Pub Date : 2025-12-10DOI: 10.1158/1557-3265.earlyonsetca25-c036
Jordan A. Steward
There has been a multitude of research across the extensively and intricately studied fields of psychoimmunology and cancer neuroscience. Research from both ends suggest a multifaceted interplay between the nervous and immune system, and how they influence the progression of tumors and of course the response to therapy. The purpose of this theoretical research paper will explore the bidirectional communication between neurological pathways; The sympathetic nervous system, HPA axis, and neurotransmitter signaling, while also exploring the dynamic of immune regulation within the tumor micro-environment (TME). Focusing on recent evidence which suggests that neural inputs have the potential to shape immune cell phenotypes and cytokine activity, while fully acknowledging the overall impact of external factors such as chronic stress, and circadian disruption on tumor dynamics led to the proposal of a consolidated model which neutral stress responses modulate tumor progression and immune surveillance. The overall framework focuses highly on therapeutic implications, specifically targeting neutral-immune communication to augment immunotherapies, incorporating behavioral interventions to control tumor growth induced by severe stress, and the utilization of neuromodulators to control tumor immunity. The overall conclusion will outline future interests by focusing on the need for transitional studies, the ethicality of neuroimmune targeting and said ethical considerations which could come into fruition, and the assurance of neuroimmunological integration in personalized cancer care. Citation Format: Jordan A. Stewar. The Neurological and Immunological Interplay in Cancer Progression and Treatment Response [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(23_Suppl): nr C036.
在广泛而复杂的心理免疫学和癌症神经科学研究领域已经有了大量的研究。两方面的研究都表明，神经和免疫系统之间存在多方面的相互作用，以及它们如何影响肿瘤的进展，当然还有对治疗的反应。本理论研究论文的目的是探讨神经通路之间的双向交流；交感神经系统，HPA轴和神经递质信号，同时也探索肿瘤微环境（TME）内免疫调节的动态。最近的证据表明，神经输入具有塑造免疫细胞表型和细胞因子活性的潜力，同时充分认识到慢性应激和昼夜节律中断等外部因素对肿瘤动力学的总体影响，从而提出了中性应激反应调节肿瘤进展和免疫监测的综合模型。总体框架高度关注治疗意义，特别是针对中性免疫通讯来增强免疫治疗，结合行为干预来控制严重应激诱导的肿瘤生长，以及利用神经调节剂来控制肿瘤免疫。总体结论将概述未来的兴趣，重点是过渡性研究的需要，神经免疫靶向的伦理性，以及可能实现的伦理考虑，以及个性化癌症治疗中神经免疫整合的保证。引用格式：Jordan A. Stewar。肿瘤进展和治疗反应中的神经和免疫相互作用[摘要]。摘自：美国癌症研究协会癌症研究特别会议论文集：早发性癌症的增加——知识差距和研究机会；2025年12月10-13日；加拿大蒙特利尔，QC。费城（PA）： AACR；临床癌症研究2025；31(23_supl): no C036。
{"title":"Abstract C036: The Neurological and Immunological Interplay in Cancer Progression and Treatment Response","authors":"Jordan A. Steward","doi":"10.1158/1557-3265.earlyonsetca25-c036","DOIUrl":"https://doi.org/10.1158/1557-3265.earlyonsetca25-c036","url":null,"abstract":"There has been a multitude of research across the extensively and intricately studied fields of psychoimmunology and cancer neuroscience. Research from both ends suggest a multifaceted interplay between the nervous and immune system, and how they influence the progression of tumors and of course the response to therapy. The purpose of this theoretical research paper will explore the bidirectional communication between neurological pathways; The sympathetic nervous system, HPA axis, and neurotransmitter signaling, while also exploring the dynamic of immune regulation within the tumor micro-environment (TME). Focusing on recent evidence which suggests that neural inputs have the potential to shape immune cell phenotypes and cytokine activity, while fully acknowledging the overall impact of external factors such as chronic stress, and circadian disruption on tumor dynamics led to the proposal of a consolidated model which neutral stress responses modulate tumor progression and immune surveillance. The overall framework focuses highly on therapeutic implications, specifically targeting neutral-immune communication to augment immunotherapies, incorporating behavioral interventions to control tumor growth induced by severe stress, and the utilization of neuromodulators to control tumor immunity. The overall conclusion will outline future interests by focusing on the need for transitional studies, the ethicality of neuroimmune targeting and said ethical considerations which could come into fruition, and the assurance of neuroimmunological integration in personalized cancer care. Citation Format: Jordan A. Stewar. The Neurological and Immunological Interplay in Cancer Progression and Treatment Response [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(23_Suppl): nr C036.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"4 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145717460","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 : 2025-12-09DOI: 10.1158/1078-0432.ccr-25-2052
Eric W Lin,Priyadarshini Pathak,Aileen O'Shea,Beatrice Awasthi,Ildiko E Phillips,Joshua R Kocher,Yuhui Song,Michael J Raabe,Katherine H Xu,Bidish K Patel,Nicole Lester,Jung Woo Bae,M Lisa Zhang,Linda T Nieman,Lawrence S Blaszkowsky,Elizabeth P Walsh,Aparna R Parikh,Andrea Hansen,Joanna Caufield,Gordon Newbert,Akwi W Asombang,Brenna Casey,Jonah Cohen,Brian C Jacobson,Kumar Krishnan,Raul Uppot,Ralph Weissleder,Nora K Horick,William L Hwang,Mukesh G Harisinghani,David T Ting,Colin D Weekes
PURPOSEPancreatic ductal adenocarcinoma (PDAC) cells exist on a spectrum of epithelial (E) and quasimesenchymal (QM) transcriptional states with differences in sensitivity to FOLFIRINOX (FFX). GSK-3b is a key regulator PDAC cell epithelial-to-mesenchymal transition (EMT).METHODSIn vitro analysis of PDAC cell lines combined with multi-omic analysis of data from GSK-3b inhibitor trial (NCT05077800) to evaluate treatment effects on EMT.RESULTSGSK-3b inhibition with elraglusib (ELRA) drives QM PDAC cells towards an E state demarcated by decreased transcription of QM genes FN1 and TGFB1 and an induction of E genes KRT8 and CEACAM6. A comparison of differentially expressed genes (DEGs) in PDAC cell lines with tumors from PDAC patients treated in a safety cohort combining FFX, ELRA and losartan (LOS) demonstrated 97 overlapping DEGs with concordant directional changes. ELRA treatment consistently suppressed EMT pathway expression. Synergy of ELRA with cytotoxic doses of FFX in 3-D culture was observed only in QM PDAC lines. The FFX/ELRA combination demonstrated initial evidence of clinical benefit with 3 of 6 patients experiencing partial response (PR) for a duration of at least 20 months. Interestingly, PRs were observed in patients with tumors demonstrating baseline high proportional QM cells that transitioned to E predominant tumors with ELRA treatment. Lastly, the influx of M1 tumor associated macrophage (TAM), CD4/CD8 lymphocytes and NK cells was observed with ELRA clinical response using a combination of GeoMx, snRNA-seq and ferumoxytol-MRI.CONCLUSIONGSK-3b blockade synergizes with FFX by modulating PDAC plasticity while promoting the development of a tumor suppressive immune microenvironment.
{"title":"Therapeutic Targeting of Epithelial Mesenchymal Cellular Plasticity in Pancreatic Cancer.","authors":"Eric W Lin,Priyadarshini Pathak,Aileen O'Shea,Beatrice Awasthi,Ildiko E Phillips,Joshua R Kocher,Yuhui Song,Michael J Raabe,Katherine H Xu,Bidish K Patel,Nicole Lester,Jung Woo Bae,M Lisa Zhang,Linda T Nieman,Lawrence S Blaszkowsky,Elizabeth P Walsh,Aparna R Parikh,Andrea Hansen,Joanna Caufield,Gordon Newbert,Akwi W Asombang,Brenna Casey,Jonah Cohen,Brian C Jacobson,Kumar Krishnan,Raul Uppot,Ralph Weissleder,Nora K Horick,William L Hwang,Mukesh G Harisinghani,David T Ting,Colin D Weekes","doi":"10.1158/1078-0432.ccr-25-2052","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2052","url":null,"abstract":"PURPOSEPancreatic ductal adenocarcinoma (PDAC) cells exist on a spectrum of epithelial (E) and quasimesenchymal (QM) transcriptional states with differences in sensitivity to FOLFIRINOX (FFX). GSK-3b is a key regulator PDAC cell epithelial-to-mesenchymal transition (EMT).METHODSIn vitro analysis of PDAC cell lines combined with multi-omic analysis of data from GSK-3b inhibitor trial (NCT05077800) to evaluate treatment effects on EMT.RESULTSGSK-3b inhibition with elraglusib (ELRA) drives QM PDAC cells towards an E state demarcated by decreased transcription of QM genes FN1 and TGFB1 and an induction of E genes KRT8 and CEACAM6. A comparison of differentially expressed genes (DEGs) in PDAC cell lines with tumors from PDAC patients treated in a safety cohort combining FFX, ELRA and losartan (LOS) demonstrated 97 overlapping DEGs with concordant directional changes. ELRA treatment consistently suppressed EMT pathway expression. Synergy of ELRA with cytotoxic doses of FFX in 3-D culture was observed only in QM PDAC lines. The FFX/ELRA combination demonstrated initial evidence of clinical benefit with 3 of 6 patients experiencing partial response (PR) for a duration of at least 20 months. Interestingly, PRs were observed in patients with tumors demonstrating baseline high proportional QM cells that transitioned to E predominant tumors with ELRA treatment. Lastly, the influx of M1 tumor associated macrophage (TAM), CD4/CD8 lymphocytes and NK cells was observed with ELRA clinical response using a combination of GeoMx, snRNA-seq and ferumoxytol-MRI.CONCLUSIONGSK-3b blockade synergizes with FFX by modulating PDAC plasticity while promoting the development of a tumor suppressive immune microenvironment.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"115 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145710781","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 : 2025-12-08DOI: 10.1158/1078-0432.ccr-25-2859
Zefeng Du, Zhicheng Lai, Yexing Huang, Hailong Chen, Ping Ma, Qijiong Li, Wei Wei, Yaojun Zhang, Minshan Chen, Binkui Li, Li Xu, Ming Shi, Anna Kan, Minke He
Purpose: Immune checkpoint inhibitors (ICIs)-related trials in hepatocellular carcinoma (HCC) have strict restrictions on HBV DNA load because of HBV reactivation. This study aimed to compare the HBV reactivation between HCC patients with low or high HBV DNA loads receiving ICIs and antiviral therapy. Patients and Methods: This prospective observational study (NCT04680598) recruited HBsAg-positive HCC patients who received concurrent antiviral therapy with initial ICI treatment. Participants were divided into HBV DNA-low (≤ 500 IU/ml) and HBV DNA-high (> 500 IU/ml) groups. The primary endpoint was the HBV reactivation rate. Results: Between December 25, 2020 and February 23, 2024, 356 and 659 participants were enrolled in the HBV DNA-low and HBV DNA-high groups. The HBV DNA-high group included significantly higher proportions of patients with HBeAg positivity (24.1% vs 7.0%, p < 0.001), ALBI grade 2-3 (49.9% vs. 33.7%, p < 0.001), and BCLC stage C (83.3% vs. 72.5%, p < 0.001). The HBV reactivation rate (4.5% vs. 6.1%, relative risk, 1.24; 95% CI: 0.81-1.89; p = 0.29), frequencies of HBV reactivation-associated hepatitis (1.7% vs. 2.3%, p = 0.53), and interruptions in ICI treatment (25.8% vs. 30.5%, p = 0.12) were comparable in the HBV DNA-low group and HBV DNA-high group. Conclusions: There was no significantly difference in the risk of HBV reactivation between HCC patients with HBV DNA ≤ 500 IU/ml or HBV DNA > 500 IU/ml when treated with ICIs and concurrent antiviral prophylaxis.
目的：免疫检查点抑制剂（ICIs）在肝细胞癌（HCC）中的相关试验由于HBV再激活对HBV DNA负荷有严格的限制。本研究旨在比较接受ICIs和抗病毒治疗的低或高HBV DNA载量HCC患者的HBV再激活情况。患者和方法：这项前瞻性观察性研究（NCT04680598）招募了同时接受抗病毒治疗和初始ICI治疗的hbsag阳性HCC患者。参与者被分为HBV dna低（≤500 IU/ml）组和HBV dna高（> 500 IU/ml）组。主要终点是HBV再激活率。结果：在2020年12月25日至2024年2月23日期间，356和659名参与者被纳入HBV dna低和HBV dna高组。HBV dna高组包括HBeAg阳性（24.1%比7.0%,p < 0.001）、ALBI 2-3级（49.9%比33.7%,p < 0.001）和BCLC C期（83.3%比72.5%,p < 0.001）的患者比例显著更高。HBV再激活率（4.5% vs. 6.1%，相对危险度1.24;95% CI: 0.81-1.89; p = 0.29）、HBV再激活相关肝炎的频率（1.7% vs. 2.3%, p = 0.53）和ICI治疗中断（25.8% vs. 30.5%, p = 0.12）在HBV dna低组和HBV dna高组中具有可比性。结论：HBV DNA≤500 IU/ml与HBV DNA≤500 IU/ml HCC患者HBV再激活风险无显著差异；500iu /ml当使用ICIs和同时进行抗病毒预防时。
{"title":"HBV Reactivation in Patients with Hepatocellular Carcinoma Treated with PD-1/L1 Antibodies and Concurrent Antiviral Prophylaxis Agents: A Prospective Observational Study","authors":"Zefeng Du, Zhicheng Lai, Yexing Huang, Hailong Chen, Ping Ma, Qijiong Li, Wei Wei, Yaojun Zhang, Minshan Chen, Binkui Li, Li Xu, Ming Shi, Anna Kan, Minke He","doi":"10.1158/1078-0432.ccr-25-2859","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2859","url":null,"abstract":"Purpose: Immune checkpoint inhibitors (ICIs)-related trials in hepatocellular carcinoma (HCC) have strict restrictions on HBV DNA load because of HBV reactivation. This study aimed to compare the HBV reactivation between HCC patients with low or high HBV DNA loads receiving ICIs and antiviral therapy. Patients and Methods: This prospective observational study (NCT04680598) recruited HBsAg-positive HCC patients who received concurrent antiviral therapy with initial ICI treatment. Participants were divided into HBV DNA-low (≤ 500 IU/ml) and HBV DNA-high (&gt; 500 IU/ml) groups. The primary endpoint was the HBV reactivation rate. Results: Between December 25, 2020 and February 23, 2024, 356 and 659 participants were enrolled in the HBV DNA-low and HBV DNA-high groups. The HBV DNA-high group included significantly higher proportions of patients with HBeAg positivity (24.1% vs 7.0%, p &lt; 0.001), ALBI grade 2-3 (49.9% vs. 33.7%, p &lt; 0.001), and BCLC stage C (83.3% vs. 72.5%, p &lt; 0.001). The HBV reactivation rate (4.5% vs. 6.1%, relative risk, 1.24; 95% CI: 0.81-1.89; p = 0.29), frequencies of HBV reactivation-associated hepatitis (1.7% vs. 2.3%, p = 0.53), and interruptions in ICI treatment (25.8% vs. 30.5%, p = 0.12) were comparable in the HBV DNA-low group and HBV DNA-high group. Conclusions: There was no significantly difference in the risk of HBV reactivation between HCC patients with HBV DNA ≤ 500 IU/ml or HBV DNA &gt; 500 IU/ml when treated with ICIs and concurrent antiviral prophylaxis.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"19 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704489","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 : 2025-12-08DOI: 10.1158/1078-0432.ccr-25-1592
Robin K. Kelley, Young Lee, James Conway, John F. Kurland, Patricia McCoon
Purpose: In the phase I/II Study 22 (NCT02519348) trial, objective response rates were 24.0% with STRIDE (Single Tremelimumab Regular Interval Durvalumab), 21.3% with durvalumab plus bevacizumab (D+B), and 11.5% with durvalumab (D) monotherapy in unresectable hepatocellular carcinoma (uHCC). Increased proliferating CD8+ T cells were associated with improved efficacy of STRIDE versus D monotherapy. Here, analyses of changes in T cell clonal expansion and gene expression signatures (GES) in peripheral blood were performed to explore the mechanisms of action associated with the anti-cancer activity of STRIDE and D+B versus D monotherapy. Patients and Methods: Participants with uHCC and no prior immune checkpoint inhibitor therapy were enrolled. DNA and RNA were isolated from peripheral blood collected at baseline and at the end of the first treatment cycle. Baseline values and changes from baseline in T cell clonality and GES were measured across treatment arms, and associations with radiographic response were assessed. Results: There were no significant differences in baseline richness or Simpson clonality of T cells across treatment arms. STRIDE, but not D+B, elicited an increase in the number of expanded T cell clones versus D monotherapy; the increase was associated with clinical response. Both STRIDE and D+B upregulated interferon-gamma response GES compared with D alone, but other immune-related changes differed, with STRIDE showing upregulation of CD4+ and T effector signatures, while D+B upregulated interferon-alpha response and both myeloid cell and endothelial GES. Conclusions: These findings suggest that STRIDE and D+B have distinct, and potentially complementary, mechanisms of action in uHCC.
{"title":"T Cell Receptor and Immune Gene Expression Pharmacodynamics for Durvalumab alone and with Tremelimumab or Bevacizumab in Unresectable Hepatocellular Carcinoma","authors":"Robin K. Kelley, Young Lee, James Conway, John F. Kurland, Patricia McCoon","doi":"10.1158/1078-0432.ccr-25-1592","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-1592","url":null,"abstract":"Purpose: In the phase I/II Study 22 (NCT02519348) trial, objective response rates were 24.0% with STRIDE (Single Tremelimumab Regular Interval Durvalumab), 21.3% with durvalumab plus bevacizumab (D+B), and 11.5% with durvalumab (D) monotherapy in unresectable hepatocellular carcinoma (uHCC). Increased proliferating CD8+ T cells were associated with improved efficacy of STRIDE versus D monotherapy. Here, analyses of changes in T cell clonal expansion and gene expression signatures (GES) in peripheral blood were performed to explore the mechanisms of action associated with the anti-cancer activity of STRIDE and D+B versus D monotherapy. Patients and Methods: Participants with uHCC and no prior immune checkpoint inhibitor therapy were enrolled. DNA and RNA were isolated from peripheral blood collected at baseline and at the end of the first treatment cycle. Baseline values and changes from baseline in T cell clonality and GES were measured across treatment arms, and associations with radiographic response were assessed. Results: There were no significant differences in baseline richness or Simpson clonality of T cells across treatment arms. STRIDE, but not D+B, elicited an increase in the number of expanded T cell clones versus D monotherapy; the increase was associated with clinical response. Both STRIDE and D+B upregulated interferon-gamma response GES compared with D alone, but other immune-related changes differed, with STRIDE showing upregulation of CD4+ and T effector signatures, while D+B upregulated interferon-alpha response and both myeloid cell and endothelial GES. Conclusions: These findings suggest that STRIDE and D+B have distinct, and potentially complementary, mechanisms of action in uHCC.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"3 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145704492","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 : 2025-12-04DOI: 10.1158/1078-0432.ccr-25-2445
Ke Zheng,Xueyi Zheng,Jue Wang,Xinke Zhang,Shiping Chen,Qunxi Chen,Sha Fu,Dan Xie,Ruixuan Wang,Junpeng Lai,Muyan Cai
PURPOSECytology is a cornerstone of pathological diagnosis. However, the development of artificial intelligence (AI) models for cytology-based diagnostics remains constrained by limited data availability and stringent privacy regulations. This study aims to develop COIN, a controllable cytology image generation foundation model, to address these challenges by synthesizing high-quality cytology images for enhancing AI diagnostics and supporting clinical applications.EXPERIMENTAL DESIGNThe COIN model was trained on a large-scale dataset of 112,226 cytology image-report pairs from 16 anatomical sites. Using diagnostic textual reports, it generates high-fidelity cytology images with morphologically and semantically coherent features. Expert cytologists evaluated the generated images for anatomical and diagnostic authenticity. The model's utility was assessed through data augmentation experiments, AI model training under data-scarce conditions, and content-based image retrieval applications.RESULTSExpert evaluations confirmed the high anatomical and diagnostic fidelity of the images generated by COIN. When used for data augmentation, COIN significantly improved the performance of diagnostic AI models across various tasks. Under data-scarce conditions, models trained exclusively on COIN-generated images demonstrated effective generalization to real-world datasets. Furthermore, COIN supported content-based image retrieval, offering a novel tool for case referencing and clinical decision support.CONCLUSIONSCOIN represents a robust and privacy-preserving framework for scalable cytology data generation. Its ability to synthesize realistic images and enhance AI diagnostics highlights its broad applicability in computational pathology, providing a valuable tool to accelerate the development and implementation of AI-based diagnostic solutions.
{"title":"A Generative Foundation Model for Scalable Cytology Image Synthesis in AI-Powered Diagnostics.","authors":"Ke Zheng,Xueyi Zheng,Jue Wang,Xinke Zhang,Shiping Chen,Qunxi Chen,Sha Fu,Dan Xie,Ruixuan Wang,Junpeng Lai,Muyan Cai","doi":"10.1158/1078-0432.ccr-25-2445","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2445","url":null,"abstract":"PURPOSECytology is a cornerstone of pathological diagnosis. However, the development of artificial intelligence (AI) models for cytology-based diagnostics remains constrained by limited data availability and stringent privacy regulations. This study aims to develop COIN, a controllable cytology image generation foundation model, to address these challenges by synthesizing high-quality cytology images for enhancing AI diagnostics and supporting clinical applications.EXPERIMENTAL DESIGNThe COIN model was trained on a large-scale dataset of 112,226 cytology image-report pairs from 16 anatomical sites. Using diagnostic textual reports, it generates high-fidelity cytology images with morphologically and semantically coherent features. Expert cytologists evaluated the generated images for anatomical and diagnostic authenticity. The model's utility was assessed through data augmentation experiments, AI model training under data-scarce conditions, and content-based image retrieval applications.RESULTSExpert evaluations confirmed the high anatomical and diagnostic fidelity of the images generated by COIN. When used for data augmentation, COIN significantly improved the performance of diagnostic AI models across various tasks. Under data-scarce conditions, models trained exclusively on COIN-generated images demonstrated effective generalization to real-world datasets. Furthermore, COIN supported content-based image retrieval, offering a novel tool for case referencing and clinical decision support.CONCLUSIONSCOIN represents a robust and privacy-preserving framework for scalable cytology data generation. Its ability to synthesize realistic images and enhance AI diagnostics highlights its broad applicability in computational pathology, providing a valuable tool to accelerate the development and implementation of AI-based diagnostic solutions.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"198200 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145663939","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 : 2025-12-04DOI: 10.1158/1078-0432.ccr-25-2426
Michael Michal,Faizan Malik,Boulos Mansour,Travis Hattery,Carina A Dehner,Petr Martinek,Veronika Hájková,Tomáš Vaněček,John S A Chrisinger,Isidro Machado,Natálie Klubíčková,Vaiyapuri P Sumathi,Tony Ng,Laura Warmke,Ming Liang Oon,Fredrik Petersson,Pedram Argani,John M Gross,Michal Michal,Cristina R Antonescu,Josephine K Dermawan
PURPOSEFusion-positive myoepithelial tumors (MET) are clinicopathologically heterogeneous and variably termed mixed tumors and myoepithelial carcinomas. Since FET-rearranged MET lack ductal/epithelial differentiation, we test whether FET-rearranged MET are epigenetically distinct from adnexal PLAG1-rearranged MET, which we hypothesize to be analogues of salivary gland MET.EXPERIMENTAL DESIGNDNA methylation profiling from a multi-institutional cohort of 52 fusion-positive skin, soft tissue and bone MET cases was performed and compared to diverse tumor types, including salivary MET. The MET subgroups harbored EWSR1::KLF15, EWSR1/FUS::KLF17, EWSR1::PBX1, EWSR1::PBX3, EWSR1/FUS::POU5F1, SS18::POU5F1, EWSR1::ZNF444 and PLAG1 rearrangements. Pooled clinicopathological and outcome analysis with new and published cases (total 185) was performed.RESULTS. The MET subgroups showed significant heterogeneity in age, site, and histology. Specifically, EWSR1::KLF15 MET affected predominantly young children (<5 years old); EWSR1::PBX1PBX3 MET were enriched in skin/bone; EWSR1/FUS::POU5F1, SS18::POU5F1 and EWSR1::KLF15 MET tended to display malignant histology. Conversely, PLAG1-rearranged tumors were predominantly benign, arising in older adults and located in the skin. DNA methylation profiling revealed that FET-rearranged MET were epigenetically related to SS18::POU5F1 MET and FET::NFATC2 sarcomas, but entirely distinct from PLAG1-rearranged adnexal and salivary MET. Histologic features were correlated with the degree of genome-wide copy number variation. Median disease-specific survival was shortest in SS18::POU5F1 (31 months), EWSR1::PBX3 (38 months), and EWSR1::KLF15 (45 months) MET. On multivariate analysis, age < 25 years old was a significant predictor of worse progression-free survival.CONCLUSIONSFET-rearranged MET are epigenetically unrelated to cutaneous and salivary gland MET, and their malignant counterparts are best classified as sarcomas rather than carcinomas.
{"title":"FET-rearranged Myoepithelial Tumors are Clinically Heterogeneous and Epigenetically Distinct from PLAG1-rearranged Adnexal and Salivary Gland Myoepithelial Tumors.","authors":"Michael Michal,Faizan Malik,Boulos Mansour,Travis Hattery,Carina A Dehner,Petr Martinek,Veronika Hájková,Tomáš Vaněček,John S A Chrisinger,Isidro Machado,Natálie Klubíčková,Vaiyapuri P Sumathi,Tony Ng,Laura Warmke,Ming Liang Oon,Fredrik Petersson,Pedram Argani,John M Gross,Michal Michal,Cristina R Antonescu,Josephine K Dermawan","doi":"10.1158/1078-0432.ccr-25-2426","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2426","url":null,"abstract":"PURPOSEFusion-positive myoepithelial tumors (MET) are clinicopathologically heterogeneous and variably termed mixed tumors and myoepithelial carcinomas. Since FET-rearranged MET lack ductal/epithelial differentiation, we test whether FET-rearranged MET are epigenetically distinct from adnexal PLAG1-rearranged MET, which we hypothesize to be analogues of salivary gland MET.EXPERIMENTAL DESIGNDNA methylation profiling from a multi-institutional cohort of 52 fusion-positive skin, soft tissue and bone MET cases was performed and compared to diverse tumor types, including salivary MET. The MET subgroups harbored EWSR1::KLF15, EWSR1/FUS::KLF17, EWSR1::PBX1, EWSR1::PBX3, EWSR1/FUS::POU5F1, SS18::POU5F1, EWSR1::ZNF444 and PLAG1 rearrangements. Pooled clinicopathological and outcome analysis with new and published cases (total 185) was performed.RESULTS. The MET subgroups showed significant heterogeneity in age, site, and histology. Specifically, EWSR1::KLF15 MET affected predominantly young children (<5 years old); EWSR1::PBX1PBX3 MET were enriched in skin/bone; EWSR1/FUS::POU5F1, SS18::POU5F1 and EWSR1::KLF15 MET tended to display malignant histology. Conversely, PLAG1-rearranged tumors were predominantly benign, arising in older adults and located in the skin. DNA methylation profiling revealed that FET-rearranged MET were epigenetically related to SS18::POU5F1 MET and FET::NFATC2 sarcomas, but entirely distinct from PLAG1-rearranged adnexal and salivary MET. Histologic features were correlated with the degree of genome-wide copy number variation. Median disease-specific survival was shortest in SS18::POU5F1 (31 months), EWSR1::PBX3 (38 months), and EWSR1::KLF15 (45 months) MET. On multivariate analysis, age < 25 years old was a significant predictor of worse progression-free survival.CONCLUSIONSFET-rearranged MET are epigenetically unrelated to cutaneous and salivary gland MET, and their malignant counterparts are best classified as sarcomas rather than carcinomas.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"91 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664050","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 : 2025-12-04DOI: 10.1158/1078-0432.ccr-25-1110
Renee R Anderko,Alexandra E Bowman,Praneel Murthy,Pranav Murthy,Asmita Chopra,Nikhil V Tirukkovalur,Sebastiaan Ceuppens,Alessandro Paniccia,Kenneth K Lee,Robbie B Mailliard,Michael T Lotze,Aatur D Singhi,Amer H Zureikat
PURPOSEUnsatisfactory outcomes in pancreatic ductal adenocarcinoma (PDAC) highlight the need to identify precision-based treatment modalities. We aimed to utilize patient-derived organoids (PDOs) to predict the most effective individual components of potential combination therapies.EXPERIMENTAL DESIGNAutologous αβ and γδ-enriched tumor infiltrating lymphocyte (TIL) and PDO cultures were established from resected PDAC tissue. PDOs were characterized by immunostaining, targeted next-generation sequencing, and drug screening with standard-of-care multidrug chemotherapeutic regimens. Expanded TIL cultures were profiled through flow cytometry, sequencing, and potency against autologous PDOs.RESULTSPDO cultures were established with an 80% success rate. In addition to faithfully recapitulating molecular and histological features of the parental tumor, PDOs were sufficiently expanded for pharmacotyping within a clinically relevant timeframe of 36 days. Notably, PDO chemotherapeutic sensitivity profiles correlated with patient serum CA 19-9 dynamics and recurrence free survival. Furthermore, expanded γδ-enriched TIL supported the activation of αβ TCR+ cells and demonstrated more potent functionality in response to autologous PDO targets. Importantly, infiltration of γδ T cells within pancreatic tumor tissue was associated with improved overall survival.CONCLUSIONSWe confirm the feasibility of generating PDOs within a clinically relevant timeframe and provide evidence of their utility for advancing therapeutic success in PDAC.
{"title":"Pancreatic cancer organoids recapitulate chemotherapy response and identify a potent cytotoxic T cell population.","authors":"Renee R Anderko,Alexandra E Bowman,Praneel Murthy,Pranav Murthy,Asmita Chopra,Nikhil V Tirukkovalur,Sebastiaan Ceuppens,Alessandro Paniccia,Kenneth K Lee,Robbie B Mailliard,Michael T Lotze,Aatur D Singhi,Amer H Zureikat","doi":"10.1158/1078-0432.ccr-25-1110","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-1110","url":null,"abstract":"PURPOSEUnsatisfactory outcomes in pancreatic ductal adenocarcinoma (PDAC) highlight the need to identify precision-based treatment modalities. We aimed to utilize patient-derived organoids (PDOs) to predict the most effective individual components of potential combination therapies.EXPERIMENTAL DESIGNAutologous αβ and γδ-enriched tumor infiltrating lymphocyte (TIL) and PDO cultures were established from resected PDAC tissue. PDOs were characterized by immunostaining, targeted next-generation sequencing, and drug screening with standard-of-care multidrug chemotherapeutic regimens. Expanded TIL cultures were profiled through flow cytometry, sequencing, and potency against autologous PDOs.RESULTSPDO cultures were established with an 80% success rate. In addition to faithfully recapitulating molecular and histological features of the parental tumor, PDOs were sufficiently expanded for pharmacotyping within a clinically relevant timeframe of 36 days. Notably, PDO chemotherapeutic sensitivity profiles correlated with patient serum CA 19-9 dynamics and recurrence free survival. Furthermore, expanded γδ-enriched TIL supported the activation of αβ TCR+ cells and demonstrated more potent functionality in response to autologous PDO targets. Importantly, infiltration of γδ T cells within pancreatic tumor tissue was associated with improved overall survival.CONCLUSIONSWe confirm the feasibility of generating PDOs within a clinically relevant timeframe and provide evidence of their utility for advancing therapeutic success in PDAC.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"113 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664103","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 : 2025-12-04DOI: 10.1158/1078-0432.ccr-25-2750
Nicolas Sayegh,Ryon P Graf,Umang Swami,Zeynep Irem Ozay,Chadi Hage Chehade,Julia A Elvin,Douglas Lin,Julia C F Quintanilha,Gerald Li,Alan H Bryce,Rana R McKay,Jeffrey S Ross,Tian Zhang,Neeraj Agarwal
BACKGROUNDImmune checkpoint inhibitors (ICIs) have shown limited efficacy in unselected patients with metastatic castration-resistant prostate cancer (mCRPC). However, ICIs are approved for biomarker-defined subsets: microsatellite instability-high (MSI-H) and/or high tumor mutational burden (TMB-H). However, the efficacy of ICIs in TMB-H but not MSI-H disease remains unclear, and limited data exists evaluating ICI outcomes associated with blood-based MSI (bMSI) in mCRPC.METHODSThis study used the US-based deidentified Flatiron Health-Foundation Medicine prostate cancer Clinico-Genomic Database (FH-FMI CGDB). Patients with tissue-assessed MSI (tMSI) and TMB (tTMB) status by an algorithm supporting an FDA-approved CDx for pembrolizumab were included if treated with single-agent ICI. Separately, outcomes on ICI associated with or bMSI were assessed. included if treated with single-agent ICI or taxane.RESULTSAmong 2,965 patients with mCRPC, tMSI-H (3.2%) was nearly always also tTMB≥10 mut/Mb (4.7%). In 84 ICI-treated patients, TTNT and OS were more favorable in tMSI-H with any TMB (TTNT HR: 0.18, 95%CI: 0.09-0.37 and OS HR: 0.32, 95%CI: 0.15-0.66) and tTMB≥10 without tMSI-H (TTNT HR: 0.18, 95%CI: 0.04-0.48 and OS HR: 0.20, 95%CI: 0.05-0.77) compared to tTMB < 10 without tMSI-H group. In intra-patient assessments, patients with tTMB≥10 had more favorable TTNT with subsequent ICI vs. prior taxane. Detection of bMSI-H was associated with more favorable TTNT on ICI (HR: 0.34, 95%CI: 0.14-0.83) and OS (HR: 0.21, 95%CI: 0.06-0.75) when tumor fraction ≥1%.CONCLUSIONThese findings add support for tTMB and tMSI in predicting ICI monotherapy benefit in mCRPC and provide evidence supporting bMSI testing when tissue is unavailable.
{"title":"Additive Clinical Utility of Microsatellite Instability and Tumor Mutational Burden to Predict Immune Checkpoint Inhibitor Effectiveness in Metastatic Castration-Resistant Prostate Cancer.","authors":"Nicolas Sayegh,Ryon P Graf,Umang Swami,Zeynep Irem Ozay,Chadi Hage Chehade,Julia A Elvin,Douglas Lin,Julia C F Quintanilha,Gerald Li,Alan H Bryce,Rana R McKay,Jeffrey S Ross,Tian Zhang,Neeraj Agarwal","doi":"10.1158/1078-0432.ccr-25-2750","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2750","url":null,"abstract":"BACKGROUNDImmune checkpoint inhibitors (ICIs) have shown limited efficacy in unselected patients with metastatic castration-resistant prostate cancer (mCRPC). However, ICIs are approved for biomarker-defined subsets: microsatellite instability-high (MSI-H) and/or high tumor mutational burden (TMB-H). However, the efficacy of ICIs in TMB-H but not MSI-H disease remains unclear, and limited data exists evaluating ICI outcomes associated with blood-based MSI (bMSI) in mCRPC.METHODSThis study used the US-based deidentified Flatiron Health-Foundation Medicine prostate cancer Clinico-Genomic Database (FH-FMI CGDB). Patients with tissue-assessed MSI (tMSI) and TMB (tTMB) status by an algorithm supporting an FDA-approved CDx for pembrolizumab were included if treated with single-agent ICI. Separately, outcomes on ICI associated with or bMSI were assessed. included if treated with single-agent ICI or taxane.RESULTSAmong 2,965 patients with mCRPC, tMSI-H (3.2%) was nearly always also tTMB≥10 mut/Mb (4.7%). In 84 ICI-treated patients, TTNT and OS were more favorable in tMSI-H with any TMB (TTNT HR: 0.18, 95%CI: 0.09-0.37 and OS HR: 0.32, 95%CI: 0.15-0.66) and tTMB≥10 without tMSI-H (TTNT HR: 0.18, 95%CI: 0.04-0.48 and OS HR: 0.20, 95%CI: 0.05-0.77) compared to tTMB < 10 without tMSI-H group. In intra-patient assessments, patients with tTMB≥10 had more favorable TTNT with subsequent ICI vs. prior taxane. Detection of bMSI-H was associated with more favorable TTNT on ICI (HR: 0.34, 95%CI: 0.14-0.83) and OS (HR: 0.21, 95%CI: 0.06-0.75) when tumor fraction ≥1%.CONCLUSIONThese findings add support for tTMB and tMSI in predicting ICI monotherapy benefit in mCRPC and provide evidence supporting bMSI testing when tissue is unavailable.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"21 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664102","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 : 2025-12-03DOI: 10.1158/1078-0432.ccr-25-0571
Filipa Lynce,Noah Graham,Bose S Kochupurakkal,Huy Nguyen,Brittany Bychkovsky,Philip D Poorvu,Victoria Attaya,Raechel Davis,Molly DiLullo,Alan D D'Andrea,Judy E Garber,Kavita Garg,Lee P Lim,Mark Li,Cloud P Paweletz,Nabihah Tayob,Geoffrey I Shapiro,Sara M Tolaney
PURPOSEWe explored the efficacy of PARP inhibition combined with sapacitabine, an orally bioavailable prodrug of the deoxycytidine analog 2'-C-cyano-2'-deoxy-1-β-D-arabino-pentofuranosylcytosine (CNDAC), in patients with germline BRCA1/2 (gBRCA1/2)-mutated HER2-negative metastatic breast cancer.PATIENTS AND METHODSIn this phase Ib investigator-sponsored study of sapacitabine and olaparib, patients who were PARP inhibitor-naive were enrolled. The primary objective was determination of the recommended phase 2 dose (RP2D) of sapacitabine with olaparib. Archival samples were subjected to immunohistochemistry (IHC) for biomarkers of homologous recombination repair (HRR) deficiency and replication stress. Serial blood samples were collected for circulating tumor DNA (ctDNA) analysis.RESULTSTen patients (3 BRCA1, 7 BRCA2) were enrolled. The RP2D was not determined due to hematological toxicities. The objective response rate (ORR) was 50% (95% CI: 18.7% - 81.3%) with median progression-free survival (mPFS) of 9.7 months (95% CI: 8.02 - NA). Three patients had clinical benefit greater than 15 months, including 2 who remained on trial for more than 40 months. Tumors from responding patients demonstrated HRR deficiency and/or replication stress by IHC. At progression, ctDNA from 2 patients had evidence of BRCA reversion mutation associated with a microhomology-mediated end-joining (MMEJ) signature, and 3 patients had acquired putative non-reversion mechanisms of resistance.CONCLUSIONSSapacitabine with olaparib produces high rates of hematologic toxicity. However, the ORR of 50%, mPFS of 9.7 months, and durability of response in some patients suggest possible combinatorial benefit. Further exploration of olaparib with different sapacitabine schedules or substitution of a PARP1-selective inhibitor to potentially decrease hematological toxicity is warranted.
{"title":"A phase Ib study of sapacitabine and olaparib in patients with BRCA1/2-mutated metastatic breast cancer.","authors":"Filipa Lynce,Noah Graham,Bose S Kochupurakkal,Huy Nguyen,Brittany Bychkovsky,Philip D Poorvu,Victoria Attaya,Raechel Davis,Molly DiLullo,Alan D D'Andrea,Judy E Garber,Kavita Garg,Lee P Lim,Mark Li,Cloud P Paweletz,Nabihah Tayob,Geoffrey I Shapiro,Sara M Tolaney","doi":"10.1158/1078-0432.ccr-25-0571","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0571","url":null,"abstract":"PURPOSEWe explored the efficacy of PARP inhibition combined with sapacitabine, an orally bioavailable prodrug of the deoxycytidine analog 2'-C-cyano-2'-deoxy-1-β-D-arabino-pentofuranosylcytosine (CNDAC), in patients with germline BRCA1/2 (gBRCA1/2)-mutated HER2-negative metastatic breast cancer.PATIENTS AND METHODSIn this phase Ib investigator-sponsored study of sapacitabine and olaparib, patients who were PARP inhibitor-naive were enrolled. The primary objective was determination of the recommended phase 2 dose (RP2D) of sapacitabine with olaparib. Archival samples were subjected to immunohistochemistry (IHC) for biomarkers of homologous recombination repair (HRR) deficiency and replication stress. Serial blood samples were collected for circulating tumor DNA (ctDNA) analysis.RESULTSTen patients (3 BRCA1, 7 BRCA2) were enrolled. The RP2D was not determined due to hematological toxicities. The objective response rate (ORR) was 50% (95% CI: 18.7% - 81.3%) with median progression-free survival (mPFS) of 9.7 months (95% CI: 8.02 - NA). Three patients had clinical benefit greater than 15 months, including 2 who remained on trial for more than 40 months. Tumors from responding patients demonstrated HRR deficiency and/or replication stress by IHC. At progression, ctDNA from 2 patients had evidence of BRCA reversion mutation associated with a microhomology-mediated end-joining (MMEJ) signature, and 3 patients had acquired putative non-reversion mechanisms of resistance.CONCLUSIONSSapacitabine with olaparib produces high rates of hematologic toxicity. However, the ORR of 50%, mPFS of 9.7 months, and durability of response in some patients suggest possible combinatorial benefit. Further exploration of olaparib with different sapacitabine schedules or substitution of a PARP1-selective inhibitor to potentially decrease hematological toxicity is warranted.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"168 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664016","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 : 2025-12-03DOI: 10.1158/1078-0432.ccr-25-2882
Eva Ciruelos,Tomás Pascual,Guillermo Villacampa,Sonia Pernas,Rodrigo Sanchez Bayona,José Ponce,Blanca Cantos,Santiago Escrivá-de-Romaní,Antonia Perelló,Esther Sanfeliu,Patricia Galvan,Alvaro Montaño,Eduardo Martínez,Ana Lopez,Mireia Mele,Juan de la Haba,Javier Cortés,Antonio Mulero-Sánchez,Juan M Ferrero-Cafiero,Mafalda Oliveira,Lorea Villanueva,Xavier Gonzalez,Patricia Villagrasa,Aleix Prat
PURPOSEBased on the results from SOLTI-PATRICIA trial (NCT02448420) cohorts A/B, a direct comparison with standard-of-care treatments is needed to evaluate the efficacy and safety of palbociclib, trastuzumab and endocrine therapy (ET) in PAM50-luminal A/B pretreated patients.PATIENTS AND METHODSSOLTI-PATRICIA cohort C is a randomised, multicentre, prospective, open-label, phase II study. Pretreated patients with HER2-positive, HR-positive, and PAM50-Luminal A/B ABC were randomised 1:1 to receive either i) the triplet regimen or ii) trastuzumab-based treatment of physician's choice (TPC). Patients allocated in the TPC arm were eligible for re-randomization upon disease progression, if the inclusion criteria were still met. The primary endpoint was investigator-assessed progression-free survival (PFS) per RECIST 1.1.RESULTS264 participants were pre-screened between August 2019-2023, and 73 patients were randomised (including seven re-randomisations). In the TPC arm: 48.5% were treated with trastuzumab plus chemotherapy, 39.4% with T-DM1 and 12.1 % with trastuzumab plus ET. The triplet was associated with a significantly better PFS compared to TPC (stratified hazard ratio=0.52 [95% CI 0.29-0.95]; two-sided p=0.03). PFS rates after 24 months were 24.0% with the triplet and 4.3% in the TPC arm. The overall response rate was 18.9% (95% CI 8.6-35.7) and 7.1% (95% CI 1.2-25.0), respectively. In the triplet arm, grade ≥3 adverse events occurred in 61.5% of patients, with neutropenia being the most frequent (53.9%). No permanent discontinuations due to toxicity were observed.CONCLUSIONSCombining palbociclib, trastuzumab, and ET was safe and improved significantly PFS, compared to TPC in previously treated HER2-positive, PAM50 luminal A/B ABC patients.
目的：基于SOLTI-PATRICIA试验（NCT02448420）队列A/B的结果，需要与标准治疗方法进行直接比较，以评估帕博西尼、曲妥珠单抗和内分泌治疗（ET）在PAM50-luminal A/B前治疗患者中的疗效和安全性。患者和方法：solti - patricia队列C是一项随机、多中心、前瞻性、开放标签的II期研究。预先治疗的her2阳性、hr阳性和PAM50-Luminal A/B ABC患者被1:1随机分组，接受i)三联方案或ii)基于曲妥珠单抗的医生选择治疗（TPC）。如果仍然符合纳入标准，分配在TPC组的患者有资格在疾病进展时重新随机化。主要终点是根据RECIST 1.1标准由研究者评估的无进展生存期（PFS）。结果2019年8月至2023年8月期间，264名参与者进行了预筛选，73名患者随机化（包括7名再随机化）。在TPC组：48.5%的患者接受曲妥珠单抗联合化疗，39.4%的患者接受T-DM1治疗，12.1%的患者接受曲妥珠单抗联合ET治疗。与TPC相比，这三组患者的PFS明显更好（分层风险比=0.52 [95% CI 0.29-0.95]；双侧p=0.03）。三胞胎组24个月后的PFS率为24.0%，TPC组为4.3%。总有效率分别为18.9% （95% CI 8.6-35.7）和7.1% （95% CI 1.2-25.0）。在三胞胎组中，61.5%的患者发生≥3级不良事件，其中中性粒细胞减少症最为常见（53.9%）。没有观察到由于毒性导致的永久性停药。与TPC相比，帕博西尼、曲妥珠单抗和ET联合治疗在先前治疗的her2阳性、PAM50腔内A/B ABC患者中是安全的，可显著改善PFS。
{"title":"Palbociclib, trastuzumab and endocrine therapy in pretreated HER2-positive and PAM50 luminal advanced breast cancer: randomised phase II, SOLTI-1303 PATRICIA trial.","authors":"Eva Ciruelos,Tomás Pascual,Guillermo Villacampa,Sonia Pernas,Rodrigo Sanchez Bayona,José Ponce,Blanca Cantos,Santiago Escrivá-de-Romaní,Antonia Perelló,Esther Sanfeliu,Patricia Galvan,Alvaro Montaño,Eduardo Martínez,Ana Lopez,Mireia Mele,Juan de la Haba,Javier Cortés,Antonio Mulero-Sánchez,Juan M Ferrero-Cafiero,Mafalda Oliveira,Lorea Villanueva,Xavier Gonzalez,Patricia Villagrasa,Aleix Prat","doi":"10.1158/1078-0432.ccr-25-2882","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2882","url":null,"abstract":"PURPOSEBased on the results from SOLTI-PATRICIA trial (NCT02448420) cohorts A/B, a direct comparison with standard-of-care treatments is needed to evaluate the efficacy and safety of palbociclib, trastuzumab and endocrine therapy (ET) in PAM50-luminal A/B pretreated patients.PATIENTS AND METHODSSOLTI-PATRICIA cohort C is a randomised, multicentre, prospective, open-label, phase II study. Pretreated patients with HER2-positive, HR-positive, and PAM50-Luminal A/B ABC were randomised 1:1 to receive either i) the triplet regimen or ii) trastuzumab-based treatment of physician's choice (TPC). Patients allocated in the TPC arm were eligible for re-randomization upon disease progression, if the inclusion criteria were still met. The primary endpoint was investigator-assessed progression-free survival (PFS) per RECIST 1.1.RESULTS264 participants were pre-screened between August 2019-2023, and 73 patients were randomised (including seven re-randomisations). In the TPC arm: 48.5% were treated with trastuzumab plus chemotherapy, 39.4% with T-DM1 and 12.1 % with trastuzumab plus ET. The triplet was associated with a significantly better PFS compared to TPC (stratified hazard ratio=0.52 [95% CI 0.29-0.95]; two-sided p=0.03). PFS rates after 24 months were 24.0% with the triplet and 4.3% in the TPC arm. The overall response rate was 18.9% (95% CI 8.6-35.7) and 7.1% (95% CI 1.2-25.0), respectively. In the triplet arm, grade ≥3 adverse events occurred in 61.5% of patients, with neutropenia being the most frequent (53.9%). No permanent discontinuations due to toxicity were observed.CONCLUSIONSCombining palbociclib, trastuzumab, and ET was safe and improved significantly PFS, compared to TPC in previously treated HER2-positive, PAM50 luminal A/B ABC patients.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"3 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145663957","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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