be novel treatment strategies for osimertinib-resistant NSCLC.
{"title":"Phosphoproteomic Analysis Identified Mutual Phosphorylation of FAK and Src as a Mechanism of Osimertinib Resistance in EGFR-Mutant Lung Cancer","authors":"Takehiro Tozuka MD , Rintaro Noro MD, PhD , Keisuke Yoshida PhD , Satoshi Takahashi MD, PhD , Mariko Hirao XX , Kuniko Matsuda XX , Yasuhiro Kato MD , Shinji Nakamichi MD, PhD , Susumu Takeuchi MD, PhD , Masaru Matsumoto MD, PhD , Akihiko Miyanaga MD, PhD , Shinobu Kunugi MD, PhD , Kazufumi Honda DDS, PhD , Jun Adachi PhD , Masahiro Seike MD, PhD","doi":"10.1016/j.jtocrr.2024.100668","DOIUrl":"https://doi.org/10.1016/j.jtocrr.2024.100668","url":null,"abstract":"<div><h3>Introduction</h3><p>Osimertinib is a standard treatment for patients with <em>EGFR</em>-mutant NSCLC. Although some osimertinib resistance mechanisms have been identified, nearly 50% of the mechanisms remain to be elucidated. This study was aimed at identifying non-genetic mechanisms underlying osimertinib resistance.</p></div><div><h3>Methods</h3><p>We established two osimertinib-resistant cell lines from <em>EGFR</em> mutation-positive PC-9 and HCC827 NSCLC cell lines (PC-9OR and HCC827OR, respectively) using a stepwise method. We compared the phosphoproteomic profiles of the osimertinib-resistant and parental cells using mass spectrometry. Upstream kinases were identified using the application Kinase Enrichment Analysis version 3.</p></div><div><h3>Results</h3><p>Phosphoproteomic analysis revealed 80 phosphorylation sites that were mutually up-regulated in PC-9OR and HCC827OR cells. The Kinase Enrichment Analysis version 3 analysis identified focal adhesion kinase (FAK) and proto-oncogene tyrosine-protein kinase Src (Src) as upstream kinases of these up-regulated phosphoproteins. The small-interfering RNA–mediated knockdown of FAK reduced Src phosphorylation and that of Src reduced FAK phosphorylation in both cell lines. Furthermore, FAK- or Src-specific small-interfering RNA treatments restored EGFR phosphorylation in PC-9OR and HCC827OR cells. The combination of FAK and Src inhibitors inhibited PC-9OR and HCC827OR cell proliferation in vitro and suppressed tumor growth in a xenograft mouse model. Immunohistochemistry of tumors from patients with <em>EGFR</em>-mutant NSCLC suggested that phosphorylated FAK and Src are involved in initial and acquired resistance to osimertinib.</p></div><div><h3>Conclusions</h3><p>Phosphoproteomic analysis may help elucidate the mechanisms of resistance to molecular-targeted therapies in lung cancer. Mutual phosphorylation of FAK and Src is involved in osimertinib resistance. Thus, FAK and Src inhibition may be novel treatment strategies for osimertinib-resistant NSCLC.</p></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666364324000389/pdfft?md5=7b6560c60e702d1983547e4ee3c5ef18&pid=1-s2.0-S2666364324000389-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140550838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Previous studies reported an association between immune checkpoint inhibitor infusion timing and the treatment effect in metastatic NSCLC. The present study assessed the association between durvalumab infusion timing and survival outcomes in patients with locally advanced NSCLC.
Methods
Patients receiving durvalumab after chemoradiotherapy for locally advanced NSCLC at a single institution were retrospectively analyzed, and the association of the proportion of durvalumab infusions greater than or equal to 20% versus less than 20% after 3 PM with progression-free survival (PFS) and overall survival was assessed.
Results
A total of 82 patients were included, with a median age of 69 years (interquartile range, 62–74 years); of these, 67 patients (82%) were of male sex, and 78 patients (95%) had a history of smoking. The median number of durvalumab infusions per patient was 16 (interquartile range, 8–24). Patients with at least 20% of their durvalumab infusions after 3 PM (n = 12/82, 15%) had a significantly shorter PFS than those who did not (median: 7.4 mo versus not available [NA]; hazard ratio [HR], 2.43; 95% confidence interval [CI]: 1.11–5.34, p = 0.027), whereas overall survival was shorter among the former compared with the latter group (median: 22.4 versus NA; HR, 1.80; 95% CI: 0.73–4.42, p = 0.20). In addition, both backward stepwise multivariable analysis and propensity score–matching analysis revealed that receiving at least 20% of durvalumab infusions after 3 PM was significantly associated with worse PFS (HR, 2.54; 95% CI: 1.03–5.67, p = 0.047; and HR, 4.64; 95% CI: 1.95–11.04; p < 0.001, respectively).
Conclusions
The time of day of durvalumab infusions may impact survival outcomes in patients with locally advanced NSCLC.
{"title":"Brief Report: Clinical Outcomes by Infusion Timing of Immune Checkpoint Inhibitors in Patients With Locally Advanced NSCLC","authors":"Tsuyoshi Hirata MD , Yuji Uehara MD , Taiki Hakozaki MD , Takayuki Kobayashi MD , Yuto Terashima MD , Kageaki Watanabe MD , Makiko Yomota MD, PhD , Yukio Hosomi MD, PhD","doi":"10.1016/j.jtocrr.2024.100659","DOIUrl":"https://doi.org/10.1016/j.jtocrr.2024.100659","url":null,"abstract":"<div><h3>Introduction</h3><p>Previous studies reported an association between immune checkpoint inhibitor infusion timing and the treatment effect in metastatic NSCLC. The present study assessed the association between durvalumab infusion timing and survival outcomes in patients with locally advanced NSCLC.</p></div><div><h3>Methods</h3><p>Patients receiving durvalumab after chemoradiotherapy for locally advanced NSCLC at a single institution were retrospectively analyzed, and the association of the proportion of durvalumab infusions greater than or equal to 20% versus less than 20% after 3 <span>PM</span> with progression-free survival (PFS) and overall survival was assessed.</p></div><div><h3>Results</h3><p>A total of 82 patients were included, with a median age of 69 years (interquartile range, 62–74 years); of these, 67 patients (82%) were of male sex, and 78 patients (95%) had a history of smoking. The median number of durvalumab infusions per patient was 16 (interquartile range, 8–24). Patients with at least 20% of their durvalumab infusions after 3 <span>PM</span> (n = 12/82, 15%) had a significantly shorter PFS than those who did not (median: 7.4 mo versus not available [NA]; hazard ratio [HR], 2.43; 95% confidence interval [CI]: 1.11–5.34, <em>p</em> = 0.027), whereas overall survival was shorter among the former compared with the latter group (median: 22.4 versus NA; HR, 1.80; 95% CI: 0.73–4.42, <em>p</em> = 0.20). In addition, both backward stepwise multivariable analysis and propensity score–matching analysis revealed that receiving at least 20% of durvalumab infusions after 3 <span>PM</span> was significantly associated with worse PFS (HR, 2.54; 95% CI: 1.03–5.67, <em>p</em> = 0.047; and HR, 4.64; 95% CI: 1.95–11.04; <em>p</em> < 0.001, respectively).</p></div><div><h3>Conclusions</h3><p>The time of day of durvalumab infusions may impact survival outcomes in patients with locally advanced NSCLC.</p></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666364324000298/pdfft?md5=d84cbc04706013262d06e8a2bc481903&pid=1-s2.0-S2666364324000298-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140351009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-01DOI: 10.1016/j.jtocrr.2023.100626
Frank Griesinger MD, PhD , Martin Sebastian MD , Wolfgang M. Brueckl MD, PhD , Horst-Dieter Hummel MD, PhD , Bastian Jaeschke MD , Jens Kern MD , Claas Wesseler MD , Martina Jänicke PdD , Annette Fleitz PhD , Stefan Zacharias PhD , Annette Hipper PhD , Annika Groth MD, PhD , Wilko Weichert MD, PhD , Steffen Dörfel , Volker Petersen MD , Jan Schröder MD , Jochen Wilke MD , Wilfried E.E. Eberhardt MD, PhD , Michael Thomas MD, PhD , Matthias Zeth
Introduction
Patients with metastatic NSCLC (mNSCLC) treated with immune checkpoint inhibitors in clinical practice may often not meet the strict inclusion criteria of clinical trials. Our aim was to assess the trial eligibility of patients with mNSCLC treated with pembrolizumab monotherapy in real-world and to compare the outcome of “trial-ineligible” and “potentially trial-eligible” patients.
Methods
Data from the prospective, clinical research platform CRISP were used to compare patient characteristics, treatment, and outcome of patients with programmed cell death-ligand 1 tumor proportion score greater than or equal to 50% tumors treated with pembrolizumab monotherapy who are deemed either “potentially trial-eligible” or “trial-ineligible” according to inclusion and exclusion criteria of the registrational studies (KEYNOTE-024 and -042).
Results
Of 746 patients included, 343 patients (46.0%) were classified as “trial-ineligible” and had significantly worse outcomes compared with “potentially trial-eligible” patients (n = 403, 54.0%): median progression-free survival: 6.2 (95% confidence interval [CI]: 5.2–8.4) versus 10.3 (95% CI: 8.4–13.8) months, hazard ratio (trial-ineligible versus potentially trial-eligible) of 1.43 (95% CI: 1.19–1.72), p less than 0.001; median overall survival: 15.9 (95% CI: 11.4–20.3) versus 25.3 (95% CI: 19.8–30.4) months, hazard ratio of 1.36 (95% CI: 1.10–1.67), p equals 0.004.
Conclusions
Our data reveal that a considerable proportion of patients with mNSCLC are not eligible to participate in a clinical trial and were found to have worse outcomes than potentially trial-eligible patients, whose outcomes were comparable with those obtained from pivotal clinical trials. This is of substantial clinical relevance for physicians discussing outcomes to be expected with their patients and stresses the need for real-world effectiveness analyses.
{"title":"Checkpoint Inhibitor Monotherapy in Potentially Trial-Eligible or Trial-Ineligible Patients With Metastatic NSCLC in the German Prospective CRISP Registry Real-World Cohort (AIO-TRK-0315)","authors":"Frank Griesinger MD, PhD , Martin Sebastian MD , Wolfgang M. Brueckl MD, PhD , Horst-Dieter Hummel MD, PhD , Bastian Jaeschke MD , Jens Kern MD , Claas Wesseler MD , Martina Jänicke PdD , Annette Fleitz PhD , Stefan Zacharias PhD , Annette Hipper PhD , Annika Groth MD, PhD , Wilko Weichert MD, PhD , Steffen Dörfel , Volker Petersen MD , Jan Schröder MD , Jochen Wilke MD , Wilfried E.E. Eberhardt MD, PhD , Michael Thomas MD, PhD , Matthias Zeth","doi":"10.1016/j.jtocrr.2023.100626","DOIUrl":"10.1016/j.jtocrr.2023.100626","url":null,"abstract":"<div><h3>Introduction</h3><p>Patients with metastatic NSCLC (mNSCLC) treated with immune checkpoint inhibitors in clinical practice may often not meet the strict inclusion criteria of clinical trials. Our aim was to assess the trial eligibility of patients with mNSCLC treated with pembrolizumab monotherapy in real-world and to compare the outcome of “trial-ineligible” and “potentially trial-eligible” patients.</p></div><div><h3>Methods</h3><p>Data from the prospective, clinical research platform CRISP were used to compare patient characteristics, treatment, and outcome of patients with programmed cell death-ligand 1 tumor proportion score greater than or equal to 50% tumors treated with pembrolizumab monotherapy who are deemed either “potentially trial-eligible” or “trial-ineligible” according to inclusion and exclusion criteria of the registrational studies (KEYNOTE-024 and -042).</p></div><div><h3>Results</h3><p>Of 746 patients included, 343 patients (46.0%) were classified as “trial-ineligible” and had significantly worse outcomes compared with “potentially trial-eligible” patients (n = 403, 54.0%): median progression-free survival: 6.2 (95% confidence interval [CI]: 5.2–8.4) versus 10.3 (95% CI: 8.4–13.8) months, hazard ratio (trial-ineligible versus potentially trial-eligible) of 1.43 (95% CI: 1.19–1.72), <em>p</em> less than 0.001; median overall survival: 15.9 (95% CI: 11.4–20.3) versus 25.3 (95% CI: 19.8–30.4) months, hazard ratio of 1.36 (95% CI: 1.10–1.67), <em>p</em> equals 0.004.</p></div><div><h3>Conclusions</h3><p>Our data reveal that a considerable proportion of patients with mNSCLC are not eligible to participate in a clinical trial and were found to have worse outcomes than potentially trial-eligible patients, whose outcomes were comparable with those obtained from pivotal clinical trials. This is of substantial clinical relevance for physicians discussing outcomes to be expected with their patients and stresses the need for real-world effectiveness analyses.</p></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666364323001698/pdfft?md5=5b8cc1593fb9bfb461f4fe4c69a65c3a&pid=1-s2.0-S2666364323001698-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139191820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-01DOI: 10.1016/j.jtocrr.2024.100648
Molly S.C. Li M.B.B.S. , Kirsty W.C. Lee MBChB , Kevin K.S. Mok MBChB , Herbert H.F. Loong M.B.B.S. , K.C. Lam MBChB , Florence S.T. Mok M.B.B.S. , Landon L. Chan MBChB , Y.M. Lau M.B.B.S. , K.P. Chan MBChB , Joyce T.Y. Ng MBChB , Wesley K.Y. Wong M.B.B.S. , Benjamin H.W. Lam M.B.B.S. , Allen C.C. Chen BM , Matthew M.P. Lee MBChB , Olivia H. Chen MD, PhD , Tony S.K. Mok MD
Introduction
Interstitial lung disease (ILD) is the most frequent cause of drug-related mortality from EGFR tyrosine kinase inhibitors (TKIs). Yet, for patients with symptomatic osimertinib-induced ILD, the risk of recurrent ILD associated with EGFR TKI rechallenge, either with osimertinib or another TKI, such as erlotinib, is unclear.
Methods
Retrospective study of 913 patients who received osimertinib treatment for EGFR mutation-positive NSCLC. Clinical characteristics, ILD treatment history, and subsequent anticancer therapy of patients with symptomatic osimertinib-induced ILD were collated. The primary end point was to compare the incidence of recurrent ILD with osimertinib versus erlotinib rechallenge.
Results
Of 913 patients, 35 (3.8%) had symptomatic osimertinib-induced ILD, of which 12 (34%), 15 (43%), and eight (23%) had grade 2, 3 to 4, and 5 ILD, respectively. On ILD recovery, 17 patients had EGFR TKI rechallenge with eight received osimertinib and nine received erlotinib. The risk of recurrent ILD was higher with osimertinib rechallenge than erlotinib (p = 0.0498). Of eight, five (63%) developed recurrent ILD on osimertinib rechallenge, including three patients with fatal outcomes. In contrast, only one of nine patients (11%) treated with erlotinib had recurrent ILD. Median time to second ILD occurrence was 4.7 (range 0.7–12) weeks. Median time-to-treatment failure of patients with erlotinib rechallenge was 13.2 months (95% confidence interval: 8.6–15.0).
Conclusions
The risk of recurrent ILD was considerably higher with osimertinib rechallenge than erlotinib. Osimertinib rechallenge should be avoided, whereas erlotinib may be considered in patients with symptomatic osimertinib-induced ILD.
{"title":"Brief Report: Risk of Recurrent Interstitial Lung Disease From Osimertinib Versus Erlotinib Rechallenge After Symptomatic Osimertinib-Induced Interstitial Lung Disease","authors":"Molly S.C. Li M.B.B.S. , Kirsty W.C. Lee MBChB , Kevin K.S. Mok MBChB , Herbert H.F. Loong M.B.B.S. , K.C. Lam MBChB , Florence S.T. Mok M.B.B.S. , Landon L. Chan MBChB , Y.M. Lau M.B.B.S. , K.P. Chan MBChB , Joyce T.Y. Ng MBChB , Wesley K.Y. Wong M.B.B.S. , Benjamin H.W. Lam M.B.B.S. , Allen C.C. Chen BM , Matthew M.P. Lee MBChB , Olivia H. Chen MD, PhD , Tony S.K. Mok MD","doi":"10.1016/j.jtocrr.2024.100648","DOIUrl":"https://doi.org/10.1016/j.jtocrr.2024.100648","url":null,"abstract":"<div><h3>Introduction</h3><p>Interstitial lung disease (ILD) is the most frequent cause of drug-related mortality from EGFR tyrosine kinase inhibitors (TKIs). Yet, for patients with symptomatic osimertinib-induced ILD, the risk of recurrent ILD associated with EGFR TKI rechallenge, either with osimertinib or another TKI, such as erlotinib, is unclear.</p></div><div><h3>Methods</h3><p>Retrospective study of 913 patients who received osimertinib treatment for <em>EGFR</em> mutation-positive NSCLC. Clinical characteristics, ILD treatment history, and subsequent anticancer therapy of patients with symptomatic osimertinib-induced ILD were collated. The primary end point was to compare the incidence of recurrent ILD with osimertinib versus erlotinib rechallenge.</p></div><div><h3>Results</h3><p>Of 913 patients, 35 (3.8%) had symptomatic osimertinib-induced ILD, of which 12 (34%), 15 (43%), and eight (23%) had grade 2, 3 to 4, and 5 ILD, respectively. On ILD recovery, 17 patients had EGFR TKI rechallenge with eight received osimertinib and nine received erlotinib. The risk of recurrent ILD was higher with osimertinib rechallenge than erlotinib (<em>p</em> = 0.0498). Of eight, five (63%) developed recurrent ILD on osimertinib rechallenge, including three patients with fatal outcomes. In contrast, only one of nine patients (11%) treated with erlotinib had recurrent ILD. Median time to second ILD occurrence was 4.7 (range 0.7–12) weeks. Median time-to-treatment failure of patients with erlotinib rechallenge was 13.2 months (95% confidence interval: 8.6–15.0).</p></div><div><h3>Conclusions</h3><p>The risk of recurrent ILD was considerably higher with osimertinib rechallenge than erlotinib. Osimertinib rechallenge should be avoided, whereas erlotinib may be considered in patients with symptomatic osimertinib-induced ILD.</p></div>","PeriodicalId":17675,"journal":{"name":"JTO Clinical and Research Reports","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666364324000183/pdfft?md5=a61f22993f5c7bf6be994155930c4030&pid=1-s2.0-S2666364324000183-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140332581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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