Pub Date : 2026-03-01Epub Date: 2026-01-23DOI: 10.1016/j.lungcan.2026.108937
Xiaorong Lu, Shanshan Yuan
{"title":"Methodological considerations in assessing the clinical impact of TP53 classifications in advanced NSCLC","authors":"Xiaorong Lu, Shanshan Yuan","doi":"10.1016/j.lungcan.2026.108937","DOIUrl":"10.1016/j.lungcan.2026.108937","url":null,"abstract":"","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":"213 ","pages":"Article 108937"},"PeriodicalIF":4.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146035673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-01-21DOI: 10.1016/j.lungcan.2026.108934
Yura Ahn , Geun Dong Lee , SeHoon Choi , Hyeong Ryul Kim , Yong-Hee Kim , Dong Kwan Kim , Seung-Il Park , Jooae Choe , Jae Kwang Yun
Objective
The optimal consolidation-to-tumor ratio (CTR) cutoff for survival stratification in radiologically solid-predominant adenocarcinoma (CTR > 0.5) remains unclear. This study aimed to evaluate the prognostic significance of CTR in clinical-stage IA non-mucinous lung adenocarcinoma with CTR > 0.5.
Materials and methods
We retrospectively analyzed patients who underwent curative resection for clinical stage IA non-mucinous adenocarcinoma with CTR > 0.5 between 2011 and 2021. Optimal cutoffs for overall survival (OS) and freedom from recurrence (FFR) were determined using maximized log-rank statistics. Patients were stratified according to the derived CTR cutoff values, and OS and FFR were compared among the CTR groups before and after propensity score matching (PSM).
Results
Among 2,789 patients included, the optimal CTR cutoffs for OS and FFR were 0.84 and 0.85, respectively. Based on the 0.85 cutoff, patients were categorized into three groups: 0.5 < CTR ≤ 0.85 (n = 672), 0.85 < CTR < 1 (n = 229), and CTR = 1 (n = 1,888). OS and FFR were significantly worse in the 0.85 < CTR < 1 group compared to the 0.5 < CTR ≤ 0.85 group (p < 0.05) but not significantly different from the CTR = 1 group (p > 0.05). These trends persisted after PSM. The 0.85 < CTR < 1 group exhibited a higher proportion of pathological risk factors (high-grade patterns, lymphovascular invasion, and nodal metastasis) than the 0.5 < CTR ≤ 0.85 group (all p < 0.05) and was comparable to the CTR = 1 group, except for lymphovascular invasion (p = 0.045). Dichotomization into 0.5 < CTR ≤ 0.85 and 0.85 < CTR ≤ 1 revealed significantly worse OS and FFR in the 0.85 < CTR ≤ 1 group across PSM cohorts for both lobectomy and sublobar resection.
Conclusion
A CTR cutoff of 0.85 effectively distinguishes survival outcomes in patients with clinical stage IA adenocarcinoma and CTR > 0.5 and may inform risk stratification and postoperative surveillance.
{"title":"Prognostic significance of consolidation-to-tumor ratio in stage IA solid predominant non-mucinous adenocarcinoma: a paradigm for risk stratification","authors":"Yura Ahn , Geun Dong Lee , SeHoon Choi , Hyeong Ryul Kim , Yong-Hee Kim , Dong Kwan Kim , Seung-Il Park , Jooae Choe , Jae Kwang Yun","doi":"10.1016/j.lungcan.2026.108934","DOIUrl":"10.1016/j.lungcan.2026.108934","url":null,"abstract":"<div><h3>Objective</h3><div>The optimal consolidation-to-tumor ratio (CTR) cutoff for survival stratification in radiologically solid-predominant adenocarcinoma (CTR > 0.5) remains unclear. This study aimed to evaluate the prognostic significance of CTR in clinical-stage IA non-mucinous lung adenocarcinoma with CTR > 0.5.</div></div><div><h3>Materials and methods</h3><div>We retrospectively analyzed patients who underwent curative resection for clinical stage IA non-mucinous adenocarcinoma with CTR > 0.5 between 2011 and 2021. Optimal cutoffs for overall survival (OS) and freedom from recurrence (FFR) were determined using maximized log-rank statistics. Patients were stratified according to the derived CTR cutoff values, and OS and FFR were compared among the CTR groups before and after propensity score matching (PSM).</div></div><div><h3>Results</h3><div>Among 2,789 patients included, the optimal CTR cutoffs for OS and FFR were 0.84 and 0.85, respectively. Based on the 0.85 cutoff, patients were categorized into three groups: 0.5 < CTR ≤ 0.85 (n = 672), 0.85 < CTR < 1 (n = 229), and CTR = 1 (n = 1,888). OS and FFR were significantly worse in the 0.85 < CTR < 1 group compared to the 0.5 < CTR ≤ 0.85 group (p < 0.05) but not significantly different from the CTR = 1 group (p > 0.05). These trends persisted after PSM. The 0.85 < CTR < 1 group exhibited a higher proportion of pathological risk factors (high-grade patterns, lymphovascular invasion, and nodal metastasis) than the 0.5 < CTR ≤ 0.85 group (all p < 0.05) and was comparable to the CTR = 1 group, except for lymphovascular invasion (p = 0.045). Dichotomization into 0.5 < CTR ≤ 0.85 and 0.85 < CTR ≤ 1 revealed significantly worse OS and FFR in the 0.85 < CTR ≤ 1 group across PSM cohorts for both lobectomy and sublobar resection.</div></div><div><h3>Conclusion</h3><div>A CTR cutoff of 0.85 effectively distinguishes survival outcomes in patients with clinical stage IA adenocarcinoma and CTR > 0.5 and may inform risk stratification and postoperative surveillance.</div></div>","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":"213 ","pages":"Article 108934"},"PeriodicalIF":4.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146078925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-02-03DOI: 10.1016/j.lungcan.2026.108935
Love Nordling , Max Backman , Artur Mezheyeuski , Joakim Lindblad , Nataša Sladoje , Patrick Micke
Background
Multiplex immunofluorescence imaging enables detailed characterization of the tumor immune microenvironment, but whether immune cell densities add prognostic value beyond established clinical factors in non-small cell lung cancer (NSCLC) remains unclear.
Methods
Tissue samples from an NSCLC cohort (n = 298) were stained with a multiplex immunofluorescence panel targeting immune cell markers (CD4, CD8, FoxP3, CD20), cancer cells (pan-cytokeratin), and cell nuclei (DAPI). We quantified immune cell densities, nuclear pleomorphism features, and clinical variables, and trained four machine learning models (logistic regression, random forest, support vector machine, and k-nearest neighbors) to predict overall survival.
Results
Clinical parameters consistently demonstrated the strongest performance in predicting long and short-term survival (logistic regression mean accuracy 0.60 ± 0.01, AUC 0.66 ± 0.01). The addition of immune cell densities revealed a small, statistically significant improvement in survival prediction (accuracy 0.62 ± 0.01, p < 0.01, AUC 0.67 ± 0.01, p = 0.04), while nuclear pleomorphism features did not improve prediction. When combined with clinical parameters, immune cell densities also improved survival stratification in Cox regression analyses numerically (HR = 0.51 vs. 0.55 for clinical parameters alone). Model interpretation analyses showed that stage and performance status have the largest effect on model performance. Selected immune cell densities (tumor CD4-helper and stroma B-cells) have a limited but consistent effect.
Conclusion
Clinical parameters remain the dominant predictors of outcome in NSCLC, with immune cell densities providing only limited prognostic value for clinical stratification. The openly available code and datasets present a unique resource for method development or focused analysis.
{"title":"Incremental prognostic value of immune cell densities beyond clinical parameters in non-small cell lung cancer","authors":"Love Nordling , Max Backman , Artur Mezheyeuski , Joakim Lindblad , Nataša Sladoje , Patrick Micke","doi":"10.1016/j.lungcan.2026.108935","DOIUrl":"10.1016/j.lungcan.2026.108935","url":null,"abstract":"<div><h3>Background</h3><div>Multiplex immunofluorescence imaging enables detailed characterization of the tumor immune microenvironment, but whether immune cell densities add prognostic value beyond established clinical factors in non-small cell lung cancer (NSCLC) remains unclear.</div></div><div><h3>Methods</h3><div>Tissue samples from an NSCLC cohort (n = 298) were stained with a multiplex immunofluorescence panel targeting immune cell markers (CD4, CD8, FoxP3, CD20), cancer cells (pan-cytokeratin), and cell nuclei (DAPI). We quantified immune cell densities, nuclear pleomorphism features, and clinical variables, and trained four machine learning models (logistic regression, random forest, support vector machine, and k-nearest neighbors) to predict overall survival.</div></div><div><h3>Results</h3><div>Clinical parameters consistently demonstrated the strongest performance in predicting long and short-term survival (logistic regression mean accuracy 0.60 ± 0.01, AUC 0.66 ± 0.01). The addition of immune cell densities revealed a small, statistically significant improvement in survival prediction (accuracy 0.62 ± 0.01, p < 0.01, AUC 0.67 ± 0.01, p = 0.04), while nuclear pleomorphism features did not improve prediction. When combined with clinical parameters, immune cell densities also improved survival stratification in Cox regression analyses numerically (HR = 0.51 vs. 0.55 for clinical parameters alone). Model interpretation analyses showed that stage and performance status have the largest effect on model performance. Selected immune cell densities (tumor CD4-helper and stroma B-cells) have a limited but consistent effect.</div></div><div><h3>Conclusion</h3><div>Clinical parameters remain the dominant predictors of outcome in NSCLC, with immune cell densities providing only limited prognostic value for clinical stratification. The openly available code and datasets present a unique resource for method development or focused analysis.</div></div>","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":"213 ","pages":"Article 108935"},"PeriodicalIF":4.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146165683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-01-12DOI: 10.1016/j.lungcan.2026.108918
Meifang Li , Haibo Wang , Wei Zhang , Dong Lin , Chongting Gao , Ying Chen , Cheng Lin , Zongyang Yu
Objective
This study aimed to evaluate the survival benefit of combined intrathecal treatment (IT) via Ommaya reservoir and whole-brain radiotherapy (WBRT) in EGFR-mutant non-small cell lung cancer (NSCLC) patients with leptomeningeal metastases (LM).
Methods
We retrospectively analyzed EGFR-mutant NSCLC patients with LM diagnosed between January 2019 and September 2024. Patients were included if they had cytologically or radiologically confirmed LM and prior EGFR-TKI exposure. Clinical data, cerebrospinal fluid (CSF) profiles (cytology, biochemistry, molecular features), and treatment details were collected. Local therapies included WBRT (30–37.5 Gy in 10–15 fractions) and IT pemetrexed via Ommaya reservoir (10–20 mg weekly for 4 weeks, then bi-weekly for 2 months, followed by monthly maintenance). Overall survival (OS) was analyzed using Kaplan-Meier method and Cox regression. A prognostic nomogram was developed and validated.
Results
Among 200 included patients, the median OS was 12.3 months (95% CI: 10.8–13.8). Patients receiving local therapy (n = 149) had longer OS than those without (n = 51) (13.1 vs. 8.8 months; HR = 0.78, p = 0.001). The combination of IT and WBRT was associated with the best survival outcome (median OS 18.5 months). In CSF analysis, the initial cytology positivity rate was 74.4% (128/172), and normal lactate dehydrogenase (LDH) and chloride levels were associated with longer OS (p < 0.05). Multivariate analysis identified ECOG score, prior third-generation TKI, third-generation TKI plus anti-angiogenic therapy, and local therapy as independent prognostic factors.
Conclusion
The combination of IT via Ommaya reservoir and WBRT may result in better survival in EGFR-mutant NSCLC patients with LM and represents a promising treatment strategy for this patient population.
{"title":"Combined intrathecal therapy via Ommaya reservoir and whole-brain radiotherapy improves survival in EGFR-mutant NSCLC patients with leptomeningeal metastases: a real-world cohort study","authors":"Meifang Li , Haibo Wang , Wei Zhang , Dong Lin , Chongting Gao , Ying Chen , Cheng Lin , Zongyang Yu","doi":"10.1016/j.lungcan.2026.108918","DOIUrl":"10.1016/j.lungcan.2026.108918","url":null,"abstract":"<div><h3>Objective</h3><div>This study aimed to evaluate the survival benefit of combined intrathecal treatment (IT) via Ommaya reservoir and whole-brain radiotherapy (WBRT) in EGFR-mutant non-small cell lung cancer (NSCLC) patients with leptomeningeal metastases (LM).</div></div><div><h3>Methods</h3><div>We retrospectively analyzed EGFR-mutant NSCLC patients with LM diagnosed between January 2019 and September 2024. Patients were included if they had cytologically or radiologically confirmed LM and prior EGFR-TKI exposure. Clinical data, cerebrospinal fluid (CSF) profiles (cytology, biochemistry, molecular features), and treatment details were collected. Local therapies included WBRT (30–37.5 Gy in 10–15 fractions) and IT pemetrexed via Ommaya reservoir (10–20 mg weekly for 4 weeks, then bi-weekly for 2 months, followed by monthly maintenance). Overall survival (OS) was analyzed using Kaplan-Meier method and Cox regression. A prognostic nomogram was developed and validated.</div></div><div><h3>Results</h3><div>Among 200 included patients, the median OS was 12.3 months (95% CI: 10.8–13.8). Patients receiving local therapy (n = 149) had longer OS than those without (n = 51) (13.1 vs. 8.8 months; HR = 0.78, p = 0.001). The combination of IT and WBRT was associated with the best survival outcome (median OS 18.5 months). In CSF analysis, the initial cytology positivity rate was 74.4% (128/172), and normal lactate dehydrogenase (LDH) and chloride levels were associated with longer OS (p < 0.05). Multivariate analysis identified ECOG score, prior third-generation TKI, third-generation TKI plus anti-angiogenic therapy, and local therapy as independent prognostic factors.</div></div><div><h3>Conclusion</h3><div>The combination of IT via Ommaya reservoir and WBRT may result in better survival in EGFR-mutant NSCLC patients with LM and represents a promising treatment strategy for this patient population.</div></div>","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":"213 ","pages":"Article 108918"},"PeriodicalIF":4.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145981118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-01-10DOI: 10.1016/j.lungcan.2026.108913
Jennifer A. Marks , Kieran Sweeney , Andrew Elliott , Brinda Gupta , Ari VanderWalde , Sonam Puri , Misty Dawn Shields , Jorge J. Nieva , Heloisa P. Soares , Patrick C. Ma , Balazs Halmos , Stephen V. Liu
<div><h3>Introduction</h3><div>Small cell lung cancer (SCLC) and extrapulmonary neuroendocrine (NE) tumors are aggressive malignancies with limited treatment options. Seizure-related homolog 6 (SEZ6) is a potential therapeutic target, but its expression in these tumors remains poorly understood. Lineage plasticity contributes to resistance in non-small cell lung cancer (NSCLC), where some cases can undergo SCLC-transformation after targeted therapy. We aimed to characterize <em>SEZ6</em> expression across NE tumors and presumed NSCLC-to-SCLC transformations.</div></div><div><h3>Methods</h3><div>DNA and RNA sequencing were performed for SCLC, NSCLC, and NE samples. Samples were stratified by SEZ6 RNA expression quartiles and classified into subtypes based on ASCL1, NEUROD1, and POU2F3 expression. Significance was tested using the Mann-Whitney <em>U</em> test. Real-world overall survival was obtained from insurance claims data, with p-values calculated using the log-rank test. Paired samples for NSCLC-to-SCLC transformation were identified by sequential biopsies classified as NSCLC followed by SCLC.</div></div><div><h3>Results</h3><div>RNA sequencing was performed on 1318 SCLC and 2218 NE samples. Median SEZ6<!--> <!-->expression was higher in SCLC (39.7 transcripts per million (TPM)) than in NE tumors (20.8 TPM, p<0.0001) and NSCLC (1.34 TPM, p<0.001). Among NE tumors, median SEZ6 expression was highest in prostate (52.0 TPM, p=0.0016 vs SCLC) and lowest in adrenal gland tumors (1.2 TPM, p<0.0001 vs SCLC). In SCLC,<!--> <!-->SEZ6<!--> <!-->expression was positively correlated with ASCL1<!--> <!-->(p=0.44, p<0.0001) and<!--> <!-->NEUROD1<!--> <!-->(p=0.16, p<0.0001) expression but not<!--> <!-->POU2F3<!--> <!-->(p=-0.04, p=0.1253). Median survival was longest in SEZ6-Q2 for both SCLC and NE (13.0 mos. and 33.7 mos., respectively). NSCLC-to-SCLC transformation samples showed numerically higher SEZ6 expression post-transformation (median: 86.2 vs 2.4 TPM).</div></div><div><h3>Conclusions</h3><div>SEZ6<!--> <!-->expression is higher in SCLC than in NE tumors, with notable heterogeneity by subtype, warranting consideration of expanded use of SEZ6-directed therapy.</div><div>Translational Relevance Statement:</div><div>This study establishes SEZ6 as a promising therapeutic target in small cell lung cancer (SCLC) and transformed non-small cell lung cancer (NSCLC), demonstrating its significantly elevated expression compared to neuroendocrine (NE) tumors and NSCLC. The positive correlation of <em>SEZ6</em> expression with NE lineage markers, particularly in <em>ASCL1</em> and <em>NEUROD1</em> subtypes, highlights its role as a lineage-specific marker, guiding the development of SEZ6-targeted antibody-drug conjugates (ADCs). Additionally, the increased <em>SEZ6</em> expression following NSCLC-to-SCLC transformation suggests that SEZ6-targeted therapies could address resistance mechanisms in transformed tumors. Importantly, the association be
小细胞肺癌（SCLC）和肺外神经内分泌（NE）肿瘤是侵袭性恶性肿瘤，治疗选择有限。癫痫相关同源物6 （SEZ6）是一个潜在的治疗靶点，但其在这些肿瘤中的表达仍然知之甚少。谱系可塑性有助于非小细胞肺癌（NSCLC）的耐药，其中一些病例在靶向治疗后可发生sclc转化。我们的目的是表征SEZ6在NE肿瘤中的表达，并推测nsclc到sclc的转化。方法对SCLC、NSCLC和NE样本进行dna和RNA测序。根据SEZ6 RNA表达四分位数对样品进行分层，并根据ASCL1、NEUROD1和POU2F3的表达情况将样品分为亚型。采用Mann-Whitney U检验进行显著性检验。真实世界的总生存率从保险索赔数据中获得，p值使用log-rank检验计算。配对样本的NSCLC到SCLC转化通过顺序活检分类为NSCLC和SCLC。结果对1318例SCLC和2218例NE样本进行了rna测序。SEZ6在SCLC中的中位表达（39.7转录本/百万（TPM））高于NE肿瘤（20.8 TPM, 0.0001）和NSCLC （1.34 TPM, p<0.001）。在NE肿瘤中，SEZ6中位表达在前列腺中最高（52.0 TPM, p=0.0016 vs SCLC），在肾上腺肿瘤中最低（1.2 TPM, p= 0.0001 vs SCLC）。在SCLC中，SEZ6表达与ASCL1 （p=0.44, p= 0.0001）和NEUROD1 （p=0.16, p= 0.0001）表达呈正相关，而与POU2F3表达无关（p=-0.04, p=0.1253）。SCLC和NE的SEZ6-Q2中位生存期最长（13.0个月）。33.7个。分别)。nsclc - sclc转化样本在转化后的SEZ6表达量更高（中位数：86.2 vs 2.4 TPM）。结论sez6在SCLC中的表达高于NE，且在亚型上存在显著的异质性，值得考虑扩大sez6定向治疗的应用。翻译相关性声明：本研究确立了SEZ6在小细胞肺癌（SCLC）和转化的非小细胞肺癌（NSCLC）中有前景的治疗靶点，与神经内分泌（NE）肿瘤和NSCLC相比，SEZ6的表达显著升高。SEZ6表达与NE谱系标记正相关，特别是在ASCL1和NEUROD1亚型中，突出了其作为谱系特异性标记的作用，指导了SEZ6靶向抗体-药物偶联物（adc）的发展。此外，在nsclc向sclc转化后SEZ6表达增加，表明SEZ6靶向治疗可以解决转化肿瘤的耐药机制。重要的是，高SEZ6表达与较短生存期之间的关联表明，将SEZ6状态整合到诊断工作流程中可以帮助根据风险对患者进行分层，并指导治疗决策。这项研究的结果将为未来的临床试验提供信息，旨在实施sez6靶向治疗，作为侵袭性NE恶性肿瘤精确肿瘤学策略的一部分。
{"title":"SEZ6 expression and lineage plasticity in small cell lung cancer and transformed non-small cell lung cancer","authors":"Jennifer A. Marks , Kieran Sweeney , Andrew Elliott , Brinda Gupta , Ari VanderWalde , Sonam Puri , Misty Dawn Shields , Jorge J. Nieva , Heloisa P. Soares , Patrick C. Ma , Balazs Halmos , Stephen V. Liu","doi":"10.1016/j.lungcan.2026.108913","DOIUrl":"10.1016/j.lungcan.2026.108913","url":null,"abstract":"<div><h3>Introduction</h3><div>Small cell lung cancer (SCLC) and extrapulmonary neuroendocrine (NE) tumors are aggressive malignancies with limited treatment options. Seizure-related homolog 6 (SEZ6) is a potential therapeutic target, but its expression in these tumors remains poorly understood. Lineage plasticity contributes to resistance in non-small cell lung cancer (NSCLC), where some cases can undergo SCLC-transformation after targeted therapy. We aimed to characterize <em>SEZ6</em> expression across NE tumors and presumed NSCLC-to-SCLC transformations.</div></div><div><h3>Methods</h3><div>DNA and RNA sequencing were performed for SCLC, NSCLC, and NE samples. Samples were stratified by SEZ6 RNA expression quartiles and classified into subtypes based on ASCL1, NEUROD1, and POU2F3 expression. Significance was tested using the Mann-Whitney <em>U</em> test. Real-world overall survival was obtained from insurance claims data, with p-values calculated using the log-rank test. Paired samples for NSCLC-to-SCLC transformation were identified by sequential biopsies classified as NSCLC followed by SCLC.</div></div><div><h3>Results</h3><div>RNA sequencing was performed on 1318 SCLC and 2218 NE samples. Median SEZ6<!--> <!-->expression was higher in SCLC (39.7 transcripts per million (TPM)) than in NE tumors (20.8 TPM, p<0.0001) and NSCLC (1.34 TPM, p<0.001). Among NE tumors, median SEZ6 expression was highest in prostate (52.0 TPM, p=0.0016 vs SCLC) and lowest in adrenal gland tumors (1.2 TPM, p<0.0001 vs SCLC). In SCLC,<!--> <!-->SEZ6<!--> <!-->expression was positively correlated with ASCL1<!--> <!-->(p=0.44, p<0.0001) and<!--> <!-->NEUROD1<!--> <!-->(p=0.16, p<0.0001) expression but not<!--> <!-->POU2F3<!--> <!-->(p=-0.04, p=0.1253). Median survival was longest in SEZ6-Q2 for both SCLC and NE (13.0 mos. and 33.7 mos., respectively). NSCLC-to-SCLC transformation samples showed numerically higher SEZ6 expression post-transformation (median: 86.2 vs 2.4 TPM).</div></div><div><h3>Conclusions</h3><div>SEZ6<!--> <!-->expression is higher in SCLC than in NE tumors, with notable heterogeneity by subtype, warranting consideration of expanded use of SEZ6-directed therapy.</div><div>Translational Relevance Statement:</div><div>This study establishes SEZ6 as a promising therapeutic target in small cell lung cancer (SCLC) and transformed non-small cell lung cancer (NSCLC), demonstrating its significantly elevated expression compared to neuroendocrine (NE) tumors and NSCLC. The positive correlation of <em>SEZ6</em> expression with NE lineage markers, particularly in <em>ASCL1</em> and <em>NEUROD1</em> subtypes, highlights its role as a lineage-specific marker, guiding the development of SEZ6-targeted antibody-drug conjugates (ADCs). Additionally, the increased <em>SEZ6</em> expression following NSCLC-to-SCLC transformation suggests that SEZ6-targeted therapies could address resistance mechanisms in transformed tumors. Importantly, the association be","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":"213 ","pages":"Article 108913"},"PeriodicalIF":4.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145981115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2026-01-03DOI: 10.1016/j.lungcan.2025.108893
Kathleen Zwijsen , Ellen Heirwegh , Eline Schillebeeckx , Elly Marcq , Adrian Covaci , Ken Op de Beeck , Jan P. van Meerbeeck , Jo Raskin , Annelies Janssens , Annemiek Snoeckx , Kevin Lamote
Objectives
Pleural mesothelioma (PM) is an aggressive thoracic cancer related to historical exposure to asbestos fibres. Symptoms often appear at an advanced stage, leading to delayed diagnosis and dismal prognosis. Early diagnosis is thus crucial in improving patient outcome. Current biomarker research for early detection focuses on different −omics research fields (genomics, proteomics, transcriptomics, metabolomics and volatomics), however with no clinically useful result. Moreover, currently no screening program is advocated for asymptomatic individuals with an established asbestos exposure. The aim of this review is to summarise the advances in different −omics fields and to pinpoint state-of-the art biomarkers with the highest potential to serve as primary targets in clinical trials for early PM detection or screening.
Methods
A literature search was performed in the databases MEDLINE and Web Of Science. Research articles published before 1 August 2025 were eligible.
Results
In total, 63 articles were included in this review, with specific focus on radiomics, genomics, transcriptomics, epigenomics, proteomics, metabolomics, and volatomics. Several research groups have focused on investigating biomarkers or screening techniques for pleural mesothelioma among individuals with a history of asbestos exposure. Notable approaches include using low-dose Computed Tomography, and determining mesothelin levels and micro-RNAs in blood, and volatile organic compounds in exhaled breath.
Discussion
Single biomarkers like miRNAs, mesothelin, and VOCs show promise, but further validation is needed in larger cohorts with correct control groups. A multi-omics approach, which integrates biomarker panels from various −omics areas, has the potential to enhance diagnostic accuracy.
目的胸膜间皮瘤（PM）是一种与石棉纤维暴露史有关的侵袭性胸部肿瘤。症状往往出现在晚期，导致诊断延误和预后不佳。因此，早期诊断对于改善患者预后至关重要。目前用于早期检测的生物标志物研究主要集中在不同的组学研究领域（基因组学、蛋白质组学、转录组学、代谢组学和挥发组学），但没有临床有用的结果。此外，目前没有筛查方案提倡无症状的个体与石棉暴露。本综述的目的是总结不同组学领域的进展，并确定最有潜力作为早期PM检测或筛查临床试验主要靶点的最先进的生物标志物。方法在MEDLINE和Web Of Science数据库中进行文献检索。在2025年8月1日之前发表的研究论文符合条件。结果本综述共纳入63篇文献，重点关注放射组学、基因组学、转录组学、表观基因组学、蛋白质组学、代谢组学和挥发组学。几个研究小组已经专注于研究有石棉暴露史的个体胸膜间皮瘤的生物标志物或筛选技术。值得注意的方法包括使用低剂量计算机断层扫描，测定血液中的间皮素水平和微rna，以及呼出气体中的挥发性有机化合物。单个生物标志物如mirna、间皮素和VOCs显示出希望，但需要在更大的队列和正确的对照组中进一步验证。多组学方法集成了来自不同组学领域的生物标志物面板，具有提高诊断准确性的潜力。
{"title":"Multi-omic screening for pleural mesothelioma in Asbestos-Exposed Populations: A literature review and Recommendations","authors":"Kathleen Zwijsen , Ellen Heirwegh , Eline Schillebeeckx , Elly Marcq , Adrian Covaci , Ken Op de Beeck , Jan P. van Meerbeeck , Jo Raskin , Annelies Janssens , Annemiek Snoeckx , Kevin Lamote","doi":"10.1016/j.lungcan.2025.108893","DOIUrl":"10.1016/j.lungcan.2025.108893","url":null,"abstract":"<div><h3>Objectives</h3><div>Pleural mesothelioma (PM) is an aggressive thoracic cancer related to historical exposure to asbestos fibres. Symptoms often appear at an advanced stage, leading to delayed diagnosis and dismal prognosis. Early diagnosis is thus crucial in improving patient outcome. Current biomarker research for early detection focuses on different −omics research fields (genomics, proteomics, transcriptomics, metabolomics and volatomics), however with no clinically useful result. Moreover, currently no screening program is advocated for asymptomatic individuals with an established asbestos exposure. The aim of this review is to summarise the advances in different −omics fields and to pinpoint state-of-the art biomarkers with the highest potential to serve as primary targets in clinical trials for early PM detection or screening.</div></div><div><h3>Methods</h3><div>A literature search was performed in the databases MEDLINE and Web Of Science. Research articles published before 1 August 2025 were eligible.</div></div><div><h3>Results</h3><div>In total, 63 articles were included in this review, with specific focus on radiomics, genomics, transcriptomics, epigenomics, proteomics, metabolomics, and volatomics. Several research groups have focused on investigating biomarkers or screening techniques for pleural mesothelioma among individuals with a history of asbestos exposure. Notable approaches include using low-dose Computed Tomography, and determining mesothelin levels and micro-RNAs in blood, and volatile organic compounds in exhaled breath.</div></div><div><h3>Discussion</h3><div>Single biomarkers like miRNAs, mesothelin, and VOCs show promise, but further validation is needed in larger cohorts with correct control groups. A multi-omics approach, which integrates biomarker panels from various −omics areas, has the potential to enhance diagnostic accuracy.</div></div>","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":"212 ","pages":"Article 108893"},"PeriodicalIF":4.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145927314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01Epub Date: 2025-12-29DOI: 10.1016/j.lungcan.2025.108891
Deborah Di-Xin Zhou , Sarah J. Lord , Frank Po-Yen Lin , Wendy A. Cooper , Milita Zaheed , Robert John Simes , Thomas John , Chee Khoon Lee
Background
In NSCLC, TP53 mutations are heterogeneous with varied effects on protein synthesis, function and clinical outcomes. We hypothesize that a refined classification of TP53 mutations, beyond binary categorization, could improve prognostication. Furthermore, specific mutations could be associated with enhanced benefit from immune checkpoint inhibitors (ICI) versus chemotherapy. To investigate this, we analyzed data from randomized trials (OAK and POPLAR) which compared atezolizumab to chemotherapy in previously treated advanced driver-negative NSCLC.
Methods
Participants were classified as TP53 mutant or wild-type using baseline plasma, and by coding mutation, and Olivier’s and Poeta’s classification. We performed multivariable Cox regression analyses to evaluate the prognostic significance of TP53 mutations, and interaction tests to assess their predictive value.
Results
Among 762 participants, 49% harbored a TP53 mutation. TP53 mutations based on binary categorization were associated with poorer but not statistically significant OS compared to wild-type (adjusted-HR 1.15; 95 %CI 0.96–1.38; P = .12). However, nonsense mutations classified by coding mutations (adjusted-HR 1.71; 95% CI 1.22–2.39; P = .002), non-missense mutations classified by Olivier’s classification (adjusted-HR 1.33; 95% CI 1.03–1.74; P = .03) and disruptive mutations classified by Poeta’s classification (adjusted-HR 1.33; 95% CI 1.37–1.77; P = .03) were associated with statistically significant poorer OS. TP53 status did not predict differential benefit from ICI versus chemotherapy (interaction P = .45).
Conclusion
In advanced driver-negative NSCLC following progression on first-line chemotherapy, nonsense, non-missense and disruptive mutations of TP53 were strongly associated with inferior OS. These data support utilizing a nuanced classification of TP53 mutations as a stratification factor in future trials, and laboratory reporting to aid prognostication.
背景：在非小细胞肺癌中，TP53突变具有异质性，对蛋白质合成、功能和临床结果的影响各不相同。我们假设TP53突变的精确分类，超越二元分类，可以改善预后。此外，特异性突变可能与免疫检查点抑制剂（ICI）与化疗的获益增强有关。为了研究这一点，我们分析了随机试验（OAK和POPLAR）的数据，这些试验比较了atezolizumab与化疗在先前治疗的晚期驱动阴性NSCLC中的疗效。方法：通过基线血浆、编码突变、Olivier和Poeta分类，将参与者分为TP53突变型和野生型。我们通过多变量Cox回归分析来评估TP53突变的预后意义，并通过相互作用试验来评估其预测价值。结果：在762名参与者中，49%的人携带TP53突变。与野生型相比，基于二元分类的TP53突变与较差的OS相关，但无统计学意义（调整后危险度1.15;95% CI 0.96-1.38; P = 0.12）。然而，编码突变分类的无义突变（校正后危险度1.71,95% CI 1.22-2.39, P = 0.002）、Olivier分类的非错义突变（校正后危险度1.33,95% CI 1.03-1.74, P = 0.03）和Poeta分类的破坏性突变（校正后危险度1.33,95% CI 1.37-1.77, P = 0.03）与较差的OS有统计学意义相关。TP53状态不能预测ICI与化疗的获益差异（相互作用P = 0.45）。结论：在一线化疗进展的晚期驱动阴性NSCLC中，无义、非错义和破坏性TP53突变与不良OS密切相关。这些数据支持在未来的试验中利用TP53突变的细微分类作为分层因素，以及实验室报告来帮助预测。
{"title":"Clinical impact of TP53 classifications in previously treated advanced driver-negative non-small cell lung cancer: A biomarker analysis of the OAK and POPLAR randomized clinical trials","authors":"Deborah Di-Xin Zhou , Sarah J. Lord , Frank Po-Yen Lin , Wendy A. Cooper , Milita Zaheed , Robert John Simes , Thomas John , Chee Khoon Lee","doi":"10.1016/j.lungcan.2025.108891","DOIUrl":"10.1016/j.lungcan.2025.108891","url":null,"abstract":"<div><h3>Background</h3><div>In NSCLC, <em>TP53</em> mutations are heterogeneous with varied effects on protein synthesis, function and clinical outcomes. We hypothesize that a refined classification of <em>TP53</em> mutations, beyond binary categorization, could improve prognostication. Furthermore, specific mutations could be associated with enhanced benefit from immune checkpoint inhibitors (ICI) versus chemotherapy. To investigate this, we analyzed data from randomized trials (OAK and POPLAR) which compared atezolizumab to chemotherapy in previously treated advanced driver-negative NSCLC.</div></div><div><h3>Methods</h3><div>Participants were classified as <em>TP53</em> mutant or wild-type using baseline plasma, and by coding mutation, and Olivier’s and Poeta’s classification. We performed multivariable Cox regression analyses to evaluate the prognostic significance of <em>TP53</em> mutations, and interaction tests to assess their predictive value.</div></div><div><h3>Results</h3><div>Among 762 participants, 49% harbored a <em>TP53</em> mutation. <em>TP53</em> mutations based on binary categorization were associated with poorer but not statistically significant OS compared to wild-type (adjusted-HR 1.15; 95 %CI 0.96–1.38; <em>P</em> = .12). However, nonsense mutations classified by coding mutations (adjusted-HR 1.71; 95% CI 1.22–2.39;<!--> <em>P</em> = .002), non-missense mutations classified by Olivier’s classification (adjusted-HR 1.33; 95% CI 1.03–1.74; <em>P</em> = .03) and disruptive mutations classified by Poeta’s classification (adjusted-HR 1.33; 95% CI 1.37–1.77; <em>P</em> = .03) were associated with statistically significant poorer OS. <em>TP53</em> status did not predict differential benefit from ICI versus chemotherapy (interaction <em>P</em> = .45).</div></div><div><h3>Conclusion</h3><div>In advanced driver-negative NSCLC following progression on first-line chemotherapy, nonsense, non-missense and disruptive mutations of <em>TP53</em> were strongly associated with inferior OS. These data support utilizing a nuanced classification of <em>TP53</em> mutations as a stratification factor in future trials, and laboratory reporting to aid prognostication.</div></div>","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":"212 ","pages":"Article 108891"},"PeriodicalIF":4.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145918105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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