Pub Date : 2025-02-01DOI: 10.1016/j.jncc.2024.12.003
Banzhou Pan, Bo Shen
{"title":"The ADRIATIC study: revolutionizing the standard treatment paradigm for concurrent chemoradiotherapy in limited-stage small cell lung cancer","authors":"Banzhou Pan, Bo Shen","doi":"10.1016/j.jncc.2024.12.003","DOIUrl":"10.1016/j.jncc.2024.12.003","url":null,"abstract":"","PeriodicalId":73987,"journal":{"name":"Journal of the National Cancer Center","volume":"5 1","pages":"Pages 1-2"},"PeriodicalIF":7.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143386660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.jncc.2024.06.007
Cai-Ning Zhao , Chi-Leung Chiang , Wan-Hang Keith Chiu , Sik-Kwan Kenneth Chan , Chun-Bong James Li , Wei-Wei Chen , Dan-Yang Zheng , Wen-Qi Chen , Ren Ji , Chung-Mau Lo , Salma K. Jabbour , Chi-Yan Albert Chan , Feng-Ming (Spring) Kong
Background
The role of systemic tumor immune environment (STIE) is unclear in hepatocellular carcinoma (HCC). This study aimed to exam the cells in the STIE, their changes after transarterial chemoembolisation (TACE), stereotactic body radiotherapy (SBRT), and immunotherapy (IO) and explore their significance in the treatment response of patients with unresectable HCC.
Methods
This is a prospective biomarker study of patients with unresectable HCC. The treatment was sequential TACE, SBRT (27.5–40 Gy/5 fractions), and IO. The treatment response was assessed according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) by magnetic resonance imaging (MRI) after 6 months of treatment. Longitudinal data of STIE cells was extracted from laboratory results of complete blood cell counts, including leukocytes, lymphocytes, neutrophils, monocytes, eosinophils, basophils, and platelets. Peripheral blood samples were collected at baseline and after TACE, SBRT, and IO for T-lymphocyte subtyping by flow cytometry. Generalized estimation equation was employed for longitudinal analyses.
Results
A total of 35 patients with unresectable HCC were enrolled: 23 patients in the exploratory cohort and 12 in the validation cohort. STIE circulating cells, especially lymphocytes, were heterogenous at baseline and changed differentially after TACE, SBRT, and IO in both cohorts. SBRT caused the greatest reduction of 0.7 × 109/L (95 % CI: 0.3 × 109/L–1.0 × 109/L, P < 0.001) in lymphocytes; less reduction was associated with significantly better treatment response. The analysis of T-lymphocyte lineage revealed that the baseline levels of CD4+ T cells (P = 0.010), type 1 T helper (Th1) cells (P = 0.007), and Th1/Th17 ratios (P = 0.001) were significantly higher in responders, while regulatory T (Treg) cells (P = 0.002), Th17 cells (P = 0.047), and Th2/Th1 ratios (P = 0.028) were significantly higher in non-responders. After treatment with TACE, SBRT and IO, T-lymphocyte lineage also changed differentially. More reductions were observed in CD25+CD8+ T cells and CD127+CD8+ T cells after SBRT in non-responders, while increases in natural killer T (NKT) cells after SBRT (10.4% vs. 3.4 %, P = 0.001) and increases in the lymphocyte counts were noted during IO in responders.
Conclusions
STIE cells are significant for treatment response, can be reshaped differentially after TACE, SBRT, and IO. The most significant changes of T-lymphocyte lineage are SBRT associated modulations in CD25+CD8+ T cells, CD127+CD8+ T cells, and NKT cells, which also have significant effects on the ultimate treatment response after TACE-SBRT-IO (ClinicalTrails.gov identifier: GCOG0001/NC
{"title":"Treatments of transarterial chemoembolization (TACE), stereotactic body radiotherapy (SBRT) and immunotherapy reshape the systemic tumor immune environment (STIE) in patients with unresectable hepatocellular carcinoma","authors":"Cai-Ning Zhao , Chi-Leung Chiang , Wan-Hang Keith Chiu , Sik-Kwan Kenneth Chan , Chun-Bong James Li , Wei-Wei Chen , Dan-Yang Zheng , Wen-Qi Chen , Ren Ji , Chung-Mau Lo , Salma K. Jabbour , Chi-Yan Albert Chan , Feng-Ming (Spring) Kong","doi":"10.1016/j.jncc.2024.06.007","DOIUrl":"10.1016/j.jncc.2024.06.007","url":null,"abstract":"<div><h3>Background</h3><div>The role of systemic tumor immune environment (STIE) is unclear in hepatocellular carcinoma (HCC). This study aimed to exam the cells in the STIE, their changes after transarterial chemoembolisation (TACE), stereotactic body radiotherapy (SBRT), and immunotherapy (IO) and explore their significance in the treatment response of patients with unresectable HCC.</div></div><div><h3>Methods</h3><div>This is a prospective biomarker study of patients with unresectable HCC. The treatment was sequential TACE, SBRT (27.5–40 Gy/5 fractions), and IO. The treatment response was assessed according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) by magnetic resonance imaging (MRI) after 6 months of treatment. Longitudinal data of STIE cells was extracted from laboratory results of complete blood cell counts, including leukocytes, lymphocytes, neutrophils, monocytes, eosinophils, basophils, and platelets. Peripheral blood samples were collected at baseline and after TACE, SBRT, and IO for T-lymphocyte subtyping by flow cytometry. Generalized estimation equation was employed for longitudinal analyses.</div></div><div><h3>Results</h3><div>A total of 35 patients with unresectable HCC were enrolled: 23 patients in the exploratory cohort and 12 in the validation cohort. STIE circulating cells, especially lymphocytes, were heterogenous at baseline and changed differentially after TACE, SBRT, and IO in both cohorts. SBRT caused the greatest reduction of 0.7 × 10<sup>9</sup>/L (95 % CI: 0.3 × 10<sup>9</sup>/L–1.0 × 10<sup>9</sup>/L, <em>P</em> < 0.001) in lymphocytes; less reduction was associated with significantly better treatment response. The analysis of T-lymphocyte lineage revealed that the baseline levels of CD4<sup>+</sup> T cells (<em>P</em> = 0.010), type 1 T helper (Th1) cells (<em>P</em> = 0.007), and Th1/Th17 ratios (<em>P</em> = 0.001) were significantly higher in responders, while regulatory T (Treg) cells (<em>P</em> = 0.002), Th17 cells (<em>P</em> = 0.047), and Th2/Th1 ratios (<em>P</em> = 0.028) were significantly higher in non-responders. After treatment with TACE, SBRT and IO, T-lymphocyte lineage also changed differentially. More reductions were observed in CD25<sup>+</sup>CD8<sup>+</sup> T cells and CD127<sup>+</sup>CD8<sup>+</sup> T cells after SBRT in non-responders, while increases in natural killer T (NKT) cells after SBRT (10.4% vs. 3.4 %, <em>P</em> = 0.001) and increases in the lymphocyte counts were noted during IO in responders.</div></div><div><h3>Conclusions</h3><div>STIE cells are significant for treatment response, can be reshaped differentially after TACE, SBRT, and IO. The most significant changes of T-lymphocyte lineage are SBRT associated modulations in CD25<sup>+</sup>CD8<sup>+</sup> T cells, CD127<sup>+</sup>CD8<sup>+</sup> T cells, and NKT cells, which also have significant effects on the ultimate treatment response after TACE-SBRT-IO (ClinicalTrails.gov identifier: GCOG0001/NC","PeriodicalId":73987,"journal":{"name":"Journal of the National Cancer Center","volume":"5 1","pages":"Pages 38-49"},"PeriodicalIF":7.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143386565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.jncc.2024.12.001
He Tian , Zhenlin Yang , Junhui Yang , Ying Chen , Lin Li , Tao Fan , Tiejun Liu , Guangyu Bai , Yibo Gao , Jie He
Background
Pulmonary blastoma (PB) is a rare subtype of lung cancer. Currently, the underlying pathogenesis mechanisms of PB have not been fully illustrated, and the therapeutic approach for this entity is limited.
Methods
Whole-exome sequencing (WES), RNA sequencing, and DNA methylation profiling are applied to seven PB patients. Multi-omics data of pulmonary sarcomatoid carcinoma (PSC) and pituitary blastoma (PitB) from previous studies are invoked to illuminate the associations among PB and these malignacies.
Results
We portray the genomic alteration spectrum of PB and find that DICER1 is with the highest alteration rate (86 %). We uncover that DICER1 alterations, Wnt signaling pathway dysregulation and IGF2 imprinting dysregulation are the potential pathogenesis mechanisms of PB. Moreover, we reveal that the integrated molecular features of PB are distinct from PSC, and the molecular characteristics of PB are more similar to PitB than to PSC. Pancancer analysis show that the tumor mutation burden (TMB) and leukocyte fraction (LF) of PB are low, while some cases are positive for PD-L1 or have CD8-positive focal areas, implying the potential applicability of immunotherapy in selected PB patients.
Conclusion
This study depicts the integrated molecular characteristics of PB and offers novel insights into the pathogenesis and therapeutic strategies of PB.
{"title":"Integrated molecular characterization reveals the pathogenesis and therapeutic strategies of pulmonary blastoma","authors":"He Tian , Zhenlin Yang , Junhui Yang , Ying Chen , Lin Li , Tao Fan , Tiejun Liu , Guangyu Bai , Yibo Gao , Jie He","doi":"10.1016/j.jncc.2024.12.001","DOIUrl":"10.1016/j.jncc.2024.12.001","url":null,"abstract":"<div><h3>Background</h3><div>Pulmonary blastoma (PB) is a rare subtype of lung cancer. Currently, the underlying pathogenesis mechanisms of PB have not been fully illustrated, and the therapeutic approach for this entity is limited.</div></div><div><h3>Methods</h3><div>Whole-exome sequencing (WES), RNA sequencing, and DNA methylation profiling are applied to seven PB patients. Multi-omics data of pulmonary sarcomatoid carcinoma (PSC) and pituitary blastoma (PitB) from previous studies are invoked to illuminate the associations among PB and these malignacies.</div></div><div><h3>Results</h3><div>We portray the genomic alteration spectrum of PB and find that <em>DICER1</em> is with the highest alteration rate (86 %). We uncover that <em>DICER1</em> alterations, Wnt signaling pathway dysregulation and IGF2 imprinting dysregulation are the potential pathogenesis mechanisms of PB. Moreover, we reveal that the integrated molecular features of PB are distinct from PSC, and the molecular characteristics of PB are more similar to PitB than to PSC. Pancancer analysis show that the tumor mutation burden (TMB) and leukocyte fraction (LF) of PB are low, while some cases are positive for PD-L1 or have CD8-positive focal areas, implying the potential applicability of immunotherapy in selected PB patients.</div></div><div><h3>Conclusion</h3><div>This study depicts the integrated molecular characteristics of PB and offers novel insights into the pathogenesis and therapeutic strategies of PB.</div></div>","PeriodicalId":73987,"journal":{"name":"Journal of the National Cancer Center","volume":"5 1","pages":"Pages 82-92"},"PeriodicalIF":7.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143386578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.jncc.2024.05.006
Giorgio Broccia , Jonathan Carter , Cansu Ozsin-Ozler , Sara De Matteis , Pierluigi Cocco
Background
The epidemiological investigation of Hodgkin's lymphoma (HL) among the genetically peculiar population of the Italian island of Sardinia might provide interesting etiological clues.
Methods
We used the database of 1974–2003 incident cases of hematological malignancies in Sardinia and Bayesian methods to explore the time trend and geographic spread of HL incidence by sex, and age whether ≤44 or ≥45 years. We also tested its association with several socio-economic and environmental risk factors.
Results
The age- and sex-standardized (world population) incidence rate of HL was 2.6 per 100,000 (95% CI, 2.5–2.8). Over the study period, HL incidence increased linearly in both sexes and among those aged ≤44 years but not above that age. Cases clustered among young women in a central-western area covering four bordering administrative units (13 cases vs. 5.7 expected, P = 0.002). The posterior probability of excess HL cases aged ≤44 years was elevated only in a commune in the suburban area of the region's capital. Cases aged ≥45 years were uniformly spread over the region. Among the risk factors we explored, urban residence was associated with an elevated and goat farming with a decreased risk of HL occurrence. We did not observe a link with socio-economic deprivation, environmental exposures, or multiple sclerosis. The geographic spread of COVID-19 was also unrelated to past HL incidence.
Conclusions
Our results prompt further in-depth investigation into the previously undetected cluster and the nature of the observed associations.
{"title":"Time and space co-ordinates of Hodgkin's lymphoma in Sardinia, Italy","authors":"Giorgio Broccia , Jonathan Carter , Cansu Ozsin-Ozler , Sara De Matteis , Pierluigi Cocco","doi":"10.1016/j.jncc.2024.05.006","DOIUrl":"10.1016/j.jncc.2024.05.006","url":null,"abstract":"<div><h3>Background</h3><div>The epidemiological investigation of Hodgkin's lymphoma (HL) among the genetically peculiar population of the Italian island of Sardinia might provide interesting etiological clues.</div></div><div><h3>Methods</h3><div>We used the database of 1974–2003 incident cases of hematological malignancies in Sardinia and Bayesian methods to explore the time trend and geographic spread of HL incidence by sex, and age whether ≤44 or ≥45 years. We also tested its association with several socio-economic and environmental risk factors.</div></div><div><h3>Results</h3><div>The age- and sex-standardized (world population) incidence rate of HL was 2.6 per 100,000 (95% CI, 2.5–2.8). Over the study period, HL incidence increased linearly in both sexes and among those aged ≤44 years but not above that age<em>.</em> Cases clustered among young women in a central-western area covering four bordering administrative units (13 cases <em>vs.</em> 5.7 expected, <em>P</em> = 0.002). The posterior probability of excess HL cases aged ≤44 years was elevated only in a commune in the suburban area of the region's capital. Cases aged ≥45 years were uniformly spread over the region. Among the risk factors we explored, urban residence was associated with an elevated and goat farming with a decreased risk of HL occurrence. We did not observe a link with socio-economic deprivation, environmental exposures, or multiple sclerosis. The geographic spread of COVID-19 was also unrelated to past HL incidence.</div></div><div><h3>Conclusions</h3><div>Our results prompt further in-depth investigation into the previously undetected cluster and the nature of the observed associations.</div></div>","PeriodicalId":73987,"journal":{"name":"Journal of the National Cancer Center","volume":"5 1","pages":"Pages 50-56"},"PeriodicalIF":7.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143386577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.jncc.2024.10.001
Xiaojie Liang , Jia Guo , Xiaofang Wang , Baiwei Luo , Ruiying Fu , Haiying Chen , Yunong Yang , Zhihao Jin , Chaoran Lin , Aimin Zang , Youchao Jia , Lin Feng , Liang Wang
Background
Previous researches mainly focused on whether cancer stem cells exist in diffuse large B-cell lymphoma (DLBCL). However, subgroups with dismal prognosis and stem cell-like characteristics have been overlooked.
Methods
Using large scale data (n = 2133), we conducted machine learning algorithms to identify a high risk DLBCL subgroup with stem cell-like features, and then investigated the potential mechanisms in shaping this subgroup using transcriptome, genome and single-cell RNA-seq data, and in vitro experiments.
Results
We identified a high-risk subgroup (25.6 % of DLBCL) with stem cell-like characteristics and dismal prognosis. This high-risk group (HRG) was featured by upregulation of key enzyme (ODC1) in polyamine metabolism and cold tumor microenvironment (TME), and had a poor prognosis with lower 3-year overall survival (OS) (54.3 % vs. 83.6 %, P < 0.0001) and progression-free survival (PFS) (42.8 % vs. 74.7 %, P < 0.0001) rates compared to the low-risk group. HRG also exhibited malignant proliferative phenotypes similar to Burkitt lymphoma. Patients with MYC rearrangement, double-hit, double-expressors, or complete remission might have either favorable or poor prognosis, which could be further distinguished by our risk stratification model. Genomic analysis revealed widespread copy number losses in the chemokine and interferon coding regions 8p23.1 and 9p21.3 in HRG. We identified ODC1 as a therapeutic vulnerability for HRG-DLBCL. Single-cell analysis and in vitro experiments demonstrated that ODC1 overexpression enhanced DLBCL cell proliferation and drove macrophage polarization towards the M2 phenotype. Conversely, ODC1 inhibition reduced DLBCL cell proliferation, induced cell cycle arrest and apoptosis, and promoted macrophage polarization towards the M1 phenotype. Finally, we developed a comprehensive database of DLBCL for clinical application.
Conclusions
Our study effectively advances the precise risk stratification of DLBCL and reveals that ODC1 and immune-deserted microenvironment jointly shape a group of DLBCL patients with stem cell-like features. Targeting ODC1 regulates immunotherapies in DLBCL, offering new insights for DLBCL treatment.
背景以往的研究主要集中在弥漫性大b细胞淋巴瘤（DLBCL）中是否存在肿瘤干细胞。然而，预后不良和干细胞样特征的亚群被忽视了。方法利用大规模数据（n = 2133），采用机器学习算法识别具有干细胞样特征的高危DLBCL亚群，然后利用转录组、基因组和单细胞RNA-seq数据以及体外实验研究塑造该亚群的潜在机制。结果我们确定了一个高风险亚组（占DLBCL的25.6 %），具有干细胞样特征，预后不佳。该高危组（HRG）多胺代谢关键酶（ODC1）和冷肿瘤微环境（TME）上调，预后较差，3年总生存率（OS）较低(54.3% % vs. 83.6 %,P <；0.0001)和无进展生存期（PFS）(42.8 % vs. 74.7 %,P <；0.0001)，与低风险组相比。HRG也表现出与伯基特淋巴瘤相似的恶性增生性表型。MYC重排、双击中、双表达或完全缓解的患者可能有良好或不良的预后，这可以通过我们的风险分层模型进一步区分。基因组分析显示，HRG中趋化因子和干扰素编码区8p23.1和9p21.3拷贝数普遍缺失。我们确定ODC1是HRG-DLBCL的治疗易损。单细胞分析和体外实验表明，ODC1过表达增强DLBCL细胞增殖，驱动巨噬细胞向M2表型极化。相反，ODC1抑制降低DLBCL细胞增殖，诱导细胞周期阻滞和凋亡，促进巨噬细胞向M1表型极化。最后，我们建立了一个完整的DLBCL数据库以供临床应用。结论我们的研究有效地推进了DLBCL的精确风险分层，揭示了ODC1和免疫遗弃微环境共同塑造了一组具有干细胞样特征的DLBCL患者。靶向ODC1调节DLBCL的免疫治疗，为DLBCL治疗提供新的见解。
{"title":"Overexpression of ornithine decarboxylase 1 mediates the immune-deserted microenvironment and poor prognosis in diffuse large B-cell lymphoma","authors":"Xiaojie Liang , Jia Guo , Xiaofang Wang , Baiwei Luo , Ruiying Fu , Haiying Chen , Yunong Yang , Zhihao Jin , Chaoran Lin , Aimin Zang , Youchao Jia , Lin Feng , Liang Wang","doi":"10.1016/j.jncc.2024.10.001","DOIUrl":"10.1016/j.jncc.2024.10.001","url":null,"abstract":"<div><h3>Background</h3><div>Previous researches mainly focused on whether cancer stem cells exist in diffuse large B-cell lymphoma (DLBCL). However, subgroups with dismal prognosis and stem cell-like characteristics have been overlooked.</div></div><div><h3>Methods</h3><div>Using large scale data (<em>n</em> = 2133), we conducted machine learning algorithms to identify a high risk DLBCL subgroup with stem cell-like features, and then investigated the potential mechanisms in shaping this subgroup using transcriptome, genome and single-cell RNA-seq data, and <em>in vitro</em> experiments.</div></div><div><h3>Results</h3><div>We identified a high-risk subgroup (25.6 % of DLBCL) with stem cell-like characteristics and dismal prognosis. This high-risk group (HRG) was featured by upregulation of key enzyme (ODC1) in polyamine metabolism and cold tumor microenvironment (TME), and had a poor prognosis with lower 3-year overall survival (OS) (54.3 % vs. 83.6 %, <em>P</em> < 0.0001) and progression-free survival (PFS) (42.8 % vs. 74.7 %, <em>P</em> < 0.0001) rates compared to the low-risk group. HRG also exhibited malignant proliferative phenotypes similar to Burkitt lymphoma. Patients with <em>MYC</em> rearrangement, double-hit, double-expressors, or complete remission might have either favorable or poor prognosis, which could be further distinguished by our risk stratification model. Genomic analysis revealed widespread copy number losses in the chemokine and interferon coding regions 8p23.1 and 9p21.3 in HRG. We identified ODC1 as a therapeutic vulnerability for HRG-DLBCL. Single-cell analysis and <em>in vitro</em> experiments demonstrated that ODC1 overexpression enhanced DLBCL cell proliferation and drove macrophage polarization towards the M2 phenotype. Conversely, ODC1 inhibition reduced DLBCL cell proliferation, induced cell cycle arrest and apoptosis, and promoted macrophage polarization towards the M1 phenotype. Finally, we developed a comprehensive database of DLBCL for clinical application.</div></div><div><h3>Conclusions</h3><div>Our study effectively advances the precise risk stratification of DLBCL and reveals that ODC1 and immune-deserted microenvironment jointly shape a group of DLBCL patients with stem cell-like features. Targeting ODC1 regulates immunotherapies in DLBCL, offering new insights for DLBCL treatment.</div></div>","PeriodicalId":73987,"journal":{"name":"Journal of the National Cancer Center","volume":"5 1","pages":"Pages 57-74"},"PeriodicalIF":7.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143386579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.jncc.2024.12.005
Lanlan Pang , Weitao Zhuang , Yihua Huang, Jun Liao, Mengjuan Yang, Li Zhang, Yaxiong Zhang, Wenfeng Fang
Background
Phenotypic transition is a common resistance mechanism of targeted therapy. While transformations from lung adenocarcinoma (LUAD) to small-cell lung cancer or squamous-cell carcinoma have been extensively studied, the conversion into sarcomatoid carcinoma (SC) is rarely reported.
Methods
Genetic and histological examinations were systematically performed on tumor re-biopsy samples obtained from patients with advanced EGFR-mutant LUAD who progressed on EGFR-tyrosine kinase inhibitors (TKIs). EGFR wild-type patients were also identified who underwent the rare transformation from adenocarcinoma to SC following the ineffectiveness of inhibitors that target distinct driver oncogenes. Furthermore, we also retrospectively collected 42 cases diagnosed with primary pulmonary SC as a comparison cohort to comprehensively characterize the biological events and clinical outcomes of transformed SC.
Results
The sarcomatoid transformation mediated drug resistance in 2.5 % and 4.8 % of patients after failure on the first/second, and third-generation EGFR-TKIs. Transformation of sarcomatoid carcinoma is characterized by a higher frequency of TP53, RB1, and MET genetic alterations compared to cases lacking histological transformation; the PI3K signaling pathway was also significantly activated. Fifteen individuals were identified with a rare transition from adenocarcinoma to SC, consisting of seven cases with EGFR-activating mutations and eight cases without EGFR mutations. All sarcomatoid-transformed samples not only retained their original driver mutations but also shared specific genetic alterations with primary LUAD. Moreover, transformed sarcomatoid carcinomas mimic the primary SC in terms of immunochemical and molecular features.
Conclusions
The transformation from lung adenocarcinoma to SC is a resistance mechanism wildly applied to inhibitors targeting different driver oncogenes. Immunotherapy plus chemotherapy shows potential to benefit patients with sarcomatoid transformation and warrants further study in larger cohorts.
{"title":"Rare transformation from lung adenocarcinoma to sarcomatoid carcinoma mediates resistance to inhibitors targeting different driver oncogenes","authors":"Lanlan Pang , Weitao Zhuang , Yihua Huang, Jun Liao, Mengjuan Yang, Li Zhang, Yaxiong Zhang, Wenfeng Fang","doi":"10.1016/j.jncc.2024.12.005","DOIUrl":"10.1016/j.jncc.2024.12.005","url":null,"abstract":"<div><h3>Background</h3><div>Phenotypic transition is a common resistance mechanism of targeted therapy. While transformations from lung adenocarcinoma (LUAD) to small-cell lung cancer or squamous-cell carcinoma have been extensively studied, the conversion into sarcomatoid carcinoma (SC) is rarely reported.</div></div><div><h3>Methods</h3><div>Genetic and histological examinations were systematically performed on tumor re-biopsy samples obtained from patients with advanced EGFR-mutant LUAD who progressed on EGFR-tyrosine kinase inhibitors (TKIs). EGFR wild-type patients were also identified who underwent the rare transformation from adenocarcinoma to SC following the ineffectiveness of inhibitors that target distinct driver oncogenes. Furthermore, we also retrospectively collected 42 cases diagnosed with primary pulmonary SC as a comparison cohort to comprehensively characterize the biological events and clinical outcomes of transformed SC.</div></div><div><h3>Results</h3><div>The sarcomatoid transformation mediated drug resistance in 2.5 % and 4.8 % of patients after failure on the first/second, and third-generation EGFR-TKIs. Transformation of sarcomatoid carcinoma is characterized by a higher frequency of <em>TP53, RB1</em>, and <em>MET</em> genetic alterations compared to cases lacking histological transformation; the PI3K signaling pathway was also significantly activated. Fifteen individuals were identified with a rare transition from adenocarcinoma to SC, consisting of seven cases with <em>EGFR</em>-activating mutations and eight cases without <em>EGFR</em> mutations. All sarcomatoid-transformed samples not only retained their original driver mutations but also shared specific genetic alterations with primary LUAD. Moreover, transformed sarcomatoid carcinomas mimic the primary SC in terms of immunochemical and molecular features.</div></div><div><h3>Conclusions</h3><div>The transformation from lung adenocarcinoma to SC is a resistance mechanism wildly applied to inhibitors targeting different driver oncogenes. Immunotherapy plus chemotherapy shows potential to benefit patients with sarcomatoid transformation and warrants further study in larger cohorts.</div></div>","PeriodicalId":73987,"journal":{"name":"Journal of the National Cancer Center","volume":"5 1","pages":"Pages 75-81"},"PeriodicalIF":7.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143386580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":73987,"journal":{"name":"Journal of the National Cancer Center","volume":"5 3","pages":"Pages 322-329"},"PeriodicalIF":9.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147185680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":73987,"journal":{"name":"Journal of the National Cancer Center","volume":"5 6","pages":"Pages 547-548"},"PeriodicalIF":9.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147054254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":73987,"journal":{"name":"Journal of the National Cancer Center","volume":"5 1","pages":"Pages 57-74"},"PeriodicalIF":9.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146338361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":73987,"journal":{"name":"Journal of the National Cancer Center","volume":"5 1","pages":"Pages 28-37"},"PeriodicalIF":9.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146338365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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