Pub Date : 2025-11-12DOI: 10.1016/j.lungcan.2025.108841
Linrui Ma , Xiangyu Zhang , Shidong Xu , Jiacheng Dai , Zhe Huang , Zhaohui Ruan , Yuda Zhang , Xuexue Zhou , Yuanze Sun , Yahui Chen , Huan Yan , Chun Zou , Si Qi Xiang , Jingyi Li , Yangqian Chen , Tian Xu , Renzhi Zhang , Dan Yang , Fang Tian , Nachuan Zou , Yongchang Zhang
Background
Small cell lung cancer (SCLC) is a highly aggressive malignancy with poor prognosis and limited therapeutic options. The lack of effective targeted therapies for SCLC is a major limitation of this field. Bromodomain and Extra-Terminal (BET) inhibitors have emerged as a promising class of anticancer agents. This study aimed to evaluate the preclinical efficacy and mechanism of action of NHWD-870, a novel BET inhibitor targeting BRD4, in SCLC.
Method
The therapeutic effects of NHWD-870 on SCLC have been validated through compassionate use. The anti-tumor effects of NHWD-870 were explored using in vitro and in vivo models. CCK-8 assays and flow cytometry were utilized to examine cell viability, apoptosis, and mechanisms of cell cycle arrest. The in vivo effectiveness of NHWD-870 was evaluated using cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models of SCLC. Mechanistic studies involving RNA sequencing, Western blotting, qPCR, and transfection were conducted to investigate and confirm the underlying mechanisms of NHWD-870.
Result
Our study observed the efficacy of NHWD-870 in a patient with SCLC. NHWD-870 demonstrated robust anti-tumor activity against SCLC in both in vitro and in vivo models, effectively halting tumor growth, inducing apoptosis, and disrupting the cell cycle. RNA sequencing confirmed that the cell cycle is its primary pathway of action, with BRD4, STRADA, and CCND1 identified as key targets.
Conclusion
NHWD-870 exhibits anti-tumor activity both in vitro and in vivo against SCLC, primarily by regulating the BRD4/STRADA/CCND1 axis and inhibiting the transition of the cell cycle from the G1 phase to the S phase. These findings highlight the therapeutic potential of NHWD-870 as a novel BET inhibitor for SCLC treatment and provide a molecular basis for further clinical development.
{"title":"NHWD-870 suppresses tumor proliferation via the BRD4/STRADA/CCND1 axis in small cell lung cancer","authors":"Linrui Ma , Xiangyu Zhang , Shidong Xu , Jiacheng Dai , Zhe Huang , Zhaohui Ruan , Yuda Zhang , Xuexue Zhou , Yuanze Sun , Yahui Chen , Huan Yan , Chun Zou , Si Qi Xiang , Jingyi Li , Yangqian Chen , Tian Xu , Renzhi Zhang , Dan Yang , Fang Tian , Nachuan Zou , Yongchang Zhang","doi":"10.1016/j.lungcan.2025.108841","DOIUrl":"10.1016/j.lungcan.2025.108841","url":null,"abstract":"<div><h3>Background</h3><div>Small cell lung cancer (SCLC) is a highly aggressive malignancy with poor prognosis and limited therapeutic options. The lack of effective targeted therapies for SCLC is a major limitation of this field. Bromodomain and Extra-Terminal (BET) inhibitors have emerged as a promising class of anticancer agents. This study aimed to evaluate the preclinical efficacy and mechanism of action of NHWD-870, a novel BET inhibitor targeting BRD4, in SCLC.</div></div><div><h3>Method</h3><div>The therapeutic effects of NHWD-870 on SCLC have been validated through compassionate use. The anti-tumor effects of NHWD-870 were explored using in vitro and in vivo models. CCK-8 assays and flow cytometry were utilized to examine cell viability, apoptosis, and mechanisms of cell cycle arrest. The in vivo effectiveness of NHWD-870 was evaluated using cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models of SCLC. Mechanistic studies involving RNA sequencing, Western blotting, qPCR, and transfection were conducted to investigate and confirm the underlying mechanisms of NHWD-870.</div></div><div><h3>Result</h3><div>Our study observed the efficacy of NHWD-870 in a patient with SCLC. NHWD-870 demonstrated robust anti-tumor activity against SCLC in both in vitro and in vivo models, effectively halting tumor growth, inducing apoptosis, and disrupting the cell cycle. RNA sequencing confirmed that the cell cycle is its primary pathway of action, with BRD4, STRADA, and CCND1 identified as key targets.</div></div><div><h3>Conclusion</h3><div>NHWD-870 exhibits anti-tumor activity both in vitro and in vivo against SCLC, primarily by regulating the BRD4/STRADA/CCND1 axis and inhibiting the transition of the cell cycle from the G1 phase to the S phase. These findings highlight the therapeutic potential of NHWD-870 as a novel BET inhibitor for SCLC treatment and provide a molecular basis for further clinical development.</div></div>","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":"210 ","pages":"Article 108841"},"PeriodicalIF":4.4,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145518092","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 : 2025-11-08DOI: 10.1016/j.lungcan.2025.108836
Hui Cai , Xiao-Ou Shu , Shenghui Wu , Yu-Tang Gao , Qing Lan , Nathaniel Rothman , Wei Zheng , Gong Yang
Background
Whether female being more susceptible to lung cancer among never smokers (LCNS) than males has been a long-standing debate.
Method
A total of 26,339 married heterosexual couples included in this cohort study. Truncated (40–89) age-standardized incidence rates and incidence rate ratio (IRR) of lung cancer were calculated and compared between the two sexes. Cox regression models were used to estimate hazard ratio (HR) for evaluating sex differences in lung cancer risk.
Results
In this large couples cohort study the prevalence of ever smoking was 2.1 % in wives and 65.4 % in husbands. Over a median follow-up of 12.5 years, incident lung cancer was documented in 293 wives and 500 husbands. The truncated age-standardized incidence rate per 100,000 person-years in all couples was significantly lower in wives (56.1) than their husbands (117.4), with an IRR of 0.48 for wives vs husbands. A similar pattern was observed among dual-smoker couples. However, the sex difference diminished when further adjusting for the duration and intensity of cigarette smoking. In contrast, among dual-nonsmoker couples, the corresponding age-standardized rate was significantly higher in wives (52.6) than their husbands (33.4), with an IRR of 1.57. Multivariable adjustment did not alter the result, with an HR for wives vs husbands of 1.54 (95 % CI, 1.05–2.27).
Conclusions
This study, for the first time, using a large cohort of married couples, demonstrates that females are more susceptible to LCNS than males.
{"title":"Higher lung cancer risk among female never-smokers than males in a large married couple study","authors":"Hui Cai , Xiao-Ou Shu , Shenghui Wu , Yu-Tang Gao , Qing Lan , Nathaniel Rothman , Wei Zheng , Gong Yang","doi":"10.1016/j.lungcan.2025.108836","DOIUrl":"10.1016/j.lungcan.2025.108836","url":null,"abstract":"<div><h3>Background</h3><div>Whether female being more susceptible to lung cancer among never smokers (LCNS) than males has been a long-standing debate.</div></div><div><h3>Method</h3><div>A total of 26,339 married heterosexual couples included in this cohort study. Truncated (40–89) age-standardized incidence rates and incidence rate ratio (IRR) of lung cancer were calculated and compared between the two sexes. Cox regression models were used to estimate hazard ratio (HR) for evaluating sex differences in lung cancer risk.</div></div><div><h3>Results</h3><div>In this large couples cohort study the prevalence of ever smoking was 2.1 % in wives and 65.4 % in husbands. Over a median follow-up of 12.5 years, incident lung cancer was documented in 293 wives and 500 husbands. The truncated age-standardized incidence rate per 100,000 person-years in all couples was significantly lower in wives (56.1) than their husbands (117.4), with an IRR of 0.48 for wives vs husbands. A similar pattern was observed among dual-smoker couples. However, the sex difference diminished when further adjusting for the duration and intensity of cigarette smoking. In contrast, among dual-nonsmoker couples, the corresponding age-standardized rate was significantly higher in wives (52.6) than their husbands (33.4), with an IRR of 1.57. Multivariable adjustment did not alter the result, with an HR for wives vs husbands of 1.54 (95 % CI, 1.05–2.27).</div></div><div><h3>Conclusions</h3><div>This study, for the first time, using a large cohort of married couples, demonstrates that females are more susceptible to LCNS than males.</div></div>","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":"210 ","pages":"Article 108836"},"PeriodicalIF":4.4,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145518089","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}
EGFR tyrosine kinase inhibitors (EGFR-TKIs) have significantly improved the outcomes of EGFR-mutant non-small cell lung cancer (NSCLC); however, resistance commonly develops. While secondary EGFR mutations (e.g., C797S) and histological transformations are known mechanisms, their coexistence at distinct sites is rarely documented.
Methods
We established patient-derived cell lines from pleural effusion and mediastinal lymph node metastasis before and after osimertinib resistance in a patient with EGFR L858R–mutated NSCLC. Resistance mechanisms were characterized using cell viability assays, Western blotting, Sanger sequencing, RNA sequencing, and whole-exome sequencing.
Results
Pleural effusion–derived cells (JFCR-330-4 and -7) retained adenocarcinoma morphology and harbored an acquired EGFR L718V mutation, causing resistance to first-, third- and next-generation TKIs but sensitivity to second-generation TKI afatinib. Conversely, mediastinal lymph node–derived cells (JFCR-330-5) exhibited small cell lung cancer (SCLC)-like morphology, low EGFR expression, high neuroendocrine marker expression, and maintained EGFR L858R. RNA sequencing revealed SCLC-associated transcriptional signatures, while whole-exome and Sanger sequencing identified a small deletion in RB1 gene around exon 19 and a concurrent TP53 mutation, collectively suggesting transformation into SCLC.
Conclusion
Spatially distinct and simultaneous resistance mechanisms, namely, EGFR L718V mutation and SCLC transformation, contributed to osimertinib resistance. The detection of RB1 2.4 kb small deletion in RB1 gene highlights the importance of deep genomic profiling. Multi-site biopsy and molecular diagnostics are necessary to guide treatment decisions in EGFR-TKI–resistant NSCLC.
{"title":"Tumor heterogeneity involving SCLC with a single exon deletion in RB1 and adenocarcinoma with EGFR-L718V mutation in EGFR-TKI–resistant lung cancer","authors":"Sho Kakuto , Ken Uchibori , Yuri Yamamoto , Eisaku Miyauchi , Makoto Nishio , Hisatoshi Sugiura , Ryohei Katayama","doi":"10.1016/j.lungcan.2025.108833","DOIUrl":"10.1016/j.lungcan.2025.108833","url":null,"abstract":"<div><h3>Introduction</h3><div>EGFR tyrosine kinase inhibitors (EGFR-TKIs) have significantly improved the outcomes of EGFR-mutant non-small cell lung cancer (NSCLC); however, resistance commonly develops. While secondary EGFR mutations (e.g., C797S) and histological transformations are known mechanisms, their coexistence at distinct sites is rarely documented.</div></div><div><h3>Methods</h3><div>We established patient-derived cell lines from pleural effusion and mediastinal lymph node metastasis before and after osimertinib resistance in a patient with EGFR L858R–mutated NSCLC. Resistance mechanisms were characterized using cell viability assays, Western blotting, Sanger sequencing, RNA sequencing, and whole-exome sequencing.</div></div><div><h3>Results</h3><div>Pleural effusion–derived cells (JFCR-330-4 and -7) retained adenocarcinoma morphology and harbored an acquired EGFR L718V mutation, causing resistance to first-, third- and next-generation TKIs but sensitivity to second-generation TKI afatinib. Conversely, mediastinal lymph node–derived cells (JFCR-330-5) exhibited small cell lung cancer (SCLC)-like morphology, low EGFR expression, high neuroendocrine marker expression, and maintained EGFR L858R. RNA sequencing revealed SCLC-associated transcriptional signatures, while whole-exome and Sanger sequencing identified a small deletion in <em>RB1</em> gene around exon 19 and a concurrent <em>TP53</em> mutation, collectively suggesting transformation into SCLC.</div></div><div><h3>Conclusion</h3><div>Spatially distinct and simultaneous resistance mechanisms, namely, EGFR L718V mutation and SCLC transformation, contributed to osimertinib resistance. The detection of RB1 2.4 kb small deletion in <em>RB1</em> gene highlights the importance of deep genomic profiling. Multi-site biopsy and molecular diagnostics are necessary to guide treatment decisions in EGFR-TKI–resistant NSCLC.</div></div>","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":"210 ","pages":"Article 108833"},"PeriodicalIF":4.4,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145564309","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 : 2025-11-07DOI: 10.1016/j.lungcan.2025.108832
Adam Khorasanchi , Mingjia Li , Songzhu Zhao , Lai Wei , Evelyn Goodyear , Kevin Ho , Hamzah Abu-Sbeih , Austin Secor , Erin M. Bertino , Peter G. Shields , Logan Roof , Jinesh Gheeya , Kai He , Jacob Kaufman , Regan Memmott , Asrar Alahmadi , David P. Carbone , Gregory A. Otterson , Alexa Meara , Carolyn J. Presley , Dwight H. Owen
Background
Patients with metastatic non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs) are at risk for severe immune-related adverse events (irAEs). Limited data exists on the association between severe irAEs requiring hospitalization (irAEh) and overall survival (OS) in patients with NSCLC who received front-line ICIs, as well as risk factors for irAEh.
Methods
Electronic medical records of consecutive patients with metastatic NSCLC treated with front-line pembrolizumab with or without chemotherapy from 2017 to 2022 were assessed retrospectively. An irAEh was defined as any severe irAE requiring hospitalization within 1 year of ICI initiation. Clinical characteristics for the entire cohort were reported descriptively. Kaplan-Meier survival analysis and the Cox proportional hazard model were used to assess the OS and HR between groups.
Results
Among 312 patients, 203 (65 %) were hospitalized for any reason within 1 year of initiating pembrolizumab, including 37 (12 %) for irAEs. irAEh and overall hospitalization rates did not differ for patients treated with pembrolizumab alone compared to pembrolizumab in combination with chemotherapy. The most common reasons for irAEh were pneumonitis and colitis. Patients with irAEh experienced significantly shorter median OS (8.6 months; 95 % CI: 5.0–19.9) compared to those without irAEh (22.7 months; 95 % CI: 18.2–27.4; P = 0.027). Patients who experienced early-onset irAEh (<6 months) had a significantly shorter median OS of 5.4 months (95 % CI: 2.7–8.6) compared to those with late-onset irAEh (≥6 months), median OS not reached (NR); 95 % CI: 8.6-NR; P = 0.003. Patients hospitalized for any reason during the first year of treatment had a shorter median OS (11.2 months; 95 % CI: 9.5–15.2) than those who were not (49.4 months; 95 % CI: 39.5–62.4; P < 0.001).
Conclusions
Severe irAEs requiring hospitalization or hospitalization for any cause within the first year of initiating pembrolizumab among patients with NSCLC was associated with worse survival outcomes.
{"title":"Impact of immune-related and non-immune related hospital admissions on survival of patients with non-small cell lung cancer receiving first-line immunotherapy","authors":"Adam Khorasanchi , Mingjia Li , Songzhu Zhao , Lai Wei , Evelyn Goodyear , Kevin Ho , Hamzah Abu-Sbeih , Austin Secor , Erin M. Bertino , Peter G. Shields , Logan Roof , Jinesh Gheeya , Kai He , Jacob Kaufman , Regan Memmott , Asrar Alahmadi , David P. Carbone , Gregory A. Otterson , Alexa Meara , Carolyn J. Presley , Dwight H. Owen","doi":"10.1016/j.lungcan.2025.108832","DOIUrl":"10.1016/j.lungcan.2025.108832","url":null,"abstract":"<div><h3>Background</h3><div>Patients with metastatic non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs) are at risk for severe immune-related adverse events (irAEs). Limited data exists on the association between severe irAEs requiring hospitalization (irAEh) and overall survival (OS) in patients with NSCLC who received front-line ICIs, as well as risk factors for irAEh.</div></div><div><h3>Methods</h3><div>Electronic medical records of consecutive patients with metastatic NSCLC treated with front-line pembrolizumab with or without chemotherapy from 2017 to 2022 were assessed retrospectively. An irAEh was defined as any severe irAE requiring hospitalization within 1 year of ICI initiation. Clinical characteristics for the entire cohort were reported descriptively. Kaplan-Meier survival analysis and the Cox proportional hazard model were used to assess the OS and HR between groups.</div></div><div><h3>Results</h3><div>Among 312 patients, 203 (65 %) were hospitalized for any reason within 1 year of initiating pembrolizumab, including 37 (12 %) for irAEs. irAEh and overall hospitalization rates did not differ for patients treated with pembrolizumab alone compared to pembrolizumab in combination with chemotherapy. The most common reasons for irAEh were pneumonitis and colitis. Patients with irAEh experienced significantly shorter median OS (8.6 months; 95 % CI: 5.0–19.9) compared to those without irAEh (22.7 months; 95 % CI: 18.2–27.4; <em>P</em> = 0.027). Patients who experienced early-onset irAEh (<6 months) had a significantly shorter median OS of 5.4 months (95 % CI: 2.7–8.6) compared to those with late-onset irAEh (≥6 months), median OS not reached (NR); 95 % CI: 8.6-NR; <em>P</em> = 0.003. Patients hospitalized for any reason during the first year of treatment had a shorter median OS (11.2 months; 95 % CI: 9.5–15.2) than those who were not (49.4 months; 95 % CI: 39.5–62.4; <em>P</em> < 0.001).</div></div><div><h3>Conclusions</h3><div>Severe irAEs requiring hospitalization or hospitalization for any cause within the first year of initiating pembrolizumab among patients with NSCLC was associated with worse survival outcomes.</div></div>","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":"210 ","pages":"Article 108832"},"PeriodicalIF":4.4,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145518052","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}
Pembrolizumab is currently used as a first-line therapy for EGFR- and ALK-negative advanced non-small cell lung cancer (NSCLC). However, whether pembrolizumab alone (P-mono) or combined with platinum chemotherapy (P-combo) provides superior long-term benefit remains unclear.
Methods
We retrospectively analyzed 392 patients with PD-L1 TPS ≥ 1 % treated first-line with P-mono (n = 194) or P-combo (n = 198) between 2019 and 2021. Propensity-score matching across 13 baseline variables yielded two well-balanced cohorts of 97 patients each, with a median follow-ups of 42.8 and 44.1 months, respectively.
Results
P-combo prolonged overall survival (OS) (median 31.8 vs 20.7 months; hazard ratio [HR] 0.67, 95 % confidence interval [CI] 0.46–0.96) and progression-free survival (12.5 vs 7.0 months; HR 0.59, 95 %CI 0.43–0.81). The 3- and 4-year OS rates were 49.8 % and 42.7 %, respectively, with P-combo, compared with 28.1 % and 22.3 % with P-mono. The 48-month restricted mean survival time also favored P-combo (p = 0.039). Additionally, greater benefits were observed among patients aged < 75 years, with ECOG performance status 0–1, PD-L1 TPS 1–49 %, and those using proton-pump inhibitors. Grade ≥ 3 treatment-related adverse events (TRAEs) were more frequent with P-combo (35 % vs 20 %, p = 0.024). However, treatment-related deaths (2 % each) and pneumonitis incidence and severity were comparable; cumulative toxicity curves plateaued after 3 years.
Conclusions
These findings suggest that P-combo showed a durable survival advantage over monotherapy and acceptable TRAEs in patients with PD-L1–positive NSCLC, identifying clinical subgroups most likely to benefit. Prospective randomized trials are warranted to validate these observations and guide optimal first-line treatment strategies.
背景：Pembrolizumab目前被用作EGFR和alk阴性晚期非小细胞肺癌（NSCLC）的一线治疗。然而，是否单独使用派姆单抗（P-mono）或联合铂化疗（P-combo）提供更好的长期获益仍不清楚。方法：我们回顾性分析了2019年至2021年间392例PD-L1 TPS≥1%的一线p -单药治疗患者（n = 194）或p -联合治疗患者（n = 198）。13个基线变量的倾向评分匹配产生了两组均衡的队列，每组97例患者，中位随访时间分别为42.8个月和44.1个月。结果：P-combo延长了总生存期（OS）（中位31.8 vs 20.7个月；风险比[HR] 0.67, 95%可信区间[CI] 0.46-0.96）和无进展生存期（12.5 vs 7.0个月；风险比0.59,95%可信区间[CI] 0.43-0.81）。P-combo组3年和4年生存率分别为49.8%和42.7%，而P-mono组分别为28.1%和22.3%。48个月的限制平均生存时间也有利于p组合（p = 0.039）。此外，在老年患者中观察到更大的获益。结论：这些发现表明，在pd - l1阳性非小细胞肺癌患者中，P-combo比单药治疗和可接受的trae具有持久的生存优势，确定了最有可能受益的临床亚组。有必要进行前瞻性随机试验来验证这些观察结果并指导最佳一线治疗策略。
{"title":"Long-term survival comparison of first-line pembrolizumab versus pembrolizumab plus chemotherapy for patients with advanced non-small cell lung cancer: A multicenter propensity-matched cohort study","authors":"Nao Shoshihara , Kinnosuke Matsumoto , Takayuki Shiroyama , Kiyohide Komuta , Akito Miyazaki , Motohiro Tamiya , Akihiro Tsukaguchi , Akihiro Tamiya , Tomoki Kuge , Yasuhiro Mihashi , Masahide Mori , Keijiro Yamauchi , Hidekazu Suzuki , Yuhei Kinehara , Hirotomo Machiyama , Satoshi Tanaka , Toshie Niki , Soichiro Kato , Yuki Nishikawa , Akio Osa , Atsushi Kumanogoh","doi":"10.1016/j.lungcan.2025.108835","DOIUrl":"10.1016/j.lungcan.2025.108835","url":null,"abstract":"<div><h3>Background</h3><div>Pembrolizumab is currently used as a first-line therapy for EGFR- and ALK-negative advanced non-small cell lung cancer (NSCLC). However, whether pembrolizumab alone (P-mono) or combined with platinum chemotherapy (P-combo) provides superior long-term benefit remains unclear.</div></div><div><h3>Methods</h3><div>We retrospectively analyzed 392 patients with PD-L1 TPS ≥ 1 % treated first-line with P-mono (n = 194) or P-combo (n = 198) between 2019 and 2021. Propensity-score matching across 13 baseline variables yielded two well-balanced cohorts of 97 patients each, with a median follow-ups of 42.8 and 44.1 months, respectively.</div></div><div><h3>Results</h3><div>P-combo prolonged overall survival (OS) (median 31.8 vs 20.7 months; hazard ratio [HR] 0.67, 95 % confidence interval [CI] 0.46–0.96) and progression-free survival (12.5 vs 7.0 months; HR 0.59, 95 %CI 0.43–0.81). The 3- and 4-year OS rates were 49.8 % and 42.7 %, respectively, with P-combo, compared with 28.1 % and 22.3 % with P-mono. The 48-month restricted mean survival time also favored P-combo (p = 0.039). Additionally, greater benefits were observed among patients aged < 75 years, with ECOG performance status 0–1, PD-L1 TPS 1–49 %, and those using proton-pump inhibitors. Grade ≥ 3 treatment-related adverse events (TRAEs) were more frequent with P-combo (35 % vs 20 %, p = 0.024). However, treatment-related deaths (2 % each) and pneumonitis incidence and severity were comparable; cumulative toxicity curves plateaued after 3 years.</div></div><div><h3>Conclusions</h3><div>These findings suggest that P-combo showed a durable survival advantage over monotherapy and acceptable TRAEs in patients with PD-L1–positive NSCLC, identifying clinical subgroups most likely to benefit. Prospective randomized trials are warranted to validate these observations and guide optimal first-line treatment strategies.</div></div>","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":"210 ","pages":"Article 108835"},"PeriodicalIF":4.4,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145495633","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 : 2025-11-07DOI: 10.1016/j.lungcan.2025.108831
Xi Chen , Caijuan Huan , Piao Yang , Mengye He , Ruiping Wang , Jianying Zhou , Jianya Zhou
Background
Immune checkpoint inhibitor-induced interstitial lung disease (ICI-ILD) is a serious adverse event. While interstitial lung abnormalities (ILA) are known risk factors, the role of preexisting pulmonary emphysema remains controversial.
Patients and methods
We enrolled patients with advanced or recurrent NSCLC who received anti-PD-1 antibody at our institution between October 2020 and October 2022. Clinical characteristics, radiographic features, time of onset, and outcomes of ICI-ILD were compared between patients with preexisting emphysema and/or ILA and those without these conditions.
Results
Among 757 patients, the overall incidence of ICI-ILD was 10.4 %. The incidence in patients with emphysema alone was significantly higher than in those without emphysema or ILA (14.1 % vs. 4.4 %, P < 0.001). The incidence in patients with ILA alone showed a trend toward higher than in those without both conditions (10.7 % vs. 4.4 %, P = 0.054). Notably, a numerically higher incidence of ICI-ILD was observed in patients with severe emphysema (E score ≥ 3; 31.3 % vs. E score = 1–2; 14.7 %, P = 0.072) and in those with baseline honeycombing compared to other ILA subtypes (41.7 % vs. 13.9 %, P = 0.056). Moreover, the presence of baseline extensive ILA was associated with a significantly higher incidence than limited ILA (42.3 % vs. 9.9 %, P < 0.001). Multivariate analysis identified preexisting emphysema (Odds Ratio [OR], 2.81; 95 % CI, 1.60–4.92; P < 0.001), preexisting ILA (OR, 1.98; 95 % CI, 1.13–3.49; P = 0.018), age (OR, 1.04; 95 % CI, 1.01–1.08; P = 0.008), and prior thoracic radiotherapy (OR, 4.10; 95 % CI, 2.12–7.94; P < 0.001) as independent risk factors for ICI-ILD.
Conclusion
Preexisting emphysema or ILA significantly increases the risk of ICI-ILD in NSCLC patients. Close monitoring is warranted, particularly in patients with severe emphysema, honeycombing, or extensive ILA.
背景：免疫检查点抑制剂诱导的间质性肺疾病（ICI-ILD）是一种严重的不良事件。虽然间质性肺异常（ILA）是已知的危险因素，但先前存在的肺气肿的作用仍然存在争议。患者和方法：我们招募了2020年10月至2022年10月期间在我们机构接受抗pd -1抗体治疗的晚期或复发性非小细胞肺癌患者。比较已有肺气肿和/或ILA患者与无这些疾病患者的临床特征、影像学特征、发病时间和ICI-ILD结局。结果：757例患者中，ICI-ILD的总发生率为10.4%。单独有肺气肿的患者的发病率明显高于无肺气肿或ILA的患者（14.1% vs. 4.4%）。结论：既往存在的肺气肿或ILA显著增加非小细胞肺癌患者ICI-ILD的风险。密切监测是必要的，特别是在严重肺气肿、蜂窝状或广泛的ILA患者中。
{"title":"Immune checkpoint inhibitor-induced interstitial lung disease in non-small cell lung cancer patients with preexisting pulmonary emphysema or interstitial lung abnormalities","authors":"Xi Chen , Caijuan Huan , Piao Yang , Mengye He , Ruiping Wang , Jianying Zhou , Jianya Zhou","doi":"10.1016/j.lungcan.2025.108831","DOIUrl":"10.1016/j.lungcan.2025.108831","url":null,"abstract":"<div><h3>Background</h3><div>Immune checkpoint inhibitor-induced interstitial lung disease (ICI-ILD) is a serious adverse event. While interstitial lung abnormalities (ILA) are known risk factors, the role of preexisting pulmonary emphysema remains controversial.</div></div><div><h3>Patients and methods</h3><div>We enrolled patients with advanced or recurrent NSCLC who received anti-PD-1 antibody at our institution between October 2020 and October 2022. Clinical characteristics, radiographic features, time of onset, and outcomes of ICI-ILD were compared between patients with preexisting emphysema and/or ILA and those without these conditions.</div></div><div><h3>Results</h3><div>Among 757 patients, the overall incidence of ICI-ILD was 10.4 %. The incidence in patients with emphysema alone was significantly higher than in those without emphysema or ILA (14.1 % vs. 4.4 %, <em>P</em> < 0.001). The incidence in patients with ILA alone showed a trend toward higher than in those without both conditions (10.7 % vs. 4.4 %, <em>P</em> = 0.054). Notably, a numerically higher incidence of ICI-ILD was observed in patients with severe emphysema (E score ≥ 3; 31.3 % vs. E score = 1–2; 14.7 %, <em>P</em> = 0.072) and in those with baseline honeycombing compared to other ILA subtypes (41.7 % vs. 13.9 %, <em>P</em> = 0.056). Moreover, the presence of baseline extensive ILA was associated with a significantly higher incidence than limited ILA (42.3 % vs. 9.9 %, <em>P</em> < 0.001). Multivariate analysis identified preexisting emphysema (Odds Ratio [OR], 2.81; 95 % CI, 1.60–4.92; <em>P</em> < 0.001), preexisting ILA (OR, 1.98; 95 % CI, 1.13–3.49; <em>P</em> = 0.018), age (OR, 1.04; 95 % CI, 1.01–1.08; <em>P</em> = 0.008), and prior thoracic radiotherapy (OR, 4.10; 95 % CI, 2.12–7.94; <em>P</em> < 0.001) as independent risk factors for ICI-ILD.</div></div><div><h3>Conclusion</h3><div>Preexisting emphysema or ILA significantly increases the risk of ICI-ILD in NSCLC patients. Close monitoring is warranted, particularly in patients with severe emphysema, honeycombing, or extensive ILA.</div></div>","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":"210 ","pages":"Article 108831"},"PeriodicalIF":4.4,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145505376","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 : 2025-11-07DOI: 10.1016/j.lungcan.2025.108830
Frank W.J. Heijboer , Jules L. Derks , Francien H. van Nederveen , Lisa M. Hillen , Michael A. den Bakker , Teodora Radonic , Ronald A.M. Damhuis
Introduction
Overall survival (OS) of patients with stage IV large cell neuroendocrine carcinoma (LCNEC) is poor and optimal systemic treatment is unknown. Here, we describe clinical outcomes per treatment strategy of patients with stage IV LCNEC, including stratification by immunohistochemical (IHC) protein RB1 (pRb) status.
Methods
Clinical data were obtained from all patients with LCNEC (2019–2022) in the Netherlands Cancer Registry (NCR). Central pathology review and IHC pRb staining were performed when tumor material was available. OS was calculated from time of diagnosis of stage IV until death, last OS update was April 2024.
Results
In total 269/530 patients (51 %) received systemic treatment, and 132 samples were eligible for pathology review. In 88/132 (67 %) the diagnosis LCNEC was confirmed (other diagnoses: SCLC (34 %), NSCLC NOS (34 %)). The median OS of all panel-reviewed LCNEC patients was 7.4 months. Patients treated with chemo-immunotherapy had a numerically, but not statistically significant different survival compared to chemotherapy (median OS 9.6 months versus OS of 6.5 months; HR 0.71, 95 % CI 0.42–1.2). This was different from the real-world LCNEC patients, where a benefit of immunotherapy was observed (median OS 10.7 months versus OS of 6.7 months; HR 0.53, 95 % CI 0.4–0.72).
Conclusion
In real-world half of patients with stage IV LCNEC do not receive systemic treatment. Accurate diagnosing LCNEC is challenging and therefore introduces bias (i.e. other diagnoses as SCLC instead of LCNEC) in real-world cohorts, which in turn has impact on analysis of treatment outcomes. Patients with panel-reviewed LCNEC have a poor prognosis and no statistically significant improvement was observed with chemo-immunotherapy.
{"title":"Treatment outcomes in patients with stage IV large cell neuroendocrine carcinoma: a nationwide registry study","authors":"Frank W.J. Heijboer , Jules L. Derks , Francien H. van Nederveen , Lisa M. Hillen , Michael A. den Bakker , Teodora Radonic , Ronald A.M. Damhuis","doi":"10.1016/j.lungcan.2025.108830","DOIUrl":"10.1016/j.lungcan.2025.108830","url":null,"abstract":"<div><h3>Introduction</h3><div>Overall survival (OS) of patients with stage IV large cell neuroendocrine carcinoma (LCNEC) is poor and optimal systemic treatment is unknown. Here, we describe clinical outcomes per treatment strategy of patients with stage IV LCNEC, including stratification by immunohistochemical (IHC) protein RB1 (pRb) status.</div></div><div><h3>Methods</h3><div>Clinical data were obtained from all patients with LCNEC (2019–2022) in the Netherlands Cancer Registry (NCR). Central pathology review and IHC pRb staining were performed when tumor material was available. OS was calculated from time of diagnosis of stage IV until death, last OS update was April 2024.</div></div><div><h3>Results</h3><div>In total 269/530 patients (51 %) received systemic treatment, and 132 samples were eligible for pathology review. In 88/132 (67 %) the diagnosis LCNEC was confirmed (other diagnoses: SCLC (34 %), NSCLC NOS (34 %)). The median OS of all panel-reviewed LCNEC patients was 7.4 months. Patients treated with chemo-immunotherapy had a numerically, but not statistically significant different survival compared to chemotherapy (median OS 9.6 months versus OS of 6.5 months; HR 0.71, 95 % CI 0.42–1.2). This was different from the real-world LCNEC patients, where a benefit of immunotherapy was observed (median OS 10.7 months versus OS of 6.7 months; HR 0.53, 95 % CI 0.4–0.72).</div></div><div><h3>Conclusion</h3><div>In real-world half of patients with stage IV LCNEC do not receive systemic treatment. Accurate diagnosing LCNEC is challenging and therefore introduces bias (i.e. other diagnoses as SCLC instead of LCNEC) in real-world cohorts, which in turn has impact on analysis of treatment outcomes. Patients with panel-reviewed LCNEC have a poor prognosis and no statistically significant improvement was observed with chemo-immunotherapy.</div></div>","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":"210 ","pages":"Article 108830"},"PeriodicalIF":4.4,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145517990","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 : 2025-11-07DOI: 10.1016/j.lungcan.2025.108834
Byoung Chul Cho , Chaiyut Charoentum , Dong-Wan Kim , Cheng-Ta Yang , Rafal Dziadziuszko , Sarayut Lucien Geater , Helen Mann , Banafsheh Afshar-Imani , Pavlo Lyfar , James Chih-Hsin Yang , Sandip Pravin Patel
Objectives
Standard-of-care therapies for metastatic non-small-cell lung cancer (mNSCLC) have mixed outcomes that remain unsatisfactory. Durvalumab (anti-PD-L1) plus oleclumab (anti-CD73) might provide a synergistic antitumor effect by antagonizing separate immune pathways. We report safety, efficacy, pharmacokinetics, and immunogenicity findings of durvalumab + chemotherapy ± oleclumab as first-line treatment of mNSCLC from Arms B1 and B3 in the phase 1B MAGELLAN (NCT03819465) study.
Methods
In Cohort B, treatment-naïve adults with histologically/cytologically confirmed mNSCLC and PD-L1 expression on < 50 % tumor cells were eligible. Patients received investigator’s choice of chemotherapy plus 1500 mg durvalumab three-weekly (Q3W) for four cycles and durvalumab Q4W thereafter in Arm B1, with addition of 2250 mg oleclumab Q3W for four cycles and 3000 mg Q4W thereafter in Arm B3. Primary endpoint was safety and tolerability; key secondary endpoint was efficacy by investigator-assessed objective response rate (ORR; RECIST v1.1).
Results
Patient demographics and disease characteristics were generally consistent between arms. All but one patient experienced treatment-emergent adverse events (AEs). Grade 3 or 4 AEs and AEs leading to discontinuation occurred in 14/33 (42.4 %) and 3/33 (9.1 %) patients in Arm B1 and 18/32 (56.3 %) and 6/32 (18.8 %) patients in Arm B3. No treatment-related deaths occurred in Arm B1; one (3.1 %) fatal AE of unknown cause was deemed possibly related to both durvalumab and oleclumab by the investigator in Arm B3. ORR was 36.4 % (95 % CI, 20.4–54.9) and 21.9 % (95 % CI, 9.3–40.0) in Arms B1 and B3, respectively − all partial responses. Median duration of response was 11.8 months (95 % CI, 3.2–26.6) and 8.8 months (95 % CI, 2.3–not calculable), respectively.
Conclusion
No new safety signals were identified for durvalumab + chemotherapy ± oleclumab in patients with mNSCLC and PD-L1 expression < 50 %. The lack of meaningful efficacy improvements limits potential further development of this combination in this disease setting.
{"title":"MAGELLAN arms B1 and B3: Durvalumab plus chemotherapy with and without oleclumab in treatment-naïve metastatic non-small-cell lung cancer","authors":"Byoung Chul Cho , Chaiyut Charoentum , Dong-Wan Kim , Cheng-Ta Yang , Rafal Dziadziuszko , Sarayut Lucien Geater , Helen Mann , Banafsheh Afshar-Imani , Pavlo Lyfar , James Chih-Hsin Yang , Sandip Pravin Patel","doi":"10.1016/j.lungcan.2025.108834","DOIUrl":"10.1016/j.lungcan.2025.108834","url":null,"abstract":"<div><h3>Objectives</h3><div>Standard-of-care therapies for metastatic non-small-cell lung cancer (mNSCLC) have mixed outcomes that remain unsatisfactory. Durvalumab (anti-PD-L1) plus oleclumab (anti-CD73) might provide a synergistic antitumor effect by antagonizing separate immune pathways. We report safety, efficacy, pharmacokinetics, and immunogenicity findings of durvalumab + chemotherapy ± oleclumab as first-line treatment of mNSCLC from Arms B1 and B3 in the phase 1B MAGELLAN (NCT03819465) study.</div></div><div><h3>Methods</h3><div>In Cohort B, treatment-naïve adults with histologically/cytologically confirmed mNSCLC and PD-L1 expression on < 50 % tumor cells were eligible. Patients received investigator’s choice of chemotherapy plus 1500 mg durvalumab three-weekly (Q3W) for four cycles and durvalumab Q4W thereafter in Arm B1, with addition of 2250 mg oleclumab Q3W for four cycles and 3000 mg Q4W thereafter in Arm B3. Primary endpoint was safety and tolerability; key secondary endpoint was efficacy by investigator-assessed objective response rate (ORR; RECIST v1.1).</div></div><div><h3>Results</h3><div>Patient demographics and disease characteristics were generally consistent between arms. All but one patient experienced treatment-emergent adverse events (AEs). Grade 3 or 4 AEs and AEs leading to discontinuation occurred in 14/33 (42.4 %) and 3/33 (9.1 %) patients in Arm B1 and 18/32 (56.3 %) and 6/32 (18.8 %) patients in Arm B3. No treatment-related deaths occurred in Arm B1; one (3.1 %) fatal AE of unknown cause was deemed possibly related to both durvalumab and oleclumab by the investigator in Arm B3. ORR was 36.4 % (95 % CI, 20.4–54.9) and 21.9 % (95 % CI, 9.3–40.0) in Arms B1 and B3, respectively − all partial responses. Median duration of response was 11.8 months (95 % CI, 3.2–26.6) and 8.8 months (95 % CI, 2.3–not calculable), respectively.</div></div><div><h3>Conclusion</h3><div>No new safety signals were identified for durvalumab + chemotherapy ± oleclumab in patients with mNSCLC and PD-L1 expression < 50 %. The lack of meaningful efficacy improvements limits potential further development of this combination in this disease setting.</div></div>","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":"211 ","pages":"Article 108834"},"PeriodicalIF":4.4,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145742946","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 : 2025-11-04DOI: 10.1016/j.lungcan.2025.108817
Xiaotao Wang , Wenwen Shi , Yang Xiao , Haoyu Wang , Huiyu Si , Yan Kang , Jiming Si , Yuanhua Liu , Shenglei Li , Jianjun Jin
Introduction
Thoracic SMARCA4-Deficient Undifferentiated Tumors (SMARCA4-UT) are highly aggressive malignancies with poor prognosis. There is currently no standardized treatment strategy. We aimed to investigate the characteristics of the tumor immune microenvironment (TIME) in SMARCA4-UT, and evaluate the impact of TIME on treatment efficacy and prognosis.
Methods
Multiplex immunofluorescence staining was performed on tumor tissue specimens from 29 SMARCA4-UT cases and 25 SMARCA4-intact non-small cell lung cancer (SMARCA4-iNSCLC) cases to quantify the density, proportion, and spatial proximity of CD8+ T cells, M2 macrophages, neutrophils, FOXP3+ cells, and IFNα+ cells within the immune landscape, and to assess their associations with treatment efficacy and prognosis.
Results
Lower infiltration of CD8+T cells and IFNα+ cells, but higher infiltration of M2 macrophages in the overall immune landscape, was observed in SMARCA4-UT compared with SMARCA4–iNSCLC (P < 0.05). Patients with higher CD8+T cells and IFNα+ cells infiltration had longer overall survival (OS) following immunotherapy. Multivariate Cox regression identified high CD8+T cell infiltration as an independent protective prognostic factor in the SMARCA4-UT group (HR = 0.204, P = 0.017). Within the TIME of SMARCA4-UT, CD8+T cells, FOXP3+ cells, and IFNα+ cells were located in closer proximity to M2 macrophages. The distance between individual M2 macrophages was significantly shorter; conversely, neutrophils were positioned further away from M2 macrophages (P < 0.05). Further, greater distance between M2 macrophages and CD8+T cells correlated with better prognosis (HR = 0.834, P = 0.047) and a significantly longer median OS (P = 0.016).
Conclusion
The TIME of SMARCA4-UT is characterized by an immune-desert phenotype, and higher CD8+T cells infiltration is associated with improved immunotherapeutic efficacy. Spatial proximity between M2 macrophages and multiple immune cell subsets within the TIME of SMARCA4-UT is markedly increased.
胸部smarca4缺陷未分化肿瘤（SMARCA4-UT）是一种预后不良的高侵袭性恶性肿瘤。目前尚无标准化的治疗策略。我们旨在探讨SMARCA4-UT中肿瘤免疫微环境（TIME）的特点，并评价TIME对治疗疗效和预后的影响。方法对29例SMARCA4-UT和25例smarca4完整非小细胞肺癌（SMARCA4-iNSCLC）患者的肿瘤组织标本进行多元免疫荧光染色，定量测定免疫景观中CD8+ T细胞、M2巨噬细胞、中性粒细胞、FOXP3+细胞和IFNα+细胞的密度、比例和空间接近度，并评估其与治疗效果和预后的关系。结果与SMARCA4-iNSCLC相比，SMARCA4-UT中CD8+T细胞和IFNα+细胞的浸润率较低，M2巨噬细胞的浸润率较高（P < 0.05）。CD8+T细胞和IFNα+细胞浸润较高的患者在免疫治疗后总生存期（OS）更长。多因素Cox回归发现，高CD8+T细胞浸润是SMARCA4-UT组患者独立的保护性预后因素（HR = 0.204, P = 0.017）。在SMARCA4-UT时间内，CD8+T细胞、FOXP3+细胞和IFNα+细胞更靠近M2巨噬细胞。M2巨噬细胞之间的距离明显缩短；相反，中性粒细胞的位置远离M2巨噬细胞（P < 0.05）。M2巨噬细胞与CD8+T细胞距离越远，预后越好（HR = 0.834, P = 0.047），中位OS越长（P = 0.016）。结论SMARCA4-UT的TIME具有免疫荒漠表型，CD8+T细胞浸润增加与免疫治疗效果提高有关。SMARCA4-UT时间内M2巨噬细胞与多个免疫细胞亚群之间的空间接近性明显增加。
{"title":"The immune desert tumor microenvironment in Thoracic SMARCA4-deficient undifferentiated tumors: spatial distribution characteristics and prognostic significance","authors":"Xiaotao Wang , Wenwen Shi , Yang Xiao , Haoyu Wang , Huiyu Si , Yan Kang , Jiming Si , Yuanhua Liu , Shenglei Li , Jianjun Jin","doi":"10.1016/j.lungcan.2025.108817","DOIUrl":"10.1016/j.lungcan.2025.108817","url":null,"abstract":"<div><h3>Introduction</h3><div>Thoracic SMARCA4-Deficient Undifferentiated Tumors (SMARCA4-UT) are highly aggressive malignancies with poor prognosis. There is currently no standardized treatment strategy. We aimed to investigate the characteristics of the tumor immune microenvironment (TIME) in SMARCA4-UT, and evaluate the impact of TIME on treatment efficacy and prognosis.</div></div><div><h3>Methods</h3><div>Multiplex immunofluorescence staining was performed on tumor tissue specimens from 29 SMARCA4-UT cases and 25 SMARCA4-intact non-small cell lung cancer (SMARCA4-iNSCLC) cases to quantify the density, proportion, and spatial proximity of CD8<sup>+</sup> T cells, M2 macrophages, neutrophils, FOXP3<sup>+</sup> cells, and IFNα<sup>+</sup> cells within the immune landscape, and to assess their associations with treatment efficacy and prognosis.</div></div><div><h3>Results</h3><div>Lower infiltration of CD8<sup>+</sup>T cells and IFNα<sup>+</sup> cells, but higher infiltration of M2 macrophages in the overall immune landscape, was observed in SMARCA4-UT compared with SMARCA4–iNSCLC (<em>P</em> < 0.05). Patients with higher CD8<sup>+</sup>T cells and IFNα<sup>+</sup> cells infiltration had longer overall survival (OS) following immunotherapy. Multivariate Cox regression identified high CD8<sup>+</sup>T cell infiltration as an independent protective prognostic factor in the SMARCA4-UT group (HR = 0.204, <em>P</em> = 0.017). Within the TIME of SMARCA4-UT, CD8<sup>+</sup>T cells, FOXP3<sup>+</sup> cells, and IFNα<sup>+</sup> cells were located in closer proximity to M2 macrophages. The distance between individual M2 macrophages was significantly shorter; conversely, neutrophils were positioned further away from M2 macrophages (<em>P</em> < 0.05). Further, greater distance between M2 macrophages and CD8<sup>+</sup>T cells correlated with better prognosis (HR = 0.834, <em>P</em> = 0.047) and a significantly longer median OS (<em>P</em> = 0.016).</div></div><div><h3>Conclusion</h3><div>The TIME of SMARCA4-UT is characterized by an immune-desert phenotype, and higher CD8<sup>+</sup>T cells infiltration is associated with improved immunotherapeutic efficacy. Spatial proximity between M2 macrophages and multiple immune cell subsets within the TIME of SMARCA4-UT is markedly increased.</div></div>","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":"210 ","pages":"Article 108817"},"PeriodicalIF":4.4,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145468743","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}
Curative surgery followed by adjuvant osimertinib according to pathological stage (pStage) is standard for resectable epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Nevertheless, recurrence remains a concern even in Stage IA, for which adjuvant osimertinib is not indicated. We evaluated the utility of circulating tumor DNA (ctDNA) to predict recurrence in patients with resected pStage I-III EGFR-mutated NSCLC and examined prognostic value of preoperative biomarkers and pathological features.
Methods
Between January 2017 and May 2020, 382 patients with lung tumors underwent surgery at Kanazawa University Hospital, including 88 with NSCLC harboring common EGFR mutations. Preoperative ctDNA was analyzed using droplet digital PCR, targeting EGFR mutations. Patients were followed for up to 6.4 years, and disease-free survival (DFS) and overall survival (OS) were evaluated.
Results
Preoperative ctDNA positivity was detected in 26.1 % and venous invasion in 39.8 %. ctDNA-positive patients had lower 60-month DFS (54.1 % vs. 84.1 %; HR = 3.25; 95 % CI, 1.13–9.21; p = 0.028) and 60-month OS (65.1 % vs. 95.9 %; HR = 6.10; 95 % CI, 1.11–33.46; p = 0.037). Venous invasion was independently associated with poorer DFS (HR = 8.73; 95 % CI, 1.81–41.93; p = 0.0068). In combined analyses, no recurrences occurred in the double-negative, whereas the double-positive had a lower 60-month DFS than the single-positive (HR = 3.61; 95 % CI, 1.19–10.93; p = 0.023).
Conclusion
Preoperative ctDNA detection and pathological venous invasion provide complementary prognostic information, and venous invasion is an independent predictor of recurrence risk in EGFR-mutated NSCLC. Combined assessment may refine postoperative risk stratification and inform perioperative management.
根据病理分期（pStage）进行根治性手术后辅以奥希替尼是可切除的表皮生长因子受体（EGFR）突变的非小细胞肺癌（NSCLC）的标准治疗方法。然而，即使在IA期，复发仍然是一个问题，辅助奥希替尼不适用。我们评估了循环肿瘤DNA （ctDNA）在预测切除的pi - iii期egfr突变的非小细胞肺癌患者复发中的应用，并检查了术前生物标志物和病理特征的预后价值。方法2017年1月至2020年5月，382例肺肿瘤患者在金泽大学医院接受了手术，其中88例患有常见EGFR突变的非小细胞肺癌。术前ctDNA分析采用液滴数字PCR，靶向EGFR突变。患者随访6.4年，评估无病生存期（DFS）和总生存期（OS）。结果术前ctDNA阳性占26.1%，静脉浸润占39.8%。ctdna阳性患者的60个月DFS（54.1%比84.1%;HR = 3.25; 95% CI, 1.13-9.21; p = 0.028）和60个月OS（65.1%比95.9%;HR = 6.10; 95% CI, 1.11-33.46; p = 0.037）较低。静脉侵犯与较差的DFS独立相关（HR = 8.73; 95% CI, 1.81 ~ 41.93; p = 0.0068）。在联合分析中，双阴性患者没有复发，而双阳性患者的60个月DFS低于单阳性患者（HR = 3.61; 95% CI, 1.19-10.93; p = 0.023）。结论术前ctDNA检测和病理性静脉浸润提供了互补的预后信息，静脉浸润是egfr突变NSCLC复发风险的独立预测因子。综合评估可细化术后风险分层，为围手术期管理提供信息。
{"title":"Prognostic value of preoperative ctDNA and pathological venous invasion for recurrence in EGFR-mutated non-small cell lung cancer","authors":"Yuya Murase , Hayato Koba , Hideharu Kimura , Isao Matsumoto , Tsukasa Ueda , Shunichi Nomura , Sachiko Arai , Nanao Terada , Liu Yifeng , Shigeki Nanjo , Yuichi Tambo , Takafumi Kobayashi , Satoshi Watanabe , Kenta Yamamura , Noriyuki Ohkura , Miki Abo , Akihiro Nomura , Seiji Yano","doi":"10.1016/j.lungcan.2025.108818","DOIUrl":"10.1016/j.lungcan.2025.108818","url":null,"abstract":"<div><h3>Introduction</h3><div>Curative surgery followed by adjuvant osimertinib according to pathological stage (pStage) is standard for resectable epidermal growth factor receptor (<em>EGFR</em>)-mutated non-small cell lung cancer (NSCLC). Nevertheless, recurrence remains a concern even in Stage IA, for which adjuvant osimertinib is not indicated. We evaluated the utility of circulating tumor DNA (ctDNA) to predict recurrence in patients with resected pStage I-III <em>EGFR</em>-mutated NSCLC and examined prognostic value of preoperative biomarkers and pathological features.</div></div><div><h3>Methods</h3><div>Between January 2017 and May 2020, 382 patients with lung tumors underwent surgery at Kanazawa University Hospital, including 88 with NSCLC harboring common <em>EGFR</em> mutations. Preoperative ctDNA was analyzed using droplet digital PCR, targeting <em>EGFR</em> mutations. Patients were followed for up to 6.4 years, and disease-free survival (DFS) and overall survival (OS) were evaluated.</div></div><div><h3>Results</h3><div>Preoperative ctDNA positivity was detected in 26.1 % and venous invasion in 39.8 %. ctDNA-positive patients had lower 60-month DFS (54.1 % vs. 84.1 %; HR = 3.25; 95 % CI, 1.13–9.21; <em>p</em> = 0.028) and 60-month OS (65.1 % vs. 95.9 %; HR = 6.10; 95 % CI, 1.11–33.46; <em>p</em> = 0.037). Venous invasion was independently associated with poorer DFS (HR = 8.73; 95 % CI, 1.81–41.93; <em>p</em> = 0.0068). In combined analyses, no recurrences occurred in the double-negative, whereas the double-positive had a lower 60-month DFS than the single-positive (HR = 3.61; 95 % CI, 1.19–10.93; <em>p</em> = 0.023).</div></div><div><h3>Conclusion</h3><div>Preoperative ctDNA detection and pathological venous invasion provide complementary prognostic information, and venous invasion is an independent predictor of recurrence risk in <em>EGFR</em>-mutated NSCLC. Combined assessment may refine postoperative risk stratification and inform perioperative management.</div></div>","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":"213 ","pages":"Article 108818"},"PeriodicalIF":4.4,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145981780","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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