bims-tumhet 2026-07-05 papers

Issue of 2026–07–05
six papers selected by
Sergio Marchini, Humanitas Research

Genome Med. 2026 Jul 03.

Multi-modal data integration reveals functionally credible predictive biomarkers in ovarian cancer.

BACKGROUND: Precision oncology aims to tailor treatment according to tumor-specific molecular alterations, but the success of aberration-guided therapies has been limited in clinical trials. Here, we develop an integrated whole-genome and transcriptome workflow to systematically distinguish functionally credible, predictive driver aberrations from non-functional alterations across all classes of genomic events.
METHODS: We applied the integrated omics workflow to 335 patients with ovarian high-grade serous carcinoma (HGSC) enrolled in the observational DECIDER study. Tumor samples were collected from multiple cancer sites as part of the standard cancer care. DNA and RNA were extracted together from snap-frozen tumor samples and sent to whole-genome and transcriptome sequencing. Sequencing data were processed with the Anduril 2 pipeline for detection and validation of short somatic changes and with the HMW toolkit and the nf-core/rnafusion pipeline for assessment of structural changes. Aberration-specific drug sensitivity was tested in patient-derived organoids with a drug screen combining targeted agents and chemotherapy.
RESULTS: Using an agnostic integrated omics analysis, we identified clinically relevant ESCAT Tier II-III alterations in more than 40% of the patients, even though 58% of all nominally pathogenic variants proved to be false positives. Credible aberrations were predominantly clonal, detected across anatomical sites, and preserved from diagnosis to relapse, indicating early establishment during tumor evolution. The most recurrent actionable event was NF1 deficiency, which was associated with a robust transcriptional footprint and marked sensitivity to KRAS- and MEK-inhibition in patient-derived organoids. Notably, integrated DNA-RNA analysis enabled discrimination of treatment-guiding aberrations from false-positive findings that would otherwise misinform treatment selection and confound clinical trial outcomes.
CONCLUSIONS: Our findings provide a strategy for more reliable biomarker detection in precision oncology, inform biomarker-guided clinical trial design, and reveal unexploited therapeutic vulnerabilities in HGSC.

Keywords: Biomarker; High-grade serous carcinoma; Multi-omics; Mutation; Ovarian cancer; Precision oncology; Targeted therapy

DOI: https://doi.org/10.1186/s13073-026-01706-x

Front Oncol. 2026 ;16 1850041

Early detection of multiple cancers: the era of methylation-based liquid biopsy.

Yajie Lin, Zekai Hu, Leyao Shuai, Zhaowei Tong, Hainv Gao, Junsheng Zhao.

Liquid biopsy based on circulating cell-free DNA (cfDNA) methylation has become a leading non-invasive strategy for multi-cancer early detection (MCED). Aberrant DNA methylation arises at the early stage of tumorigenesis and displays cancer-type-specific signatures, enabling early capture of tumor-derived epigenetic signals. High-throughput sequencing, digital PCR and machine learning algorithms have greatly improved the sensitivity and specificity of methylation-based assays. Large-scale clinical trials including CCGA, PATHFINDER, THUNDER and GUIDE have validated that MCED tests achieve high specificity (>99%) and reliable accuracy for tissue of origin prediction. Integrating methylomics with fragmentomics further boosts early detection performance, especially for early-stage tumors with low ctDNA shedding. Nevertheless, clinical translation still faces notable hurdles, including technical standardization, biological confounding factors, high cost and the demand for large-scale prospective mortality endpoint validation. Future development will rely on multi-omics integration, optimized bioinformatic pipelines and standardized interventional trials to lower cancer-specific mortality. In summary, methylation liquid biopsy is poised to reshape cancer screening from single-organ late diagnosis to multi-cancer early intervention, offering profound prospects for precision oncology.

Keywords: DNA methylation; biomarker; circulating tumor DNA (ctDNA); liquid biopsy; multi-cancer early detection

DOI: https://doi.org/10.3389/fonc.2026.1850041

J Liq Biopsy. 2026 Sep;13 100477

Longitudinal methylated ctDNA increases predict immunotherapy progression across solid tumors.

Muhammad Anees, Patrick L Wagner, Ashten Omstead, Erin Grayhack, Christopher Sherry, Lee D McDaniel, Matthew G Varga, Seyed Mohammad Hossein Hosseiny, William Laframboise, John Nakayama, Thomas Krivak, Benny Weksler, Neda Dadgar, Shurjeel Uddin Qazi, Nathan Bahary, David L Bartlett, David S Tsao, Ali H Zaidi.

Timely identification of treatment failure during immune checkpoint blockade remains a critical unmet need in oncology. We evaluated a tissue-free, methylation-based circulating tumor DNA (ctDNA) assay applied serially across 142 patients with advanced solid tumors receiving immune checkpoint inhibitor monotherapy or chemo-immunotherapy in two independent prospective cohorts. Blood was collected pre-treatment, C2D1, and C3D1. Molecular progression, mPD, was defined as an increase in ctDNA while on therapy. mPD stratified progression-free and overall survival across both cohorts (PFS HR 5.8 95% CI 3.4-9.9; OS HR 4.1 95%CI 2.3-7.0). Notably, incorporating ctDNA at C2 identified more molecular rebounders, and mPD was significant for OS in RECIST 6-month BOR stable disease subgroup where imaging is least informative (HR 8.4, 95% CI 1.4 to 48.7). Monitoring with ctDNA continued to predict progression after C3 and identified progression with median lead time of 62 days. These findings confirm prior studies that have shown that ctDNA is predictive for immunotherapy response and furthermore demonstrate the utility of a clinically practical molecular progression rule across the multiple cancer types treated by immune checkpoint inhibitors.

Keywords: DNA methylation; Immune checkpoint inhibitors; Liquid biopsy; Northstar; Pan-cancer; Response monitoring; Tumor-naive assay; ctDNA

DOI: https://doi.org/10.1016/j.jlb.2026.100477

Cell Death Discov. 2026 Jun 30.

Spatial transcriptomics in cancer research: insights into tumorigenesis, diagnosis and therapeutics.

Qiang Wen, Qing Lan, Jianjian Yin, Fei Guo, Xiaosong Wei, Caiyun Wu, Lei Jin, Xu D Zhang, Jinyan Li, Lirong Zhang, Tao Liu.

Spatial transcriptomics is an innovative technology that enables high-throughput, genome-wide analysis of transcript expression and spatial localization within tissues. By preserving structural organization, it provides critical insights into tumor sub-regions, substructures, and the heterogeneity and plasticity of cancer, stromal, and immune cells, as well as cell-cell interactions. Spatial transcriptomics also offers an unprecedented understanding of the tumor microenvironment, including immune cell infiltration, activation and repression, and immune suppression mediated by stromal cells. Importantly, it deepens our understanding of malignant transformation from precancerous lesions, tumorigenesis, and immune escape. Furthermore, spatial transcriptomics is reshaping cancer subtype diagnosis and risk stratification, uncovering factors associated with drug resistance, predicting therapy responses, and informing the development of personalized cancer treatments and potentially prevention. In summary, spatial transcriptomics serves as a cornerstone of cancer research, transforming the research landscape and unlocking groundbreaking opportunities for precision cancer diagnosis, risk stratification, targeted therapy, and prevention.

DOI: https://doi.org/10.1038/s41420-026-03092-0

J Liq Biopsy. 2026 Jun;12 100466

Breaking news from ESMO 2025: liquid biopsy novelties in gastrointestinal cancer.

Serena Pillozzi, Giulia Petroni, Daniele Lavacchi, Daniele Rossini, Lorenzo Antonuzzo.

Liquid biopsy (LB) has emerged as a minimally invasive approach to characterize tumor biology and support treatment decision-making across gastrointestinal (GI) malignancies. Advances in circulating biomarkers have expanded its potential clinical applications. While colorectal cancer appears closest to clinical implementation, with ctDNA increasingly integrated into adjuvant and metastatic decision-making, applications in other GI tumors remain largely exploratory. Emerging approaches, including cfDNA methylation profiling, multi-omic assays, and circulating protein or metabolite analyses, have shown promising early signals but require prospective validation. This review summarizes key LB findings presented at ESMO 2025, highlighting translational relevance, current limitations, and future directions for clinical integration.

Keywords: Circulating tumor DNA (ctDNA); Gastrointestinal cancers; Liquid biopsy; Minimal residual disease (MRD); Personalized medicine

DOI: https://doi.org/10.1016/j.jlb.2026.100466

Cancer. 2026 Jul 15. 132(14): e70517

Maintenance therapy in gynecologic malignancies: Current and future state.

Page C Widick, Alexi A Wright, Joyce F Liu.

Although there have been significant advances in the management of gynecologic malignancies in recent years, individuals with advanced disease continue to have high rates of recurrence. Strategies to decrease rates of recurrence and increase time to recurrence are urgently needed. Historically, prolonged chemotherapy treatment and consolidation therapy were unsuccessful. However, continuation of maintenance therapy after initial chemotherapy may offer improved progression-free survival (PFS) and overall survival (OS) in select circumstances. In recent years, maintenance agents including VEGF and poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors have improved PFS and sometimes even OS among women with ovarian cancer when used as monotherapy or in combination. PARP inhibitors demonstrate particularly robust results in patients with BRCA-mutated disease or other homologous recombination-deficient cancers. In endometrial and cervical cancers, immune checkpoint inhibitors combined with chemotherapy and used as maintenance thereafter have improved PFS and OS, with particular benefits noted in mismatch repair-deficient endometrial cancer and PD-L1-positive cervical cancer. Beyond currently available therapies, ongoing trials are exploring additional options for maintenance therapy, including antibody-drug conjugates, hormone-directed therapies, and novel targeted therapies such as XPO-1 inhibitors. Maintenance therapy can be accompanied by increased toxicity and cost; as such, careful consideration must be made about the relative benefit of any given maintenance strategy weighed against potential impacts on quality of life or financial toxicity. This review focuses on current maintenance therapy practices, emerging areas of research, and challenges in this area of study.

Keywords: cervical cancer; chemotherapy; clinical trials; endometrial cancer; immunotherapy; maintenance therapy; ovarian cancer

DOI: https://doi.org/10.1002/cncr.70517