bims-tumhet 2026-10-25 papers

Issue of 2026–10–25
five papers selected by
Sergio Marchini, Humanitas Research

J Liq Biopsy. 2026 Dec;14 100668

Prognostic utility of copy number variations in circulating tumor DNA in head and neck cancer.

Edward S Sim, Daniel A Ruiz-Torres, Pan Du, Yong Huang, Frank Zhang, Shidong Jia, Adam S Fisch, Ross D Merkin, Jonathan J Paly, Daniel L Faden.

Background: Plasma circulating tumor DNA (ctDNA) is a minimally invasive biomarker in head and neck squamous cell carcinoma (HNSCC). Most commercially available assays for human papillomavirus-unrelated HNSCC are tumor-informed assays that require tissue sampling and may not comprehensively capture tumor heterogeneity. We evaluated a tumor-agnostic approach using genome-wide ctDNA copy-number variation (CNV) profiling to derive blood copy-number burden (CNB) for prognostication in non-surgically treated HNSCC.
Methods: ctDNA was extracted from 250 longitudinal plasma samples from 33 patients and analyzed using PredicineSCORE low-pass whole-genome sequencing (LP-WGS). CNB was dichotomized as positive (CNB+) or negative (CNB-) using a predefined threshold. Associations with overall survival (OS) and progression-free survival (PFS) were assessed with Kaplan-Meier models.
Results: Median age was 63 years; 67% were male; 67% had recurrent/metastatic disease; 15% were HPV-associated. Treatment included chemoradiation (39%) and immune checkpoint blockade-based regimens (60%). The most frequent CNV was 3q gain. Baseline plasma was available for 30 patients, of whom 17 (56%) were CNB+. Baseline CNB+ was associated with inferior OS (HR 4.38, 95% CI 1.22-15.72; p = 0.01) but not PFS (HR 1.41, 95% CI 0.62-3.20; p = 0.41) over a median follow-up of 23.4 months. CNB + at any post-treatment timepoint occurred in 26/33 (79%) and showed a non-significant trend toward worse OS (HR 3.03; p = 0.12) and PFS (HR 2.70; p = 0.06). Detection rates were modest, highlighting potential utility mainly in CNV-high, HPV-independent tumors over time.
Conclusions: LP-WGS enables tumor-agnostic detection of CNV signals in plasma from non-surgically treated HNSCC, and baseline CNB stratifies OS. Larger, more homogeneous cohorts with matched tumor sequencing are needed to validate ctDNA-derived CNV metrics and define which molecular subtypes benefit most from blood-based CNB detection and monitoring.
Level of evidence: 3.

Keywords: Circulating tumor DNA; Head and neck squamous cell carcinoma; Liquid biopsy; Minimal residual disease; Next-generation sequencing

DOI: https://doi.org/10.1016/j.jlb.2026.100668

Front Oncol. 2026 ;16 1947939

Endometrial cancer molecular classification: research advances and clinical application.

Ya Liu, Yueying Li, Liping Zhang.

As research in molecular biology continues to advance, the classification of endometrial cancer has gradually shifted from traditional histology toward risk stratification based on the integration of molecular subtyping with clinicopathologic factors. Molecular subtyping has not only transformed our understanding of the biological heterogeneity of endometrial cancer but also provided new evidence for prognostic assessment and treatment selection. However, the maturity of clinical evidence and the translational therapeutic value vary across molecular subtypes. This review systematically summarizes the molecular characteristics and clinical significance of the POLE ultramutated(POLE-mut)subtype, mismatch repair deficient (dMMR) subtype, p53 abnormal (p53-abn) subtype, and no specific molecular profile (NSMP) subtype, with a focus on evaluating whether different molecular features can be further translated from risk stratification into specific treatment decisions. Centering on key issues such as de-escalated therapy for the POLE-mut subtype, the predictive value of immunotherapy for the dMMR subtype, intensified therapy for the p53-abn subtype, and further risk stratification of the NSMP subtype, this review analyzes the clinical basis and limitations of existing evidence and further discusses the challenges that tumors with multiple molecular features pose for classification and treatment decision making. Building on this, the paper compares how major international guidelines integrate molecular information with clinical and pathologic factors and analyzes real world implementation barriers such as testing standardization, result interpretation, and healthcare accessibility. Finally, it outlines the potential value of emerging technologies, including liquid biopsy, artificial intelligence, and multiomics, in dynamic risk assessment and precision therapy. This review aims to trace the continuum of evidence from molecular discovery to clinical action, clarifying which clinical decisions can be supported by existing molecular markers and identifying questions that current evidence cannot yet answer, thereby providing guidance for the precise application and clinical translation of molecular subtyping in endometrial cancer.

Keywords: clinical translation; endometrial cancer; molecular classification; precision medicine; prognosis; treatment prediction

DOI: https://doi.org/10.3389/fonc.2026.1947939

Front Immunol. 2026 ;17 1977503

The cGAS-STING pathway in ovarian cancer: from genomic instability to immunotherapeutic vulnerability.

Hui-Hui Chen, Feng-Xian Ni, Dong-Hui Huang, Ze-Bo Jiang.

Ovarian cancer remains the most lethal gynecologic malignancy, a status largely attributable to late-stage diagnosis and inevitable chemoresistance. The cGAS-STING pathway, a cornerstone of innate immune surveillance, has emerged as a critical nexus linking genomic instability to antitumor immunity-a connection of particular relevance in ovarian cancer, where chromosomal instability is a defining hallmark. This review synthesizes current understanding of the cGAS-STING pathway in ovarian cancer, spanning molecular mechanisms to translational opportunities. We delineate the dualistic nature of STING signaling, which orchestrate robust T cell-mediated antitumor immunity under certain conditions yet paradoxically foster immunosuppression and tumor progression in others. Particular emphasis is placed on the intricate interplay between DNA damage repair deficiencies-especially in BRCA1/2 and homologous recombination-and STING-dependent immune activation, which forms the mechanistic basis for the immunomodulatory effects of PARP inhibitors. We critically examine the TME, where CAFs and myeloid cells integrate STING signals to either potentiate or constrain antitumor immunity. The landscape of STING-modulating therapeutic strategies is surveyed, encompassing direct agonists, nanoparticle-based delivery platforms, and rational combinations with immune checkpoint blockade and DNA-damaging agents. Finally, we identify key unresolved questions, including the need for predictive biomarkers, strategies to overcome resistance, and the challenge of balancing therapeutic efficacy against potential toxicities. By integrating recent discoveries with established paradigms and explicitly addressing the "double-edged sword" duality of STING signaling, the stromal response, and a proposed roadmap for biomarker-guided therapeutic development, this review aims to provide a framework that distinguishes itself from prior comprehensive reviews by integrating recent discoveries with established paradigms and explicitly addressing the 'double-edged sword' duality of STING signaling, the stromal response, and a proposed roadmap for biomarker-guided therapeutic development.

Keywords: DNA damage response; PARP inhibitors; cGAS-STING; genomic instability; immune checkpoint blockade; innate immunity; ovarian cancer; tumor microenvironment

DOI: https://doi.org/10.3389/fimmu.2026.1977503

Ann Oncol. 2026 Oct 21. pii: S0923-7534(26)06651-2. [Epub ahead of print]

The ESMO Scale for Clinical Actionability of Molecular Targets, version 2 (ESCAT v2): an evidence-based framework for ranking alterations as actionability and resistance biomarkers in precision oncology.

BACKGROUND: Since the publication of the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) in 2018, precision oncology has evolved substantially. Tumour-agnostic therapy approvals, expanding real-world evidence datasets, and the clinical recognition of genomic resistance biomarkers have created the need to revise the original framework.
METHODS: The ESMO Precision Oncology and Taxonomy Committee convened an international expert panel to revise the ESCAT classification. Through iterative review of the evolving evidence-base, structured feedback rounds, and consensus discussions, the panel developed an updated actionability scale and a novel resistance scale. The revision followed three principles: explicit grading of uncertainty within actionable tiers, formal inclusion of tumour-agnostic eligibility criteria, and systematic classification of resistance biomarkers to complement sensitivity designations.
RESULTS: ESCAT version 2 (ESCAT v2) introduces several substantive changes. Tier I is restructured into three categories, proven, inferred, and extrapolated, that carry the same clinical directive but differ in the level of certainty within the supporting evidence. The guideline introduces formal tumour-agnostic gating criteria, the ESMO Tumour-Agnostic Classifier and Screener (ETAC-S). Tier II is refined into three sub-tiers graded by prospective interventional evidence, high-quality real-world or non-prospective evidence, and replicated case-level evidence. Tier X is subdivided into alterations that are tested and found not to be predictive (X-A) and biomarker-therapy matches in which the therapy lacks meaningful activity in the biomarker-defined population (X-B). A parallel four-level resistance scale ranges from clinically validated resistance (contraindication) to preclinical or computational evidence (research use only).
CONCLUSIONS: ESCAT v2 provides a comprehensive, evidence-graded framework for interpreting actionability and resistance biomarkers in cancer, enabling more nuanced communication among clinicians, patients, regulators, and researchers while preserving a clear directive to act when evidence supports patient benefit.

Keywords: ESCAT; biomarkers; precision medicine; resistance biomarkers; targeted therapies; tumour-agnostic therapy

DOI: https://doi.org/10.1016/j.annonc.2026.09.008

Adv Anat Pathol. 2026 Oct 19.

Updates on the Molecular Classification of Endometrial Carcinoma.

Koen K Van de Vijver, C Blake Gilks, Tjalling Bosse.

The risk of recurrence and metastasis in patients with endometrial carcinoma varies widely, making evaluation of risk in individual patients critically important for planning effective adjuvant treatment. Tumor histotype and grade have been used, along with stage and lymphovascular space invasion (LVSI), but suboptimal reproducibility of histotype assignment (especially for high-grade tumors) and tumor grade have made risk assessment challenging. Similarly, single biomarkers such as L1CAM and beta-catenin have shown potential but none have emerged as well-validated and reproducible markers of risk in endometrial carcinoma. This changed with the finding of The Cancer Genome Atlas that there are 4 molecular subtypes of endometrial carcinoma, based on genomic architecture. Subsequently, a clinically applicable approach to endometrial carcinoma molecular subtype has emerged, based on sequencing of POLE to detect a limited number of pathogenic mutations, and immunostaining for mismatch repair (MMR) proteins and p53. This approach places each endometrial carcinoma into one of 4 molecular subtypes (POLEmut, MMRd, p53abn, and no specific molecular profile [NSMP]) that can be reproducibly diagnosed, show excellent concordance between the biopsy and hysterectomy specimen, are of prognostic significance, predict response to specific adjuvant therapies, and can be used to screen for underlying hereditary cancer susceptibility syndromes. Molecular subtype is now integrated into widely used endometrial carcinoma risk assessment guidelines and is a key component of the 2023 update to the International Federation of Gynecology and Obstetrics (FIGO) staging system for endometrial carcinoma. Recently, prognostic refinement of the 4 molecular groups introduces a possible fifth group showing absence of estrogen receptor (ER) expression and/or high histologic grade within the NSMP subtype. We will review the key features of endometrial carcinoma molecular subtypes, focusing on recent advances in molecular subtype diagnosis in practice.

Keywords: MMR; POLE; endometrial carcinoma; molecular subtype; p53

DOI: https://doi.org/10.1097/PAP.0000000000000556