Journal of Thoracic Oncology最新文献

{"title":"Safety, efficacy and biomarker analysis of deulorlatinib (TGRX-326) in ALK-positive non-small-cell lung cancer: a multicentre, open-label, phase 1/1b trial.","authors":"Shen Zhao, Huaqiang Zhou, Nong Yang, Zhehai Wang, Wenjian Jin, Yuxiang Ma, Jinhui Xue, Xingya Li, Yunpeng Liu, Rui Meng, Jianying Zhou, Ying Cheng, Yongsheng Wang, Zhuang Yu, Yu Cao, Yuanyuan Zhao, Yan Huang, Wenfeng Fang, Yang Zhang, Shaodong Hong, Bo Wu, Yanxia Shi, Jingrong Cao, Mingyan Xu, Xiaoni Zhang, Longyu Hu, Bo Peng, Yunpeng Yang, Li Zhang, Hongyun Zhao","doi":"10.1016/j.jtho.2024.11.010","DOIUrl":"https://doi.org/10.1016/j.jtho.2024.11.010","url":null,"abstract":"<p><strong>Introduction: </strong>Patients with ALK-positive NSCLC developing resistance to second-generation inhibitors have limited treatment options. Deulorlatinib is a highly brain-penetrant, new-generation ALK/ROS1 inhibitor. We evaluated the safety, efficacy and pharmacokinetics of deulorlatinib in ALK-positive NSCLC.</p><p><strong>Methods: </strong>This 3-part (dose-escalation/dose-expansion/cohort-expansion), open-label, phase 1/1b trial was conducted at 22 sites in China (ClinicalTrials.gov, NCT05441956). Eligible patients had advanced ALK/ROS1-positive NSCLC. Patients enrolled into dose-escalation/dose-expansion parts were previously treated with ≥1 second-generation ALK inhibitors (ALK-positive) or crizotinib (ROS1-positive); received deulorlatinib 5-125mg once daily. Patients enrolled into cohort-expansion parts were either crizotinib-treated, second-generation TKI-treated or TKI-naïve; received deulorlatinib at recommended phase 2 dose (RP2D). Primary outcomes were safety and tolerability. Here, we report safety analysis in all patients and efficacy analysis in ALK-positive patients.</p><p><strong>Results: </strong>Between April 2021 and March 2023, 198 patients were enrolled (ALK-positive=171, ROS1-positive=27). Most common treatment-related adverse events (TRAEs) were hypercholesterolemia (79.3%), hypertriglyceridemia (77.3%) and weight gain (53.0%). 40.4% of patients had grade≥3 TRAEs. TRAE-associated dose interruptions, reduction and discontinuation occurred in 11.1%, 3.0% and 1.5% of patients, respectively. The RP2D was set at 60mg once daily. A total of 144 ALK-positive patients were treated at RP2D. For crizotinib-treated (n=14), second-generation TKI-treated (n=97) and TKI-naïve (n=33) patients, ORR to deulorlatinib at RP2D was 71.4%, 38.1%, and 87.9%, respectively. Intracranial ORR was 50%, 70.4%, and 75%. Median duration of response was 18.0 months for second-generation TKI-treated patients, and not reached for crizotinib-treated and TKI-naïve patients. Biomarker analyses identified undetectable ALK alterations at baseline and ALK ctDNA clearance at week 6 as potential predictive biomarkers.</p><p><strong>Conclusions: </strong>Deulorlatinib showed desirable tolerability and efficacy in ALK-positive NSCLC, demonstrating the potential to become a new treatment option in this population.</p>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PCI for Patients with Small Cell Lung Cancer: A New Perspective in the Immunotherapy Era.","authors":"Antonin Levy, Chad G Rusthoven, Paul D Brown, Cécile Le Péchoux, Corinne Faivre-Finn","doi":"10.1016/j.jtho.2024.11.011","DOIUrl":"https://doi.org/10.1016/j.jtho.2024.11.011","url":null,"abstract":"<p><p>Prophylactic cranial irradiation (PCI) has long been used for small-cell lung cancer (SCLC) to reduce the risk of brain metastases and potentially improve overall survival. However, recent immunotherapy trials have provided limited data on its impact, as few patients were treated with PCI. The ADRIATIC trial demonstrated improved outcomes with consolidation immunotherapy in limited-stage SCLC, and PCI was a stratification factor. Notably, patients receiving PCI in both arms had better outcomes compared to those who did not. Ongoing studies, such as EORTC-1901 PRIMALung (NCT04790253) and SWOG 1827-MAVERICK (NCT04155034), are further investigating PCI's role in the era of immunotherapy, highlighting its potential importance in evolving treatment strategies.</p>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicted effect of incidental pulmonary nodule findings on Non-Small Cell Lung Cancer mortality.","authors":"S Tuminello, R Flores, M Untalan, T Ivic-Pavlicic, C I Henschke, R Yip, D F Yankelevitz, E Taioli","doi":"10.1016/j.jtho.2024.11.009","DOIUrl":"10.1016/j.jtho.2024.11.009","url":null,"abstract":"<p><strong>Introduction: </strong>Despite the reduction in mortality shown by Low dose computer tomography (LDCT) lung cancer screening, the uptake is still low. Patients undergo chest imaging for several other medical reasons, and this is a unique opportunity to detect lung nodules.</p><p><strong>Methods: </strong>In a cohort of NSCLC patients from the Surveillance, Epidemiology and End Results (SEER)-Medicare linked data, tumor size at previous imaging was calculated as: VDT = [(T₂-T₁)·ln2]/ln(V₂/V₁), solving for diameter of V₁. V₁ and V₂ are tumor volume at times T₁ (previous imaging) and T₂ (diagnostic procedure) according to three different growth models. 10-year lung cancer-specific mortality was calculated as: lung cancer survival rate = (-0.0098 × maximum tumor diameter) + 1.</p><p><strong>Results: </strong>1,007 patients who had a chest imaging performed up to one year prior to lung cancer diagnosis. The median size of the tumor at diagnosis was 25 mm, the predicted median tumor size at previous imaging was 12.16 mm, 17.3 mm, and 20.42 mm under the fast, medium and slow growth model. Under the fast growth model, a detection of the nodule at previous imaging would have yield a decrease in mortality of 7.79%; the corresponding values for the medium growth model is 4.5%, for the slow growth model 2.45%.</p><p><strong>Conclusions: </strong>Identifying malignant lung nodules in imaging performed for other clinical reasons can help decreasing the burden of NSCLC, especially for non-LDCT eligible patients and the medically vulnerable. We show here that clinical benefits, especially among patients with aggressive disease, can be considerable.</p>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DSTYK Inhibition Sensitizes Non-Small Cell Lung Cancer To Taxane-Based Chemotherapy.","authors":"Mirari Echepare, Beñat Picabea, Andrea Arricibita, Álvaro Teijeira, Andrea Pasquier, Carolina Zandueta, Nerea Otegui, Enrique Santamaría, Joaquín Fernández-Irigoyen, Octavio Romero, Montse Sanchez-Cespedes, Fernando Lecanda, Javier Hernández, Enriqueta Felip, Alberto Cruz-Bermúdez, Mariano Provencio, Marco Gentili, Federica Facchinetti, Luca Roz, Luis M Montuenga, Karmele Valencia","doi":"10.1016/j.jtho.2024.11.003","DOIUrl":"https://doi.org/10.1016/j.jtho.2024.11.003","url":null,"abstract":"<p><p>Chemotherapy continues to be the standard treatment for patients non-eligible to targeted or immune-based therapies; however, treatment resistance remains a major clinical challenge. We previously found that expression levels of DSTYK, a poorly explored dual serine/threonine and tyrosine kinase frequently amplified in cancer, identifies lung cancer patients exhibiting poor response to immune checkpoint inhibitors and showed that its inhibition sensitizes to immunotherapy. Seeking to explore the potential of DSTYK targeting in additional indications, we investigated the functional relevance and actionability of DSTYK in lung cancer chemoresistance. We show that DSTYK depletion specifically sensitizes lung cancer cells to taxane-based chemotherapy, particularly in combination with carboplatin. Mechanistically, DSTYK ablation remodels the cytoskeleton and impairs distant invasion and metastatic outgrowth in vivo. DSTYK downregulation sensitizes both primary and metastatic lung tumors to chemoimmunotherapy treatment leading to tumor regression in mouse models. Consistently, clinical data of early - in the neoadjuvant and adjuvant settings- and advanced lung cancer patients show a strong correlation between DSTYK amplification and taxane resistance, underscoring the clinical significance of our findings to inform treatment decision-making. Collectively, our data indicates that DSTYK amplification may be a predictor of resistance to taxane-based treatments and represents an actionable target for these patients.</p>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142635770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Durvalumab Versus Chemotherapy as First-line Treatment for Metastatic NSCLC With Tumor PD-L1 Expression ≥25%: Results from the Randomized Phase 3 PEARL Study.","authors":"Shun Lu, Lin Wu, Qiming Wang, Ziping Wang, Dongqing Lv, Rui Ma, Bo Zhu, Ngoc van Tran, Liyan Jiang, Kejun Nan, Konstantin Laktionov, Stephen Clarke, Minghao Song, Helen Mann, Yinglei Liu, Xiaojin Shi, Yi-Long Wu","doi":"10.1016/j.jtho.2024.10.024","DOIUrl":"https://doi.org/10.1016/j.jtho.2024.10.024","url":null,"abstract":"<p><strong>Introduction: </strong>PEARL (NCT03003962) is an open-label, phase 3 study comparing first-line durvalumab monotherapy with chemotherapy in patients with metastatic non-small cell lung cancer (mNSCLC [EGFR/ALK wild type]) with PD-L1 tumor cell (TC) membrane expression status ≥25%. We report the final analysis of PEARL.</p><p><strong>Methods: </strong>Adults (N=669) with previously untreated Stage IV mNSCLC were randomized (1:1) to durvalumab 20mg/kg every 4 weeks or chemotherapy every 3 weeks for 4 to 6 cycles. Dual primary endpoints were overall survival (OS) in the PD-L1 TC ≥25% and the PD-L1 TC ≥25% low risk of early mortality (LREM) populations.</p><p><strong>Results: </strong>Durvalumab was associated with a numerical reduction in the risk of death versus chemotherapy in the PD-L1 TC ≥25% population (OS hazard ratio [HR] 0.84, 95% confidence interval [CI] 0.71, 0.99, p = 0.037; median OS 14.6 months [95% CI: 12.2, 16.9] versus 12.8 months [95% CI: 10.1, 14.7], respectively). In the PD-L1 TC ≥25% LREM population the OS HR for durvalumab versus chemotherapy was 0.96 (95% CI: 0.79, 1.15, p = 0.628); median OS 14.6 months (95% CI: 12.6, 17.2) versus 15.0 months (95% CI: 13.1, 16.8), respectively. In the safety population, the incidence of grade 3/4 treatment-related adverse events was 15.5% (durvalumab) and 45.9% (chemotherapy).</p><p><strong>Conclusions: </strong>Durvalumab did not statistically significantly improve OS versus chemotherapy as first-line treatment in patients with mNSCLC and PD-L1 TC ≥25%. The numerical improvement in OS was consistent with previous studies of first-line immune checkpoint inhibitor monotherapy in patients with mNSCLC.</p>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Phase 3 KEYLYNK-006 Study of Pembrolizumab plus Olaparib versus Pembrolizumab plus Pemetrexed as Maintenance Therapy for Metastatic Nonsquamous Non-Small-Cell Lung Cancer.","authors":"Jhanelle E Gray, Michael Schenker, Mehmet Ali Nahit Şendur, Viktoriya Leonova, Dariusz Kowalski, Terufumi Kato, Rashida Orlova, James Chih-Hsin Yang, Adrian Langleben, Arnold Pilz, Andrei Ungureanu, Milena Perez Mak, Flavia De Angelis, Himani Aggarwal, Zachary Zimmer, Bin Zhao, Mark Shamoun, Tae Min Kim","doi":"10.1016/j.jtho.2024.10.026","DOIUrl":"https://doi.org/10.1016/j.jtho.2024.10.026","url":null,"abstract":"<p><strong>Background: </strong>Poly (ADP-ribose) inhibitors, including olaparib, upregulate programmed cell death ligand 1 (PD-L1), which may increase efficacy of anti-PD-(L)1 therapies.</p><p><strong>Methods: </strong>In the phase 3 KEYLYNK-006 trial (NCT03976323), eligible adults with previously untreated metastatic nonsquamous NSCLC without targetable genetic alterations who had complete response (CR), partial response (PR), or stable disease (SD) following induction therapy with 4 cycles of pembrolizumab 200 mg Q3W, pemetrexed 500 mg/m² , and carboplatin AUC5 or cisplatin 75 mg/m² were randomized 1:1 to olaparib 300 mg orally twice daily or pemetrexed Q3W, both given with ≤31 cycles of pembrolizumab Q3W. Dual primary endpoints were progression-free survival (PFS) and overall survival (OS). PFS was tested at interim analysis 2 (IA2; ie, final PFS analysis), OS at final analysis (FA).</p><p><strong>Results: </strong>Of 1003 patients who received induction therapy, 672 (67.0%) were randomized to pembrolizumab plus olaparib (n=337) or pembrolizumab plus pemetrexed (n=335) in the intention-to-treat population. Median follow-up at FA was 39.9 (range, 28.1-51.5) months. At IA2, median (95% CI) PFS was 7.1 (5.6-8.7) months versus 8.3 (6.9-11.5) months in the olaparib versus pemetrexed groups (HR, 1.12; 95% CI, 0.92-1.36; P=0.87). At FA, median (95% CI) OS was 20.7 (18.0-24.8) months versus 23.0 (19.0-26.4) months (HR, 1.04; 95% CI, 0.87-1.25; P=0.6649). Grade 3-5 maintenance treatment-related AEs occurred in 26.1% versus 30.1% patients.</p><p><strong>Conclusion: </strong>Pembrolizumab plus maintenance olaparib did not improve PFS or OS versus pembrolizumab plus pemetrexed in previously untreated metastatic nonsquamous NSCLC without targetable genetic alterations.</p>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Radiomics-Based Support Vector Machine Distinguishes Molecular Events Driving the Progression of Lung Adenocarcinoma.","authors":"Hong-Ji Li, Zhen-Bin Qiu, Meng-Min Wang, Chao Zhang, Hui-Zhao Hong, Rui Fu, Li-Shan Peng, Chen Huang, Qian Cui, Jia-Tao Zhang, Jing-Yun Ren, Lei Jiang, Yi-Long Wu, Wen-Zhao Zhong","doi":"10.1016/j.jtho.2024.09.1431","DOIUrl":"10.1016/j.jtho.2024.09.1431","url":null,"abstract":"<p><strong>Introduction: </strong>An increasing number of early-stage lung adenocarcinomas (LUAD) are detected as lung nodules. The radiological features related to LUAD progression warrant further investigation. Exploration is required to bridge the gap between radiomics-based features and molecular characteristics of lung nodules.</p><p><strong>Methods: </strong>Consensus clustering was applied to the radiomic features of 1212 patients to establish stable clustering. Clusters were illustrated using clinicopathological and next-generation sequencing. A classifier was constructed to further investigate the molecular characteristics in patients with paired computed tomography and RNA sequencing data.</p><p><strong>Results: </strong>Patients were clustered into four clusters. Cluster 1 was associated with a low consolidation-to-tumor ratio, preinvasion, grade I disease, and good prognosis. Clusters 2 and 3 reported increasing malignancy with a higher consolidation-to-tumor ratio, higher pathologic grade, and poor prognosis. Cluster 2 possessed more spread through air spaces and cluster 3 reported a higher proportion of pleural invasion. Cluster 4 had similar clinicopathological features as cluster 1 except but a proportion of grade II disease. RNA sequencing indicated that cluster 1 represented nodules with indolent growth and good differentiation, whereas cluster 4 reported progression in cell development but still had low proliferative activity. Nodules with high proliferation were classified into clusters 2 and 3. In addition, the radiomics classifier distinguished cluster 2 as nodules harboring an activated immune environment, whereas cluster 3 represented nodules with a suppressive immune environment. Furthermore, signatures associated with the prognosis of early-stage LUAD were validated in external datasets.</p><p><strong>Conclusions: </strong>Radiomics features can manifest molecular events driving the progression of LUAD. Our study provides molecular insight into radiomics features and assists in the diagnosis and treatment of early-stage LUAD.</p>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142290063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The International Association for the Study of Lung Cancer Staging Project for Lung Cancer: Proposals for the Revision of the N Descriptors in the Forthcoming Ninth Edition of the TNM Classification for Lung Cancer","authors":"James Huang MD ,&nbsp;Raymond U. Osarogiagbon M.B.B.S., FACP ,&nbsp;Dorothy J. Giroux MS ,&nbsp;Katherine K. Nishimura PhD, MPH ,&nbsp;Andrea Bille MD, PhD ,&nbsp;Giuseppe Cardillo FRCS, FETCS ,&nbsp;Frank Detterbeck MD ,&nbsp;Kemp Kernstine MD, PhD ,&nbsp;Hong Kwan Kim MD, PhD ,&nbsp;Yolande Lievens MD, PhD ,&nbsp;Eric Lim MB, ChB, MD, MSc, FRCS(C-Th) ,&nbsp;Edith Marom MD ,&nbsp;Helmut Prosch MD ,&nbsp;Paul Martin Putora MD, PhD, MA, MHI ,&nbsp;Ramon Rami-Porta MD ,&nbsp;David Rice MB, BCh ,&nbsp;Gaetano Rocco MD, FACS, FRCSEd, FEBTS ,&nbsp;Valerie W. Rusch MD ,&nbsp;Isabelle Opitz MD ,&nbsp;Francisco Suarez Vasquez MD ,&nbsp;Hisao Asamura MD","doi":"10.1016/j.jtho.2023.10.012","DOIUrl":"10.1016/j.jtho.2023.10.012","url":null,"abstract":"<div><h3>Introduction</h3><p>The accurate assessment of nodal (N) status is crucial to the management and prognostication of nonmetastatic NSCLC. We sought to determine whether the current N descriptors should be maintained or revised for the upcoming ninth edition of the international TNM lung cancer staging system.</p></div><div><h3>Methods</h3><p>Data were assembled by the International Association for the Study of Lung Cancer on patients with NSCLC, detailing both clinical and pathologic N status, with information about anatomical location and individual station-level identification. Survival was calculated by the Kaplan-Meier method and prognostic groups were assessed by a Cox regression analysis.</p></div><div><h3>Results</h3><p>Data for clinical N and pathologic N status were available in 45,032 and 35,009 patients, respectively. The current N0 to N3 descriptors for both clinical N and pathologic N categories reflect prognostically distinct groups. Furthermore, single-station N2 involvement (N2a) exhibited a better prognosis than multistation N2 involvement (N2b) in both clinical and pathologic classifications, and the differences between all neighboring nodal subcategories were highly significant. The prognostic differences between N2a and N2b were robust and consistent across resection status, histologic type, T category, and geographic region.</p></div><div><h3>Conclusions</h3><p>The current N descriptors should be maintained, with the addition of new subdescriptors to N2 for single-station involvement (N2a) and multiple-station involvement (N2b).</p></div>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":"19 5","pages":"Pages 766-785"},"PeriodicalIF":20.4,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1556086423023109/pdfft?md5=00a02583623d5c7262d416c2781bd6d6&pid=1-s2.0-S1556086423023109-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49691184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microsatellite Instability and Mismatch Repair Deficiency Define a Distinct Subset of Lung Cancers Characterized by Smoking Exposure, High Tumor Mutational Burden, and Recurrent Somatic MLH1 Inactivation","authors":"Soo-Ryum Yang MD ,&nbsp;Erika Gedvilaite MA ,&nbsp;Ryan Ptashkin MS ,&nbsp;Jason Chang MD ,&nbsp;John Ziegler MS ,&nbsp;Douglas A. Mata MD, MPH ,&nbsp;Liliana B. Villafania BS ,&nbsp;Khedoudja Nafa PharmD, PhD ,&nbsp;Jaclyn F. Hechtman MD ,&nbsp;Ryma Benayed PhD ,&nbsp;Ahmet Zehir PhD ,&nbsp;Jamal Benhamida MD ,&nbsp;Maria E. Arcila MD ,&nbsp;Diana Mandelker MD, PhD ,&nbsp;Charles M. Rudin MD, PhD ,&nbsp;Paul K. Paik MD ,&nbsp;Alexander Drilon MD ,&nbsp;Adam J. Schoenfeld MD ,&nbsp;Marc Ladanyi MD","doi":"10.1016/j.jtho.2023.10.004","DOIUrl":"10.1016/j.jtho.2023.10.004","url":null,"abstract":"<div><h3>Introduction</h3><p><span>Microsatellite instability (MSI) and </span>mismatch repair<span> (MMR) deficiency represent a distinct oncogenic process and predict response to immune checkpoint inhibitors (ICIs). The clinicopathologic features of MSI-high (MSI-H) and MMR deficiency (MMR-D) in lung cancers remain poorly characterized.</span></p></div><div><h3>Methods</h3><p>MSI status from 5171 patients with NSCLC and 315 patients with SCLC was analyzed from targeted next-generation sequencing data using two validated bioinformatic pipelines.</p></div><div><h3>Results</h3><p>MSI-H and MMR-D were identified in 21 patients with NSCLC (0.41%) and six patients with SCLC (1.9%). Notably, all patients with NSCLC had a positive smoking history, including 11 adenocarcinomas. Compared with microsatellite stable cases, MSI-H was associated with exceptionally high tumor mutational burden (37.4 versus 8.5 muts/Mb, <em>p</em> &lt; 0.0001), MMR mutational signatures (43% versus 0%, <em>p</em> &lt; 0.0001), and somatic biallelic alterations in <em>MLH1</em> (52% versus 0%, <em>p</em><span> &lt; 0.0001). Loss of MLH1 and PMS2 expression by immunohistochemistry was found in </span><em>MLH1</em> altered and wild-type cases. Similarly, the majority of patients with MSI-H SCLC had evidence of <em>MLH1</em> inactivation, including two with <em>MLH1</em> promoter hypermethylation. A single patient with NSCLC with a somatic <em>MSH2</em><span> mutation had Lynch syndrome as confirmed by the presence of a germline </span><em>MSH2</em> mutation. Among patients with advanced MSI-H lung cancers treated with ICIs, durable clinical benefit was observed in three of eight patients with NSCLC and two of two patients with SCLC. In NSCLC, <em>STK11</em>, <em>KEAP1</em>, and <em>JAK1</em> were mutated in nonresponders but wild type in responders.</p></div><div><h3>Conclusions</h3><p>We present a comprehensive clinicogenomic landscape of MSI-H lung cancers and reveal that MSI-H defines a rare subset of lung cancers associated with smoking, high tumor mutational burden, and <em>MLH1</em> inactivation. Although durable clinical benefit to ICI was observed in some patients, the broad range of responses suggests that clinical activity may be modulated by co-mutational landscapes.</p></div>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":"19 3","pages":"Pages 409-424"},"PeriodicalIF":20.4,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41204197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MUC1-C Is a Common Driver of Acquired Osimertinib Resistance in NSCLC","authors":"Naoki Haratake MD, PhD ,&nbsp;Hiroki Ozawa MD, PhD ,&nbsp;Yoshihiro Morimoto MD, PhD ,&nbsp;Nami Yamashita MD, PhD ,&nbsp;Tatsuaki Daimon MD, PhD ,&nbsp;Atrayee Bhattacharya PhD ,&nbsp;Keyi Wang MD ,&nbsp;Ayako Nakashoji MD, PhD ,&nbsp;Hideko Isozaki PhD ,&nbsp;Mototsugu Shimokawa PhD ,&nbsp;Chie Kikutake PhD ,&nbsp;Mikita Suyama PhD ,&nbsp;Asato Hashinokuchi MD ,&nbsp;Kazuki Takada MD, PhD ,&nbsp;Tomoyoshi Takenaka MD, PhD ,&nbsp;Tomoharu Yoshizumi MD, PhD ,&nbsp;Tetsuya Mitsudomi MD, PhD ,&nbsp;Aaron N. Hata MD, PhD ,&nbsp;Donald Kufe MD","doi":"10.1016/j.jtho.2023.10.017","DOIUrl":"10.1016/j.jtho.2023.10.017","url":null,"abstract":"<div><h3>Introduction</h3><p>Osimertinib is an irreversible EGFR tyrosine kinase inhibitor approved for the first-line treatment of patients with metastatic NSCLC harboring <em>EGFR</em> exon 19 deletions or L858R mutations. Patients treated with osimertinib invariably develop acquired resistance by mechanisms involving additional <em>EGFR</em> mutations, <em>MET</em> amplification, and other pathways. There is no known involvement of the oncogenic MUC1-C protein in acquired osimertinib resistance.</p></div><div><h3>Methods</h3><p>H1975/EGFR (L858R/T790M) and patient-derived NSCLC cells with acquired osimertinib resistance were investigated for MUC1-C dependence in studies of EGFR pathway activation, clonogenicity, and self-renewal capacity.</p></div><div><h3>Results</h3><p>We reveal that MUC1-C is up-regulated in H1975 osimertinib drug-tolerant persister cells and is necessary for activation of the EGFR pathway. H1975 cells selected for stable osimertinib resistance (H1975-OR) and MGH700-2D cells isolated from a patient with acquired osimertinib resistance are found to be dependent on MUC1-C for induction of (1) phospho (p)-EGFR, p-ERK, and p-AKT, (2) EMT, and (3) the resistant phenotype. We report that MUC1-C is also required for p-EGFR, p-ERK, and p-AKT activation and self-renewal capacity in acquired osimertinib-resistant (1) <em>MET-</em>amplified MGH170-1D #2 cells and (2) MGH121 Res#2/EGFR (T790M/C797S) cells. Importantly, targeting MUC1-C in these diverse models reverses osimertinib resistance. In support of these results, high MUC1 mRNA and MUC1-C protein expression is associated with a poor prognosis for patients with EGFR-mutant NSCLCs.</p></div><div><h3>Conclusions</h3><p>Our findings reveal that MUC1-C is a common effector of osimertinib resistance and is a potential target for the treatment of osimertinib-resistant NSCLCs.</p></div>","PeriodicalId":17515,"journal":{"name":"Journal of Thoracic Oncology","volume":"19 3","pages":"Pages 434-450"},"PeriodicalIF":20.4,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1556086423023481/pdfft?md5=489687c09cb071e4f202ac91b19cce29&pid=1-s2.0-S1556086423023481-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71483033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}