Clinical Cancer Research最新文献

{"title":"Multi-Omics and Single-Cell Insights Reveal a Lysophosphatidic Acid (LPA)-Mediated Resistant Mechanism to Third Generation EGFR-TKI in Non-Small Cell Lung Cancer","authors":"Ruyun Gao, Ning Lou, Sheng Yang, Mengwei Yang, Guangyu Fan, Liyuan Dai, Le Tang, Jiarui Yao, Xiaohong Han, Yuankai Shi","doi":"10.1158/1078-0432.ccr-25-0993","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0993","url":null,"abstract":"Introduction: Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of EGFR-sensitive-mutant non-small cell lung cancer (NSCLC). However, acquired resistance remains a significant challenge. This study investigates the metabolic mechanisms driving third-generation EGFR-TKI resistance. Methods: We conducted plasma metabolomics analysis on 216 longitudinal samples from 186 NSCLC patients enrolled in the clinical trial of rezivertinib (NCT03386955). Additionally, multi-omics profiling of rezivertinib-resistant cell lines, functional in vitro experiments, and single-cell RNA sequencing (scRNA-seq) analyses of 215 NSCLC patients were integrated to reveal underlying mechanisms. Results: Non-responder patients exhibited elevated glycerophospholipids and dysregulated lysophospholipid (LPL) metabolism. Unsupervised clustering identified two patient subgroups, with Cluster 1 (characterized by high LPL levels) associated with poorer survival (P = 0.022). Metabolite-based predictive model achieved robust performance (AUC: 0.7762 [training], 0.7485 [test]). Longitudinal analyses demonstrated LPLs and lysophosphatidic acid (LPA) accumulation during the resistance process. Integrated multi-omics analyses highlighted epithelial-mesenchymal transition (EMT) and glycerophospholipid reprogramming in rezivertinib-resistant cells. Functional assays confirmed that LPA promoted cell migration and invasion, and attenuated the efficacy of third-generation EGFR-TKI, while disruption of the LPA-LPAR signaling axis reversed LPA-mediated resistance. scRNA-seq identified an LPA-secreting malignant subset (cluster c4), characterized by enhanced EMT activation and extensive microenvironmental crosstalk through Wnt, TGF-β, and ECM signals. Conclusions: Our study highlights the pivotal role of LPA-mediated signaling and metabolic reprogramming in third-generation EGFR-TKI resistance. Targeting LPA production or its downstream pathways may offer novel therapeutic strategies to overcome resistance. This study provides critical metabolic insights for managing EGFR-sensitive-mutant NSCLC.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"132 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899119","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}

{"title":"Circulating tumor cells dynamics after CDK4/6 inhibitor for hormone-receptor positive metastatic breast cancer: a biomarker analysis from the PACE phase II study.","authors":"Lorenzo Gerratana, Carolina Reduzzi, Yue Ren, Rinath Jeselsohn, Reshma L. Mahtani, Cynthia X. Ma, Angela DeMichele, Jane L. Meisel, Kathy Miller, Yara Abdou, Elizabeth C. Riley, Rubina Qamar, Priyanka Sharma, Sonya A. Reid, Naomi Ko, Yuan Liu, Eric Gauthier, Harold J. Burstein, Michelle DeMeo, Sara M. Tolaney, Meredith M. Regan, Massimo Cristofanilli, Erica L. Mayer","doi":"10.1158/1078-0432.ccr-25-0327","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0327","url":null,"abstract":"Purpose: Circulating tumor cells (CTCs) are biomarkers associated with poor prognosis and treatment resistance in hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer (MBC). This analysis evaluates the prognostic role of baseline CTC enumeration and its interaction with treatment regimens in patients progressing on CDK4/6 inhibitors. Experimental Design: The PACE trial is a phase II, multicenter, randomized study of HR+/HER2- MBC patients experiencing progression on aromatase inhibitors (AI) and CDK4/6 inhibitors. Patients were randomized 1:2:1 to receive fulvestrant (F), F+palbociclib (F+P), or F+P+avelumab (F+P+A). Baseline CTCs were enumerated using CellSearch™ with a threshold of ≥5 CTCs/7.5 mL to classify patients as StageIV indolent or StageIV aggressive. Concurrent ctDNA analysis was performed using Guardant360®. Progression-free survival (PFS) was the primary endpoint. Results: Among 220 randomized patients, 203 were evaluable for baseline CTCs; 76% had detectable CTCs, and 49% were StageIV aggressive. Patients with de novo MBC were more frequently StageIV aggressive (47.5% vs. 30.8%). Baseline CTCs were prognostic, with median PFS of 5.7 months for StageIV indolent and 3.5 months for StageIV aggressive patients (HR 1.69, 90% CI 1.27-2.24, P<0.001). In StageIV aggressive patients, F+P and F+P+A improved PFS versus F alone (HR 0.43, 90% CI 0.25-0.71 and HR 0.26, 90% CI 0.14-0.49, respectively). No benefit was observed in StageIV indolent patients (interaction p=0.0148 and p=0.0033, respectively). Conclusions: Baseline CTC enumeration provides significant prognostic information in HR+/HER2- MBC. StageIV aggressive patients derive greater benefit from F+P or F+P+A over F alone, independent of clinical or ctDNA features. This highlights the potential of to guide treatment decision-making.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"24 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899118","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}

{"title":"Preclinical Fluorescence-Guided Imaging Leveraging Surrounding Sentinel Tumor Microenvironment Identifies High-Risk Premalignant Pancreatic Lesions","authors":"Shilpa Sharma, Xiaoxia Wen, Jianbo Wang, Beibei Huang, Denise Hernandez, Cong-Dat Pham, Zhiwen Liu, Susanne Je-Han. Lin, Aiko Yamaguchi, Dimitra K. Georgiou, Ryan P. Coll, H. Charles Manning","doi":"10.1158/1078-0432.ccr-25-1092","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-1092","url":null,"abstract":"Purpose: With surgery being the only potential cure for pancreatic cancer, high-risk premalignant pancreatic lesions often go unnoticed by palpation or white light visualization, leading to recurrence. We asked whether near-infrared fluorescence imaging of tumor-associated inflammation could identify high-risk premalignant lesions, leveraging the tumor microenvironment (TME) as a sentinel of local disease and, thus, enhance surgery outcomes. Experimental Design: Fluorescence-guided surgery was performed on genetically engineered mice (Ptf1a-Cre; LSL-KrasG12D/+; Smad4flox/flox [KSC]) at discrete stages of disease progression, histologically confirmed high-risk, premalignant lesions in postnatal mice to locally advanced pancreatic tumors in adults, using the imaging agent V-1520, a translocator protein (TSPO) ligand. Age-matched wild-type littermates were used as controls, while Ptf1a-Cre; LSL-KrasG12D/+(KC) mice modeled pancreatitis and precursors of low penetrance. Localization of V-1520 and tumor-associated macrophages amongst the TME was detected by immunofluorescence imaging. Results: V-1520 exhibited robust accumulation in the pancreata of KSC mice from the early postnatal stage. Increased accumulation was observed in the pancreata of adolescent- and adult-aged mice with greater ductal lesion and stromal burden. Confocal microscopy of ex vivo pancreas specimens co-localized V-1520 accumulation primarily with CD68-expressing macrophage in KSC mice. Unlike the pancreata of KSC mice, accumulation of V-1520 did not exceed background levels in the pancreata of KC mice with pancreatitis. Conclusion: V-1520 exhibited differential accumulation in pancreatic cancer-associated inflammation compared to pancreatitis. Given the robust tracer uptake in tissues associated with early yet high-risk lesions, we envision V-1520 could enhance surgical resection and reduce the potential for recurrence from residual disease.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"22 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899114","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}

{"title":"Immune-MRD status informs tumor-MRD outcome prognostication in patients with multiple myeloma on lenalidomide maintenance","authors":"Ross S. Firestone, Anish K. Simhal, Devin McAvoy, Eric M. Jurgens, Juan-Jose Garcés, David Nemirovsky, Andriy Derkach, Kylee H. Maclachlan, Malin Hultcrantz, Sham Mailankody, Urvi A. Shah, Carlyn R. Tan, Neha Korde, Hani Hassoun, Sridevi Rajeeve, Hamza Hashmi, Heather J. Landau, Michael Scordo, Gunjan L. Shah, Sergio A. Giralt, Benjamin T. Diamond, Francesco Maura, Kinga Hosszu, David J. Chung, Ola Landgren, Saad Z. Usmani, Alexander M. Lesokhin","doi":"10.1158/1078-0432.ccr-25-0572","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0572","url":null,"abstract":"Purpose: Lenalidomide maintenance is the most frequently utilized approach for newly diagnosed multiple myeloma (MM) patients following induction therapy with/without consolidative high-dose melphalan and autologous stem cell transplantation. Baseline and longitudinal measurable residual disease (MRD) negative status is a well-established positive predictive sign in lenalidomide maintenance patients. However, the clinical utility of serial MRD assessments remains uncertain, as there is no consensus on the clinical management of MRD-resurgence (MRDres) or stable remissions in patients positive for MRD. Experimental Design: Here we report the complete and final results of a phase 2, single-arm study of 5 years of continuous lenalidomide maintenance in MM patients following unrestricted upfront therapy, along with exploratory peripheral blood T cell profiling experiments performed via high-dimensional spectral cytometry. Results: Patients with MRDres had inferior PFS to those with sustained MRD-negativity at the 1- and 2-year landmarks (P=0.036, P=0.0014 respectively); however, myeloma progression only occurred within 2 years of MRDres in 36% of patients, with no progression observed in the remaining 64% of patients at last follow-up. Exploratory peripheral blood T cell profiling experiments throughout the trial period identified an immune signature of early relapse in patient cohorts both negative and positive for MRD at the start of maintenance therapy. T cell profiles enriched with activated cytotoxic effectors predicted early relapse while quiescent T cell profiles enriched with naïve T cell populations predicted durable remissions. Conclusions: This “immune-MRD” status showed predictive potential, and segregated patients with MRDres and early disease progression from patients with sustained remission despite MRDres.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"37 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899116","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}

{"title":"HIGH-DOSE CHEMOTHERAPY FOR MULTIPLY OR POOR-RISK RELAPSED GERM-CELL TUMORS","authors":"Yago Nieto, John F. Ward, Wayne Hofstetter, David Rice, Jose A. Karam, Louis Pisters, Jean-Nicolas Vauthey, Amishi Shah, John K. Lin, Andrew C. Johns, John Araujo, Shi-Ming Tu, Jianbo Wang, Jing Li, Ala Abudayyeh, Peter F. Thall, Roland Bassett, Melissa Barnett, Alison Gulbis, Terri Lynn Shigle, Jeremy Ramdial, Uday Popat, Muzaffar Qazilbash, Roy B. Jones, Borje S. Andersson, Elizabeth J. Shpall, Irtiza Sheikh, Lance Pagliaro, Matthew T. Campbell","doi":"10.1158/1078-0432.ccr-25-1917","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-1917","url":null,"abstract":"Purpose: Sequential high-dose chemotherapy (HDC) using carboplatin/etoposide (CE) with autologous stem-cell transplant can be curative in relapsed germ-cell tumors (GCT). However, outcomes are poor for multiply relapsed/refractory tumors. We studied gemcitabine/docetaxel/melphalan/carboplatin (GemDMC), which exploits DNA damage repair inhibition. We hypothesized that concurrent bevacizumab, targeting the high vascularity of GCT, would synergize with HDC. Methods: Trial eligibility included 2nd or later relapse or poor-risk 1st relapse, and adequate end-organ function. Treatment consisted of sequential bevacizumab-GemDMC (HDC cycle 1, C1) and bevacizumab-ifosfamide/carboplatin/etoposide (ICE) (C2), in 3 consecutive cohorts: bevacizumab/full-dose GemDMC (cohort 1), bevacizumab/reduced-dose GemDMC (cohort 2), and no bevacizumab/reduced-dose GemDMC (cohort 3). The trial was powered to distinguish a target 50% 2-year RFS rate from an expected <25%. We validated its results in an off-trial 4th cohort treated the same as cohort 3. Findings: We treated 165 male patients (65 trial, 100 cohort 4), after a median of 3 prior therapy lines; mostly cisplatin-refractory tumors at relapse (45% refractory, 23% absolutely refractory); 19% primary mediastinal tumors. Overall response rate: 84.5% (77% CR/PRm-). The treatment-related mortality rates in cohorts 1 to 4 were 13%, 8%, 4%, and 4%, respectively. Resection of residual lesions in 74 patients found no viable GCT in 76%. The 5-year RFS and overall survival rates were 57.1% and 58.3%, respectively, without differences between trial and cohort 4 patients, or between patients receiving bevacizumab (cohorts 1/2) or not (cohorts 3/4). Conclusions: Sequential GemDMC-(I)CE in multiply poor-risk relapsed GCT shows outcomes that exceed the anticipated results. Bevacizumab did not improve outcomes.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"22 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899123","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}

{"title":"Evolution and co-occurrence of PI3K pathway gene mutations in endometrial carcinoma molecular subtypes at the single-cell level","authors":"Arnaud Da Cruz Paula, Yingjie Zhu, David N. Brown, Shirin Issa Bhaloo, Fresia Pareja, Timothy J. Hoang, Hunter Green, Thais Basili, Higinio Dopeso, Pier Selenica, Edaise M. da Silva, Nadeem Riaz, Sarat Chandarlapaty, Nadeem R. Abu-Rustum, Jorge S. Reis-Filho, Britta Weigelt","doi":"10.1158/1078-0432.ccr-25-1237","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-1237","url":null,"abstract":"Purpose: The PI3K pathway is altered in >85% of endometrioid endometrial carcinomas (EECs), with multiple mutations commonly co-occurring. Yet, the therapeutic effects of single-agent PI3K pathway inhibitors have been limited. We used single-cell sequencing to determine whether co-occurring PTEN, PIK3CA, and/or PIK3R1 somatic mutations in EECs stratified by molecular subtype originated through convergent or linear evolution. Methods: Banked frozen EECs with co-occurring PI3K pathway mutations of no specific molecular profile (NSMP; n=5), mismatch repair-deficient (MMRd;n=3), and POLE (n=3) subtype were selected for single-nucleus DNA sequencing targeting hotspot variants of 64 cancer-related genes and the PTEN, PIK3R1 and PIK3CA coding sequences. EEC cell lines and non-malignant samples were used to define error rates and filter false-positive calls. Results: Single-nucleus analyses (n=50,009 cells) revealed that in NSMP EECs, the co-occurring PIK3CA, PIK3R1, and/or PTEN mutations affected nearly all cells through linear evolution. MMRd EECs displayed higher levels of genetic heterogeneity, harboring PI3K pathway gene mutations in subsets of cells ranging from 3.9%-96%. POLE EECs had the highest level of clonal diversity and harbored multiple minor subclonal structures in all cases, through convergent evolution. We found a clear distinction between nearly clonal PI3K pathway gene alterations (>95%) and multiple minor, mutually-exclusive subclones only affecting 1.4%-27% of the tumor cells sequenced. Conclusions: Our exploratory, hypothesis-generating analysis suggest that PI3K pathway alterations evolve distinctly in MMRd/POLE compared to NSMP EECs, which may have therapeutic consequences. Further studies on the signaling output and PI3K pathway inhibitor response in EECs with subclonal PI3K pathway alterations are warranted.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"27 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899188","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}

{"title":"Diversity by Design: Real-World Data to Enhance Representation in Clinical Cancer Research","authors":"Thao T. Vo, Sangmi Kim, Ashley Jaksa, Benjamin Bates, Wei Zhou, Mark D. Stewart, Mehmet Burcu","doi":"10.1158/1078-0432.ccr-25-1255","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-1255","url":null,"abstract":"Inclusive and diverse enrollment in clinical trials promotes trust in clinical research and its findings by improving generalizability and fostering health and healthcare equities. Diverse participation also facilitates the detection of potential differences in treatment response across subgroups, thereby enhancing precision medicine efforts. Yet, cancer patients who participate in clinical trials are more likely to be Caucasian, younger, and healthier compared to their representation in the broader cancer population. Given emerging health authority guidance and other related initiatives calling for more representative trials, there is an urgent need to develop and implement strategies to improve enrollment of a study population that reflects the intended use population. Real-world data/evidence (RWD/E) can help set trial enrollment targets and strategy, identify drivers and barriers in recruiting diverse populations, and provide supplemental evidence on under-represented populations, thus improving external validity of clinical trial results. In this perspective review, we outline a diversity dimension framework that includes demographic, clinical, treatment environment and other elements, and discuss opportunities and challenges with which RWD/E could enhance clinical trial representativeness and diversity. Specifically, we discuss the diversity dimensions relevant to oncology clinical development and various approaches in utilizing RWD to improve diversity across stages of clinical development, with use cases.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"25 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899189","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}

{"title":"The Impact of Concordance Between Liquid and Tissue Biopsy for Actionable Mutations: Insights from the Rome Trial","authors":"Andrea Botticelli, Chiara Cremolini, Simone Scagnoli, Mauro Biffoni, Sara Lonardi, Lorenzo Fornaro, Valentina Guarneri, Ugo De Giorgi, Paolo Ascierto, Giovanni Blandino, Giulia d'Amati, Massimo Aglietta, Pierfranco Conte, Edoardo Crimini, Maurizio Ceracchi, Simona Pisegna, Sofia Verkhovskaia, Roberto Bordonaro, Sergio Bracarda, Giovanni Butturini, Lucia Del Mastro, Andrea De Censi, Agnese Fabbri, Elisabetta Fenocchio, Stefania Gori, Giulio Metro, Annamaria Pessino, Daniele Pozzessere, Fabio Puglisi, Stefano Tamberi, Alberto Zambelli, Donatella Marino, Ettore Capoluongo, Federico Cappuzzo, Bruna Cerbelli, Giuseppe Giannini, Umberto Malapelle, Federica Mazzuca, Marianna Nuti, Giancarlo Pruneri, Maurizio Simmaco, Lidia Strigari, Giuseppe Tonini, Nello Martini, Giuseppe Curigliano, Paolo Marchetti","doi":"10.1158/1078-0432.ccr-25-0430","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0430","url":null,"abstract":"Purpose: This analysis evaluated the influence of tissue and liquid biopsy concordance on outcomes in patients enrolled in the ROME Trial. Experimental design: The ROME trial, a phase II multicenter study, enrolled 1,794 patients with advanced solid tumors. Next-generation sequencing (NGS) was performed on tissue and liquid biopsies using FoundationOne CDx and FoundationOne Liquid CDx, A centralized Molecular Tumor Board (MTB) reviewed results to identify actionable alterations, with 400 patients randomized to tailored therapy (TT) or standard-of-care (SoC).TT improved objective response rate and progression-free survival (PFS) in the Intention to Treat population. Concordance was defined as the detection of the same druggable alteration in both biopsy types; discordance indicated detection in only one. Results: Concordance was present in 49% of cases, with alterations detected exclusively in tissue (35%) or liquid (16%) biopsies. Patients in the concordant group receiving TT experienced improved survival outcomes. Median overall survival (OS) was 11.05 vs. 7.70 months in the SoC group (HR 0.74; 95% CI: 0.51-1.07), and median PFS was 4.93 vs. 2.80 months (HR 0.55; 95% CI: 0.40-0.76). In contrast, the survival benefit of TT was less pronounced or absent in patients with discordant results. OS was higher in the T+L group (11.05 months), followed by tissue-only (9.93 months), and liquid-only groups (4.05months). PFS followed a similar pattern, with the longest PFS in T+L group (4.93 months) vs 3.06 months in tissue-only and 2.07 months in liquid-only groups. Conclusions: The study highlights the potential value of integrating both biopsy modalities in selected clinical contexts.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"31 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899186","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}

{"title":"Proliferation of tumor-related regulatory T cells in circulation dictates efficacy of chemoimmunotherapy in triple-negative breast cancer","authors":"Seung Hyuck Jeon, Koung Jin Suh, Sungmin Jung, Minwoo Jeon, Ho Cheol Jang, Eui-Soon Kim, Se Hyun Kim, Kyung-Hun Lee, Seock-Ah Im, Min Hwan Kim, Joohyuk Sohn, Jae Ho Jeong, Kyung Hae Jung, Kyoung Eun Lee, Yeon Hee Park, Hee-Jun Kim, Eun Kyung Cho, In Sil Choi, So Yeon Park, Milim Kim, Jee Hyun Kim, Eui-Cheol Shin","doi":"10.1158/1078-0432.ccr-24-3283","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3283","url":null,"abstract":"Purpose: PD-1/PD-L1 blockade modulates the responses of T cells including regulatory T (TREG) cells. Understanding the changes of TREG cells upon PD-1/PD-L1 blockade in cancer patients and their association with therapeutic response will provide clues regarding the mechanisms underlying resistance to treatment. Experimental Design: Peripheral blood samples were acquired before and at 1-week post-treatment from 65 patients (triple-negative [TN], n = 35; luminal, n = 30) enrolled in KORNELIA phase 2 trial, which evaluated the efficacy of chemoimmunotherapy combining nivolumab and eribulin in HER2 negative breast cancer (BC) patients. Immunophenotype of circulating immune cells was analyzed using flow cytometry. T-cell receptor sequencing was used to track the clonotypes of circulating TREG cells in relation to the tumor-related clonotypes. Results: In both breast cancer subtypes, chemoimmunotherapy increased the proportion of circulating TREG cells as well as their proliferative response. Notably, we observed an increased frequency of the circulating TREG-cell population with tumor-related clonotypes after treatment in TNBC. Moreover, increased proliferation of circulating TREG cells was associated with poor response to treatment, only in TNBC. This association between circulating TREG-cell proliferation and poor clinical response was further supported by analysis of publicly available single-cell transcriptomic data from TNBC patients. A TREG-cell-based biomarker predicted both clinical response and survival outcomes in TNBC. Conclusions: Our results indicate that the proliferation and expansion of tumor-related clonotypes among circulating TREG cells are related to chemoimmunotherapy resistance particularly in TNBC.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"12 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899183","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}

{"title":"FDA Approval Summary: Blinatumomab for the Treatment of B-cell Precursor Acute Lymphoblastic Leukemia in the Consolidation Phase of Multiphase Chemotherapy.","authors":"Cara A Rabik, Shu Wang, Ritu Chadda, Donna Przepiorka, Jonathon Vallejo, Xiling Jiang, Marc R Theoret, R Angelo de Claro","doi":"10.1158/1078-0432.CCR-25-1034","DOIUrl":"10.1158/1078-0432.CCR-25-1034","url":null,"abstract":"<p><p>On June 14, 2024, the FDA approved blinatumomab (Blincyto; Amgen, Inc) in the consolidation phase of treatment for CD19-positive, Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia (BCP ALL). FDA reviewed results from three randomized trials using blinatumomab in consolidation: Study E1910 (adult patients with newly diagnosed BCP ALL without minimal residual disease), Study 20120215 (pediatric patients with high-risk BCP ALL in first relapse), and Study AALL1331 (pediatric and young adult patients with BCP ALL in first relapse). Study E1910 demonstrated a significant improvement in overall survival (OS) when comparing alternating blinatumomab and chemotherapy cycles versus chemotherapy cycles alone (HR 0.42; 95% CI 0.24, 0.75; p = 0.003). In Study 20120215, the efficacy of blinatumomab as an alternative to a third cycle of chemotherapy was primarily supported by descriptive analyses of the secondary endpoint of OS (HR 0.35; 95% CI 0.17, 0.7) and a post-hoc analysis of relapse-free survival (RFS) (HR 0.38; 95% CI 0.22, 0.66). AALL1331 did not meet its primary objectives for the randomizations in the high/intermediate-risk arm comparing blinatumomab vs chemotherapy or in the low-risk arm comparing blinatumomab cycles and chemotherapy cycles versus chemotherapy cycles alone. A meta-analysis of OS performed using the above studies and the infant study NL59901.078.17 was consistent with a treatment effect of blinatumomab during consolidation . The safety profile of blinatumomab cycles was consistent with previous studies. The benefit of blinatumomab during the consolidation phase of therapy is consistent across line of therapy (newly diagnosed versus relapsed) and patient age (adult versus pediatric).</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12367060/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144871687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}