bims-tumhet Biomed News
on Tumor Heterogeneity
Issue of 2025–03–09
sixteen papers selected by
Sergio Marchini, Humanitas Research
  1. Epigenetic modification and tumor immunity: Unraveling the interplay with the tumor microenvironment and its therapeutic vulnerability and implications.
  2. LINE-1 ORF1p expression occurs in clear cell ovarian carcinoma precursors and is a candidate blood biomarker.
  3. Cellular origins of mucinous ovarian carcinoma.
  4. Putting comprehensive genomic profiling of ctDNA to work: 10 proposed use cases.
  5. Global research trends in liquid biopsy for ovarian cancer from 1999 to 2023: A 25-year bibliometric analysis.
  6. ENACT: End-to-end Analysis of Visium High Definition (HD) Data.
  7. Benchmarking copy number aberrations inference tools using single-cell multi-omics datasets.
  8. ctDNA-based liquid biopsy reveals wider mutational profile with therapy resistance and metastasis susceptibility signatures in early-stage breast cancer patients.
  9. Treatment of Pleural Mesothelioma: ASCO Guideline Clinical Insights.
  10. Liquid biopsy into the clinics: Current evidence and future perspectives.
  11. Advances in the management of endometrial cancer.
  12. Exploring the clinical utility of liquid biopsy with cfDNA in cancer: A systematic review.
  13. Global alliances in translational cancer research.
  14. Liquid biopsy: Cell-free DNA based analysis in breast cancer.
  15. Pembrolizumab plus chemotherapy in advanced or recurrent endometrial cancer: overall survival and exploratory analyses of the NRG GY018 phase 3 randomized trial.
  16. Early Circulating Tumor DNA Kinetics as a Dynamic Biomarker of Cancer Treatment Response.
  1. Cancer Lett. 2025 Feb 27. pii: S0304-3835(25)00151-X. [Epub ahead of print]616 217587
    Epigenetic modification and tumor immunity: Unraveling the interplay with the tumor microenvironment and its therapeutic vulnerability and implications.
    Huaijin Zheng, Yuze Hua, Sen Yang, Vincent Liu, Nan Huang, Jiayi Li, Jorg Kleeff, Quan Liao, Qiaofei Liu.
      In the ever-evolving arena of molecular biology, epigenetic modifications stand out as crucial determinants in the orchestration of cellular identity, function, and fate. This review analyzes the close relationship between epigenetics and tumor immunity, emphasizing the intricate interplay with the tumor microenvironment (TME). Rooted in the knowledge that the incidence of cancer correlates strongly with the biological and genetic age, we highlight DNA methylation as a cornerstone of the "epigenetic aging" process with close ties to tumorigenesis. The TME, with its diverse cellular and acellular constituents, is an active participant in tumor biology, further complicated by epigenetic alterations. These modifications, from DNA methylation to histone changes, not only shape the TME but are reciprocally influenced by it, reinforcing a cycle that propels malignancy. Through this exploration, we underline the importance of understanding this mutual relationship, as it holds significant implications for tumor growth, heterogeneity, and therapeutic resistance. Ultimately, this review illuminates the potential of harnessing epigenetic insights for innovative cancer therapeutic strategies, pointing towards a promising avenue for future cancer management.
    Keywords:  Epigenetics; TME; Therapeutic resistance; Tumor immunity
    DOI:  https://doi.org/10.1016/j.canlet.2025.217587
  2. NPJ Precis Oncol. 2025 Mar 06. 9(1): 62
    LINE-1 ORF1p expression occurs in clear cell ovarian carcinoma precursors and is a candidate blood biomarker.
    Pamela R de Santiago, Sho Sato, Stephanie J Zhang, Meaghan C Dougher, Kyle M Devins, Agnes J Bilecz, Sagar Rayamajhi, Gabriel Mingo, Hannah S Rendulich, Yi Feng, Connie Wu, Martin S Taylor, Yelena Zhuravlev, Euihye Jung, Dalia K Omran, Tian-Li Wang, Ie-Ming Shih, Lauren E Schwartz, Sarah Kim, Mark A Morgan, Janos L Tanyi, Kathleen H Burns, Ernst Lengyel, Carlos Parra-Herran, Andrew K Godwin, David R Walt, Ronny Drapkin.
      Long interspersed element 1 (LINE-1) retrotransposons are repetitive sequences that can move within the genome by an autonomous mechanism. To limit their mutagenic potential, benign cells restrict LINE-1 expression through molecular mechanisms such as DNA methylation and histone modification, but these mechanisms are usually impaired in cancer. Clear cell ovarian carcinoma (CCOC) represents 5-10% of ovarian cancers and is thought to arise from endometriosis. Women with advanced CCOC face poor prognoses, highlighting the importance of understanding early disease pathogenesis. In our study, 33 of 40 cases (over 82%) of CCOC tumors express ORF1p, a LINE-1-encoded protein. We found that LINE-1 de-repression is an early event in CCOC, as ORF1p is enhanced during the transition from typical to atypical endometriosis and persists in invasive cancer. Finally, using single-molecule array (Simoa) assays, we detected ORF1p in patient blood, suggesting it as a potential minimally invasive biomarker for this disease.
    DOI:  https://doi.org/10.1038/s41698-025-00849-1
  3. J Pathol. 2025 Mar 03.
    Cellular origins of mucinous ovarian carcinoma.
    Nicola S Meagher, Martin Köbel, Anthony N Karnezis, Aline Talhouk, Michael S Anglesio, Andrew Berchuck, Simon A Gayther, Paul Pd Pharoah, Penelope M Webb, Susan J Ramus, Kylie L Gorringe.
      Mucinous ovarian carcinoma (MOC) is a rare histotype of epithelial ovarian cancer. Its origins are obscure: while many mucinous tumours in the ovary are metastases from the gastrointestinal tract, MOC can occur as an ovarian primary; however, the cell of origin is not well established. In this review we summarise the pathological, epidemiological, and molecular evidence for the cellular origins of MOC. We propose a model for the origins of the various tumours of the ovary with mucinous differentiation. We distinguish Müllerian from gastrointestinal-type mucinous differentiation. A small proportion of the latter arise from teratoma and a distinct terminology has been proposed. Other gastrointestinal mucinous tumours are associated with Brenner tumours and arise from their associated benign lesions, Walthard nests. The remaining mucinous tumours develop either through mucinous metaplasia in established Müllerian tumours or with even greater plasticity through gastrointestinal metaplasia of epithelial or mesothelial ovarian inclusions. This model remains to be validated and mechanistically understood and we discuss future research directions. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
    Keywords:  cell of origin; mucinous; ovarian cancer
    DOI:  https://doi.org/10.1002/path.6407
  4. J Liq Biopsy. 2024 Jun;4 100140
    Putting comprehensive genomic profiling of ctDNA to work: 10 proposed use cases.
    Aakash Desai, Lincoln W Pasquina, Candice Nulsen, Rachel B Keller-Evans, Douglas A Mata, Hanna Tukachinsky, Geoffrey R Oxnard.
      Liquid biopsy profiling of circulating tumor DNA (ctDNA) has become established as a compelling, pragmatic diagnostic in the care of cancer patients and is now endorsed by multiple cancer care guidelines. Moreover, ctDNA profiling technologies have advanced significantly and offer increasingly comprehensive and reliable insights into cancer. In this review, we focus on applications of ctDNA and propose that a critical untapped opportunity is in considering how we utilize these accessible, scalable technologies across diverse potential applications. With a specific focus on clinical applications, rather than research uses, we describe 10 use cases for ctDNA profiling across four categories: (1) established and (2) emerging applications of ctDNA profiling for therapy selection, (3) incidental detection of secondary genomic findings, and (4) quantification of plasma DNA tumor content.
    Keywords:  Circulating tumor DNA; Comprehensive genomic profiling; Liquid biopsy
    DOI:  https://doi.org/10.1016/j.jlb.2024.100140
  5. J Liq Biopsy. 2024 Sep;5 100158
    Global research trends in liquid biopsy for ovarian cancer from 1999 to 2023: A 25-year bibliometric analysis.
    Jixian Wan, Zechuan Rao, Huaichao Liu, Jipeng Wan.
       Background: Ovarian cancer (OC) is a major cause of gynecological cancer-related death in the world. Liquid biopsy has shown great potential in improving the ovarian cancer detection and treatment. The aim of this study is to explore the previous studies, current hotspots, and future trends of liquid biopsy for OC from a bibliometric perspective.
    Methods: Articles on liquid biopsy in the field of OC were collected from Web of Science (Clarivate Analytics). Subsequently, bibliometric and visual analyses was conducted using bibliometrix, VOSviewer, CiteSpace, and Microsoft Excel.
    Results: A total of 504 scientific papers were retrieved over a 25-year period, of which 285 papers were in the language of English. China has the highest number and other papers came from 41 countries or regions. The journal with the highest publication count was Cancers. There were 2013 authors in total, and Kasimir-Bauer S emerged as the most productive author. The key words that are still exploding are recurrence, predictive value and survival.
    Conclusion: Research on liquid biopsy is booming in the field of OC. This article comprehensively elucidates the subject matter over recent years, and points out emerging trends for in-depth exploration.
    Keywords:  Bibliometric analysis; Circulating tumor DNA; Circulating tumor cells; Exosomes; Liquid biopsy; Ovarian cancer
    DOI:  https://doi.org/10.1016/j.jlb.2024.100158
  6. Bioinformatics. 2025 Mar 07. pii: btaf094. [Epub ahead of print]
    ENACT: End-to-end Analysis of Visium High Definition (HD) Data.
    Mena Kamel, Yiwen Song, Ana Solbas, Sergio Villordo, Amrut Sarangi, Pavel Senin, Mathew Sunaal, Luis Cano Ayestas, Clement Levin, Seqian Wang, Marion Classe, Ziv Bar-Joseph, Albert Pla Planas.
       MOTIVATION: Spatial transcriptomics (ST) enables the study of gene expression within its spatial context in histopathology samples. To date, a limiting factor has been the resolution of sequencing based ST products. The introduction of the Visium High Definition (HD) technology opens the door to cell resolution ST studies. However, challenges remain in the ability to accurately map transcripts to cells and in assigning cell types based on the transcript data.
    RESULTS: We developed ENACT, a self-contained pipeline that integrates advanced cell segmentation with Visium HD transcriptomics data to infer cell types across whole tissue sections. Our pipeline incorporates novel bin-to-cell assignment methods, enhancing the accuracy of single-cell transcript estimates. Validated on diverse synthetic and real datasets, our approach is both scalableto samples with hundreds of thousands of cells and effective, offering a robust solution for spatially resolved transcriptomics analysis.
    AVAILABILITY AND IMPLEMENTATION: ENACT source code is available at https://github.com/Sanofi-Public/enact-pipeline. Experimental data is available at https://zenodo.org/records/14748859.
    SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
    Keywords:  Analysis Pipeline; Machine Learning; Spatial Transcriptomics
    DOI:  https://doi.org/10.1093/bioinformatics/btaf094
  7. Brief Bioinform. 2025 Mar 04. pii: bbaf076. [Epub ahead of print]26(2):
    Benchmarking copy number aberrations inference tools using single-cell multi-omics datasets.
    Minfang Song, Shuai Ma, Gong Wang, Yukun Wang, Zhenzhen Yang, Bin Xie, Tongkun Guo, Xingxu Huang, Liye Zhang.
      Copy number alterations (CNAs) are an important type of genomic variation which play a crucial role in the initiation and progression of cancer. With the explosion of single-cell RNA sequencing (scRNA-seq), several computational methods have been developed to infer CNAs from scRNA-seq studies. However, to date, no independent studies have comprehensively benchmarked their performance. Herein, we evaluated five state-of-the-art methods based on their performance in tumor versus normal cell classification; CNAs profile accuracy, tumor subclone inference, and aneuploidy identification in non-malignant cells. Our results showed that Numbat outperformed others across most evaluation criteria, while CopyKAT excelled in scenarios when expression matrix alone was used as input. In specific tasks, SCEVAN showed the best performance in clonal breakpoint detection and Numbat showed high sensitivity in copy number neutral LOH (cnLOH) detection. Additionally, we investigated how referencing settings, inclusion of tumor microenvironment cells, tumor type, and tumor purity impact the performance of these tools. This study provides a valuable guideline for researchers in selecting the appropriate methods for their datasets.
    Keywords:  copy number aberrations; copy number alteration; copy number variations; loss of heterozygosity; single cell multi-omics; single-cell RNA sequencing
    DOI:  https://doi.org/10.1093/bib/bbaf076
  8. J Liq Biopsy. 2025 Mar;7 100284
    ctDNA-based liquid biopsy reveals wider mutational profile with therapy resistance and metastasis susceptibility signatures in early-stage breast cancer patients.
    Atul Bharde, Snigdha Nadagouda, Manoj Dongare, Kanchan Hariramani, Madhura Basavalingegowda, Sumit Haldar, Alain D'Souza, Bhagwat Jadhav, Sangeeta Prajapati, Vikas Jadhav, Sujit Joshi, Aravindan Vasudevan, Mohan Uttarwar, Wenhui Zhou, Sirish Kishore, Kumar Prabhash, Jayant Khandare, Gowhar Shafi.
      A minimally invasive analysis of plasma cell-free DNA (cfDNA) offers a genomic profiling of early-stage breast cancer (EBC), potentially identifying mutational signatures linked to metastasis and therapy resistance. In this study, paired plasma and tissue samples from 40 hormone receptor-positive (HR+) EBC patients were sequenced using a custom-designed comprehensive gene panel, OncoIndx. The genomic landscape of circulating tumor DNA (ctDNA) showed a broader mutation spectrum compared to tumor tissue DNA (tDNA), and provided reliable assessments of microsatellite instability (MSI), tumor mutation burden (TMB), homologous recombination deficiency (HRD), and loss of heterogeneity (LOH), all indicating high genomic instability. Importantly, early detection of estrogen receptor α (ESR1) mutations in ctDNA was achieved, highlighting its potential to identify patients at risk for endocrine resistance, a standard of care for HR + breast tumors. Mutations, particularly in DNA damage response (DDR) and proliferative signaling pathways (phosphatidyl inositol-4,5-bisphosphate 3-kinase; PIK3CA) suggest an increased risk of therapy resistance, pointing to opportunities for risk stratification and tailored treatment strategies in EBC. ctDNA-based liquid biopsy may provide minimally invasive comprehensive genomic analysis of EBC for identifying actionable targets and risk prediction for better disease management.
    DOI:  https://doi.org/10.1016/j.jlb.2024.100284
  9. JCO Oncol Pract. 2025 Mar 07. OP2500035
    Treatment of Pleural Mesothelioma: ASCO Guideline Clinical Insights.
    Hedy L Kindler, Ibiayi Dagogo-Jack, Marc de Perrot, Michael W Drazer, Nofisat Ismaila, Raffit Hassan.
      
    DOI:  https://doi.org/10.1200/OP-25-00035
  10. J Liq Biopsy. 2024 Jun;4 100146
    Liquid biopsy into the clinics: Current evidence and future perspectives.
    Myrto Boukovala, C Benedikt Westphalen, Victoria Probst.
      As precision oncology has become a major part of the treatment landscape in oncology, liquid biopsies have developed as a particularly powerful tool as it surmounts several limitations of traditional tissue biopsies. These biopsies involve most commonly the isolation of circulating extracellular nucleic acids, including cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA), as well as circulating tumor cells (CTCs), typically from blood. The clinical applications of liquid biopsies are diverse, encompassing the initial diagnosis and cancer detection, the application as a tool for prognostication in early and advanced tumor settings, the identification of potentially actionable alterations, the monitoring of response and resistance under systemic therapy and the detection of resistance mechanisms, the differentiation of distinct immune checkpoint blockade response patterns through serial samples, the prediction of immune checkpoint blockade responses based on initial liquid biopsy characteristics and the assessment of tumor heterogeneity. Moreover, molecular relapse monitoring in early-stage cancers and the personalization of adjuvant or additive therapy via MRD have become a major field of research in recent years. Compared to tissue biopsies, liquid biopsies are less invasive and can be collected serially, offering real-time molecular insights. Furthermore, liquid biopsies may allow for a more holistic evaluation of a patient's disease, as they assess material from all tumor sites and can theoretically reflect tumor heterogeneity. Furthermore, quicker turnaround-time also constitutes an advantage of liquid biopsies. Disadvantages or hurdles include the challenge of detecting low amounts of tumor deposits in peripheral blood or other fluids and the potential of different amounts tumor-shedding from different metastatic sites, as well as potentially false-positive from clonal hematopoietic mutations of indeterminate potential (CHIP) mutations. The clinical utility of liquid biopsies still must be validated in most settings and further research has to be done. Clinal trials including alternate bodily fluids and leveraging AI-technology are expected to revolutionize the field of liquid biopsies.
    Keywords:  Clinical application; Liquid biopsy; Minimal residual disease; ctDNA
    DOI:  https://doi.org/10.1016/j.jlb.2024.100146
  11. BMJ. 2025 Mar 05. 388 e080978
    Advances in the management of endometrial cancer.
    Bradley R Corr, Britt K Erickson, Emma L Barber, Christine M Fisher, Brian Slomovitz.
      Endometrial cancer is now the most lethal gynecologic malignancy, with incidence rates rising globally. Treatment strategies have historically been focused on a combination of surgery, radiation, and/or chemotherapy based primarily on histology and extent of tumor. Advances in the evaluation and treatment of endometrial cancers are occurring at a rapid pace, with a new focus on genomic profiling and targeted therapies. Surgical removal of the tumor remains the mainstay of therapy, but adjuvant treatments are a shifting paradigm. In the realm of gynecologic malignancies, endometrial cancer leads in the evolution of precision medicine. The ability to analyze patients, tumors, and therapy has increased over the past 10 years. Gaps in knowledge about racial and ethnic disparities, as well as pre-invasive disease prevention, are closing. This review describes the advances in endometrial cancer with a focus on people at risk, molecular classification, and modern therapeutic strategies.
    DOI:  https://doi.org/10.1136/bmj-2024-080978
  12. J Liq Biopsy. 2024 Sep;5 100150
    Exploring the clinical utility of liquid biopsy with cfDNA in cancer: A systematic review.
    Keerthi Ranganathan, Neethu Sheri Kurian, Hitesh M Goswami, Kshitij D Rishi, Vidya H Veldore.
      Various tumor cells may exhibit different genetic or phenotypic characteristics. This phenomenon of cancer cells, known as Tumor Heterogeneity, is responsible for multiple cancer sites caused in a single patient through metastases. It is possible that the biopsy of the most accessible metastasis will not provide enough information to reexamine tumor features and make therapeutic recommendations. Liquid biopsy is a diagnostic technique that probes metastatic deposits from biofluids like peripheral blood for cell-free DNA (cfDNA)/circulating tumor DNA (ctDNA) from cancer patients. This analysis provides researchers and oncologists a comprehensive insight into therapeutic targets and treatment resistance-causing gene alterations. Various studies have validated that cfDNA/ctDNA may be essential in tumor analysis, constituting the need for the identification of cancer cells that may reactivate and proliferate, causing the disease to reoccur. This detection is also called Minimal Residual Disease (MRD) and shares insights on the efficiency of the treatment regimen and if the cancer cells have developed resistance to a specific treatment regimen. In this review, the significance of cfDNA/ctDNA as a possible diagnostic, prognostic, or monitoring biomarker for solid tumors has been evaluated in recent studies, and its clinical relevance in routine cancer clinics in India has been reviewed.
    Keywords:  Cell-free DNA (cfDNA); Circulating tumor DNA (ctDNA); Clinical utility; Liquid biopsy; Minimal residual disease (MRD); Tumor; Tumor heterogeneity
    DOI:  https://doi.org/10.1016/j.jlb.2024.100150
  13. Cancer Cell. 2025 Feb 25. pii: S1535-6108(25)00057-1. [Epub ahead of print]
    Global alliances in translational cancer research.
    Hui-Yan Luo, Yun-Xin Lu, Kohei Shitara, Heinz-Josef Lenz, Rui-Hua Xu.
      Translating basic cancer biology into effective clinical therapies remains a major challenge due to differences in research models, communication gaps, and limited funding. This commentary underscores the transformative potential of international collaborations, which integrate diverse resources, multidisciplinary talents, and innovative trial designs to bridge the gap between laboratory discoveries and clinical applications. By fostering global alliances, sharing knowledge, and harmonizing regulatory and funding frameworks, we can accelerate breakthroughs in cancer treatment, improving patient outcomes worldwide.
    DOI:  https://doi.org/10.1016/j.ccell.2025.02.005
  14. J Liq Biopsy. 2023 Sep;1 100002
    Liquid biopsy: Cell-free DNA based analysis in breast cancer.
    Konstantinos Venetis, Giulia Cursano, Carlo Pescia, Marianna D'Ercole, Francesca Maria Porta, Marta Cruz Blanco, Chiara Frascarelli, Mariia Ivanova, Elena Guerini Rocco, Nicola Fusco.
      Breast cancer management has witnessed significant advancements, especially in the diagnosis and treatment response monitoring through the implementation of imaging techniques and tissue biopsy procedures. Nevertheless, there is potential for further improvement by integrating less invasive approaches that offer timely and precise information. Liquid biopsy, which involves isolating tumor-derived components such as circulating cell-free DNA (cfDNA) and its subset known as circulating tumor DNA (ctDNA), can greatly enhance the prognosis, identification of specific genomic alterations, and selection of targeted therapies for breast cancer patients. While the incorporation of ctDNA-based testing into clinical practice has been primarily focused on metastatic breast cancer (MBC), there is growing interest in its applicability in early-stage breast cancer given the ability to capture tumor heterogeneity. Additionally, the minimally invasive nature of ctDNA testing allows for multiple serial samplings, providing a dynamic assessment of tumor characteristics and monitoring treatment response over time. However, the analysis of ctDNA in breast cancer encounters a significant challenge related to its abundance and the temporal aspect of the disease. The quantity of ctDNA in relation to the disease stage poses an important obstacle that often hinders its accurate analysis. Therefore, it is crucial to ensure timely sample collection, employ sensitive detection methods, and carefully manage the pre-analytical phase to overcome these challenges and facilitate successful ctDNA analysis in breast cancer. This article aims to summarize the methodologies employed in the detection of ctDNA, provide a comprehensive review of the current applications of ctDNA analysis in breast cancer, and elucidate the underlying rationale for its potential extension into broader clinical contexts. Furthermore, models that could facilitate the widespread adoption of ctDNA testing in various healthcare institutions are discussed.
    Keywords:  Biomarkers; Breast cancer; Liquid biopsy; cfDNA; ctDNA
    DOI:  https://doi.org/10.1016/j.jlb.2023.100002
  15. Nat Med. 2025 Mar 05.
    Pembrolizumab plus chemotherapy in advanced or recurrent endometrial cancer: overall survival and exploratory analyses of the NRG GY018 phase 3 randomized trial.
    Ramez N Eskander, Michael W Sill, Lindsey Beffa, Richard G Moore, Joanie M Hope, Fernanda B Musa, Robert S Mannel, Mark S Shahin, Guilherme H Cantuaria, Eugenia Girda, Elizabeth Lokich, Juraj Kavecansky, Charles A Leath, Lilian T Gien, Emily M Hinchcliff, Shashikant B Lele, Lisa M Landrum, Floor Backes, Roisin E O'Cearbhaill, Tareq Al Baghdadi, Emily K Hill, Premal H Thaker, Veena S John, Stephen Welch, Amanda N Fader, Matthew A Powell, Carol Aghajanian.
      Historically, the treatment of patients with advanced stage or recurrent endometrial cancer included paclitaxel plus carboplatin. Immunotherapy in combination with chemotherapy resulted in improved clinical outcomes in several solid tumors. In the phase 3 NRG GY018 study, pembrolizumab plus chemotherapy significantly improved investigator-assessed progression-free survival (PFS; primary endpoint) versus placebo plus chemotherapy in patients with advanced/metastatic/recurrent endometrial cancer regardless of mismatch repair status. Here we report on key secondary endpoints and exploratory analyses. Patients were women ≥18 years old with newly diagnosed stage III or IVA endometrial cancer with measurable disease, or stage IVB or recurrent endometrial cancer with or without measurable disease. Patients (n = 810) were randomized (1:1) to pembrolizumab or placebo plus paclitaxel-carboplatin followed by maintenance pembrolizumab or placebo for up to 24 months. Overall survival was a secondary endpoint and PFS per RECIST v.1.1 by blinded independent central review was an exploratory endpoint. Overall survival data were immature; hazard ratios favored pembrolizumab (mismatch repair-proficient: 0.79 (0.53-1.17); 1-sided nominal P = 0.1157; mismatch repair-deficient: 0.55 (0.25-1.19); 1-sided nominal P = 0.0617). Hazard ratios (95% confidence intervals) for PFS per blinded independent central review favored pembrolizumab (mismatch repair-proficient: 0.64 (0.49-0.85); P = 0.0008; mismatch repair-deficient: 0.45 (0.27-0.73); P = 0.0005). These findings further support the use of pembrolizumab plus chemotherapy as first-line treatment for patients with advanced stage or recurrent endometrial cancer regardless of mismatch repair status. ClinicalTrials.gov identifier: NCT03914612 .
    DOI:  https://doi.org/10.1038/s41591-025-03566-1
  16. JCO Clin Cancer Inform. 2025 Mar;9 e2400160
    Early Circulating Tumor DNA Kinetics as a Dynamic Biomarker of Cancer Treatment Response.
    Aaron Li, Emil Lou, Kevin Leder, Jasmine Foo.
       PURPOSE: Circulating tumor DNA (ctDNA) assays are promising tools for the prediction of cancer treatment response. Here, we build a framework for the design of ctDNA biomarkers of therapy response that incorporate variations in ctDNA dynamics driven by specific treatment mechanisms. These biomarkers are based on novel proposals for ctDNA sampling protocols, consisting of frequent sampling within a compact time window surrounding therapy initiation-which we hypothesize to hold valuable prognostic information on longer-term treatment response.
    METHODS: We develop mathematical models of ctDNA kinetics driven by tumor response to several therapy classes and use them to simulate randomized virtual patient cohorts to test candidate biomarkers.
    RESULTS: Using this approach, we propose specific biomarkers, on the basis of ctDNA longitudinal features, for targeted therapy and radiation therapy. We evaluate and demonstrate the efficacy of these biomarkers in predicting treatment response within a randomized virtual patient cohort data set.
    CONCLUSION: This study highlights a need for tailoring ctDNA sampling protocols and interpretation methodology to specific biologic mechanisms of therapy response, and it provides a novel modeling and simulation framework for doing so. In addition, it highlights the potential of ctDNA assays for making early, rapid predictions of treatment response within the first days or weeks of treatment and generates hypotheses for further clinical testing.
    DOI:  https://doi.org/10.1200/CCI-24-00160
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