Clinical Cancer Research最新文献

{"title":"Facts and hopes of CD40 agonists as a cancer immunotherapy","authors":"John C. McVey, Gregory L. Beatty","doi":"10.1158/1078-0432.ccr-24-1660","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1660","url":null,"abstract":"CD40 agonists are a promising class of immunotherapeutic agents that potentiate both innate and adaptive immunity. This review examines the established facts and prospects of CD40 agonists in cancer immunotherapy. CD40, a co-stimulatory receptor of the TNF receptor superfamily, is found on antigen-presenting cells. CD40 activation licenses dendritic cells to prime tumor-specific T cells, polarizes macrophages to a pro-inflammatory phenotype, activates B cells, and facilitates tumor fibrosis remodeling. Preclinical models demonstrate the significant potential of CD40 agonists to induce anti-tumor immunity, leading to the development of various CD40-activating therapeutics, including monoclonal antibodies, recombinant CD40L, and ectopic expression of CD40L via gene transfer. While clinical trials show modest antitumor activity, some patients experience durable responses, especially when CD40 agonists are combined with other therapies such as immune checkpoint inhibitors and chemotherapy. These combinations, tested in traditionally difficult-to-treat cancers like pancreatic cancer, provide hope for improved outcomes. Current research focuses on refining CD40 agonist therapies through novel combination strategies, improving patient selection, and the development of tumor-targeted CD40 agonists and Fc-engineered antibodies which aim to enhance efficacy while mitigating toxicity. However, significant challenges remain, particularly in identifying patients most likely to benefit from CD40 immunotherapy and understanding resistance mechanisms. Addressing these challenges is crucial for guiding effective combination strategies and optimizing treatment outcomes. By examining both established facts and ongoing developments, this review provides a comprehensive overview of the status and potential of CD40 agonists in cancer immunotherapy.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"22 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143672338","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":"Precision Endocrine Therapy in Endometrial Cancer: Has its time finally come?","authors":"Vikas Garg, Amit M. Oza","doi":"10.1158/1078-0432.ccr-24-3905","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3905","url":null,"abstract":"Endocrine therapy (ET) has been underexplored in endometrial cancer (EC). Emerging data suggest that combining ET with CDK4/6 inhibitors improve outcomes in EC. This commentary complements a recent CCR manuscript and reviews opportunities to improve precision ET, and the potential to overcome resistance mechanisms associated with ET failure.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"20 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143672339","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":"A phase 1 study of nilotinib in combination with paclitaxel in patients with advanced solid tumors.","authors":"Sarah J Shin, Geraldine O'Sullivan Coyne, Shivaani Kummar, Sarah B Miller, Barry C Johnson, Larry Anderson, Larry Rubinstein, Brandon Miller, Deborah F Wilsker, Katherine V Ferry-Galow, Richard Piekarz, Jennifer Zlott, Murielle Hogu, Lamin Juwara, Julia Krushkal, Mariam Konaté, Alida Palmisano, Yingdong Zhao, Jerry Collins, Ralph E Parchment, James H Doroshow, Alice P Chen","doi":"10.1158/1078-0432.CCR-24-3049","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-3049","url":null,"abstract":"<p><strong>Purpose: </strong>We assessed the safety, maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D), efficacy, pharmacokinetic, and pharmacodynamics of the nilotinib-paclitaxel combination in 44 patients with solid tumors.</p><p><strong>Patients and methods: </strong>Paclitaxel was administered intravenously (days 1, 8, and 15) and nilotinib was administered twice daily orally beginning on cycle 1 day 2 (C1D2, escalation) or C1D3 (expansion) in 28-day cycles using a 3+3 dose escalation design. Pharmacodynamic biomarkers of drug action were assessed in paired tumor biopsies and circulating tumor cells (CTCs) at the RP2D.</p><p><strong>Results: </strong>The RP2D was 300 mg nilotinib twice daily with 80 mg/m2 paclitaxel. Grade 4 (Gr4) neutropenia and Gr3 rash, photosensitivity, and transaminase elevation were dose-limiting. The most common Gr3-4 toxicities were hematological and hypophosphatemia; 1 patient (2%) experienced Gr3 peripheral neuropathy. Three patients (2 with adult ovarian granulosa cell tumors [AOGCT] and 1 with endometrial carcinoma) had confirmed partial responses (cPR); the patients with AOGCT remained on study for 5 and 6+ years and mesenchymal-like CTCs were measured prior to progression or during treatment holiday (patients 12 and 10, respectively).</p><p><strong>Conclusions: </strong>This study determined the MTD of this combination, demonstrated sustained cPRs in patients with AOGCT, and profiled molecular pharmacodynamic responses that will inform further mechanism of action studies. The rate of peripheral neuropathy suggests enhanced tolerability of this combination.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656486","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":"RECLASSIFICATION OF ATM MISSENSE VARIANTS OF UNCERTAIN SIGNIFICANCE BY INTEGRATING RESULTS FROM SYSTEMATIC FUNCTIONAL ASSAYS INTO AN ACMG POINTS-BASED FRAMEWORK.","authors":"Helmut Hanenberg, Fan Zhang, Nikita Malev, Constanze Wiek, Brett G Klamer, Nicolas Nassar, Tyler Hesselbrock, Judith H Hanenberg, Amber M Aeilts, Julia Hentschel, Ulrike Faust, Andrea Gehrig, Christoph Engel, Jan Hauke, Dieter Niederacher, Amanda E Toland, Paul R Andreassen","doi":"10.1158/1078-0432.CCR-24-3936","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-3936","url":null,"abstract":"<p><strong>Purpose: </strong>ATM is a moderate-risk cancer susceptibility gene which harbors thousands of missense variants of uncertain significance (VUS) that limit the power of clinical genetic testing for cancer risk management and personalized medicine. Functional tests provide a valuable basis for testing the impact of variants but have been lacking for ATM.</p><p><strong>Experimental design: </strong>We developed a systematic approach to functionally characterize missense ATM variants, based on correction of various DNA damage-related phenotypes, via re-expression of ATM in either of two ATM-deficient human cell lines.</p><p><strong>Results: </strong>A pKAP1 phospho-flow assay for ATM VUS observed in hereditary cancer patients was calibrated using 48 benign and pathogenic controls, achieving 100% specificity and 97% sensitivity. This system distinguished 82 of 88 (93%) missense ATM VUS of the FATKIN region as functionally neutral or deleterious. Importantly, for clinical classification of VUS, functional results were incorporated into an American College of Medical Genetics (ACMG) points-based framework, also considering conservation and properties of amino acids/substitutions, along with genetic data; 79 of 88 (90%) were thereby reclassified as benign/likely benign or pathogenic/likely pathogenic. As additional validation of our approach, clinical characteristics from a database of 1,134 breast cancer patients were distinct for carriers of neutral vs deleterious ATM variants. Also, utilizing our functional results we identified hotspots for deleterious VUS and controls at amino acids 2702-2730 and 2891-2951 of ATM.</p><p><strong>Conclusions: </strong>We have established functional assays as a reliable tool that will better interpret the clinical impact of ATM variants and guide improved cancer prevention measures for carriers.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656487","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":"Longitudinal Genomic Analysis to Fine-Tune Targeted Therapy: Results of the Phase II LOGIC 2 Trial in Patients With BRAF V600-Mutant Metastatic Melanoma","authors":"Reinhard Dummer, Shahneen Sandhu, Wilson H. Miller, Marcus O. Butler, Matthew H. Taylor, Lucie Heinzerling, Christian U. Blank, Eva Munoz-Couselo, Howard A. Burris, Michael A. Postow, Bartosz Chmielowski, Mark R. Middleton, Carola Berking, Jessica C. Hassel, Anja Heike. Gesierich, Cornelia Mauch, Joseph F. Kleha, Anna Polli, Allison S. Harney, Alessandra di Pietro, Paolo A. Ascierto","doi":"10.1158/1078-0432.ccr-24-0254","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-0254","url":null,"abstract":"Purpose: LOGIC 2 (NCT02159066), a multicenter, open-label, two-part, phase II study assessed encorafenib plus binimetinib combined with a third targeted agent after tumor progression on encorafenib plus binimetinib in patients with locally advanced unresectable or metastatic BRAF Patients and Methods: Adults with locally advanced unresectable or metastatic BRAF V600-mutant melanoma who were BRAF inhibitor/MEK inhibitor (BRAFi/MEKi)-treatment naive or pretreated received encorafenib plus binimetinib (Part I/Run-in). Based on the genomic testing at disease progression following encorafenib plus binimetinib, patients were assigned to one of four treatment arms to receive encorafenib plus binimetinib with an appropriate molecularly targeted agent (ribociclib, infigratinib, capmatinib, or buparlisib; Part II). The primary endpoint was best overall response; safety, biomarkers, pharmacokinetics, and other efficacy endpoints were also assessed. Results: In Part I/Run-in, 75 BRAFi/MEKi-naive patients and 83 BRAFi/MEKi-pretreated patients were treated; in Part II, 58 patients were treated (ribociclib, n=38; infigratinib, n=1; capmatinib, n=13; buparlisib, n=6). The overall confirmed response rate was 73.3% (95% CI, 61.9–82.9) in BRAFi/MEKi-naive patients, 25.3% (95% CI, 16.4–36.0) in pretreated patients, 2.6% (95% CI, 0.1–13.8) in the ribociclib arm, and 0% in the other three arms. Adverse events were manageable and consistent with the known safety profile of each drug. Conclusions: LOGIC 2 supports the use of encorafenib plus binimetinib for treatment naive and previously treated locally advanced unresectable or metastatic BRAF V600-mutant melanoma. However, adding a third targeted agent following disease progression did not show meaningful efficacy; further research is needed to identify other therapeutic targets to circumvent resistance.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"37 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143661328","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":"Phase I study of the mutant IDH1 inhibitor ivosidenib: long-term safety and clinical activity in patients with conventional chondrosarcoma","authors":"William D. Tap, Gregory M. Cote, Howard Burris, Lia Gore, Anthony Elias, Murali Beeram, Anthony P. Conley, Diego A. Gianolio, Zhe Qu, Susan Pandya, Jonathan C. Trent","doi":"10.1158/1078-0432.ccr-24-4128","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-4128","url":null,"abstract":"Purpose: A phase I study demonstrated that ivosidenib, a mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor, showed manageable toxicity and durable disease control in patients with mIDH1 conventional chondrosarcoma (CS). Here we present long-term follow-up data on the safety and clinical activity of ivosidenib in patients with mIDH1 conventional CS from this phase I study. Patients and Methods: This phase I open-label dose-escalation and expansion study assessed ivosidenib monotherapy in patients with advanced mIDH1 solid tumors, including CS. An ivosidenib dose of 500 mg/day was identified in the dose-escalation phase and used for the expansion phase. The primary outcome was safety and tolerability. Secondary outcomes included objective response rate (ORR) and progression-free survival (PFS). The database lock date for this analysis was 18 March 2024. Results: Of 168 patients with advanced mIDH1 solid tumors receiving ivosidenib in this study, 21 patients had CS, of which 13 had conventional histology. Six (46.2%), 4 (30.8%) and 3 (23.1%) patients with conventional CS continued ivosidenib treatment for &amp;gt;1 year, &amp;gt;6 years and &amp;gt;7 years, respectively. Of the 21 patients with CS, 71.4% and 28.6% had treatment-related and serious adverse events (SAEs), respectively, but no SAEs were considered related to ivosidenib. The ORR for patients with conventional CS was 23.1% and median duration of response was 53.5 months. The median PFS of patients with conventional CS treated with ivosidenib was 7.4 months. Conclusions: Ivosidenib demonstrated long-term disease control and manageable toxicity for some patients with mIDH1 conventional CS and is under further investigation (NCT06127407).","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"183 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653419","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":"Bevacizumab, atezolizumab and acetylsalicylic acid in recurrent, platinum-resistant ovarian cancer: the EORTC 1508-GCG phase II study","authors":"Susana Banerjee, Eleonora Ghisoni, Anita Wolfer, Petronella Beatrix. Ottevanger, Ronan Le Scodan, Apostolos Sarivalasis, Ana Montes, Judith Kroep, Margarita Romeo Marin, Petr Szturz, Matteo Morotti, Julien Dagher, Lana Kandalaft, Fernanda Herrera, Corneel Coens, Denarda Dangaj Laniti, George Coukos","doi":"10.1158/1078-0432.ccr-24-3368","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3368","url":null,"abstract":"Purpose: Treatment options for platinum-resistant ovarian cancer (PROC) are limited and new therapeutic strategies are urgently needed. This phase II, randomized, multicentre trial evaluated the safety and activity of the anti-PD-L1 antibody atezolizumab (atezo) combined with the VEGF-inhibitor bevacizumab (bev) and the irreversible cyclooxygenase inhibitor aspirin (ASA) in PROC. Patients and Methods: Patients were randomized to bev monotherapy 15 mg/kg (arm 1), atezo 1200 mg plus placebo (pbo)(arm 2), atezo plus ASA 320 mg/daily (arm 3), bev plus atezo plus pbo (arm 4) or bev plus atezo plus ASA (arm 5). Primary endpoint was progression-free survival at 6 months (PFS-6). Secondary objectives included overall survival (OS), PFS, PFS2 and tolerability. Time to first subsequent therapy (TFST) was evaluated in a post-hoc analysis. Results: In arms 1, 4 and 5, there were 7/32 (21.9%, 70% CI, 14.0-32.0), 8/32 (25.0%, 70% CI, 16.6-35.3), and 8/32 (25.0%, 70% CI, 16.6-35.3) patients alive and progression-free at 6 months. The primary objective was not reached in any arm. Median PFS were 2.3 for bev monotherapy, 4.1 for bev-atezo-pbo, and 4.0 months for bev-atezo-ASA. TFST suggested benefit of adding bev to atezo-ASA (p&amp;lt;0.001). Tumour-infiltrating lymphocytes (TILs) increased in the atezo containing arms and increased TILs were associated with longer TFST. Conclusions: The addition of ASA to bev-atezo was well tolerated but did not improve efficacy in PROC. Relative to bev, the bev-atezo combination numerically improved PFS. Exploratory analyses suggest clinical benefit in a subgroup of patients characterised by high TILs infiltration and PD-L1+ tumours at baseline.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"44 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653439","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":"Large scale multi-omic analysis identifies anatomic differences and immunogenic potential in subtypes of leiomyosarcoma","authors":"Galina Lagos, Roman Groisberg, Andrew Elliott, Don S. Dizon, Andreas Seeber, Geoffrey Thomas. Gibney, Margaret von Mehren, Kenneth Cardona, Michael J. Demeure, Richard F. Riedel, Vaia Florou, Alexander J. Chou, Jaime F. Modiano, Abhijeet Kumar, Moh'd M. Khushman, Gina Z. D'Amato, Andrea P. Espejo Freire, Bradley DeNardo, Jonathan C. Trent","doi":"10.1158/1078-0432.ccr-24-2503","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2503","url":null,"abstract":"Purpose: Comprehensive molecular profiling was used to define the genomic and immune landscapes of leiomyosarcomas (LMS) by anatomic subtype, which have not been completely characterized. Design: 1115 LMS samples, categorized into uterine (uLMS), retroperitoneal (rpLMS), or other (oLMS), underwent DNA/RNA sequencing (Caris Life Sciences). Genomic/transcriptomic profiles were compared across subtypes. Immune profiling was compared to melanoma (n=1255), an immunogenic tumor. Insurance claims data were used to infer real-world outcomes with immune checkpoint inhibitors (ICI) in LMS. Results: uLMS (n=701) were molecularly distinct from rpLMS (n=166) and oLMS (n=248). RB1 mutations and MAP2K4 copy number amplification were more common in non-uLMS. MED12 mutations were almost exclusive to uLMS. Traditional ICI response biomarkers (i.e. PD-L1) didn’t vary by anatomic site. Non-uLMS demonstrated upregulated immune-related gene sets, including interferon and inflammatory response pathways, and higher immune cell infiltration, especially CD8+ T cells and B cells (&amp;gt;2-fold increase, p&amp;lt;0.0001). LMS had lower immune cell abundance and T-cell inflamed scores (TIS) compared to melanoma, though 11% of oLMS samples had high TIS scores. In a real-world cohort (n=138), 29% of LMS patients receiving ICI were treated &amp;gt;6 months, indicating potential clinical benefit. Conclusion: Comprehensive profiling suggested that uLMS represents a molecularly distinct disease from non-uLMS. While traditional ICI response biomarkers were similar across anatomic subtypes, uLMS were immune cold compared to non-uLMS. Signals for ICI responsiveness, such as high TIS and immune cell abundance, in some tumors suggest that further research into immunotherapies for LMS is warranted.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"69 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653416","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":"IDO Believe in Immunotherapy","authors":"Peter D. Zang, Tanya B. Dorff","doi":"10.1158/1078-0432.ccr-24-4264","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-4264","url":null,"abstract":"IDO1 is central to immune downregulation. A recent phase I/II study tested the IDO1 inhibitor linrodostat with nivolumab +/- ipilimumab in patients with advanced solid tumors. While efficacy was not augmented, correlative analyses identified TDO2 as a resistance mechanism; dual targeting may be necessary to realize improved response to PD-1 inhibition.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"90 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653421","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":"Clinical validity of repeated circulating tumor cell enumeration as an early treatment monitoring tool for metastatic breast cancer in the PREDICT global pooled analysis","authors":"Wolfgang Janni, Thomas W.P. Friedl, Tracy C. Yab, Francois-Clément Bidard, Massimo Cristofanilli, Daniel F. Hayes, Michail Ignatiadis, Meredith M. Regan, Catherine Alix-Panabieres, William E. Barlow, Carlos Caldas, Lisa A. Carey, Luc Dirix, Tanja Fehm, Jose A. Garcia-Saenz, Paola Gazzaniga, Daniele Generali, Lorenzo Gerratana, Rafael Gisbert-Criado, William Jacot, Zefei Jiang, Simon A. Joosse, Evi Lianidou, Rafael López López, Mark J.M. Magbanua, Luis Manso, Dimitris Mavroudis, Volkmar Müller, Elisabetta Munzone, Klaus Pantel, Jean-Yves Pierga, Brigitte Rack, Sabine Riethdorf, Hope S. Rugo, Kostandinos Sideras, Stefan Sleijfer, Jeffrey Smerage, Justin Stebbing, Leon W.M.M. Terstappen, Jose Vidal-Martínez, Markus Wallwiener, Karthik V. Giridhar, Minetta C. Liu","doi":"10.1158/1078-0432.ccr-24-3108","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3108","url":null,"abstract":"Purpose: The aim of PREDICT was to confirm clinical validity and the potential for clinical utility of serial circulating tumor cell (CTC) enumeration in metastatic breast cancer (MBC) patients focusing on its prognostic value in different breast cancer subtypes and clinical settings. Experimental design: In total, 4436 individual patient-level data with CTC results from both baseline and one follow-up (CellSearch®; Menarini Silicon Biosystems) were analyzed to evaluate the association between CTC detection and overall survival (OS) in the full patient cohort and separately for tumor and treatment types. Results: Using the cutoff ≥ 1 CTC for CTC positivity, 913 (20.6%) patients had 0 CTCs at both time points (neg/neg), 325 (7.3%) and 1189 (26.8%) patients converted from CTC negative to CTC positive (neg/pos) or vice versa (pos/neg), while 2009 (45.3%) patients had at least one CTC at both time points (pos/pos). Median OS for the neg/neg, neg/pos, pos/neg and pos/pos group was 45.6, 26.1, 32.3, and 17.3 months, respectively (P &amp;lt; 0.0001, global log-rank test). CTC responders (pos/neg) showed a lower risk of death compared to CTC non-responders (pos/pos) (HR 0.48, 95% CI 0.44 – 0.53). Similar results were obtained in subgroup analyses according to hormone receptor and HER2 subtype, treatment type, and with a ≥ 5 CTC cutoff for CTC positivity. Conclusions: Follow-up CTC assessments strongly predict OS independently from tumor subtype and treatment. New randomized trials to define the clinical utility of CTC monitoring for risk stratification and as an early response marker in MBC are urgently needed.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"92 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653426","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}