Clinical Cancer Research最新文献

{"title":"The Society for Immunotherapy of Cancer Perspective on Tissue-Based Technologies for Immuno-Oncology Biomarker Discovery and Application","authors":"Anne Monette, Adriana Aguilar-Mahecha, Emre Altinmakas, Mathew G. Angelos, Nima Assad, Gerald Batist, Praveen K. Bommareddy, Diana L. Bonilla, Christoph H. Borchers, Sarah E. Church, Gennaro Ciliberto, Alexandria P. Cogdill, Luigi Fattore, Nir Hacohen, Mohammad Haris, Vincent Lacasse, Wen-Rong Lie, Arnav Mehta, Marco Ruella, Houssein Abdul. Sater, Alan Spatz, Bachir Taouli, Imad Tarhoni, Edgar Gonzalez-Kozlova, Itay Tirosh, Xiaodong Wang, Sacha Gnjatic","doi":"10.1158/1078-0432.ccr-24-2469","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2469","url":null,"abstract":"With immuno-oncology becoming the standard of care for a variety of cancers, identifying biomarkers that reliably classify patient response, resistance, or toxicity becomes the next critical barrier towards improving care. Multi-parametric, multi-omics, and computational platforms generating an unprecedented depth of data are poised to usher in the discovery of increasingly robust biomarkers for enhanced patient selection and personalized treatment approaches. Deciding which developing technologies to implement in clinical settings ultimately, applied either alone or in combination, relies on weighing pros and cons, from minimizing patient sampling to maximizing data outputs, and assessing reproducibility and representativeness of findings, while lessening data fragmentation towards harmonization. These factors are all assessed while taking into consideration the shortest turnaround time. The Society for Immunotherapy of Cancer (SITC) Biomarkers Committee convened to identify important advances in biomarker technologies and to address advances in biomarker discovery using multiplexed immunohistochemistry and immunofluorescence, their coupling to single cell transcriptomics, along with mass spectrometry-based quantitative and spatially resolved proteomics imaging technologies. We summarize key metrics obtained, ease of interpretation, limitations and dependencies, technical improvements, and outward comparisons of these technologies. By highlighting the most interesting recent data contributed by these technologies, and by providing ways to improve their outputs, we hope to guide correlative research directions and assist in their evolution towards becoming clinically useful in IO.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"16 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142763425","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":"Oncology Combination Drug Development Strategies for Project Optimus.","authors":"Timothy A Yap, Julie Bullock, Susan Chong, Megan K Doyle, Azher Hussain, Jackie Kline, Amandine Manon, Karthik Venkatakrishnan, Vijay V Upreti","doi":"10.1158/1078-0432.CCR-24-1836","DOIUrl":"10.1158/1078-0432.CCR-24-1836","url":null,"abstract":"<p><p>The Project Optimus initiative from the FDA introduced a new dose optimization and selection paradigm in oncology drug development. The FDA has outlined approaches to dose optimization for single agents, but multiple oncology drugs are being developed for use in combination with other therapies. Dose optimization in the context of combination drug development is complex and requires a case-by-case approach. It necessitates commitment to the totality of available evidence, leveraging all relevant data on mechanism of action, nonclinical and clinical pharmacology, safety, and principles of model-informed drug development. In this article, we outline key considerations for sponsors and investigators pursuing dose optimization with combinatorial regimens. We illustrate important strategies for dose optimization in the combination setting using a range of hypothetical case examples that represent typical drug development scenarios. Close discussions and collaboration with regulators regarding the optimal approaches to these scenarios will continue to be critical.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"5237-5241"},"PeriodicalIF":10.0,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375226","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":"Pilot Trial of Perampanel on Peritumoral Hyperexcitability in Newly Diagnosed High-grade Glioma.","authors":"Steven Tobochnik, Michael S Regan, Maria K C Dorotan, Dustine Reich, Emily Lapinskas, Md Amin Hossain, Sylwia Stopka, David M Meredith, Sandro Santagata, Melissa M Murphy, Omar Arnaout, Wenya Linda Bi, E Antonio Chiocca, Alexandra J Golby, Michael A Mooney, Timothy R Smith, Keith L Ligon, Patrick Y Wen, Nathalie Y R Agar, Jong Woo Lee","doi":"10.1158/1078-0432.CCR-24-1849","DOIUrl":"10.1158/1078-0432.CCR-24-1849","url":null,"abstract":"<p><strong>Purpose: </strong>Glutamatergic neuron-glioma synaptogenesis and peritumoral hyperexcitability promote glioma growth in a positive feedback loop. The objective of this study was to evaluate the feasibility and estimated effect sizes of the targeted AMPA receptor antagonist perampanel on peritumoral hyperexcitability.</p><p><strong>Experimental design: </strong>An open-label trial was performed comparing perampanel with standard of care (SOC) in patients undergoing resection of newly diagnosed radiologic high-grade glioma. Perampanel was administered as a preoperative loading dose followed by maintenance therapy until progressive disease or up to 12 months. SOC treatment involved levetiracetam for 7 days or as clinically indicated. The primary outcome of hyperexcitability was defined by intraoperative electrocorticography high-frequency oscillation (HFO) rates. Seizure freedom and overall survival were estimated by the Kaplan-Meier method. Tissue concentrations of perampanel, levetiracetam, and correlative biomarkers were measured by mass spectrometry.</p><p><strong>Results: </strong>HFO rates were similar between patients treated with perampanel and levetiracetam. The trial was terminated early after a planned interim analysis, and outcomes assessed in 11 patients (seven perampanel treated; four treated with SOC). Over a median 281 days of postenrollment follow-up, 27% of patients had seizures, including 14% maintained on perampanel and 50% treated with SOC. Overall survival in perampanel-treated patients was similar to that in a glioblastoma reference cohort. Glutamate concentrations in surface biopsies were positively correlated with HFO rates in adjacent electrode contacts and were not significantly associated with treatment assignment or drug concentrations.</p><p><strong>Conclusions: </strong>Glioma peritumoral glutamate concentrations correlated with high-gamma oscillation rates. Targeting glutamatergic activity with perampanel achieved similar electrocorticographic hyperexcitability levels as in levetiracetam-treated patients.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"5365-5373"},"PeriodicalIF":10.0,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11611619/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582102","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}

{"title":"Tissue-Based Profiling Techniques to Achieve Precision Medicine in Cancer: Opportunities and Challenges in Melanoma.","authors":"Tuba N Gide, Yizhe Mao, Richard A Scolyer, Georgina V Long, James S Wilmott","doi":"10.1158/1078-0432.CCR-24-1109","DOIUrl":"10.1158/1078-0432.CCR-24-1109","url":null,"abstract":"<p><p>Immunotherapies targeting the programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) checkpoint receptors have revolutionized the treatment of metastatic melanoma. However, half of the treated patients do not respond to or eventually progress on standard therapies and many experience adverse events as a result of drug toxicity. The identification of accurate biomarkers of clinical outcomes are required in order to move away from the one-size-fits-all treatment approach of standard clinical practice and toward a more personalized approach to enable the administration of the optimal therapy for any given patient and further improve patient outcomes. Recent clinical trials have proven the potential of multiomics analyses, including genomic, gene expression, and tumor immune profiling, of patients' tumor biopsies, to predict a patient's response to subsequently administered immunotherapies. However, reproducibility of such multiomics analyses, tissue requirements, and clinical validation have limited the practical application of these approaches in routine clinical workflows. In this review, we discuss several pivotal tissue-based profiling techniques that can be utilized to identify potential genomic, transcriptomic, and immune biomarkers predictive of clinical outcomes following treatment with immune checkpoint inhibitors in melanoma. Furthermore, we highlight the key opportunities and challenges associated with the use of each of these techniques. The development and implementation of multimodal predictive models that combine data derived from these various methods is the future for achieving precision medicine for patients with melanoma.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"5270-5280"},"PeriodicalIF":10.0,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380140","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":"Active surveillance in patients with extra-abdominal desmoid-type fibromatosis: a pooled analysis of three prospective observational studies","authors":"Chiara Colombo, Stefanie Hakkesteegt, Axel Le Cesne, Francesco Barretta, Jean-Yves Blay, Dirk J. Grünhagen, Nicolas Penel, Laurent Lam, Marco Fiore, Elena Palassini, Giovanni Grignani, Francesco Tolomeo, Paola Collini, Alessandra Merlini, Federica Perrone, Silvia Stacchiotti, Cornelis Verhoef, Sylvie Bonvalot, Alessandro Gronchi","doi":"10.1158/1078-0432.ccr-24-2340","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2340","url":null,"abstract":"Purpose: Three prospective observational studies (Italy, the Netherlands, France) on active surveillance (AS) in patients with extra-abdominal desmoid-type fibromatosis (DTF) support AS as a frontline approach. Identifying prognostic factors for the failure of AS will help determine the strategy. The aim of this study was to investigate the prognostic impact of clinical and molecular variables in a larger series. Experimental design: Data available as of January 31st, 2024, from the three studies, in which patients were followed for ≥3 years, were pooled. Patients ≥18 years old, with primary sporadic DTF and with CTNNB1 mutations available, were eligible. The primary study endpoint was treatment-free survival (TFS). Secondary endpoints included the incidence of RECIST progression, spontaneous RECIST regression and regression post-RECIST progression. Results: Two hundred and eighty-two patients (n = 282) with a median follow-up of 53 months (IQR, 39-63) were included. Three-year and five-year TFS were 67% and 66%, crude cumulative incidences (CCI) of RECIST progression were 33% and 34%, of RECIST regression 26% and 34% and of regression post-RECIST progression 33% and 38%. In multivariable analysis, larger tumour size, mutation type, tumor locations were associated to lower TFS. The specific mutation (S45F), larger tumor size, and extremity and trunk location were all associated with a lower probability of spontaneous RECIST regression. Conclusions: This study confirms that spontaneous regression occurs in a significant proportion of patients and that two-thirds are treatment-free at 5 years. Initial tumor size, CTNNB1 mutation, and location should be factored into the initial decision-making process.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"527 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142760337","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":"Editor's Note: BRAF Status in Personalizing Treatment Approaches for Pediatric Gliomas.","authors":"Aleksandra Olow, Sabine Mueller, Xiaodong Yang, Rintaro Hashizume, Justin Meyerowitz, William Weiss, Adam C Resnick, Angela J Waanders, Lukas J A Stalpers, Mitchel S Berger, Nalin Gupta, C David James, Claudia K Petritsch, Daphne A Haas-Kogan","doi":"10.1158/1078-0432.CCR-24-3478","DOIUrl":"10.1158/1078-0432.CCR-24-3478","url":null,"abstract":"","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"30 23","pages":"5494"},"PeriodicalIF":10.0,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766704","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":"Association of Tumor Mutational Burden and PD-L1 with the Efficacy of Pembrolizumab with or without Chemotherapy versus Chemotherapy in Advanced Urothelial Carcinoma.","authors":"Aude Fléchon, Rafael Morales-Barrera, Thomas Powles, Ajjai Alva, Mustafa Özgüroğlu, Tibor Csöszi, Yohann Loriot, Alejo Rodriguez-Vida, Lajos Géczi, Susanna Y Cheng, Yves Fradet, Stéphane Oudard, Christof Vulsteke, Seyda Gunduz, Ronac Mamtani, Evan Y Yu, Alvaro Montesa Pino, Urbano Anido, Mehmet A N Sendur, Gwenaelle Gravis, János Révész, Vladimir Kostorov, Olivier Huillard, Junshui Ma, Mohini Rajasagi, Amir Vajdi, Jared Lunceford, Razvan Cristescu, Kentaro Imai, Blanca Homet Moreno, Nobuaki Matsubara","doi":"10.1158/1078-0432.CCR-23-3518","DOIUrl":"10.1158/1078-0432.CCR-23-3518","url":null,"abstract":"<p><strong>Purpose: </strong>The three-arm, phase III KEYNOTE-361 study did not meet its dual primary endpoints of progression-free survival (PFS) or overall survival (OS) with first-line pembrolizumab plus chemotherapy versus chemotherapy in advanced urothelial carcinoma. This prespecified exploratory analysis assessed the association of tumor mutational burden (TMB) and PD-L1 combined positive score (CPS) with clinical outcomes.</p><p><strong>Patients and methods: </strong>TMB and PD-L1 CPS were determined via whole-exome sequencing and PD-L1 IHC 22C3 pharmDx, respectively. The association was evaluated in each treatment arm using logistic regression [objective response rate (ORR)] and Cox proportional hazards regression models (PFS and OS); one-sided (pembrolizumab monotherapy; pembrolizumab plus chemotherapy) and two-sided (chemotherapy) nominal P values were calculated. Significance was prespecified at α = 0.05 without multiplicity adjustment. Efficacy was evaluated by prespecified cutoffs of 175 mutations/exome (TMB) and CPS 10 (PD-L1).</p><p><strong>Results: </strong>Of the 993 treated patients, 820 (82.6%) and 993 (100%) had evaluable TMB and CPS data, respectively. Continuous TMB was positively associated with ORR, PFS, and OS for pembrolizumab monotherapy (one-sided P < 0.001, P < 0.001, and P = 0.007, respectively); PFS and OS for pembrolizumab plus chemotherapy (one-sided P = 0.007 and P = 0.010, respectively); and OS for chemotherapy alone (two-sided P = 0.040). Continuous PD-L1 CPS showed evidence of anticipated association with ORR and PFS for pembrolizumab monotherapy. The subgroup with TMB ≥175 mutations/exome and PD-L1 CPS ≥10 had the highest PFS and OS improvements with pembrolizumab alone or with chemotherapy versus chemotherapy alone.</p><p><strong>Conclusions: </strong>These data suggest that TMB may be predictive of the response to pembrolizumab alone or with chemotherapy in advanced urothelial carcinoma.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"5353-5364"},"PeriodicalIF":10.0,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11609623/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544088","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}

{"title":"Determination of MYD88 and CXCR4 Mutations for Clinical Detection and Their Significance in Waldenström Macroglobulinemia.","authors":"Yuting Yan, Ying Yu, Wenjie Xiong, Jun Wang, Yao Yao, Yujiao Jia, Yanshan Huang, Yuxi Li, Tingyu Wang, Rui Lyu, Hao Sun, Haoxu Wang, Qi Wang, Wei Liu, Gang An, Weiwei Sui, Yan Xu, Wenyang Huang, Zhen Yu, Dehui Zou, Mu Hao, Zhijian Xiao, Jianxiang Wang, Lugui Qiu, Shuhua Yi","doi":"10.1158/1078-0432.CCR-23-3939","DOIUrl":"10.1158/1078-0432.CCR-23-3939","url":null,"abstract":"<p><strong>Purpose: </strong>This study aims to explore the incidence and clinical features of MYD88 and CXCR4 mutations in patients with Waldenström macroglobulinemia (WM) and determine the optimal method for routine clinical practice. Additionally, we seek to evaluate the prognostic significance of these features across various therapeutic backgrounds [the cytotoxic group, the rituximab/bortezomib-based group, and the Bruton tyrosine kinase inhibitor (BTKi) group].</p><p><strong>Experimental design: </strong>A total of 385 symptomatic patients with WM were analyzed for MYD88 and CXCR4 mutations using Sanger sequencing, next-generation sequencing, allele-specific qPCR (AS-PCR), and/or droplet digital PCR (ddPCR).</p><p><strong>Results: </strong>The overall MYD88 mutation rate was 87.8%, relatively lower than that in the Western cohort. Both AS-PCR and ddPCR demonstrated high sensitivity in unsorted samples, detecting 98.5% and 97.7% of mutations, respectively, including those with low tumor burdens. The total CXCR4 mutation rate was 30.9%, with next-generation sequencing exhibiting the highest sensitivity of 78.0%. CXCR4 mutation was significantly linked to shorter OS only within the BTKi treatment group. The multivariate analysis indicated that MYD88 and CXCR4 mutations were not independent prognostic factors in the non-BTKi group when considering the International Prognostic Scoring System for Waldenström macroglobulinemia (IPSSWM) clinical staging. However, in the BTKi treatment group, these mutations emerged as independent adverse prognostic factors, overshadowing the prognostic significance of the IPSSWM classification (MYD88: HR, 0.229; P = 0.030; CXCR4: HR, 3.349; P = 0.012).</p><p><strong>Conclusions: </strong>Testing for MYD88 mutations using AS-PCR or ddPCR in unsorted samples is viable for routine clinical practice. Under BTKi treatment, MYD88 and CXCR4 mutations hold greater prognostic importance than IPSSWM staging in WM.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"5483-5493"},"PeriodicalIF":10.0,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11609624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380139","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}

{"title":"The Prostaglandin EP4 Antagonist Vorbipiprant Combined with PD-1 Blockade for Refractory Microsatellite Stable Metastatic Colorectal Cancer: A Phase 1b/2a Trial","authors":"Filippo Pietrantonio, Federica Morano, Monica Niger, Filippo Ghelardi, Claudia Chiodoni, Michele Palazzo, Federico Nichetti, Paolo Manca, Eleonora Cristarella, Valentina Doldi, Nadia Zaffaroni, Giovanna Sabella, Nadia Brambilla, Elena Benincasa, Giampaolo Giacovelli, Cristina Vitalini, Federica Girolami, Lucio C. Rovati","doi":"10.1158/1078-0432.ccr-24-2611","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2611","url":null,"abstract":"Purpose: Novel combinations are required to overcome resistance to immune checkpoint inhibitors (ICIs) in proficient mismatch repair (pMMR) or microsatellite stable (MSS) metastatic colorectal cancer (mCRC). We aimed to determine whether vorbipiprant, a prostaglandin EP4 receptor antagonist, can convert immune-resistant mCRC into a tumor responsive to anti-PD-1 inhibition. Patients and Methods: This phase 1b/2a prospective, open-label, single-arm trial followed a 3 + 3 dose escalation and dose optimization design. A total of 28 patients with chemorefractory pMMR/MSS mCRC were given dose-escalated oral vorbipiprant (30, 90, or 180 mg twice daily), along with biweekly intravenous balstilimab (3 mg/kg), an anti-PD-1 antibody. The primary endpoints included safety and the disease control rate (DCR). Secondary endpoints were the objective response rate (ORR), duration of response, progression-free survival (PFS) and overall survival (OS). Results: No dose-limiting toxicities were observed. Out of the 28 patients, seven (25%) experienced serious adverse events, but only one was attributed to vorbipiprant and one to balstilimab. The trial achieved a DCR of 50% observed across the entire cohort. In the subgroup of patients with liver metastases (n = 12) DCR was 25%. The ORR was 11%, with three patients showing a partial response (median duration of response: 7.4 months). Median PFS was 2.6 months and median OS was 14.2 months. Translational exploratory analyses suggested that vorbipiprant may boost response to anti-PD-1 in patients with immunogenic tumors. Conclusions: The combination of vorbipiprant and a PD-1 inhibitor (balstilimab) yielded sufficient activity in refractory pMMR/MSS mCRC, worth of confirmation in future clinical trials in biomarker-enriched populations.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"46 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142760312","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":"Non-invasive multi-cancer detection using DNA hypomethylation of LINE-1 retrotransposons","authors":"Marc Michel, Maryam Heidary, Anissa Mechri, Kévin Da Silva, Marine Gorse, Victoria Dixon, Klaus von Grafenstein, Charline Bianchi, Caroline Hego, Aurore Rampanou, Constance Lamy, Maud Kamal, Christophe Le Tourneau, Mathieu Séné, Ivan Bieche, Cécile Reyes, David Gentien, Marc-Henri Stern, Olivier Lantz, Luc Cabel, Jean-Yves Pierga, Francois-Clement Bidard, Chloé-Agathe Azencott, Charlotte Proudhon","doi":"10.1158/1078-0432.ccr-24-2669","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2669","url":null,"abstract":"Purpose: The detection of circulating tumor DNA, which allows non-invasive tumor molecular profiling and disease follow-up, promises optimal and individualized management of patients with cancer. However, detecting small fractions of tumor DNA released when the tumor burden is reduced remains a challenge. Experimental Design: We implemented a new highly sensitive strategy to detect base-pair resolution methylation patterns from plasma DNA and assessed the potential of hypomethylation of LINE-1 retrotransposons as a non-invasive multi-cancer detection biomarker. The DIAMOND (Detection of Long Interspersed Nuclear Element Altered Methylation ON plasma DNA) method targets 30-40,000 young L1 scattered throughout the genome, covering about 100,000 CpG sites and is based on a reference-free analysis pipeline. Results: Resulting machine learning-based classifiers showed powerful correct classification rates discriminating healthy and tumor plasmas from 6 types of cancers (colorectal, breast, lung, ovarian, gastric cancers and uveal melanoma including localized stages) in two independent cohorts (AUC = 88% to 100%, N = 747). DIAMOND can also be used to perform copy number alterations (CNA) analysis which improves cancer detection. Conclusions: This should lead to the development of more efficient non-invasive diagnostic tests adapted to all cancer patients, based on the universality of these factors.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"45 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142760313","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}