Clinical Cancer Research最新文献

{"title":"Glypican-3-Targeted PET Imaging for Precise Diagnosis of Hepatocellular Carcinoma: From Bench to Bedside.","authors":"Zhaoguo Lin,Mengting Li,Zhidi Pan,Wenzhu Hu,Yuan Feng,Xiao Zhang,Haiyang Yin,Shusheng Wang,Zhangyi Song,Xiaoying Lv,Xiangming Song,Danzha Zheng,Weiwei Ruan,Yongkang Gai,Ming Yang,Dawei Jiang,Xiong Cai,Jianwei Zhu,Xiaoli Lan","doi":"10.1158/1078-0432.ccr-25-1856","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-1856","url":null,"abstract":"PURPOSEThis study aims to develop and evaluate a novel Glypican-3 (GPC3)-targeted single-chain variable fragment (scFv)-based PET radiotracer for noninvasive assessment of GPC3 expression and precise diagnosis of hepatocellular carcinoma (HCC) in both preclinical models and a first-in-human clinical study.EXPERIMENTAL DESIGNThe novel anti-GPC3 scFv, namely XH-06, was labeled with Gallium-68 (68Ga) to obtain [68Ga]Ga-XH-06. Cell uptake assays, small-animal PET imaging, and biodistribution studies were performed to evaluate its targeting ability. In the first-in-human study, 8 patients with suspected HCC underwent [68Ga]Ga-XH-06 PET/magnetic resonance imaging (PET/MR). Radiotracer uptake in tumors and normal tissues was quantified, and tumor-to-blood ratios (TBR) and tumor-to-liver ratios (TLR) were calculated.RESULTS[68Ga]Ga-XH-06 was synthesized with high radiochemical purity and exhibited specific uptake and efficient internalization in GPC3-positive cells. In subcutaneous and orthotopic animal models, [68Ga]Ga-XH-06 effectively visualized HCC tumors. Eight patients underwent [68Ga]Ga-XH-06 PET/MR scans and no adverse events were observed. The radiotracer successfully detected HCC lesions, including sub-centimeter tumors, with high imaging contrast. Among 7 patients with HCC, the median maximum standardized uptake value (SUVmax) of the lesions was 16.9 (range, 8.2-51.8), the median TLR was 6.2 (range, 2.8-24.7) and the median TBR was 16.6 (range, 3.0-57.6) at 2.5 h post-injection.CONCLUSIONS[68Ga]Ga-XH-06 is clinically promising for detecting GPC3-positive HCC with a favorable safety profile. Further investigation is warranted to validate the clinical value of GPC3-targeted PET imaging in HCC management.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"3 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182551","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":"Prognostic significance and predictive value of circulating tumor cells in invasive lobular breast carcinoma - an exploratory analysis of the STIC CTC trial.","authors":"Jose Luis Sandoval,Nicolas Kiavue,Lounes Djerroudi,William Jacot,Thomas Bachelot,Hugues Bourgeois,Anthony Goncalves,Etienne Brain,Jean-Yves Pierga,Catherine Alix-Panabieres,Frédérique Berger,Sylvain Dureau,François-Clement Bidard","doi":"10.1158/1078-0432.ccr-25-0807","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0807","url":null,"abstract":"PURPOSEIn patients with metastatic breast cancer (MBC), ≥5 circulating tumor cells (CTC)/7.5mL of blood is a validated adverse prognostic marker. The STIC CTC phase III trial (N=778, HR+ HER2- MBC) showed that ≥5 CTC/7.5mL before treatment predicted greater benefit from first-line chemotherapy over endocrine therapy for progression-free (PFS) and overall survival (OS). This exploratory analysis examines these results by histological subtype, comparing invasive lobular carcinoma (ILC) and carcinoma of no special type (NST).PATIENTS AND METHODSBaseline CTC count (CellSearch®) and its impact on PFS and OS were compared between ILC (N=159) and NST (N=571). The survival benefit of chemotherapy in patients with high CTC counts was then re-evaluated separately for each subtype.RESULTSBefore treatment, ILC had significantly higher CTC counts than NST (median: 10 [Q1=2, Q3=40] vs. 1 [Q1=0, Q3=7]). ≥5 CTC/7.5mL was found in 64% (95%CI [56-71]) of ILC and 31% (95%CI [28-35]) of NST patients, correlating with shorter PFS and OS in both. However, ILC patients with ≥5 CTC/7.5mL saw no significant benefit from CTC-informed chemotherapy (PFS: HR=0.91 [0.55-1.52]; OS: HR=0.83 [0.46-1.52]). In contrast, NST patients with ≥5 CTC/7.5mL had markedly improved outcomes with chemotherapy (PFS: HR=0.54 [0.37-0.81]; OS: HR=0.37 [0.21-0.66]).CONCLUSIONSILC shed more CTCs than NST, likely due to biological differences. While the ≥5 CTC/7.5mL threshold remained a valid prognostic marker for both, it was predictive of chemotherapy benefit in NST, but not ILC. These findings highlight differences in biomarker utility between ILC and NST, affecting both threshold relevance and treatment response.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"20 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182552","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":"Personalized Thyroidology: Molecular Rewiring of Thyroid Nodule Management.","authors":"Kartik Sehgal","doi":"10.1158/1078-0432.ccr-25-2474","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2474","url":null,"abstract":"Multi-gene molecular testing panels demonstrated excellent performance characteristics for evaluation of indeterminate thyroid nodules and independently risk-stratified advanced tumor stage in the Chinese population. Findings support incorporating cost-conscious molecular diagnostics in an integrated pathway along with clinical, sonographic and cytologic features, while underscoring need for prospective validation in future studies.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"66 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145153356","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":"Spatial profiling identifies tumor-associated stroma enrichment and MIF as potential immunotherapy targets in primary Ewing sarcomas.","authors":"Christopher Kuo,Krinio Giannikou,Nuoya Wang,Mikako Warren,Andrew Goodspeed,Nick Shillingford,Masanori Hayashi,Micha Sam Brickman Raredon,James F Amatruda","doi":"10.1158/1078-0432.ccr-25-0635","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0635","url":null,"abstract":"PURPOSEThe Tumor Microenvironment (TME) has a vital role in cancer survival and progression, and may play roles in drug resistance and immune escape. To date, few studies have detailed the TME of Ewing sarcoma (EwS).EXPERIMENTAL DESIGNWe performed spatially resolved transcriptomics of primary treatment-naïve EwS tumor biopsies from patients with or without clinical metastasis, complemented by high-plex spatial proteomic analysis.RESULTSWe discovered greater stromal enrichment in localized EwS primary tumors compared to metastasis-associated EwS primary tumors. Through spatial ligand-receptor analysis, we show that the stromal enriched regions harbor unique extracellular matrix related cytokines, immune recruitment and proinflammatory microenvironmental signals, implying EwS stroma may play an anti-tumor role by acting as an immune recruitment center. All EwS tumors expressed pro-tumorigenic MIF-CD74 immune signaling connectivity, suggesting a potential immune-evasive mechanism.CONCLUSIONSIn addition to the immune recruitment role of tumor-associated stroma, our findings provide spatial insight into the TME of EwS and provide a rationale for the preclinical investigation of MIF as a potential target for Ewing sarcoma immunotherapy.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"88 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127132","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":"E7386 enhances lenvatinib's antitumor activity in preclinical models and human hepatocellular carcinoma.","authors":"Agavni Mesropian,Albert Gris-Oliver,Ugne Balaseviciute,Alka A Potdar,Takayuki Kimura,Jialing Shen,Martí Torres-Marcén,Jordi Abril-Fornaguera,Marta Piqué-Gili,David Camell-Raventos,Judit Peix,Elisa Fernández-Martínez,Júlia Huguet-Pradell,Ana Hernández de Sande,Ieva Keraite,Roger Esteban-Fabró,Marina Barcena-Varela,Katherine E Lindblad,Amaia Lujambio,Ernesto Guccione,Swan Thung,Masafumi Ikeda,Masatoshi Kudo,Daniela Sia,Roser Pinyol,Josep M Llovet","doi":"10.1158/1078-0432.ccr-25-0725","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0725","url":null,"abstract":"PURPOSEAberrant activation of β-catenin (CTNNB1) occurs in ~30% of hepatocellular carcinomas (HCC) and is associated with immune evasion and limited response to immunotherapy. However, it remains an undruggable target. Here, we studied the antitumor and antiangiogenic activity of combining E7386 (an oral protein-protein interaction inhibitor targeting CREB-binding protein (CBP)/β-catenin) with lenvatinib and elucidated a novel mechanism of action of E7386 that boosts antitumor response.EXPERIMENTAL DESIGNWe generated a genetically engineered CTNNB1-mutant murine HCC model and randomized the animals to receive vehicle, E7386, lenvatinib, or the combination (n=22-23/arm). We evaluated survival and analyzed the tumors transcriptomically and by immunohistochemistry. Also, we analyzed five patient-derived organoids (PDOs), four HCC cell lines, and seven paired pre-/on- treatment specimens from HCC patients receiving E7386 in combination with lenvatinib in the context of a phase 1b/2 trial (NCT04008797).RESULTSE7386 in combination with lenvatinib significantly prolonged mouse survival versus monotherapy. Cell lines and PDO data corroborated that sensitivity to E7386 involves processes beyond CBP/β-catenin interaction blockade. Mechanistically, E7386 promoted Activating Transcription Factor 4 (ATF4) activation, triggering integrated stress response in preclinical models of HCC. In vivo, E7386 concomitantly potentiated the antiangiogenic effects of lenvatinib, resulting in increased antitumor efficacy. Upregulation of ATF4 gene expression signatures was confirmed in four out of seven E7386+lenvatinib-treated HCC patients, three of which exhibited tumor diameter shrinkage >30%.CONCLUSIONSE7386 sensitized tumors to lenvatinib, thereby enhancing survival in mice compared with either monotherapy. In patients, E7386 combined with lenvatinib promoted tumor shrinkage and, in parallel, activated ATF4 signaling.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"318 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127033","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":"Combination of olaparib, durvalumab and fulvestrant in patients with advanced ER+/HER2- breast cancer and selected genomic alterations: results of the DOLAF trial.","authors":"Séverine Guiu,Judith Balmaña,Pablo Lemercier,Philippe Follana,Anthony Gonçalves,Frédéric Bigot,Jean-Sebastien Frenel,Etienne Brain,Audrey Mailliez,Camille Chakiba Brugere,Elsa Curtit,Olfa Derbel,Florence Dalenc,Fanny Derquin,Francois Duhoux,Jean-Luc Canon,Isabel Pimentel,Louise Marie Chevalier,Adrien Buisson,Clara Guyonneau,Jérôme Lemonnier,Suzette Delaloge,Thomas Bachelot","doi":"10.1158/1078-0432.ccr-24-4221","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-4221","url":null,"abstract":"PURPOSEPrevious data suggest synergy between PARP inhibition and immune checkpoint blockade in different genetic settings. The estrogen receptor (ER) pathway remains a key target in metastatic breast cancer whatever the genomic context. This study assess the activity of the combination of PARP, ER, and PDL1 inhibition among patients with metastatic breast cancer and relevant genomic alterations.PATIENTS AND METHODSIn this multicenter single arm phase II clinical trial, we used a Simon's two-stage design to evaluate the activity and safety of a combination of durvalumab, olaparib and fulvestrant as second- or third-line in patients with ER+/HER2- metastatic breast cancer. Patients with either somatic or germline mutations of an HRR-gene, an MSI status or an endocrine resistance-related mutation were eligible. Primary endpoint was 24-week progression-free survival rate (PFSR).RESULTSThe 172 (100%) patients included received prior endocrine therapy for metastatic breast cancer, 86% a CDK4/6 inhibitor, and 67 (39%) had a previously documented gBRCA1/2m. The 24-week PFSR was 66.7% (95% CI: 58.6-74.1) in the evaluable population and 76.3% (95% CI: 63.4-86.4) in gBRCA1/2m patients. Median PFS was 9.3 months (95% CI: 7.5-12.7) and 12.6 months (95% CI: 8.2-16.7) in the ITT and gBRCA1/2m populations, respectively. Median OS was 30 months (95% CI: 26.6-NR). Most common adverse events of any grade were nausea (59%) and asthenia (43%). No new toxicity warning was detected.CONCLUSIONIn patients with ER+/HER2- metastatic breast cancer and selected genomic alterations, this triplet combination was active and had an acceptable toxicity profile (NCT04053322).","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"16 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127034","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":"Bridging EGFR/TGF-β signaling to bypass resistance to immune checkpoint blockade.","authors":"Noura J Choudhury,Aditi Kothari,Christine M Bestvina,Natalia Issaeva","doi":"10.1158/1078-0432.ccr-25-2727","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2727","url":null,"abstract":"Although EGFR is a common target in squamous cancers, anti-EGFR monotherapies have shown modest success due to existing or acquired activation of other oncogenic pathways and tumor heterogeneity. A bifunctional fusion protein ficerafusp alfa in combination with pembrolizumab represents a potential solution to overcome resistance in early phase clinical investigation.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"88 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127035","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":"Patient-derived organoids predict treatment response in metastatic colorectal cancer.","authors":"Lidwien P Smabers,G Emerens Wensink,Carla S Verissimo,Mayke Doorn,Tao Yang,Timo Voskuilen,Maarten A Huismans,Liselot Valkenburg-van Iersel,Geert A Cirkel,Elske C Gootjes,Henk M W Verheul,Frank J Jeurissen,Guus M Bol,Hilde H Nienhuis,Manon N G J A Braat,Edwin Cuppen,Robert G J Vries,Frederieke H van der Baan,Sjoerd G Elias,Onno Kranenburg,Miriam Koopman,Sylvia F Boj,Jeanine M L Roodhart","doi":"10.1158/1078-0432.ccr-25-1564","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-1564","url":null,"abstract":"PURPOSEAccurately predicting treatment response in metastatic colorectal cancer (mCRC) is critical to avoid unnecessary toxicity and improve patient outcomes. Patient-derived organoids (PDOs) are promising models, but larger prospective studies are needed to confirm their predictive value.EXPERIMENTAL DESIGNmCRC patients underwent a metastatic biopsy for PDO establishment, before starting new systemic treatment. Predictors of PDO establishment were identified. PDOs were incubated with a seven-drug panel, including the patient's treatment, to determine drug sensitivity as measured by CyQUANT cell viability (AUC, GRAUC, IC50, and GR50). Patient response was measured by size change of biopsied and all target lesions. The diagnostic performance was evaluated by PPV, NPV, and AUROC. Additionally, the association between PDO response and survival was assessed.RESULTSA total of 232 patients were included and 205 biopsies were obtained. PDO establishment success increased from 22% to 75%, yielding 52% overall. Male sex, increased lactate dehydrogenase, biopsy in academic hospitals, optimized culture conditions and experience were related to PDO establishment success. In this interim analysis, focused on oxaliplatin-based doublet chemotherapy, 42 PDOs were screened. PDO drug sensitivity significantly correlated with response of the biopsied lesion (R=0.41-0.49, p<0.011) and all target lesions (R=0.54-0.60, p<0.001) for all treatments combined. The 5-FU & oxaliplatin PDO screens demonstrated high predictive accuracy (PPV: 0.78, NPV: 0.80, AUROC: 0.78-0.88) and were associated with PFS and OS (p=0.016 and 0.049).CONCLUSIONSWe identified predictors for successful mCRC PDO establishment and validated that PDOs can accurately predict patient outcomes during systemic treatment, specifically with 5-FU & oxaliplatin.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"50 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145103338","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":"Clonal hematopoiesis of indeterminate potential influences breast cancer outcomes in a genotype-specific manner.","authors":"Sarah C Reed,Chad R Potts,Leo Luo,Brad A Davidson,Riley E Bergman,Justin D J Kemp,Ethan K Fox,Bryce A Thomas,Lauren Ha,Vani Arora,Justin Cartailler,Melinda E Sanders,Violeta Sanchez,Paula Gonzalez-Ericsson,Sarah Croessmann,Paula J Hurley,Alex Bick,P Brent Ferrell,Ben Ho Park","doi":"10.1158/1078-0432.ccr-25-2009","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2009","url":null,"abstract":"PURPOSEClonal hematopoiesis of indeterminate potential (CHIP) has been associated with adverse outcomes in some solid tumor settings, but its impact on breast cancer remains unclear. We sought to investigate the genotype-specific effects of CHIP on breast cancer outcomes and the tumor microenvironment.EXPERIMENTAL DESIGNWe examined a retrospective cohort of 125 patients with breast cancer, using targeted sequencing to identify CHIP. Metastatic events were recorded, and distant metastasis-free survival probability was analyzed. In parallel, we developed chimeric mouse models of the two most mutated CHIP genes, DNMT3A and TET2. CHIP and control mice were orthotopically injected with syngeneic breast cancer cells. Tumor growth was measured, and immune infiltrate was profiled via mass cytometry.RESULTSCHIP was present in 18.4% of patients. High-burden CHIP and non-DNMT3A CHIP were associated with significantly shorter distant metastasis-free survival. In vivo, mice with Tet2-CHIP developed larger primary tumors and were more likely to experience lung metastasis, while Dnmt3a-CHIP did not differ from controls. The general immune subsets observed in both CHIP models were similar, but immunophenotyping revealed clonal expansion and immune cell subset skewing specific to the Tet2-CHIP model.CONCLUSIONSOur findings demonstrate a genotype-specific impact of CHIP on breast cancer across human and mouse data. Further, the chimeric mouse models we generated offer a clinically relevant tool to study solid tumors in a CHIP background. This work underscores the need for further functional studies and personalized risk assessment to clearly define the impact of various CHIP genotypes on breast cancer.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"78 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145083481","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 prognostic impact of early ctDNA kinetics in metastatic pancreatic cancer using the ctDNA Response Evaluation Criteria in Solid Tumors (ctDNA-RECIST).","authors":"Mette M Steiniche,Sidsel C Lindgaard,Inna M Chen,Julia S Johansen,Rikke F Andersen,Torben F Hansen,Lars H Jensen,Louise S Rasmussen,Malene W Johansen,Morten Ladekarl,Anders K M Jakobsen,Karen-Lise G Spindler","doi":"10.1158/1078-0432.ccr-25-0758","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0758","url":null,"abstract":"INTRODUCTIONChanges in ctDNA levels during systemic treatment may predict treatment efficacy in patients with metastatic pancreatic ductal adenocarcinoma (PDAC), but quantitative response criteria are not yet established. This study evaluates our recently proposed ctDNA Response Evaluation Criteria in Solid Tumors (ctDNA-RECIST).MATERIAL AND METHODBlood samples were collected pre-treatment, before the second treatment cycle, and at time of the first CT-evaluation from 220 patients with metastatic PDAC receiving first line palliative chemotherapy. Plasma ctDNA levels were measured using digital droplet PCR (ddPCR) with HOXA9 methylation assays. ctDNA response was determined according to ctDNA-RECIST and correlated with overall survival (OS).RESULTSctDNA was positive pre-treatment in 71% of the patients, and was related with OS (HR=1.61, 95% CI 1.19-2.19, p=0.002). Among ctDNA-positive patients, ctDNA Maximal Response (MR) (n=41) and ctDNA Disease Control (DC) (n=107) before the second treatment cycle had longer OS compared with ctDNA Progressive Disease (PD) (n=5) (median OS: MR 11.9 months, DC 7.2 months, PD 3.6 months; p=0.002). In Cox regression ctDNA DC (HR=1.55, 95% CI 1.07-2.26, p=0.021) and ctDNA PD (HR=4.50, 1.74-11.6, p=0.002) showed shorter OS compared to ctDNA MR. The same applied to ctDNA response from the second treatment cycle (p<0.001) and at time of the first CT-evaluation assessed from treatment start (p<0.001) Conclusion: ctDNA-RECIST applied to liquid biopsies holds potential for early evaluation of treatment benefit in patients with metastatic PDAC, offering a novel, minimally invasive method to guide early clinical decision making. Future studies should validate ctDNA-RECIST prospectively, preferably in randomised controlled trials.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"16 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145083436","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}