Pub Date : 2026-03-06DOI: 10.1158/1078-0432.ccr-25-3726
Sandra J Casak,Yiming Zhang,Chi Song,Pallavi S Mishra-Kalyani,Shenghui Tang,Doris Auth,R Angelo de Claro,Richard Pazdur,Steven J Lemery
On May 5, 2021 and March 19, 2025, the Food and Drug Administration (FDA) granted accelerated and regular approval for pembrolizumab plus trastuzumab and platinum-based chemotherapy for unresectable or metastatic human epidermal growth factor receptor-2 (HER2) gastric or gastroesophageal junction carcinoma. Both approvals were based on KEYNOTE-811, a randomized, multiregional trial, comparing pembrolizumab plus trastuzumab and chemotherapy versus placebo plus trastuzumab and chemotherapy. Accelerated approval was granted based on overall response rate (ORR) in the first 264 patients randomized, showing a statistically significant improvement with pembrolizumab (74.4% vs. 51.9%, p= 0.00006). The final overall survival (OS) analysis demonstrated a clinically meaningful improvement, with a median OS of 20.0 months (95% CI 17.8, 22.1) and 16.8 months (95% CI 14.9, 18.7) in the pembrolizumab and placebo arms respectively (HR 0.80 [95% CI 0.67, 0.94]; p= 0.004). However, in exploratory subgroup analyses treatment benefit appeared to be driven by the PD-L1 CPS ≥1 population (85% of patients, with an OS HR of 0.79 [95% CI 0.66, 0.95]), whereas in the CPS <1 subgroup (15% of patients) treatment with pembrolizumab did not show improvement (HR 1.10, [95% CI 0.72-1.68]). These results are consistent with analysis of pembrolizumab and other immune checkpoint inhibitors across multiple clinical trials in patients with gastric cancer. KEYNOTE-811 utilized a "one-trial" approach allowing accelerated approval based on response rate with subsequent conversion to regular approval based on survival outcomes. KEYNOTE-811 also provided data for earlier access to therapies in a frontline metastatic setting, following FDA's Project Frontrunner approach.
在2021年5月5日和2025年3月19日，美国食品和药物管理局（FDA）批准了派姆单抗联合曲妥珠单抗和铂基化疗治疗不可切除或转移性人表皮生长因子受体-2 （HER2）胃癌或胃食管结癌的加速和常规批准。这两项批准均基于KEYNOTE-811，这是一项随机的多区域试验，比较了派姆单抗加曲妥珠单抗和化疗与安慰剂加曲妥珠单抗和化疗。基于首批264名随机患者的总缓解率（ORR）， pembrolizumab获得了加速批准，显示统计学上显着改善（74.4% vs. 51.9%, p= 0.00006）。最终总生存期（OS）分析显示有临床意义的改善，派姆单抗组和安慰剂组的中位生存期分别为20.0个月（95% CI 17.8, 22.1）和16.8个月（95% CI 14.9, 18.7） （HR 0.80 [95% CI 0.67, 0.94]; p= 0.004）。然而，在探索性亚组分析中，治疗获益似乎是由PD-L1 CPS≥1的人群（85%的患者，OS HR为0.79 [95% CI 0.66, 0.95]）驱动的，而在CPS <1的亚组（15%的患者）中，使用派姆单抗治疗没有显示出改善（HR 1.10, [95% CI 0.72-1.68]）。这些结果与pembrolizumab和其他免疫检查点抑制剂在胃癌患者的多个临床试验中的分析一致。KEYNOTE-811采用了“一次试验”方法，允许根据反应率加速批准，随后根据生存结果转换为定期批准。KEYNOTE-811还根据FDA的项目领跑者方法，为一线转移性疾病的早期治疗提供了数据。
{"title":"FDA Approval Summary: Pembrolizumab for the Treatment of HER2-Positive Gastric Cancer.","authors":"Sandra J Casak,Yiming Zhang,Chi Song,Pallavi S Mishra-Kalyani,Shenghui Tang,Doris Auth,R Angelo de Claro,Richard Pazdur,Steven J Lemery","doi":"10.1158/1078-0432.ccr-25-3726","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-3726","url":null,"abstract":"On May 5, 2021 and March 19, 2025, the Food and Drug Administration (FDA) granted accelerated and regular approval for pembrolizumab plus trastuzumab and platinum-based chemotherapy for unresectable or metastatic human epidermal growth factor receptor-2 (HER2) gastric or gastroesophageal junction carcinoma. Both approvals were based on KEYNOTE-811, a randomized, multiregional trial, comparing pembrolizumab plus trastuzumab and chemotherapy versus placebo plus trastuzumab and chemotherapy. Accelerated approval was granted based on overall response rate (ORR) in the first 264 patients randomized, showing a statistically significant improvement with pembrolizumab (74.4% vs. 51.9%, p= 0.00006). The final overall survival (OS) analysis demonstrated a clinically meaningful improvement, with a median OS of 20.0 months (95% CI 17.8, 22.1) and 16.8 months (95% CI 14.9, 18.7) in the pembrolizumab and placebo arms respectively (HR 0.80 [95% CI 0.67, 0.94]; p= 0.004). However, in exploratory subgroup analyses treatment benefit appeared to be driven by the PD-L1 CPS ≥1 population (85% of patients, with an OS HR of 0.79 [95% CI 0.66, 0.95]), whereas in the CPS <1 subgroup (15% of patients) treatment with pembrolizumab did not show improvement (HR 1.10, [95% CI 0.72-1.68]). These results are consistent with analysis of pembrolizumab and other immune checkpoint inhibitors across multiple clinical trials in patients with gastric cancer. KEYNOTE-811 utilized a \"one-trial\" approach allowing accelerated approval based on response rate with subsequent conversion to regular approval based on survival outcomes. KEYNOTE-811 also provided data for earlier access to therapies in a frontline metastatic setting, following FDA's Project Frontrunner approach.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"1 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147359318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-06DOI: 10.1158/1078-0432.ccr-25-4540
Helena A Yu,Kwan Ho Tang,Aleksandra A Markovets,Ryan Hartmaier,Paul E Smith,Byoung Chul Cho,Adrianus Johannes De Langen,Sarah B Goldberg,Jonathan W Goldman,Xiuning Le,Eiji Iwama,Jan Cosaert,Jonathan W Riess,Zofia Piotrowska
PURPOSEOsimertinib is standard-of-care for first-line treatment for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Understanding the tumor molecular profile of patients following progression on osimertinib could help inform optimal second-line treatment.PATIENTS AND METHODSORCHARD (NCT03944772), a phase II biomarker-directed study, enrolled patients with EGFR-mutated NSCLC who progressed on first-line osimertinib to receive treatment based on their tumor molecular profile post-progression. The study comprised three groups into which patients were allocated based on the molecular profile of their tumor, determined via next-generation sequencing (NGS) of a tumor biopsy. We report results from a pre-specified, exploratory analysis of baseline tumor tissue and plasma samples to evaluate mechanisms of resistance to first-line osimertinib identified by tissue and plasma NGS. Agreement between tissue and plasma NGS was also assessed.RESULTSThe study provided a comprehensive dataset exploring tissue (n = 400) and plasma (n = 191) genomics, enabling characterization of the histo-genomic landscape post-first-line osimertinib treatment. TP53 and MDM2/4 alterations were mutually exclusive and occurred in 85% of tumors. When combining tissue and plasma genomics, resistance alterations were detected in 87% of samples, with multiple resistance alterations in 46%. Alterations in the PI3K pathway, SOX2, and MYC were frequently detected in histologically transformed tumors. Additionally, differential patterns of co-occurring EGFR mutations in tumors with L858R versus exon 19 deletion were observed.CONCLUSIONSThis comprehensive analysis highlights potential heterogeneous resistance to first-line osimertinib treatment, providing a rationale for combining treatments with broad activity to improve patient outcomes.
{"title":"Genomic Profiling of Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer Post-Progression on First-Line Osimertinib: Phase II ORCHARD Study.","authors":"Helena A Yu,Kwan Ho Tang,Aleksandra A Markovets,Ryan Hartmaier,Paul E Smith,Byoung Chul Cho,Adrianus Johannes De Langen,Sarah B Goldberg,Jonathan W Goldman,Xiuning Le,Eiji Iwama,Jan Cosaert,Jonathan W Riess,Zofia Piotrowska","doi":"10.1158/1078-0432.ccr-25-4540","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-4540","url":null,"abstract":"PURPOSEOsimertinib is standard-of-care for first-line treatment for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Understanding the tumor molecular profile of patients following progression on osimertinib could help inform optimal second-line treatment.PATIENTS AND METHODSORCHARD (NCT03944772), a phase II biomarker-directed study, enrolled patients with EGFR-mutated NSCLC who progressed on first-line osimertinib to receive treatment based on their tumor molecular profile post-progression. The study comprised three groups into which patients were allocated based on the molecular profile of their tumor, determined via next-generation sequencing (NGS) of a tumor biopsy. We report results from a pre-specified, exploratory analysis of baseline tumor tissue and plasma samples to evaluate mechanisms of resistance to first-line osimertinib identified by tissue and plasma NGS. Agreement between tissue and plasma NGS was also assessed.RESULTSThe study provided a comprehensive dataset exploring tissue (n = 400) and plasma (n = 191) genomics, enabling characterization of the histo-genomic landscape post-first-line osimertinib treatment. TP53 and MDM2/4 alterations were mutually exclusive and occurred in 85% of tumors. When combining tissue and plasma genomics, resistance alterations were detected in 87% of samples, with multiple resistance alterations in 46%. Alterations in the PI3K pathway, SOX2, and MYC were frequently detected in histologically transformed tumors. Additionally, differential patterns of co-occurring EGFR mutations in tumors with L858R versus exon 19 deletion were observed.CONCLUSIONSThis comprehensive analysis highlights potential heterogeneous resistance to first-line osimertinib treatment, providing a rationale for combining treatments with broad activity to improve patient outcomes.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"1 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147359319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-05DOI: 10.1158/1078-0432.ccr-25-3749
Huaibin Ge,Housaiyin Li,Aditi Kulkarni,Zhangguo Chen,Pragati Upadhyay,Robert L Ferris,Jing H Wang
PURPOSEImmune checkpoint inhibitors (ICI) elicit variable responses in head and neck squamous cell carcinoma (HNSCC), yet mechanisms driving major pathological responses (MPR) remain poorly defined. We sought to evaluate longitudinal CD8 T-cell repertoire evolution to identify determinants of MPR.EXPERIMENTAL DESIGNWe analyzed high-resolution single-cell TCR sequencing data from paired pre- and post-treatment CD8 tumor-infiltrating lymphocytes (TILs) obtained from HNSCC patients treated with neoadjuvant anti-PD-1 combined with either anti-CTLA-4 or anti-LAG-3.RESULTSContrary to "clonal replacement" hypothesis, post-treatment CD8 T-cell pools were dominated by pre-existing TCR clones regardless of clinical outcome. MPR was uniquely characterized by higher abundance and greater expansion magnitude of "super-expanded" clones. We developed the TCR Adaptivity Index (TAI) to quantify coordinate flux (expansion and contraction) of all TCR clones detected across pre- and post-treatment timepoints; this index emerged as the most significant parameter associated with MPR. Importantly, clonal expansion in non-MPR was "uncoupled" from the productive, therapy-induced transcriptional reprogramming-characterized by markers of effector vigor and cellular fitness-that was observed in MPR. Furthermore, expansion dynamics positively correlated with predicted tumor reactivity as calculated by the Tumor Reactive Signature (TRS) score. Finally, a TRS-integrated TAI remained significantly correlated with MPR.CONCLUSIONSDual ICI drives MPR predominantly through the adaptivity and functional reprogramming of pre-existing immunity. Successful therapy relies on a coordinate repertoire response that promotes transition of putative tumor-reactive super-expanders into productive functional states. TRS-integrated TAI provides a high-throughput framework incorporating clonal dynamics and functional reprogramming to predict therapeutic efficacy.
{"title":"Pre-existing TCR clones drive major pathological responses in HNSCC patients treated with dual immune checkpoint inhibitors.","authors":"Huaibin Ge,Housaiyin Li,Aditi Kulkarni,Zhangguo Chen,Pragati Upadhyay,Robert L Ferris,Jing H Wang","doi":"10.1158/1078-0432.ccr-25-3749","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-3749","url":null,"abstract":"PURPOSEImmune checkpoint inhibitors (ICI) elicit variable responses in head and neck squamous cell carcinoma (HNSCC), yet mechanisms driving major pathological responses (MPR) remain poorly defined. We sought to evaluate longitudinal CD8 T-cell repertoire evolution to identify determinants of MPR.EXPERIMENTAL DESIGNWe analyzed high-resolution single-cell TCR sequencing data from paired pre- and post-treatment CD8 tumor-infiltrating lymphocytes (TILs) obtained from HNSCC patients treated with neoadjuvant anti-PD-1 combined with either anti-CTLA-4 or anti-LAG-3.RESULTSContrary to \"clonal replacement\" hypothesis, post-treatment CD8 T-cell pools were dominated by pre-existing TCR clones regardless of clinical outcome. MPR was uniquely characterized by higher abundance and greater expansion magnitude of \"super-expanded\" clones. We developed the TCR Adaptivity Index (TAI) to quantify coordinate flux (expansion and contraction) of all TCR clones detected across pre- and post-treatment timepoints; this index emerged as the most significant parameter associated with MPR. Importantly, clonal expansion in non-MPR was \"uncoupled\" from the productive, therapy-induced transcriptional reprogramming-characterized by markers of effector vigor and cellular fitness-that was observed in MPR. Furthermore, expansion dynamics positively correlated with predicted tumor reactivity as calculated by the Tumor Reactive Signature (TRS) score. Finally, a TRS-integrated TAI remained significantly correlated with MPR.CONCLUSIONSDual ICI drives MPR predominantly through the adaptivity and functional reprogramming of pre-existing immunity. Successful therapy relies on a coordinate repertoire response that promotes transition of putative tumor-reactive super-expanders into productive functional states. TRS-integrated TAI provides a high-throughput framework incorporating clonal dynamics and functional reprogramming to predict therapeutic efficacy.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"32 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PURPOSEDespite the clinical adoption of immunotherapy in small cell lung cancer (SCLC), reliable biomarkers predicting clinical benefit are limited. Although HERV-K (HML-2) subfamily has been reported to modulate tumor immune response in multiple malignancies, its functional role in SCLC remains poorly defined, particularly the association with an inflamed microenvironment and favorable immunotherapy outcomes.EXPERIMENTAL DESIGNThe expression profile of locus-specific HERV-K was identified by TELESCOPE in the IMpower133 (n =271) and PKUPH cohort (n = 40). Immunohistochemistry and RNA-fluorescence in situ hybridization were performed on a tissue microarray (n = 48) to validate the expression of HERV-K transcripts. Single-cell RNA sequencing and multiplex immunohistochemistry, including PhenoCycler-Fusion, were used to characterize tumor immune microenvironment.RESULTSAlthough the HERV-K subfamily as a whole lacked prognostic value for immunotherapy in SCLC, a locus-specific HERV-K transcript, ERVK18, was associated with improved outcomes and exhibited the strongest positive correlation with immune-related signatures, representing multiple immune-activated pathways and increased immune cell infiltration. Single-cell and spatial analysis further revealed that high ERVK18 expression indicated elevated cytotoxicity signatures in T cells, along with enhanced spatial proximity between tumor and T cells. In the IMpower133 cohort, high ERVK18 expression was not only associated with better prognosis within atezolizumab+chemotherapy group, but also predicted improved overall survival in patients treated with atezolizumab+chemotherapy versus chemotherapy alone, confirming ERVK18 as a dual prognostic and predictive biomarker for first-line PD-L1 inhibitor response in SCLC.CONCLUSIONSElevated expression of ERVK18 represents inflamed microenvironment and indicates favorable immunochemotherapy prognosis of patients in SCLC.
{"title":"Locus-specific human endogenous retrovirus ERVK18 expression indicates an inflamed microenvironment and favorable immunotherapy outcome in small cell lung cancer.","authors":"Xingyuan Wu,Kunkun Sun,Jingwei Zhang,Songyan Hou,Zihang Yuan,Yan Ju,Jiaming Deng,Jiaming Zhao,Yueqi Jin,Jianqi She,Minghao Du,Mantang Qiu,Fan Yang,Hao Li,Xiao Li,Ence Yang","doi":"10.1158/1078-0432.ccr-25-3302","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-3302","url":null,"abstract":"PURPOSEDespite the clinical adoption of immunotherapy in small cell lung cancer (SCLC), reliable biomarkers predicting clinical benefit are limited. Although HERV-K (HML-2) subfamily has been reported to modulate tumor immune response in multiple malignancies, its functional role in SCLC remains poorly defined, particularly the association with an inflamed microenvironment and favorable immunotherapy outcomes.EXPERIMENTAL DESIGNThe expression profile of locus-specific HERV-K was identified by TELESCOPE in the IMpower133 (n =271) and PKUPH cohort (n = 40). Immunohistochemistry and RNA-fluorescence in situ hybridization were performed on a tissue microarray (n = 48) to validate the expression of HERV-K transcripts. Single-cell RNA sequencing and multiplex immunohistochemistry, including PhenoCycler-Fusion, were used to characterize tumor immune microenvironment.RESULTSAlthough the HERV-K subfamily as a whole lacked prognostic value for immunotherapy in SCLC, a locus-specific HERV-K transcript, ERVK18, was associated with improved outcomes and exhibited the strongest positive correlation with immune-related signatures, representing multiple immune-activated pathways and increased immune cell infiltration. Single-cell and spatial analysis further revealed that high ERVK18 expression indicated elevated cytotoxicity signatures in T cells, along with enhanced spatial proximity between tumor and T cells. In the IMpower133 cohort, high ERVK18 expression was not only associated with better prognosis within atezolizumab+chemotherapy group, but also predicted improved overall survival in patients treated with atezolizumab+chemotherapy versus chemotherapy alone, confirming ERVK18 as a dual prognostic and predictive biomarker for first-line PD-L1 inhibitor response in SCLC.CONCLUSIONSElevated expression of ERVK18 represents inflamed microenvironment and indicates favorable immunochemotherapy prognosis of patients in SCLC.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"130 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Purpose: Treatment of Locally Advanced Cervical Cancer (LACC) is guided notably by the European Society of Gynaecological Oncology (ESGO) guidelines; unfortunately, relapse remains frequent despite standard chemoradiotherapy and brachytherapy. We evaluated whether histological assessment of non-metastatic para-aortic lymph node (PAoLN) provides prognostic value in LACC. Experimental design: Primary tumor and PAoLNs from 137 non-metastatic LACC patients were stratified by pre-therapeutic 18F-FDG PET/CT into pelvic PET-positive (pPET+, N= 72) and negative (pPET-, N= 65) groups. Immunohistochemistry on whole sections assessed germinal centers, CD4+, CD8+, FOXP3+ cells, neutrophils (CD66b+, neutrophil extracellular traps: NETs) and high-endothelial venules (HEVs). Associations with progression-free survival (PFS) were examined via univariate and multivariate analyses after a median follow-up of 55.4 months. Results: Primary tumor profile was not associated with outcome, whereas PAoLN features were strongly predictive. In pPET- patients, higher NETs were associated with shorter PFS (p=0.015; HR=2.768), while elevated CD4/CD8 ratio improved outcomes (p=0.047, HR=0.497). In pPET+ patients, shorter PFS was linked to FOXP3+ (p=0.04, HR=1.918) and proliferating FOXP3+ cells (p=0.018, HR=1.668) density. Across the full cohort, abundant germinal centers (p=0.0355, HR=0.273) and elevated CD4/CD8 ratio (p=0.001, HR=0.490) independently correlated with lower recurrence risk. Internal validation was conducted through a bootstrap resampling method. Combinatorial analyses revealed distinct predictive signatures according to pPET status: higher NETs, fewer germinal centers and FIGO-IIA1-IIIB status predicted relapse in pPET- patients. Conclusions: Integrating pPET status with PAoLN histological analyses improves recurrence risk stratification in LACC. PAoLN evaluation may serve as a complementary tool to guide treatment intensification and surveillance strategies.
{"title":"Non-metastatic para-aortic lymph node remodeling as a predictor of outcome in locally advanced cervical cancer","authors":"Louis Baudin, Léa Zanella, Alizée Lebeau, Clémence Pleyers, Noémie Gubbels, Silvia Blacher, Laurence Seidel, Athanasios Kakkos, Frédéric Goffin, Pierre Lovinfosse, Christine Gennigens, Sébastien Pirson, Frédéric Kridelka, Agnès Noël","doi":"10.1158/1078-0432.ccr-25-3894","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-3894","url":null,"abstract":"Purpose: Treatment of Locally Advanced Cervical Cancer (LACC) is guided notably by the European Society of Gynaecological Oncology (ESGO) guidelines; unfortunately, relapse remains frequent despite standard chemoradiotherapy and brachytherapy. We evaluated whether histological assessment of non-metastatic para-aortic lymph node (PAoLN) provides prognostic value in LACC. Experimental design: Primary tumor and PAoLNs from 137 non-metastatic LACC patients were stratified by pre-therapeutic 18F-FDG PET/CT into pelvic PET-positive (pPET+, N= 72) and negative (pPET-, N= 65) groups. Immunohistochemistry on whole sections assessed germinal centers, CD4+, CD8+, FOXP3+ cells, neutrophils (CD66b+, neutrophil extracellular traps: NETs) and high-endothelial venules (HEVs). Associations with progression-free survival (PFS) were examined via univariate and multivariate analyses after a median follow-up of 55.4 months. Results: Primary tumor profile was not associated with outcome, whereas PAoLN features were strongly predictive. In pPET- patients, higher NETs were associated with shorter PFS (p=0.015; HR=2.768), while elevated CD4/CD8 ratio improved outcomes (p=0.047, HR=0.497). In pPET+ patients, shorter PFS was linked to FOXP3+ (p=0.04, HR=1.918) and proliferating FOXP3+ cells (p=0.018, HR=1.668) density. Across the full cohort, abundant germinal centers (p=0.0355, HR=0.273) and elevated CD4/CD8 ratio (p=0.001, HR=0.490) independently correlated with lower recurrence risk. Internal validation was conducted through a bootstrap resampling method. Combinatorial analyses revealed distinct predictive signatures according to pPET status: higher NETs, fewer germinal centers and FIGO-IIA1-IIIB status predicted relapse in pPET- patients. Conclusions: Integrating pPET status with PAoLN histological analyses improves recurrence risk stratification in LACC. PAoLN evaluation may serve as a complementary tool to guide treatment intensification and surveillance strategies.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"1 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-04DOI: 10.1158/1078-0432.ccr-25-3535
David A. Gewirtz, Beverly Teicher, Edward Greenberg
It is well established that the majority of anti-cancer agents identified and developed through preclinical studies in cell culture and animal models do not prove to be sufficiently effective in the clinic to move into later stage clinical trials. The simple explanations are that tumor cells in culture or implanted in mice cannot predict what will occur in patients, due in large part to the lack of pharmacokinetics in cell culture and because a mouse is not a miniature human being. Factors such as drug absorption, distribution, metabolism, and excretion (ADME) are likely to be markedly different in mice and humans, and cross-species ADME good laboratory practice (GLP) toxicology findings are often not fully incorporated into later investigational rodent studies. Furthermore, the frequent use of immune-deficient mice to host human tumors eliminates the critical involvement of the immune system. A colleague once remarked that we can cure virtually all cancers in mice. While this is certainly hyperbole, it is true that drug efficacy often appears significantly greater in rodent experiments than in humans. This article attempts to highlight and place in perspective many of the issues that limit the utility of preclinical models in common use for the development of antitumor drugs. We further identify factors that could and should be modified to improve their ultimate translation to the clinic, particularly given current efforts to replace the use of animal models with human cell-based and computer-based assays for drug development.
{"title":"Why preclinical models for cancer drug development fail","authors":"David A. Gewirtz, Beverly Teicher, Edward Greenberg","doi":"10.1158/1078-0432.ccr-25-3535","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-3535","url":null,"abstract":"It is well established that the majority of anti-cancer agents identified and developed through preclinical studies in cell culture and animal models do not prove to be sufficiently effective in the clinic to move into later stage clinical trials. The simple explanations are that tumor cells in culture or implanted in mice cannot predict what will occur in patients, due in large part to the lack of pharmacokinetics in cell culture and because a mouse is not a miniature human being. Factors such as drug absorption, distribution, metabolism, and excretion (ADME) are likely to be markedly different in mice and humans, and cross-species ADME good laboratory practice (GLP) toxicology findings are often not fully incorporated into later investigational rodent studies. Furthermore, the frequent use of immune-deficient mice to host human tumors eliminates the critical involvement of the immune system. A colleague once remarked that we can cure virtually all cancers in mice. While this is certainly hyperbole, it is true that drug efficacy often appears significantly greater in rodent experiments than in humans. This article attempts to highlight and place in perspective many of the issues that limit the utility of preclinical models in common use for the development of antitumor drugs. We further identify factors that could and should be modified to improve their ultimate translation to the clinic, particularly given current efforts to replace the use of animal models with human cell-based and computer-based assays for drug development.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"42 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-04DOI: 10.1158/1078-0432.ccr-25-3052
Susan Slovin, Xin Gao, Xiao X. Wei, David Y. Oh, Rana R. McKay, Gerald Falchook, Arif Hussain, Meredith McKean, Andreas Wibmer, Alan Ho, Jeff D. Eskew, Rajesh Belani, Julia Coronella, Sabrina Haag, Christopher E. Martin, Joanne McCaigue, June Mendoza, Ann Murphy, Hamid Namini, Matthew A. Spear, Devon J. Shedlock, Tanya B. Dorff
Purpose: Chimeric antigen receptor (CAR)-T cell therapies have potential in solid tumors. A higher proportion of stem cell-like memory T cells (TSCM) in CAR-T products could enhance engraftment, persistence, and prolong immune activity. This phase 1 trial (NCT04249947) evaluated the safety and efficacy of P-PSMA-101, an autologous TSCM-rich bone tropic CAR-T therapy targeting prostate-specific membrane antigen (PSMA), in metastatic castrate-resistant prostate carcinoma (mCRPC) patients. Secondary endpoints included objective response rate, PSA response, radiographic progression-free survival (PFS). Patients and Methods: P-PSMA-101 was produced from leukapheresis using the piggyBac® DNA transposon-based platform, which integrates a multi-cistronic transgene encoding an iCasp9 safety switch in addition to the CAR, generating TSCM-rich CAR-T cells. Results: Among 33 treated patients, 18% (n=6) had dose-limiting toxicities (DLTs). Cytokine release syndrome (CRS) occurred in 61% (n=20), with Grade ≥ 3 CRS in 9% (n=3). Activation of the iCasp9-based safety switch was required in 24% (n=8) of cases including one fatal toxicity, and successful resolution in the other seven. P-PSMA-101 yielded ≥50% PSA decline in 21% (n=7) of patients. Among 13 RECIST evaluable patients, one partial response was observed. Stable disease occurred in 61% (n=20), with 21% (n=7) maintaining stability for ≥3 months. Two patients' remissions exceeded 12 months characterized by PSA declines > 90%, corroborated by pharmacokinetic, biomarker, and PSMA-PET imaging data. Conclusions: Robust expansion of P-PSMA-101 CAR T cells resulted in toxicity but also durable responses in patients with mCRPC. Future trials of CAR T may be informed by the results with this nonviral engineering, TSCM cell-enriched approach.
目的：嵌合抗原受体(CAR)-T细胞治疗实体瘤有潜力。CAR-T产品中较高比例的干细胞样记忆T细胞（stem cell-like memory T cells， TSCM）可以增强植入性、持久性和延长免疫活性。这项i期试验（NCT04249947）评估了P-PSMA-101治疗转移性去势抵抗性前列腺癌（mCRPC）患者的安全性和有效性。P-PSMA-101是一种针对前列腺特异性膜抗原（PSMA）的自体富含tscm的骨致性CAR-T疗法。次要终点包括客观缓解率、PSA反应、放射学无进展生存期（PFS）。患者和方法：P-PSMA-101是利用基于piggyBac®DNA转座子的平台从白细胞分离中产生的，该平台除了CAR外，还集成了编码iCasp9安全开关的多顺反子转基因，产生富含tscm的CAR- t细胞。结果：在33名接受治疗的患者中，18% （n=6）出现剂量限制性毒性（dlt）。细胞因子释放综合征（CRS）发生率为61% (n=20)， CRS≥3级发生率为9% （n=3）。24% （n=8）的病例需要激活基于icasp9的安全开关，其中包括1例致命毒性，其他7例成功解决。P-PSMA-101使21% （n=7）患者的PSA下降≥50%。在13例可评估的RECIST患者中，观察到1例部分缓解。61% （n=20）患者病情稳定，21% （n=7）患者病情稳定≥3个月。2例患者缓解超过12个月，以PSA下降为特征；90%，经药代动力学、生物标志物和PSMA-PET成像数据证实。结论：P-PSMA-101 CAR - T细胞的强大扩增在mCRPC患者中产生毒性，但也产生持久的反应。这种非病毒工程、TSCM细胞富集方法的结果可能会为CAR - T的未来试验提供信息。
{"title":"Phase 1 Trial of P-PSMA-101 CAR-T Cells in Patients with Metastatic Castration Resistant Prostate Cancer (mCRPC)","authors":"Susan Slovin, Xin Gao, Xiao X. Wei, David Y. Oh, Rana R. McKay, Gerald Falchook, Arif Hussain, Meredith McKean, Andreas Wibmer, Alan Ho, Jeff D. Eskew, Rajesh Belani, Julia Coronella, Sabrina Haag, Christopher E. Martin, Joanne McCaigue, June Mendoza, Ann Murphy, Hamid Namini, Matthew A. Spear, Devon J. Shedlock, Tanya B. Dorff","doi":"10.1158/1078-0432.ccr-25-3052","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-3052","url":null,"abstract":"Purpose: Chimeric antigen receptor (CAR)-T cell therapies have potential in solid tumors. A higher proportion of stem cell-like memory T cells (TSCM) in CAR-T products could enhance engraftment, persistence, and prolong immune activity. This phase 1 trial (NCT04249947) evaluated the safety and efficacy of P-PSMA-101, an autologous TSCM-rich bone tropic CAR-T therapy targeting prostate-specific membrane antigen (PSMA), in metastatic castrate-resistant prostate carcinoma (mCRPC) patients. Secondary endpoints included objective response rate, PSA response, radiographic progression-free survival (PFS). Patients and Methods: P-PSMA-101 was produced from leukapheresis using the piggyBac® DNA transposon-based platform, which integrates a multi-cistronic transgene encoding an iCasp9 safety switch in addition to the CAR, generating TSCM-rich CAR-T cells. Results: Among 33 treated patients, 18% (n=6) had dose-limiting toxicities (DLTs). Cytokine release syndrome (CRS) occurred in 61% (n=20), with Grade ≥ 3 CRS in 9% (n=3). Activation of the iCasp9-based safety switch was required in 24% (n=8) of cases including one fatal toxicity, and successful resolution in the other seven. P-PSMA-101 yielded ≥50% PSA decline in 21% (n=7) of patients. Among 13 RECIST evaluable patients, one partial response was observed. Stable disease occurred in 61% (n=20), with 21% (n=7) maintaining stability for ≥3 months. Two patients' remissions exceeded 12 months characterized by PSA declines &gt; 90%, corroborated by pharmacokinetic, biomarker, and PSMA-PET imaging data. Conclusions: Robust expansion of P-PSMA-101 CAR T cells resulted in toxicity but also durable responses in patients with mCRPC. Future trials of CAR T may be informed by the results with this nonviral engineering, TSCM cell-enriched approach.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"53 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-04DOI: 10.1158/1078-0432.ccr-25-4600
Chang Liu, Jiarui Li, Dan Liu, Panpan Zhang, Miao Zhang, Ran Xue, Jifang Gong, Lian Liu, Min Tao, Siyuan Cheng, Ting Xu, Jiajia Yuan, Yanshuo Cao, Zhenghang Wang, Yakun Wang, Jun Zhou, Ming Lu, Zhi Peng, Zhihao Lu, Jian Li, Xiaotian Zhang, Tian Wang, Min Wang, Licui Jiang, Huimin Meng, Lin Yang, Changsong Qi, Lin Shen
Purpose: To evaluate the safety, pharmacokinetics, and preliminary clinical activity of UTAA06, an "off-the-shelf" allogeneic B7-H3-targeted chimeric antigen receptor (CAR)-Vδ1T cell therapy, in patients with pretreated, advanced B7-H3-positive solid tumors. Patients and Methods: In this first-in-human, phase I, dose-escalation study (NCT06372236), ten patients with advanced solid tumors (including gastric, colorectal, hepatocellular, ovarian, and neuroendocrine cancers) were enrolled. Following lymphodepletion chemotherapy (cyclophosphamide and fludarabine), patients received UTAA06 infusion across three dose levels (5×10⁸, 8×10⁸, or 1×10⁹ cells). The primary endpoint was safety. Secondary endpoints included pharmacokinetics and anti-tumor efficacy. Results: UTAA06 demonstrated a manageable safety profile; no graft-versus-host disease (GvHD) was observed, and cytokine release syndrome (CRS) was limited to two transient Grade 1 events. A single dose-limiting toxicity (Grade 3 pneumonitis) was reported in one patient at the 5×10⁸ cells dose level. While UTAA06 demonstrated signals of biological activity, including transient reductions in serum tumor markers in 50% of patients, no objective response by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria was observed. Further analysis identified that the limited CAR-T cell persistence was likely driven by subclinical host-versus-graft rejection (HvGR). Conclusions: This study provides clinical proof-of-concept for allogeneic B7-H3-targeted CAR-Vδ1T cells as a safe platform with low risk of GvHD and demonstrable biological activity in solid tumors. However, clinical efficacy was constrained by limited cellular persistence caused by host immune rejection. Future strategies are required to enhance the durability and therapeutic potential of this allogeneic approach.
{"title":"Allogeneic B7-H3-targeted CAR-Vδ1T cell therapy in advanced solid tumors: A phase I study","authors":"Chang Liu, Jiarui Li, Dan Liu, Panpan Zhang, Miao Zhang, Ran Xue, Jifang Gong, Lian Liu, Min Tao, Siyuan Cheng, Ting Xu, Jiajia Yuan, Yanshuo Cao, Zhenghang Wang, Yakun Wang, Jun Zhou, Ming Lu, Zhi Peng, Zhihao Lu, Jian Li, Xiaotian Zhang, Tian Wang, Min Wang, Licui Jiang, Huimin Meng, Lin Yang, Changsong Qi, Lin Shen","doi":"10.1158/1078-0432.ccr-25-4600","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-4600","url":null,"abstract":"Purpose: To evaluate the safety, pharmacokinetics, and preliminary clinical activity of UTAA06, an \"off-the-shelf\" allogeneic B7-H3-targeted chimeric antigen receptor (CAR)-Vδ1T cell therapy, in patients with pretreated, advanced B7-H3-positive solid tumors. Patients and Methods: In this first-in-human, phase I, dose-escalation study (NCT06372236), ten patients with advanced solid tumors (including gastric, colorectal, hepatocellular, ovarian, and neuroendocrine cancers) were enrolled. Following lymphodepletion chemotherapy (cyclophosphamide and fludarabine), patients received UTAA06 infusion across three dose levels (5×10⁸, 8×10⁸, or 1×10⁹ cells). The primary endpoint was safety. Secondary endpoints included pharmacokinetics and anti-tumor efficacy. Results: UTAA06 demonstrated a manageable safety profile; no graft-versus-host disease (GvHD) was observed, and cytokine release syndrome (CRS) was limited to two transient Grade 1 events. A single dose-limiting toxicity (Grade 3 pneumonitis) was reported in one patient at the 5×10⁸ cells dose level. While UTAA06 demonstrated signals of biological activity, including transient reductions in serum tumor markers in 50% of patients, no objective response by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria was observed. Further analysis identified that the limited CAR-T cell persistence was likely driven by subclinical host-versus-graft rejection (HvGR). Conclusions: This study provides clinical proof-of-concept for allogeneic B7-H3-targeted CAR-Vδ1T cells as a safe platform with low risk of GvHD and demonstrable biological activity in solid tumors. However, clinical efficacy was constrained by limited cellular persistence caused by host immune rejection. Future strategies are required to enhance the durability and therapeutic potential of this allogeneic approach.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"42 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-04DOI: 10.1158/1078-0432.ccr-25-3953
Zhi Lin, Cheng Tang, Tong Liu, Xingyi Wang, Zaijie Wu, Fan Hu, Yongkang Gai, Weiwei Ruan, Xiao Zhang, Xiaoli Lan
Purpose: The study aims to compare the diagnostic performance of the novel melanin-targeted [18F]PFPN PET and [18F]FDG PET in mucosal melanoma, evaluate their impact on clinical staging, and assess correlations between imaging metrics and molecular markers. Experimental Design: This prospective study enrolled 65 participants with histologically confirmed mucosal melanoma from February 2021 to January 2025. All participants underwent both [18F]FDG PET and [18F]PFPN PET within one week. Lesion-based and participant-based analyses compared detection sensitivity, false-positive rate, and staging concordance. Quantitative PET parameters were analyzed, and correlations with HMB45, SOX10, MelanA, S100, and mutation status (BRAF, CKIT, NRAS) were evaluated using nonparametric tests, correlation analysis with Bonferroni correction. Decision curve analysis was used to evaluate clinical benefit. Results: Sixty-five participants were included. [18F]PFPN PET showed higher lesion-based sensitivity than [18F]FDG PET (363/399 [91.0%] vs 332/399 [83.2%]) and no false positives (0/363 [0%] vs 4/336 [1.2%]). Normalized SUVmax was significantly higher for [18F]PFPN across all lesion types (P < 0.05). PFPN-based staging was more consistent with clinical staging (6.2% vs 18.5% discordant cases). [18F]PFPN uptake showed significant positive correlations with HMB45 and SOX10 expression, while [18F]FDG parameters showed no such associations. Conclusion: [18F]PFPN PET outperforms [18F]FDG PET in lesion detection and clinical staging in mucosal melanoma, especially for liver and bone metastases. Its association with melanin differentiation markers may support its use in personalized imaging strategies.
目的：本研究旨在比较新型黑色素靶向[18F]PFPN PET和[18F]FDG PET在粘膜黑色素瘤中的诊断性能，评估其对临床分期的影响，并评估影像学指标与分子标志物之间的相关性。实验设计：本前瞻性研究于2021年2月至2025年1月招募了65名组织学证实的粘膜黑色素瘤患者。所有参与者在一周内都接受了[18F]FDG PET和[18F]PFPN PET检查。基于病变和基于参与者的分析比较了检测灵敏度、假阳性率和分期一致性。定量分析PET参数，并使用非参数检验、Bonferroni校正相关分析评估与HMB45、SOX10、MelanA、S100和突变状态（BRAF、CKIT、NRAS）的相关性。采用决策曲线分析法评价临床获益。结果：共纳入65名受试者。[18F]PFPN PET的病变敏感性高于[18F]FDG PET (363/399 [91.0%] vs 332/399[83.2%])，无假阳性（0/363 [0%]vs 4/336[1.2%]）。归一化SUVmax在所有病变类型中均显著高于[18F]PFPN （P < 0.05）。基于pfpn的分期与临床分期更为一致（6.2% vs 18.5%不一致的病例）。[18F]PFPN摄取与HMB45和SOX10表达呈显著正相关，而[18F]FDG参数未显示出这种相关性。结论：[18F]PFPN PET在粘膜黑色素瘤的病变检测和临床分期方面优于[18F]FDG PET，尤其是在肝脏和骨转移方面。它与黑色素分化标志物的关联可能支持其在个性化成像策略中的应用。
{"title":"Comparison of [18F]PFPN and [18F]FDG PET in mucosal melanoma: diagnostic performance, staging impact, and correlation with molecular markers","authors":"Zhi Lin, Cheng Tang, Tong Liu, Xingyi Wang, Zaijie Wu, Fan Hu, Yongkang Gai, Weiwei Ruan, Xiao Zhang, Xiaoli Lan","doi":"10.1158/1078-0432.ccr-25-3953","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-3953","url":null,"abstract":"Purpose: The study aims to compare the diagnostic performance of the novel melanin-targeted [18F]PFPN PET and [18F]FDG PET in mucosal melanoma, evaluate their impact on clinical staging, and assess correlations between imaging metrics and molecular markers. Experimental Design: This prospective study enrolled 65 participants with histologically confirmed mucosal melanoma from February 2021 to January 2025. All participants underwent both [18F]FDG PET and [18F]PFPN PET within one week. Lesion-based and participant-based analyses compared detection sensitivity, false-positive rate, and staging concordance. Quantitative PET parameters were analyzed, and correlations with HMB45, SOX10, MelanA, S100, and mutation status (BRAF, CKIT, NRAS) were evaluated using nonparametric tests, correlation analysis with Bonferroni correction. Decision curve analysis was used to evaluate clinical benefit. Results: Sixty-five participants were included. [18F]PFPN PET showed higher lesion-based sensitivity than [18F]FDG PET (363/399 [91.0%] vs 332/399 [83.2%]) and no false positives (0/363 [0%] vs 4/336 [1.2%]). Normalized SUVmax was significantly higher for [18F]PFPN across all lesion types (P &lt; 0.05). PFPN-based staging was more consistent with clinical staging (6.2% vs 18.5% discordant cases). [18F]PFPN uptake showed significant positive correlations with HMB45 and SOX10 expression, while [18F]FDG parameters showed no such associations. Conclusion: [18F]PFPN PET outperforms [18F]FDG PET in lesion detection and clinical staging in mucosal melanoma, especially for liver and bone metastases. Its association with melanin differentiation markers may support its use in personalized imaging strategies.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"227 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-04DOI: 10.1158/1078-0432.ccr-25-3846
Ehsan Irajizad, Johannes F. Fahrmann, Ranran Wu, Hamid Rudsari, Jennifer B. Dennison, Edwin Ostrin, Jaffer Ajani, Samir Hanash
Purpose: Recent evidence suggests a significant association between microplastic (MPs), forever chemicals, and plasticizers and various diseases including cancer. Here, we evaluated the circulating levels of plastic-associated chemicals for lung cancer incidence and mortality among smokers in the Prostate Lung Colorectal and Ovarian (PLCO) study. Experimental Design: Using mass spectrometry, we screened for 29 known MPs, forever plastics (per- and polyfluoroalkyl substances [PFAS]), and plasticizers chemicals in 245 sera collected preceding a lung cancer diagnosis and 1,200 non-case sera from participants in the PLCO study who had a history of smoking. Five PFAS and 3 plasticizers were detected and quantified in sera. A PFAP model, consisting of PFOS + PFHA + mono-iso-nonyl-phthalate, was developed for predicting lung cancer mortality and risk strata based on quantiles established. Results: Higher circulating levels of PFOS, PFHA, and mono-iso-nonyl-phthalate were associated (p<0.05) with increased risk of lung cancer death but not incidence. Compared to the lowest quantile (reference), individuals with PFAP scores in the highest quantile were at markedly higher risk of death from lung cancer (p<0.0001), with respective cause-specific and sub-distributional HRs of 1.86 (95% CI: 1.18-2.93) and 1.82 (95% CI: 1.15 - 2.88). Sub-stratified analyses confirmed that the PFAP model remained an independent predictor of lung cancer–specific mortality (p < 0.05) across strata defined by age, sex, smoking history, histologic subtype, and stage at diagnosis. Conclusions: In the PLCO cohort elevated levels of PFOS, PFHA, and mono-iso-nonyl-phthalate were associated with increased lung cancer mortality among ever smokers across disease subgroups.
{"title":"Association of blood levels of forever plastics with lung cancer mortality among ever smokers in the Prostate Lung Colorectal and Ovarian (PLCO) cohort study.","authors":"Ehsan Irajizad, Johannes F. Fahrmann, Ranran Wu, Hamid Rudsari, Jennifer B. Dennison, Edwin Ostrin, Jaffer Ajani, Samir Hanash","doi":"10.1158/1078-0432.ccr-25-3846","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-3846","url":null,"abstract":"Purpose: Recent evidence suggests a significant association between microplastic (MPs), forever chemicals, and plasticizers and various diseases including cancer. Here, we evaluated the circulating levels of plastic-associated chemicals for lung cancer incidence and mortality among smokers in the Prostate Lung Colorectal and Ovarian (PLCO) study. Experimental Design: Using mass spectrometry, we screened for 29 known MPs, forever plastics (per- and polyfluoroalkyl substances [PFAS]), and plasticizers chemicals in 245 sera collected preceding a lung cancer diagnosis and 1,200 non-case sera from participants in the PLCO study who had a history of smoking. Five PFAS and 3 plasticizers were detected and quantified in sera. A PFAP model, consisting of PFOS + PFHA + mono-iso-nonyl-phthalate, was developed for predicting lung cancer mortality and risk strata based on quantiles established. Results: Higher circulating levels of PFOS, PFHA, and mono-iso-nonyl-phthalate were associated (p&lt;0.05) with increased risk of lung cancer death but not incidence. Compared to the lowest quantile (reference), individuals with PFAP scores in the highest quantile were at markedly higher risk of death from lung cancer (p&lt;0.0001), with respective cause-specific and sub-distributional HRs of 1.86 (95% CI: 1.18-2.93) and 1.82 (95% CI: 1.15 - 2.88). Sub-stratified analyses confirmed that the PFAP model remained an independent predictor of lung cancer–specific mortality (p &lt; 0.05) across strata defined by age, sex, smoking history, histologic subtype, and stage at diagnosis. Conclusions: In the PLCO cohort elevated levels of PFOS, PFHA, and mono-iso-nonyl-phthalate were associated with increased lung cancer mortality among ever smokers across disease subgroups.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"32 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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