We sought to compare the latest data on postoperative pain between robot-assisted thoracic surgery (RATS) and video-assisted thoracoscopic surgery (VATS), and to clarify the relationship between the number or placement of ports and postoperative pain in patients with lung cancer.
Methods
Patients who underwent anatomical lung resection by RATS or VATS and whose chest tube was removed within 7 days were enrolled. The primary endpoint was the percentage of patients with a numeric rating scale (NRS) score ≤ 3 on postoperative day 30 (POD30). The target sample size was 400 patients.
Results
Four hundred five patients (RATS, n = 196; VATS, n = 209) managed at 12 institutions were included. Ninety-nine patients in the VATS group underwent a uniport procedure. Significant differences were observed between the RATS and VATS groups in the mean number of inserted ports (5.0 vs. 2.2), number of injured intercostal sites (2.9 vs. 1.9), largest wound size (3.4 vs. 3.7 cm), operation time (202 vs. 165 min), and use of epidural anesthesia or continuous nerve block (45 vs. 31 %). In the RATS and VATS groups, the rates of NRS≤3 on POD30 were 82.0 % and 94.7 % (95 %CI: −19.0 to −6.6 %), respectively, which could not prove noninferiority. However, in a multivariable analysis, the RATS approach was not proven to be a significant risk factor.
Conclusion
In the current status of minimally invasive thoracic surgery in Japan, RATS involves a greater number of ports, longer operation time, and higher frequency of local anesthesia than VATS and may be inferior in terms of postoperative pain.
{"title":"A prospective multi-institutional study to verify the non-inferiority of postoperative pain in robot-assisted thoracic surgery in comparison with video-assisted thoracoscopic surgery for lung cancer: The Japanese RATS interest group 01 (J-RATSIG 01)","authors":"Koji Kawaguchi , Toru Ogura , Shinji Kaneda , Takuya Watanabe , Junichi Soh , Kumiko Hashimoto , Noriaki Sakakura , Mikio Okazaki , Shoichi Mori , Masaki Hashimoto , Koichi Fukumoto , Masahiro Miyajima , Shuhei Yoshida , Satoru Moriyama , Satoshi Tamaru , Motoshi Takao","doi":"10.1016/j.lungcan.2024.107961","DOIUrl":"10.1016/j.lungcan.2024.107961","url":null,"abstract":"<div><h3>Objectives</h3><div>We sought to compare the latest data on postoperative pain between robot-assisted thoracic surgery (RATS) and video-assisted thoracoscopic surgery (VATS), and to clarify the relationship between the number or placement of ports and postoperative pain in patients with lung cancer.</div></div><div><h3>Methods</h3><div>Patients who underwent anatomical lung resection by RATS or VATS and whose chest tube was removed within 7 days were enrolled. The primary endpoint was the percentage of patients with a numeric rating scale (NRS) score ≤ 3 on postoperative day 30 (POD30). The target sample size was 400 patients.</div></div><div><h3>Results</h3><div>Four hundred five patients (RATS, n = 196; VATS, n = 209) managed at 12 institutions were included. Ninety-nine patients in the VATS group underwent a uniport procedure. Significant differences were observed between the RATS and VATS groups in the mean number of inserted ports (5.0 vs. 2.2), number of injured intercostal sites (2.9 vs. 1.9), largest wound size (3.4 vs. 3.7 cm), operation time (202 vs. 165 min), and use of epidural anesthesia or continuous nerve block (45 vs. 31 %). In the RATS and VATS groups, the rates of NRS≤3 on POD30 were 82.0 % and 94.7 % (95 %CI: −19.0 to −6.6 %), respectively, which could not prove noninferiority. However, in a multivariable analysis, the RATS approach was not proven to be a significant risk factor.</div></div><div><h3>Conclusion</h3><div>In the current status of minimally invasive thoracic surgery in Japan, RATS involves a greater number of ports, longer operation time, and higher frequency of local anesthesia than VATS and may be inferior in terms of postoperative pain.</div></div>","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":"196 ","pages":"Article 107961"},"PeriodicalIF":4.5,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-19DOI: 10.1016/j.lungcan.2024.107960
Melissa Johnson , Diana Younan , Shia T. Kent , Marco Mesa-Frias , M. Alan Brookhart , Akhila Balasubramanian , Alexander Spira
Objectives
To evaluate the comparative effectiveness of sotorasib monotherapy versus docetaxel as monotherapy or combination therapy in patients with pretreated KRAS G12C-mutated advanced NSCLC in the real-world.
Methods
A US-based electronic health record–derived de-identified database was used in this study. Patients with pretreated KRAS G12C-mutated advanced NSCLC who initiated sotorasib between May 28, 2021, and September 30, 2022, and docetaxel between January 1, 2019, and September 30, 2022 (to enhance sample size), were included, with a minimum of 12-month opportunity for follow-up. Treatment groups were balanced via overlap weighting propensity score methods. Median OS in the 2L and 2L+ settings were calculated using Kaplan-Meier estimates. Hazard ratios (HRs) were estimated via Cox proportional hazard models.
Results
Overall, the clinical characteristics in sotorasib and docetaxel cohorts were balanced after propensity score weighting. At baseline, most patients were > 65 years of age, had ECOG performance status of 0–1, were from the community practice setting, had advanced stage at initial diagnosis, and had prior anti-PD-(L)1 treatment and/or platinum-based chemotherapy. In the 2L setting, the median OS (95 % CI) for sotorasib (N=102) and docetaxel (N=58) patients was 10.2 (7.6–16.3) and 6.0 (4.2–11.0) months, respectively, with a corresponding mortality HR (95 % CI) of 0.62 (0.41–0.93). In the 2L+ setting, the median OS (95 % CI) for sotorasib (N=164) and docetaxel (N=116) was 10.2 (8.0–14.6) and 7.2 (5.1–10.6) months, respectively, with a corresponding mortality HR (95 % CI) of 0.65 (0.49–0.87). In patients with prior anti-PD-(L)1 treatment, the mortality HR (95 % CI) in the sotorasib group versus docetaxel was 0.61 (0.39–0.94) and 0.65 (0.48–0.89) in the 2L and 2L+ settings, respectively. Findings from other subgroups were consistent with the primary analyses.
Conclusion
In this real-world comparative analysis of patients with pretreated KRAS G12C-mutated advanced NSCLC, sotorasib monotherapy demonstrated a longer median OS compared to docetaxel monotherapy or combination therapy.
{"title":"Real-world comparative effectiveness of sotorasib versus docetaxel in second line and beyond among patients with advanced non-small cell lung cancer (NSCLC)","authors":"Melissa Johnson , Diana Younan , Shia T. Kent , Marco Mesa-Frias , M. Alan Brookhart , Akhila Balasubramanian , Alexander Spira","doi":"10.1016/j.lungcan.2024.107960","DOIUrl":"10.1016/j.lungcan.2024.107960","url":null,"abstract":"<div><h3>Objectives</h3><div>To evaluate the comparative effectiveness of sotorasib monotherapy versus docetaxel as monotherapy or combination therapy in patients with pretreated <em>KRAS</em> G12C-mutated advanced NSCLC in the real-world.</div></div><div><h3>Methods</h3><div>A US-based electronic health record–derived de-identified database was used in this study. Patients with pretreated <em>KRAS</em> G12C-mutated advanced NSCLC who initiated sotorasib between May 28, 2021, and September 30, 2022, and docetaxel between January 1, 2019, and September 30, 2022 (to enhance sample size), were included, with a minimum of 12-month opportunity for follow-up. Treatment groups were balanced via overlap weighting propensity score methods. Median OS in the 2L and 2L+ settings were calculated using Kaplan-Meier estimates. Hazard ratios (HRs) were estimated via Cox proportional hazard models.</div></div><div><h3>Results</h3><div>Overall, the clinical characteristics in sotorasib and docetaxel cohorts were balanced after propensity score weighting. At baseline, most patients were > 65 years of age, had ECOG performance status of 0–1, were from the community practice setting, had advanced stage at initial diagnosis, and had prior anti-PD-(L)1 treatment and/or platinum-based chemotherapy. In the 2L setting, the median OS (95 % CI) for sotorasib (N=102) and docetaxel (N=58) patients was 10.2 (7.6–16.3) and 6.0 (4.2–11.0) months, respectively, with a corresponding mortality HR (95 % CI) of 0.62 (0.41–0.93). In the 2L+ setting, the median OS (95 % CI) for sotorasib (N=164) and docetaxel (N=116) was 10.2 (8.0–14.6) and 7.2 (5.1–10.6) months, respectively, with a corresponding mortality HR (95 % CI) of 0.65 (0.49–0.87). In patients with prior anti-PD-(L)1 treatment, the mortality HR (95 % CI) in the sotorasib group versus docetaxel was 0.61 (0.39–0.94) and 0.65 (0.48–0.89) in the 2L and 2L+ settings, respectively. Findings from other subgroups were consistent with the primary analyses.</div></div><div><h3>Conclusion</h3><div>In this real-world comparative analysis of patients with pretreated <em>KRAS</em> G12C-mutated advanced NSCLC, sotorasib monotherapy demonstrated a longer median OS compared to docetaxel monotherapy or combination therapy.</div></div>","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":"197 ","pages":"Article 107960"},"PeriodicalIF":4.5,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-19DOI: 10.1016/j.lungcan.2024.107959
Li Li , Ning Liu , Tao Zhou , Xueting Qin , Xiaoyu Song , Song Wang , Jiaohui Pang , Qiuxiang Ou , Yong Wang , Dexian Zhang , Jiaran Li , Fuhao Xu , Shuming Shi , Jinming Yu , Shuanghu Yuan
Background
Small-cell lung cancer (SCLC) is an aggressive malignancy with a poor prognosis. Limited-stage (LS)-SCLC comprises only one-third of SCLC cases, resulting in limited molecularly targeted therapies and treatment options. Despite advances in thoracic and cranial irradiation leading to improved outcomes, a notable proportion of patients develop brain metastasis (BM), highlighting the importance of identifying high-risk patients for tailored screening and treatment strategies.
Materials and Methods
We analyzed baseline tumor biopsies from 180 LS-SCLC patients who received frontline definitive chemoradiotherapy (dCRT) using a 474-gene pan-cancer panel. The cumulative incidence of BM was calculated with death scored as a competing risk. Independent prognostic factors for BM risk were identified using the Fine-Gray model.
Results
Alterations in the cell cycle pathway, particularly RB1 mutations, were more common in patients with BM, while FLT4 mutations were more frequent in those without BM (P=0.002 and P=0.021, respectively). Significant risk factors for BM include smoking (subdistribution hazard ratio [SHR]: 1.73; 95 % confidence interval [CI]: 1.11–2.70; P=0.016), RB1 mutations (SHR: 2.19; 95 % CI: 1.27–3.81; P=0.005), and BCL3 amplification (SHR: 2.27; 95 % CI: 1.09–4.71; P=0.028). Conversely, prophylactic cranial irradiation (PCI) (SHR: 0.39; 95 % CI: 0.25–1.60; P<0.001), FLT4 mutations (SHR: 0.26; 95 % CI: 0.07–0.98; P=0.047), and NOTCH pathway alterations (SHR: 0.65; 95 % CI: 0.43–1.00; P=0.049) were associated with a lower incidence of BM in LS-SCLC. Notably, consolidation PCI therapy did not reduce the BM risk in patients with baseline RB1 mutations, with BM occurrence probabilities of 34.7 % at 20 months and 62.6 % at 40 months.
Conclusion
Our study yields valuable insights into the genetic characteristics of LS-SCLC patients with and without BM, aiding the development of personalized treatment strategies. Identifying risk factors associated with the incidence and timing of BM, within the standard regimen of dCRT followed by PCI, may help optimize clinical decision-making for LS-SCLC.
{"title":"A biomarker exploration in small-cell lung cancer for brain metastases risk and prophylactic cranial irradiation therapy efficacy","authors":"Li Li , Ning Liu , Tao Zhou , Xueting Qin , Xiaoyu Song , Song Wang , Jiaohui Pang , Qiuxiang Ou , Yong Wang , Dexian Zhang , Jiaran Li , Fuhao Xu , Shuming Shi , Jinming Yu , Shuanghu Yuan","doi":"10.1016/j.lungcan.2024.107959","DOIUrl":"10.1016/j.lungcan.2024.107959","url":null,"abstract":"<div><h3>Background</h3><div>Small-cell lung cancer (SCLC) is an aggressive malignancy with a poor prognosis. Limited-stage (LS)-SCLC comprises only one-third of SCLC cases, resulting in limited molecularly targeted therapies and treatment options. Despite advances in thoracic and cranial irradiation leading to improved outcomes, a notable proportion of patients develop brain metastasis (BM), highlighting the importance of identifying high-risk patients for tailored screening and treatment strategies.</div></div><div><h3>Materials and Methods</h3><div>We analyzed baseline tumor biopsies from 180 LS-SCLC patients who received frontline definitive chemoradiotherapy (dCRT) using a 474-gene pan-cancer panel. The cumulative incidence of BM was calculated with death scored as a competing risk. Independent prognostic factors for BM risk were identified using the Fine-Gray model.</div></div><div><h3>Results</h3><div>Alterations in the cell cycle pathway, particularly <em>RB1</em> mutations, were more common in patients with BM, while <em>FLT4</em> mutations were more frequent in those without BM (<em>P</em>=0.002 and <em>P</em>=0.021, respectively). Significant risk factors for BM include smoking (subdistribution hazard ratio [SHR]: 1.73; 95 % confidence interval [CI]: 1.11–2.70; <em>P</em>=0.016), <em>RB1</em> mutations (SHR: 2.19; 95 % CI: 1.27–3.81; <em>P</em>=0.005), and <em>BCL3</em> amplification (SHR: 2.27; 95 % CI: 1.09–4.71; <em>P</em>=0.028). Conversely, prophylactic cranial irradiation (PCI) (SHR: 0.39; 95 % CI: 0.25–1.60; <em>P</em><0.001), <em>FLT4</em> mutations (SHR: 0.26; 95 % CI: 0.07–0.98; <em>P</em>=0.047), and NOTCH pathway alterations (SHR: 0.65; 95 % CI: 0.43–1.00; <em>P</em>=0.049) were associated with a lower incidence of BM in LS-SCLC. Notably, consolidation PCI therapy did not reduce the BM risk in patients with baseline <em>RB1</em> mutations, with BM occurrence probabilities of 34.7 % at 20 months and 62.6 % at 40 months.</div></div><div><h3>Conclusion</h3><div>Our study yields valuable insights into the genetic characteristics of LS-SCLC patients with and without BM, aiding the development of personalized treatment strategies. Identifying risk factors associated with the incidence and timing of BM, within the standard regimen of dCRT followed by PCI, may help optimize clinical decision-making for LS-SCLC.</div></div>","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":"196 ","pages":"Article 107959"},"PeriodicalIF":4.5,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142327838","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}
Certain guidelines recommend caution when administering immunotherapy in patients with pre-existing interstitial lung disease (ILD) owing to the high incidence of pneumonitis induced by anti-cancer therapy. A prospective clinical trial assessing the safety of chemoimmunotherapy in patients with small-cell lung cancer (SCLC) and pre-existing ILD is warranted. Therefore, this study evaluated the safety and efficacy of chemoimmunotherapy in patients with extensive-stage (ES)-SCLC and mild idiopathic interstitial pneumonia (IIP).
Methods
In this multicenter prospective trial, patients with ES-SCLC and pre-existing mild chronic fibrosing IIP were recruited. Mild IIP was defined as the exclusion of poor pulmonary function, a definite usual interstitial pneumonia (UIP) pattern, and positivity for autoantibodies in blood tests. The patients received durvalumab, etoposide, and carboplatin every three weeks (induction phase), followed by 1,500 mg durvalumab every four weeks (maintenance phase). The primary endpoint was severe pneumonitis-free rate.
Results
Twenty-one patients were included in the analysis. Among them, 13 patients displayed a probable UIP pattern, whereas eight patients exhibited an indeterminate for UIP pattern. Two patients (9.5 %) had pneumonitis of any grade during the induction phase; one had Grade 1 and the other had Grade 5 pneumonitis. No other patient developed pneumonitis during the maintenance phase. The severe pneumonitis-free rate was 95.2 % (95 % confidence interval (CI): 77.3–99.2 %). The median progression-free survival was 5.5 months (95 % CI: 3.6–6.4 months). Median overall survival was 10.7 months (95 % CI: 6.0 months to not reached).
Conclusions
Chemoimmunotherapy is a feasible treatment approach for patients with ES-SCLC and mild IIP.
{"title":"Durvalumab with etoposide and carboplatin for patients with extensive-stage small cell lung cancer and interstitial lung disease: A multicenter, open-label prospective trial","authors":"Ryota Shibaki , Daichi Fujimoto , Eisaku Miyauchi , Yoko Tsukita , Ichiro Nakachi , Daisuke Arai , Yoshihiko Sakata , Naoki Shingu , Toshio Shimokawa , Takashi Kijima , Motohiro Tamiya , Sachiko Kawana , Satoshi Hara , Go Saito , Yuki Sato , Toshihide Yokoyama , Shinya Sakata , Yoshihiko Taniguchi , Akito Hata , Hirotaka Matsumoto , Nobuyuki Yamamoto","doi":"10.1016/j.lungcan.2024.107958","DOIUrl":"10.1016/j.lungcan.2024.107958","url":null,"abstract":"<div><h3>Objectives</h3><div>Certain guidelines recommend caution when administering immunotherapy in patients with pre-existing interstitial lung disease (ILD) owing to the high incidence of pneumonitis induced by anti-cancer therapy. A prospective clinical trial assessing the safety of chemoimmunotherapy in patients with small-cell lung cancer (SCLC) and pre-existing ILD is warranted. Therefore, this study evaluated the safety and efficacy of chemoimmunotherapy in patients with extensive-stage (ES)-SCLC and mild idiopathic interstitial pneumonia (IIP).</div></div><div><h3>Methods</h3><div>In this multicenter prospective trial, patients with ES-SCLC and pre-existing mild chronic fibrosing IIP were recruited. Mild IIP was defined as the exclusion of poor pulmonary function, a definite usual interstitial pneumonia (UIP) pattern, and positivity for autoantibodies in blood tests. The patients received durvalumab, etoposide, and carboplatin every three weeks (induction phase), followed by 1,500 mg durvalumab every four weeks (maintenance phase). The primary endpoint was severe pneumonitis-free rate.</div></div><div><h3>Results</h3><div>Twenty-one patients were included in the analysis. Among them, 13 patients displayed a probable UIP pattern, whereas eight patients exhibited an indeterminate for UIP pattern. Two patients (9.5 %) had pneumonitis of any grade during the induction phase; one had Grade 1 and the other had Grade 5 pneumonitis. No other patient developed pneumonitis during the maintenance phase. The severe pneumonitis-free rate was 95.2 % (95 % confidence interval (CI): 77.3–99.2 %). The median progression-free survival was 5.5 months (95 % CI: 3.6–6.4 months). Median overall survival was 10.7 months (95 % CI: 6.0 months to not reached).</div></div><div><h3>Conclusions</h3><div>Chemoimmunotherapy is a feasible treatment approach for patients with ES-SCLC and mild IIP.</div></div>","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":"196 ","pages":"Article 107958"},"PeriodicalIF":4.5,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142308072","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 : 2024-09-18DOI: 10.1016/j.lungcan.2024.107957
Meng-Zhu Zheng , Zhan-Qun Yang , Sun-Li Cai , Li-Ting Zheng , Yuan Xue , Long Chen , Jian Lin
Lung cancer is the leading cause of cancer deaths worldwide. Brain metastasis of lung cancer, which counts for nearly 50% of late-stage lung cancer patients, is a sign of a really poor prognosis. However, the presence of blood–brain barrier (BBB) and blood–brain tumor barrier (BBTB) limits the penetration of drugs from the blood into the brain and thus restricts their accumulation in brain tumors. Systematic delivery of drugs into brain and brain tumor lesion using BBB and BBTB penetrating vehicles represents a promising strategy to overcome the BBB and BBTB limitations. Hence, we validated one of our previously identified BBB/BBTB penetrating peptide and its drug conjugate form for the treatment of lung cancer brain metastasis. With in vitro experiment, we first validated that the receptor LRP1, which mediated the peptide penetration of the BBB, was expressed on lung cancer cells and thus can be targeted by the peptide to overcome BBTB. With this delivery peptide, we constructed peptide-paclitaxel conjugate (the PDC) and in vitro validation showed that the PDC can across the BBB and efficiently kill lung cancer cells. We therefore constructed mouse lung cancer brain metastasis xenograft. In vivo anti-tumor validations showed that the PDC efficiently inhibited the proliferation of the brain resident lung cancer cells and significantly expanded the survival of the mouse xenograft, with no visible damages to the organs. Overall, our study provided potential therapeutic drugs for the treatment of lung cancer brain metastasis that may be clinically effective in the near future.
{"title":"Blood-brain barrier and blood-brain tumor barrier penetrating peptide-drug conjugate as targeted therapy for the treatment of lung cancer brain metastasis","authors":"Meng-Zhu Zheng , Zhan-Qun Yang , Sun-Li Cai , Li-Ting Zheng , Yuan Xue , Long Chen , Jian Lin","doi":"10.1016/j.lungcan.2024.107957","DOIUrl":"10.1016/j.lungcan.2024.107957","url":null,"abstract":"<div><p>Lung cancer is the leading cause of cancer deaths worldwide. Brain metastasis of lung cancer, which counts for nearly 50% of late-stage lung cancer patients, is a sign of a really poor prognosis. However, the presence of blood–brain barrier (BBB) and blood–brain tumor barrier (BBTB) limits the penetration of drugs from the blood into the brain and thus restricts their accumulation in brain tumors. Systematic delivery of drugs into brain and brain tumor lesion using BBB and BBTB penetrating vehicles represents a promising strategy to overcome the BBB and BBTB limitations. Hence, we validated one of our previously identified BBB/BBTB penetrating peptide and its drug conjugate form for the treatment of lung cancer brain metastasis. With in vitro experiment, we first validated that the receptor LRP1, which mediated the peptide penetration of the BBB, was expressed on lung cancer cells and thus can be targeted by the peptide to overcome BBTB. With this delivery peptide, we constructed peptide-paclitaxel conjugate (the PDC) and in vitro validation showed that the PDC can across the BBB and efficiently kill lung cancer cells. We therefore constructed mouse lung cancer brain metastasis xenograft. In vivo anti-tumor validations showed that the PDC efficiently inhibited the proliferation of the brain resident lung cancer cells and significantly expanded the survival of the mouse xenograft, with no visible damages to the organs. Overall, our study provided potential therapeutic drugs for the treatment of lung cancer brain metastasis that may be clinically effective in the near future.</p></div>","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":"196 ","pages":"Article 107957"},"PeriodicalIF":4.5,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142274410","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 : 2024-09-16DOI: 10.1016/j.lungcan.2024.107956
Henry M. Marshall, Kwun M. Fong
Lung cancer screening can reduce the mortality of lung cancer, the leading cause of cancer death worldwide. Real world screening experience highlights areas for improvement in a complex and changing world, particularly ethnic disparity, and the potential for new and emerging risk factors, in addition to well known risk of smoking and asbestos exposure. Biomarkers offer the promise of objective risk assessment but are not yet ready for clinical practice. This review discusses some of the major issues faced by lung cancer screening and the potential role for biomarkers.
{"title":"Lung cancer screening – Time for an update?","authors":"Henry M. Marshall, Kwun M. Fong","doi":"10.1016/j.lungcan.2024.107956","DOIUrl":"10.1016/j.lungcan.2024.107956","url":null,"abstract":"<div><div>Lung cancer screening can reduce the mortality of lung cancer, the leading cause of cancer death worldwide. Real world screening experience highlights areas for improvement in a complex and changing world, particularly ethnic disparity, and the potential for new and emerging risk factors, in addition to well known risk of smoking and asbestos exposure. Biomarkers offer the promise of objective risk assessment but are not yet ready for clinical practice. This review discusses some of the major issues faced by lung cancer screening and the potential role for biomarkers.</div></div>","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":"196 ","pages":"Article 107956"},"PeriodicalIF":4.5,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0169500224004902/pdfft?md5=071bc5b4254ab122d6d6b12bb00daade&pid=1-s2.0-S0169500224004902-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142315326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-16DOI: 10.1016/j.lungcan.2024.107955
F.O. Mildner , M.M. Sykora , H. Hackl , A. Amann , B. Zelger , S. Sprung , M.L. Buch , F. Nocera , P. Moser , H. Maier , F. Augustin , C. Manzl , F. Kocher , A. Pircher , J. Lindenmann , I Mykoliuk , S. Raftopoulou , J. Kargl , D. Wolf , S. Sopper , G. Gamerith
Background
Cancer immune evasion is critical in non-small cell lung cancer (NSCLC) and has been targeted by immunotherapy. High soluble (s)PD-L1 is associated with reduced survival and treatment failure in advanced stages. Here we evaluated the effects of sPD-L1 on T cells, relapse free survival, and overall survival in early stage NSCLC.
Methods
In vitro T cell stimulation was performed in the presence of sPD-L1 to evaluate its immunomodulatory activity. Data from The Cancer Genome Atlas (TCGA) were investigated for PD-L1 splice variants and enzymes involved in proteolytic cleavage (i.e. ADAM10). Plasma from 74 NSCLC (stage IA-IIIB), as well as an additional 73 (control cohort) patients was collected prior to curative surgery. Thereafter sPD-L1 levels from an immunosorbent assay were correlated with patient outcome.
Results
In vitro sPD-L1 inhibited IFN-γ production and proliferation of T cells and induced a terminal effector CD4 T cell subtype expressing CD27. Data from the TCGA demonstrated that elevated mRNA levels of ADAM10 is a negative predictor of outcome in NSCLC patients. To investigate the clinical relevance of these in vitro and TCGA findings, we quantified sPD-L1 in the plasma of early-stage NSCLC patients. In the first cohort we found significantly higher sPD-L1 levels in relapsing NSCLC patients, with a multivariate analysis revealing high sPD-L1 (>1000 pg/mL) as an independent predictor of survival. However, these findings could not be validated in two independent control cohorts.
Discussion
Although in vitro and TCGA data support the suppressive effect of sPD-L1 we were unable to translate this in our clinical setting. These results may be due to the small patient number and their heterogeneity as well as the lack of a standardized sPD-L1 ELISA. Our inconclusive results regarding the value of sPD-L1 in early stage NSCLC warrant assay validation and further investigation in larger (neo-)adjuvant trials.
{"title":"Soluble PD-L1 shows no association to relapse and overall survival in early stage non-small cell lung cancer (NSCLC)","authors":"F.O. Mildner , M.M. Sykora , H. Hackl , A. Amann , B. Zelger , S. Sprung , M.L. Buch , F. Nocera , P. Moser , H. Maier , F. Augustin , C. Manzl , F. Kocher , A. Pircher , J. Lindenmann , I Mykoliuk , S. Raftopoulou , J. Kargl , D. Wolf , S. Sopper , G. Gamerith","doi":"10.1016/j.lungcan.2024.107955","DOIUrl":"10.1016/j.lungcan.2024.107955","url":null,"abstract":"<div><h3>Background</h3><p>Cancer immune evasion is critical in non-small cell lung cancer (NSCLC) and has been targeted by immunotherapy. High soluble (s)PD-L1 is associated with reduced survival and treatment failure in advanced stages. Here we evaluated the effects of sPD-L1 on T cells, relapse free survival, and overall survival in early stage NSCLC.</p></div><div><h3>Methods</h3><p><em>In vitro</em> T cell stimulation was performed in the presence of sPD-L1 to evaluate its immunomodulatory activity. Data from The Cancer Genome Atlas (TCGA) were investigated for PD-L1 splice variants and enzymes involved in proteolytic cleavage (<em>i.e.</em> ADAM10). Plasma from 74 NSCLC (stage IA-IIIB), as well as an additional 73 (control cohort) patients was collected prior to curative surgery. Thereafter sPD-L1 levels from an immunosorbent assay were correlated with patient outcome.</p></div><div><h3>Results</h3><p><em>In vitro</em> sPD-L1 inhibited IFN-γ production and proliferation of T cells and induced a terminal effector CD4 T cell subtype expressing CD27. Data from the TCGA demonstrated that elevated mRNA levels of ADAM10 is a negative predictor of outcome in NSCLC patients. To investigate the clinical relevance of these <em>in vitro</em> and TCGA findings, we quantified sPD-L1 in the plasma of early-stage NSCLC patients. In the first cohort we found significantly higher sPD-L1 levels in relapsing NSCLC patients, with a multivariate analysis revealing high sPD-L1 (>1000 pg/mL) as an independent predictor of survival. However, these findings could not be validated in two independent control cohorts.</p></div><div><h3>Discussion</h3><p>Although <em>in vitro</em> and TCGA data support the suppressive effect of sPD-L1 we were unable to translate this in our clinical setting. These results may be due to the small patient number and their heterogeneity as well as the lack of a standardized sPD-L1 ELISA. Our inconclusive results regarding the value of sPD-L1 in early stage NSCLC warrant assay validation and further investigation in larger (neo-)adjuvant trials.</p></div>","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":"196 ","pages":"Article 107955"},"PeriodicalIF":4.5,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0169500224004896/pdfft?md5=6fb15516e5a0f75c49b45de97233b970&pid=1-s2.0-S0169500224004896-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142274411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lorlatinib, a third-generation anaplastic lymphoma kinase (ALK) inhibitor, causes distinct adverse events (AEs), including hyperlipidemia and central nervous system (CNS) disorders. Although dose modifications are recommended to manage these AEs, whether dose modifications can achieve optimal blood lorlatinib concentrations and reduce the incidence of lorlatinib-induced AEs remains unclear. Therefore, we investigated the association between lorlatinib exposure and AEs in each patient.
Materials and methods
We retrospectively reviewed patients with advanced ALK-rearranged non-small cell lung cancer treated with lorlatinib between November 2018 and July 2022. Serum lorlatinib concentrations were assessed using high-performance liquid chromatography–tandem mass spectrometry. All AEs were evaluated using the Common Terminology Criteria for Adverse Events version 5.0.
Results
The median age of the 55 eligible patients was 59 years (range: 23–79 years). All patients were administered lorlatinib after first line ALK-tyrosine kinase inhibitor failure. Grade ≥ 3 AEs occurred in 25 patients (25/55, 45 %), including hyperlipidemia in 17 (17/55, 31 %), CNS disorders in 7 (7/55, 13 %), and edema in 6 (6/55, 11 %). Dose modification was required in 23 patients (23/55, 42 %). Among the 36 patients with available data on serum lorlatinib levels at day 28 (±14) and no drug dose modifications, lorlatinib serum concentrations were significantly higher in patients with grade ≥ 3 AEs than in those without AEs (median: 462 ng/mL vs. 177 ng/mL, p < 0.01). In eight patients with data on serial lorlatinib serum concentrations following dose modifications, lorlatinib serum concentrations were effectively reduced, facilitating the ongoing administration of lorlatinib. Additionally, no significant difference was observed in the landmark analysis of progression-free survival between patients with dose modification within the first 16 weeks and those without (median: 24.8 months vs. 10.1 months, p = 0.46).
Conclusion
Dose modification of lorlatinib was associated with successful management of AEs and decreased serum concentration of lorlatinib.
目的 洛拉替尼是第三代无性淋巴瘤激酶（ALK）抑制剂，可引起明显的不良反应（AEs），包括高脂血症和中枢神经系统（CNS）紊乱。虽然建议通过调整剂量来控制这些不良反应，但剂量调整能否达到最佳的罗拉替尼血药浓度并降低罗拉替尼引起的不良反应发生率仍不清楚。因此，我们研究了每位患者的lorlatinib暴露与AEs之间的关联。材料与方法我们回顾性地回顾了2018年11月至2022年7月期间接受lorlatinib治疗的晚期ALK重排非小细胞肺癌患者。使用高效液相色谱-串联质谱法评估了血清中洛拉替尼的浓度。所有AE均采用不良事件通用术语标准5.0版进行评估。结果55名符合条件的患者的中位年龄为59岁（范围：23-79岁）。所有患者均在一线ALK-酪氨酸激酶抑制剂治疗失败后接受了罗拉替尼治疗。25名患者（25/55，45%）发生了≥3级AE，其中17人（17/55，31%）出现高脂血症，7人（7/55，13%）出现中枢神经系统紊乱，6人（6/55，11%）出现水肿。23名患者（23/55，42%）需要调整剂量。在36名有第28天（±14）血清lorlatinib水平数据且未调整药物剂量的患者中，发生≥3级AE的患者血清lorlatinib浓度明显高于未发生AE的患者（中位数：462 ng/mL vs. 177 ng/mL，p <0.01）。剂量调整后，有8例患者的系列lorlatinib血清浓度数据显示，lorlatinib血清浓度有效降低，有利于继续服用lorlatinib。此外，在无进展生存期的标志性分析中，在最初16周内进行剂量调整的患者与未进行剂量调整的患者之间未观察到明显差异（中位数：24.8个月对10.1个月，p = 0.46）。
{"title":"Association between lorlatinib blood concentration and adverse events and clinical impact of dose modification","authors":"Yukiko Shimoda Igawa , Tatsuya Yoshida , Reiko Makihara , Masahiro Torasawa , Akiko Tateishi , Yuji Matsumoto , Yuki Shinno , Yusuke Okuma , Yasushi Goto , Hidehito Horinouchi , Noboru Yamamoto , Yuichiro Ohe","doi":"10.1016/j.lungcan.2024.107954","DOIUrl":"10.1016/j.lungcan.2024.107954","url":null,"abstract":"<div><h3>Objectives</h3><p>Lorlatinib, a third-generation anaplastic lymphoma kinase (ALK) inhibitor, causes distinct adverse events (AEs), including hyperlipidemia and central nervous system (CNS) disorders. Although dose modifications are recommended to manage these AEs, whether dose modifications can achieve optimal blood lorlatinib concentrations and reduce the incidence of lorlatinib-induced AEs remains unclear. Therefore, we investigated the association between lorlatinib exposure and AEs in each patient.</p></div><div><h3>Materials and methods</h3><p>We retrospectively reviewed patients with advanced ALK-rearranged non-small cell lung cancer treated with lorlatinib between November 2018 and July 2022. Serum lorlatinib concentrations were assessed using high-performance liquid chromatography–tandem mass spectrometry. All AEs were evaluated using the Common Terminology Criteria for Adverse Events version 5.0.</p></div><div><h3>Results</h3><p>The median age of the 55 eligible patients was 59 years (range: 23–79 years). All patients were administered lorlatinib after first line ALK-tyrosine kinase inhibitor failure. Grade ≥ 3 AEs occurred in 25 patients (25/55, 45 %), including hyperlipidemia in 17 (17/55, 31 %), CNS disorders in 7 (7/55, 13 %), and edema in 6 (6/55, 11 %). Dose modification was required in 23 patients (23/55, 42 %). Among the 36 patients with available data on serum lorlatinib levels at day 28 (±14) and no drug dose modifications, lorlatinib serum concentrations were significantly higher in patients with grade ≥ 3 AEs than in those without AEs (median: 462 ng/mL vs. 177 ng/mL, p < 0.01). In eight patients with data on serial lorlatinib serum concentrations following dose modifications, lorlatinib serum concentrations were effectively reduced, facilitating the ongoing administration of lorlatinib. Additionally, no significant difference was observed in the landmark analysis of progression-free survival between patients with dose modification within the first 16 weeks and those without (median: 24.8 months vs. 10.1 months, p = 0.46).</p></div><div><h3>Conclusion</h3><p>Dose modification of lorlatinib was associated with successful management of AEs and decreased serum concentration of lorlatinib.</p></div>","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":"196 ","pages":"Article 107954"},"PeriodicalIF":4.5,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142274409","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 : 2024-09-07DOI: 10.1016/j.lungcan.2024.107953
Carolyn J. Presley , Joy Tang , Jason Benedict , Madison Grogan , Sarah Reisinger , Sarah Janse , Melisa L. Wong , Nicole A. Arrato , Ashley Davenport , Peter G. Shields , Barbara L. Andersen
Purpose
As more treatments emerge for advanced, stage IV non-small-cell lung cancer (NSCLC), oncologists have difficulty predicting functional resiliency versus functional decline throughout cancer treatment. Our study evaluates functional resilience among patients with advanced NSCLC.
Methods
Functional status was evaluated through 12 months of follow-up based on disability score using the modified EQ-5D-5L (mEQ-5D-5L) survey. Participants were classified into 4 groups: functional maintenance, decline, resilient, or variable. Characteristics of 207 participants with newly diagnosed NSCLC included demographics, comorbidities, baseline Eastern Cooperative Oncology Group (ECOG) performance status (PS), mEQ-5D-5L scores, psychological symptoms, and lung cancer-specific symptoms. Treatment toxicity and grade were recorded. Resilience was defined as improvement from baseline disability scores. A 1-point increase in functional status score represents a 0.5 standard deviation change on the mEQ-5D-5L. Differences between the 4 groups were determined through Fisher’s exact test or ANOVA. Kaplan-Meier curves describe overall survival (baseline through 18 months) stratified by baseline mEQ-5D-5L scores.
Results
Among participants, 42.0 % maintained functional status, 37.7 % experienced functional decline, 10.6 % were resilient, and 9.7 % had variable functional status. Participants with the best baseline function (score of 0) had the longest overall survival and participants with the worst baseline function (score of 5 + ) had the shortest overall survival. Among the healthiest patients, early score increases indicated shorter overall survival. Baseline ECOG PS was not associated with overall survival (p = 0.47).
Conclusion
Baseline functional status may help better predict functional resiliency and overall survival than ECOG PS among patients receiving treatment for advanced NSCLC.
{"title":"Functional resilience and overall survival in adults treated for advanced non-small-cell lung cancer","authors":"Carolyn J. Presley , Joy Tang , Jason Benedict , Madison Grogan , Sarah Reisinger , Sarah Janse , Melisa L. Wong , Nicole A. Arrato , Ashley Davenport , Peter G. Shields , Barbara L. Andersen","doi":"10.1016/j.lungcan.2024.107953","DOIUrl":"10.1016/j.lungcan.2024.107953","url":null,"abstract":"<div><h3>Purpose</h3><p>As more treatments emerge for advanced, stage IV non-small-cell lung cancer (NSCLC), oncologists have difficulty predicting functional resiliency versus functional decline throughout cancer treatment. Our study evaluates functional resilience among patients with advanced NSCLC.</p></div><div><h3>Methods</h3><p>Functional status was evaluated through 12 months of follow-up based on disability score using the modified EQ-5D-5L (mEQ-5D-5L) survey. Participants were classified into 4 groups: functional maintenance, decline, resilient, or variable. Characteristics of 207 participants with newly diagnosed NSCLC included demographics, comorbidities, baseline Eastern Cooperative Oncology Group (ECOG) performance status (PS), mEQ-5D-5L scores, psychological symptoms, and lung cancer-specific symptoms. Treatment toxicity and grade were recorded. Resilience was defined as improvement from baseline disability scores. A 1-point increase in functional status score represents a 0.5 standard deviation change on the mEQ-5D-5L. Differences between the 4 groups were determined through Fisher’s exact test or ANOVA. Kaplan-Meier curves describe overall survival (baseline through 18 months) stratified by baseline mEQ-5D-5L scores.</p></div><div><h3>Results</h3><p>Among participants, 42.0 % maintained functional status, 37.7 % experienced functional decline, 10.6 % were resilient, and 9.7 % had variable functional status. Participants with the best baseline function (score of 0) had the longest overall survival and participants with the worst baseline function (score of 5 + ) had the shortest overall survival. Among the healthiest patients, early score increases indicated shorter overall survival. Baseline ECOG PS was not associated with overall survival (p = 0.47).</p></div><div><h3>Conclusion</h3><p>Baseline functional status may help better predict functional resiliency and overall survival than ECOG PS among patients receiving treatment for advanced NSCLC.</p></div>","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":"196 ","pages":"Article 107953"},"PeriodicalIF":4.5,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142229698","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 : 2024-09-02DOI: 10.1016/j.lungcan.2024.107935
Jennifer A. Marks , Nishant Gandhi , Balazs Halmos , Melina E. Marmarelis , So Yeon Kim , Lyudmila Bazhenova , Suresh S. Ramalingam , Joanne Xiu , Phillip Walker , Matthew J. Oberley , Patrick C. Ma , Stephen V. Liu
Objectives
MET exon 14 skipping alterations (METex14+) represent a heterogeneous subgroup of non-small cell lung cancer (NSCLC) with distinct biological and genomic features. We characterized this heterogeneity in a large cohort, integrating genomic and transcriptomic profiling with clinical outcomes, to elucidate the histologic and molecular traits and survival patterns of METex14+ NSCLC.
Materials and methods
NSCLC tissue samples (n = 28,739) underwent DNA-based next-generation sequencing (592 genes, NextSeq) or whole-exome sequencing (NovaSeq), RNA-sequencing including whole transcriptome sequencing (WTS, NovaSeq), and PD-L1 IHC (Dako 22C3) at Caris Life Sciences. Immune cell fractions were estimated from bulk RNA sequencing (quanTIseq). Real-world survival data (mOS) was calculated from insurance claims. Statistical analyses employed Chi-square, Fisher’s exact, or Mann-Whitney U and log-rank tests and were corrected for hypothesis testing where applicable.
Results
A total of 711 METex14+ cases were detected. Of 575 cases of defined histology, 77 (13.6 %) were squamous (Sq), 474 (82.3 %) were nSq (non-squamous), and 24 (4.1 %) were adenosquamous. Mutations in POT1 and BRCA2 were enriched, and amplifications in MDM2, HMGA2, CDK4, and MET were common in METex14+ tumors. TMB-high and TP53 mutated tumors were reduced in METex14+ independent of histology. KEAP1 (2.1 vs 14.7 %) and STK11 mutations (0.8 vs 17.1 %) were reduced only in METex14+ nSq (vs METex14+ Sq, q < 0.05). While the prevalence of PD-L1 high tumors was enriched in METex14+ independent of histology, T-cell inflamed tumors were enriched only in nSq METex14+. B-cells and CD8+ T-cells (1.07–1.43-fold) were enriched in nSq METex14+, and dendritic cells (0.32 fold) were reduced only in METex14+ Sq. METex14+ tumors had a modest improvement in mOS compared to METex14- tumors (mOS = 22.9 m vs 18.6 m, HR = 0.914, p = 0.04). Moreover, METex14+ tumors who received immunotherapy (IO) had a modest improvement in survival (mOS = 27.5 m vs 21.8 m; HR = 0.803, p = 0.03) compared to those who did not receive IO. METex14+ nSq tumors were associated with improved mOS compared to METex14+ Sq tumors (mOS = 27.7 vs 8.9 m, HR = 0.493, p < 0.0001).
Conclusion
METex14+ alterations are a heterogeneous subgroup of NSCLC. Our analysis reveals that METex14+ nSq exhibit improved survival compared to METex14+ Sq. The distinct genomic and transcriptomic variations across histologies warrant clinical consideration.
{"title":"Molecular profiling METex14+ non-small cell lung cancer (NSCLC): Impact of histology","authors":"Jennifer A. Marks , Nishant Gandhi , Balazs Halmos , Melina E. Marmarelis , So Yeon Kim , Lyudmila Bazhenova , Suresh S. Ramalingam , Joanne Xiu , Phillip Walker , Matthew J. Oberley , Patrick C. Ma , Stephen V. Liu","doi":"10.1016/j.lungcan.2024.107935","DOIUrl":"10.1016/j.lungcan.2024.107935","url":null,"abstract":"<div><h3>Objectives</h3><p><em>MET</em> exon 14 skipping alterations (<em>MET</em>ex14+) represent a heterogeneous subgroup of non-small cell lung cancer (NSCLC) with distinct biological and genomic features. We characterized this heterogeneity in a large cohort, integrating genomic and transcriptomic profiling with clinical outcomes, to elucidate the histologic and molecular traits and survival patterns of <em>MET</em>ex14+ NSCLC.</p></div><div><h3>Materials and methods</h3><p>NSCLC tissue samples (n = 28,739) underwent DNA-based next-generation sequencing (592 genes, NextSeq) or whole-exome sequencing (NovaSeq), RNA-sequencing including whole transcriptome sequencing (WTS, NovaSeq), and PD-L1 IHC (Dako 22C3) at Caris Life Sciences. Immune cell fractions were estimated from bulk RNA sequencing (quanTIseq). Real-world survival data (mOS) was calculated from insurance claims. Statistical analyses employed Chi-square, Fisher’s exact, or Mann-Whitney U and log-rank tests and were corrected for hypothesis testing where applicable.</p></div><div><h3>Results</h3><p>A total of 711 <em>MET</em>ex14+ cases were detected. Of 575 cases of defined histology, 77 (13.6 %) were squamous (Sq), 474 (82.3 %) were nSq (non-squamous), and 24 (4.1 %) were adenosquamous. Mutations in <em>POT1</em> and <em>BRCA2</em> were enriched, and amplifications in <em>MDM2</em>, <em>HMGA2</em>, <em>CDK4,</em> and <em>MET</em> were common in <em>MET</em>ex14+ tumors. TMB-high and <em>TP53</em> mutated tumors were reduced in <em>MET</em>ex14+ independent of histology. <em>KEAP1</em> (2.1 vs 14.7 %) and <em>STK11</em> mutations (0.8 vs 17.1 %) were reduced only in <em>MET</em>ex14+ nSq (vs <em>MET</em>ex14+ Sq, q < 0.05). While the prevalence of PD-L1 high tumors was enriched in <em>MET</em>ex14+ independent of histology, T-cell inflamed tumors were enriched only in nSq <em>MET</em>ex14+. B-cells and CD8+ T-cells (1.07–1.43-fold) were enriched in nSq <em>MET</em>ex14+, and dendritic cells (0.32 fold) were reduced only in <em>MET</em>ex14+ Sq. <em>MET</em>ex14+ tumors had a modest improvement in mOS compared to <em>MET</em>ex14- tumors (mOS = 22.9 m vs 18.6 m, HR = 0.914, p = 0.04). Moreover, <em>MET</em>ex14+ tumors who received immunotherapy (IO) had a modest improvement in survival (mOS = 27.5 m vs 21.8 m; HR = 0.803, p = 0.03) compared to those who did not receive IO. <em>MET</em>ex14+ nSq tumors were associated with improved mOS compared to <em>MET</em>ex14+ Sq tumors (mOS = 27.7 vs 8.9 m, HR = 0.493, p < 0.0001).</p></div><div><h3>Conclusion</h3><p><em>MET</em>ex14+ alterations are a heterogeneous subgroup of NSCLC. Our analysis reveals that <em>MET</em>ex14+ nSq exhibit improved survival compared to <em>MET</em>ex14+ Sq. The distinct genomic and transcriptomic variations across histologies warrant clinical consideration.</p></div>","PeriodicalId":18129,"journal":{"name":"Lung Cancer","volume":"196 ","pages":"Article 107935"},"PeriodicalIF":4.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145945","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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