bims-tumhet Biomed News
on Tumor heterogeneity
Issue of 2025–06–01
seven papers selected by
Sergio Marchini, Humanitas Research
  1. Clinical value of circulating tumor DNA for patients with epithelial ovarian cancer.
  2. Cell-free DNA methylation and its potential as a biomarker in liquid biopsy: A systematic review.
  3. Chromosomal instability in development and disease: Beyond cancer evolution.
  4. Mucinous Ovarian Carcinoma: Integrating Molecular Stratification into Surgical and Therapeutic Management.
  5. Early detection of multiple cancer types using multidimensional cell-free DNA fragmentomics.
  6. Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated Colorectal Cancer.
  7. Circulating tumor DNA monitoring and blood tumor mutational burden in patients with metastatic solid tumors treated with atezolizumab.
  1. Int J Gynecol Cancer. 2025 May 10. pii: S1048-891X(25)01045-X. [Epub ahead of print]35(7): 101925
    Clinical value of circulating tumor DNA for patients with epithelial ovarian cancer.
    Émilie Laude, Henri Azaïs, Mehdi Ben Sassi, Anne-Sophie Bats, Valérie Taly, Pierre Laurent-Puig.
      Despite progress in recent years, epithelial ovarian cancer remains a pathology with a poor prognosis, primarily because of late and invasive diagnosis. Conventional follow-up relies on imaging, CA125, and predictive tools such as KELIM-CA125 and the chemotherapy response score. However, these methods are non-specific and result in delays before obtaining results. Recently, many research teams have focused on liquid biopsies, which provide direct access to tumor material in biological fluids. This review examines the clinical potential of circulating tumor DNA (ctDNA) in epithelial ovarian cancer. A systematic search of the PubMed database was conducted. Inclusion criteria were studies published in English, original research articles, reviews, or meta-analyses focused on ctDNA and ovarian cancer. Exclusion criteria included non-peer-reviewed sources, articles with insufficient data, and studies not directly related to the topic. In epithelial ovarian cancer, ctDNA allows quantitative evaluation of tumor burden and qualitative analysis by detecting specific tumor DNA variations, such as epigenetic modifications or genetic mutations. Furthermore, its half-life is less than 2 hours, enabling dynamic monitoring of tumor evolution. This capability could facilitate earlier diagnosis, better screening, and more effective therapeutic follow-up. The qualitative approach also has the potential to predict chemoresistance. Technologies used to detect ctDNA in blood include quantitative polymerase chain reaction, digital polymerase chain reaction, and next-generation sequencing, which allow quantification and identification of DNA molecule modifications. CtDNA is a promising biomarker for epithelial ovarian cancer and could address several challenges in its management. However, further research is needed to establish its role in routine clinical practice, particularly, to identify a detection method that is highly sensitive, specific, and generalizable to a wide patient population.
    Keywords:  Biomarker; Circulating Tumor DNA; Liquid Biopsy; Ovarian Cancer
    DOI:  https://doi.org/10.1016/j.ijgc.2025.101925
  2. Clin Chim Acta. 2025 May 28. pii: S0009-8981(25)00282-7. [Epub ahead of print] 120403
    Cell-free DNA methylation and its potential as a biomarker in liquid biopsy: A systematic review.
    Min Pan, Xinling Cheng, Huike Chen, Yuxian Feng, Zeyu Ma, Qinyu Ge, Jing Tu.
      DNA methylation is a critical epigenetic modification that regulates gene expression. Changes in cell-free DNA (cfDNA) methylation typically precede the clinical manifestations of diseases. Trace amounts in body fluid samples, fragmented feature, and high background noise are the challenges to be addressed before implementation of cfDNA methylation assay in clinical application. With advances in genomic analysis and methylation detection technologies, analysis of cfDNA methylation has emerged as a promising biomarker for early diagnosis, prognostic prediction, and tracing tissue origin. The tissue-specific methylation patterns of cfDNA further facilitate the determination of its tissue of origin, making cfDNA methylation invaluable in liquid biopsies. This review highlights the advanced technologies to analyze methylated cfDNA, summarizes the recent progress of cfDNA methylation assays in clinical applications, and underscores the value of the integration of cfDNA methylation with multi-omics analysis in future research.
    Keywords:  Cell-free DNA; Epigenetic biomarker; Liquid biopsy; Methylation; Sequencing
    DOI:  https://doi.org/10.1016/j.cca.2025.120403
  3. Curr Opin Cell Biol. 2025 May 28. pii: S0955-0674(25)00075-4. [Epub ahead of print]95 102537
    Chromosomal instability in development and disease: Beyond cancer evolution.
    Marco Milán.
      Chromosomal instability (CIN), an increased rate of changes in chromosome structure and number, has been classically associated with human disease as a way of evolving the cancer genome. In recent years, three additional research lines concerning the impact of CIN on human disease have been consolidated. First, beyond the generation of genomic copy number heterogeneity, CIN acts as a source of tumor growth, metastasis, and malignancy through additional mechanisms. Second, CIN is pervasive in early human development, and the resulting aneuploid cells are selectively removed from the fetus to give rise to healthy births. Third, CIN is associated with mosaic variegated aneuploidy, a rare familial disease that compromises brain development and contributes to tumor formation. Here, I will review recent advances in these three topics, with a particular focus on the use of model systems and organisms to understand the increasing impact of CIN on human biology and disease.
    DOI:  https://doi.org/10.1016/j.ceb.2025.102537
  4. Biomedicines. 2025 May 14. pii: 1198. [Epub ahead of print]13(5):
    Mucinous Ovarian Carcinoma: Integrating Molecular Stratification into Surgical and Therapeutic Management.
    Mauro Francesco Pio Maiorano, Brigida Anna Maiorano, Gennaro Cormio, Vera Loizzi.
      Background/Objectives: Mucinous ovarian carcinoma (MOC) is a rare and biologically distinct subtype of epithelial ovarian cancer, typically presenting at an early stage in younger women. Unlike high-grade serous carcinoma, MOC is characterized by unique molecular features-including frequent KRAS mutations and HER2 amplifications-and exhibits limited sensitivity to platinum-based chemotherapy. These differences highlight the need for individualized treatment strategies guided by molecular and histological profiling. This review aims to integrate current evidence on the clinical management of MOC with emerging insights into its molecular biology, with a focus on how these factors influence surgical decision-making, fertility preservation, and adjuvant therapy selection. Methods: We performed a comprehensive narrative review of the literature, synthesizing findings from retrospective cohorts, molecular studies, and clinical guidelines relevant to the surgical, reproductive, and therapeutic management of MOC. Results: Histologic subtype-expansile versus infiltrative-plays a critical role in guiding lymphadenectomy as lymph node metastases are rare (<1%) in expansile tumors but occur in up to 23% of infiltrative cases. Complete surgical staging remains essential for accurate prognostication, yet tailored approaches may reduce overtreatment in low-risk patients. Fertility-sparing surgery (FSS) appears safe in FIGO stage IA expansile MOC, with favorable reproductive outcomes, while higher-stage or infiltrative cases warrant caution. Given MOC's chemoresistance, the role of adjuvant therapy in early-stage disease remains debated. Targeted strategies, including MEK inhibitors and HER2-directed therapies, are under investigation and may benefit selected molecular subgroups. Conclusions: MOC requires a nuanced, biomarker-informed approach. This review advocates for personalized, evidence-based management supported by multidisciplinary evaluation while underscoring the urgent need for prospective studies and biomarker-driven clinical trials.
    Keywords:  mucinous ovarian cancer HER2; mucinous ovarian cancer KRAS; mucinous ovarian cancer adjuvant therapy; mucinous ovarian cancer staging; mucinous ovarian cancer treatment; mucinous ovarian carcinoma; mucinous ovarian carcinoma chemotherapy; mucinous ovarian carcinoma histology; mucinous ovarian tumor; ovarian cancer fertility sparing surgery
    DOI:  https://doi.org/10.3390/biomedicines13051198
  5. Nat Med. 2025 May 27.
    Early detection of multiple cancer types using multidimensional cell-free DNA fragmentomics.
    Hua Bao, Shanshan Yang, Xiaoxi Chen, Guangqiang Dong, Yuan Mao, Shuyu Wu, Xi Cheng, Xuxiaochen Wu, Wanxiangfu Tang, Min Wu, Shiting Tang, Wenhua Liang, Zheng Wang, Liu Yang, Jiaqi Liu, Tao Wang, Bingzhong Zhang, Kuirong Jiang, Qin Xu, Jierong Chen, Hairong Huang, Junjie Peng, Xiaomeng Xia, Yumei Wu, Shun Xu, Ji Tao, Li Chong, Dongqin Zhu, Ruowei Yang, Shuang Chang, Peng He, Xiuxiu Xu, JinPeng Zhang, Yi Shen, Ya Jiang, Sisi Liu, Xian Zhang, Xue Wu, Xiaonan Wang, Yang Shao.
      The multicancer early detection (MCED) test has the potential to enhance current cancer-screening methods. We evaluated a new MCED test that analyzes plasma cell-free DNA using genetic- and fragmentomics-based features from whole-genome sequencing. The present study included an internal validation cohort of 3,021 patients with cancer and 3,370 noncancer controls, and an independent cohort of 677 patients with cancer and 687 noncancer individuals. The results demonstrated an overall sensitivity of 87.4%, specificity of 97.8% and tissue-of-origin prediction accuracy of 82.4% in the independent validation cohort. Preliminary results from a prospective study of 3,724 asymptomatic participants showed a sensitivity of 53.5% (predominantly early stage cancers) and specificity of 98.1%. These findings indicate that the MCED test has strong potential to improve early cancer detection and support clinical decision-making.
    DOI:  https://doi.org/10.1038/s41591-025-03735-2
  6. N Engl J Med. 2025 May 30.
    Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated Colorectal Cancer.
    BREAKWATER Trial Investigators
       BACKGROUND: First-line treatment with encorafenib plus cetuximab (EC) with or without chemotherapy (oxaliplatin, leucovorin, and fluorouracil [mFOLFOX6]) for BRAF V600E-mutated metastatic colorectal cancer, an aggressive subtype with a poor prognosis, was compared with standard care (chemotherapy with or without bevacizumab) in an open-label, phase 3 trial, which showed significance regarding one of the two primary end points, objective response according to blinded independent central review (odds ratio for EC+mFOLFOX6 vs. standard care, 2.44; one-sided P<0.001). This result led to accelerated Food and Drug Administration approval of this investigational combination therapy for BRAF V600E-mutated metastatic colorectal cancer, including as first-line therapy. Data on progression-free survival (the second primary end point) and an updated interim analysis of overall survival are now available.
    METHODS: We randomly assigned patients with untreated BRAF V600E-mutated metastatic colorectal cancer to receive EC, EC+mFOLFOX6, or standard care. The two primary end points were objective response (reported previously) and progression-free survival according to blinded independent central review in the EC+mFOLFOX6 group and the standard-care group. The key secondary end point was overall survival.
    RESULTS: Significantly longer progression-free survival was seen with EC+mFOLFOX6 than with standard care (median, 12.8 vs. 7.1 months; hazard ratio for progression or death, 0.53; 95% confidence interval [CI], 0.41 to 0.68; P<0.001). In an interim analysis, overall survival was significantly longer with EC+mFOLFOX6 than with standard care (median, 30.3 vs. 15.1 months; hazard ratio for death, 0.49; 95% CI, 0.38 to 0.63; P<0.001). The incidence of serious adverse events during treatment was 46.1% with EC+mFOLFOX6 and 38.9% with standard care. Safety profiles were consistent with those known for each agent.
    CONCLUSIONS: This trial showed significantly longer progression-free survival and overall survival with first-line treatment with EC+mFOLFOX6 than with standard care among patients with BRAF V600E-mutated metastatic colorectal cancer. (Funded by Pfizer and others; BREAKWATER ClinicalTrials.gov number, NCT04607421.).
    DOI:  https://doi.org/10.1056/NEJMoa2501912
  7. Mol Oncol. 2025 May 28.
    Circulating tumor DNA monitoring and blood tumor mutational burden in patients with metastatic solid tumors treated with atezolizumab.
    Charles Swanton, Russell W Madison, Candice Francheska B Tambaoan, Funda Meric-Bernstam, Christopher J Sweeney, Razelle Kurzrock, Howard A Burris, David R Spigel, Hanna Tukachinsky, Jason Hughes, Julia Malato, Bongin Yoo, Tania Szado, Cheryl Schwab, Lincoln W Pasquina, Amaya Gasco, Katja Schulze, Claire F Friedman.
      Immune checkpoint inhibitors are important for treatment across tumor types but are not universally effective in controlling disease. Early understanding of tumor response, or lack thereof, can inform treatment decisions. This study evaluates changes in circulating tumor DNA (ctDNA) and blood tumor mutational burden (bTMB) for associations with response to programmed cell death 1 ligand 1 (PD-L1) blockade. We sequenced cell-free DNA collected at the start of therapy, on treatment, and at the end of therapy for 153 patients treated with atezolizumab as part of the pan-tumor MyPathway study (NCT02091141). ctDNA tumor fraction (TF) and bTMB were assessed for correlation with progression-free survival (PFS) and overall survival (OS). We found that molecular response (MR, ≥50% decrease in TF at cycle 3 day 1) was associated with improved PFS (9.7 vs 1.5 months from C3D1; HR = 0.27) and OS (21.1 vs 14.3 months from C3D1; HR = 0.44). These findings were consistent when limited to patients with stable disease (SD; PFS HR = 0.55; OS HR = 0.39). bTMB was correlated with tissue-based TMB (tTMB) when TF was high (≥1%), but not with OS in this cohort. In total, 61% of baseline samples had predicted clonal hematopoiesis (CH) variants. No correlation between maximum variant allele frequency (maxVAF) of predicted CH and TF was seen. In summary, MR is associated with outcomes for patients treated with atezolizumab and could stratify patients with SD. While CH was common, maxVAF for CH variants was not associated with ctDNA TF. Quantification of ctDNA enables therapy response monitoring and is critical for interpretation of bTMB as a proxy for tTMB.
    Keywords:  ctDNA tumor fraction; immune checkpoint inhibitors; tumor mutational burden
    DOI:  https://doi.org/10.1002/1878-0261.70054
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