bims-tumhet 2026-10-04 papers

Issue of 2026–10–04
six papers selected by
Sergio Marchini, Humanitas Research

Cancer Discov. 2026 Oct 01. 16(10): 1973-1991

Immunologic Consequences of Genomic Instabilities.

Emily Alouani, Jean-David Fumet, Paul Johannet, Aurélien Marabelle, Benoit Rousseau.

Genomic instability manifests in two distinct ways based on DNA alteration scale, differentially affecting the tumor-immune microenvironment. Mutational instability involves excessive accumulation of small-scale alterations, such as substitutions and indels, from defective DNA repair or aberrant mutagenic processes, generating neoantigens and increased immunogenicity. Chromosomal instability encompasses large-scale alterations in which cells gain, lose, or rearrange chromosomes, resulting in aneuploidy and immune evasion through chronic innate activation and myeloid remodeling. This review outlines differences between mutational and chromosomal instability and discuss how their interplay shapes tumor immunogenicity and response to immunotherapy. Understanding these opposing mechanisms could inform immunotherapeutic approaches in cancer.
SIGNIFICANCE: Mutational and chromosomal alterations exert opposing effects on antitumor immunity. Hypermutated tumors can generate abundant neoantigens that prime adaptive immunity and sensitize tumors to checkpoint blockade. In contrast, chromosomal instability triggers chronic innate immune signaling that is paradoxically immunosuppressive, in part through myeloid cell and T-cell dysfunction. Integrating both processes into a unified framework could help uncover mechanisms of immune evasion and guide personalized immunotherapeutic strategies.

DOI: https://doi.org/10.1158/2159-8290.CD-25-2063

Int J Gynecol Pathol. 2026 Sep 28.

Interobserver Variability in Diagnosing STIC With Frequent Underdiagnosis of Early High-grade Serous Carcinoma: Insights From a Multicenter Review From the CANSTIC Study.

Sarah E J Khan, Martin Köbel, Elisabeth Spénard, Lien Hoang, Katherine Grondin, Marcus Q Bernardini, Marjan Rouzbahman.

It has become widely accepted that most cases of tubo-ovarian high-grade serous carcinoma (HGSC) arise from precursor lesions in the fallopian tube called serous tubal intraepithelial carcinoma (STIC). This study evaluated the interobserver reproducibility of STIC diagnosis and its diagnostic boundaries from a multicentre Canadian cohort study. The multicentre CANSTIC study included patients with isolated STIC diagnosed between 1998 and 2020 across 15 Canadian centres. A blinded panel of 4 subspecialized gynecologic pathologists independently reviewed scanned slides (hematoxylin and eosin, p53, and Ki67) from 57 cases and met for a consensus meeting. Diagnoses were grouped as HGSC, STIC, and serous tubal intraepithelial lesion/other. The initial interobserver agreement for the diagnostic categories was moderate (Fleiss's kappa =0.495, 95% CI: 0.269-0.675; Cohen's kappa =0.492, 95% CI: 0.226-0.758, percent agreement 83.3%). A concordant diagnosis among all 4 reviewers was initially reached in 68% (39/57; 95% CI: 55.5%-79.0%), which increased to 91% (52/57; 95% CI: 81.1%-96.2%) after the consensus meeting. Consensus or majority (3 of 4 reviewers) was considered the final diagnosis; this resulted in STIC in 79% (45/57; 95% CI: 66.7-87.5), in agreement with the original diagnosis. Nine percent of cases were downgraded to serous tubal intraepithelial lesion/other (5/57; 95% CI: 1.8%-14.4%), while 12% were upgraded to HGSC (7/57; 95% CI: 6.1%-23.2%). Six patients developed HGSC clinically (11%; 95% CI: 4.9%-21.1%), of whom 3 had a review diagnosis of HGSC and 3 of STIC. This study shows suboptimal interobserver reproducibility for a diagnosis of STIC, despite consideration of ancillary p53/Ki67 testing. This study offers guidance to increase interobserver reproducibility in this challenging area, particularly in avoiding an underdiagnosis of HGSC.

Keywords: Fallopian tube; High-grade serous carcinoma; Ovary; Serous tubal intraepithelial carcinoma

DOI: https://doi.org/10.1097/PGP.0000000000001218

Trends Biochem Sci. 2026 Oct 01. pii: S0968-0004(26)00285-9. [Epub ahead of print]

Cell-free RNA fragmentomics: rethinking the biology of RNA liquid biopsies.

Valentina Blanco, Mauricio Castellano, Juan Pablo Tosar.

Cell-free RNA (cfRNA) is emerging as a promising analyte for liquid biopsy because it captures dynamic changes in gene expression across tissues and disease states. However, interpretation of cfRNA profiles remains limited by the lack of a unifying framework describing how extracellular RNAs are released, processed, and stabilized. Here, we propose that concepts from cell-free DNA fragmentomics provide a useful lens to interpret cfRNA biology and introduce the concept of cfRNA fragmentomics. We argue that many cfRNAs originate as intracellular ribonucleoprotein complexes that undergo extracellular ribonuclease processing, generating stable fragmented RNAs associated with proteins and other carriers. Under this framework, informative cfRNA signatures may arise not only from diseased tissues but also from indirect systemic responses to disease.

Keywords: RNA fragmentomics; cancer biomarkers; cfRNA; extracellular RNA

DOI: https://doi.org/10.1016/j.tibs.2026.09.007

Clin Chim Acta. 2026 Oct 02. pii: S0009-8981(26)02053-X. [Epub ahead of print] 122871

Liquid biopsy in head and neck tumors: novel approaches and clinical applications.

Alexei Yumashev, Shavkat Amonov, Aisher Soliyev, Farmon Nurbayev, Doston Tairov, Nilufar Sultonova, Muna Barakat, Babamuratov Bekzod.

Head and neck cancers (HNCs) represent one of the most prevalent and lethal types of cancer, accounting for 4.7% of annual cancer new cases and 4.9% of cancer-related mortalities. These high prevalence and mortality rates have positioned HNCs as a global health issue. Despite advances in disease treatment methods, the prognosis of patients with advanced or recurrent diseases remains poor. The difficulty of early-stage diagnosis of HNCs is one of the primary contributors to this reduced long-term survival. Currently available diagnostic and disease-monitoring tools, such as tissue biopsy and imaging techniques, are associated with several limitations, including invasiveness, limited repeatability, and limited sensitivity for detecting minimal residual disease (MRD) and microscopic metastases. In recent years, liquid biopsy has emerged as a promising approach, enabling minimally invasive detection of tumor-related biomarkers in body fluids. This review aims to provide a comprehensive overview of the progress and pitfalls of liquid biopsy in the context of HNCs. In this regard, we discuss the principles of liquid biopsy, applicable biomarker types, sample sources, and advanced detection methods. Furthermore, the current status of liquid biopsy in clinical trials of HNCs and the challenges of its clinical translation are also comprehensively explored.

Keywords: Circulating tumor DNA; Circulating tumor cells; Clinical translation; Extracellular vesicles; Head and neck cancer; Liquid biopsy

DOI: https://doi.org/10.1016/j.cca.2026.122871

JAMA Oncol. 2026 Oct 01.

Rethinking Treatment Intensification in Poorly Chemosensitive Ovarian Cancer: A Review.

Importance: Despite the integration of bevacizumab and poly(ADP-ribose) polymerase inhibitors into first-line treatment of advanced high-grade serous ovarian cancer, survival remains poor for the substantial subset of patients whose tumors respond insufficiently to platinum-based chemotherapy and who, therefore, frequently do not achieve complete cytoreductive surgery (the 2 red flags population). This Review examines the rationale, current evidence, and emerging strategies for systemic treatment intensification-or chemosensitization-aimed at improving tumor response before initiating maintenance therapy.
Observations: Achieving minimal residual disease before maintenance depends on 2 key determinants: surgical completeness and intrinsic tumor chemosensitivity. Pragmatic indicators of chemosensitivity-KELIM (modeled cancer antigen 125 elimination rate constant K), pathological chemotherapy response score, and radiologic response-are now cited in European Society for Medical Oncology-European Society of Gynaecological Oncology and American Society of Clinical Oncology guidelines, while BRCA/homologous recombination deficiency status may not reliably predict neoadjuvant carboplatin-paclitaxel response. Across post hoc analyses of phase 3 trials (ICON-7, GOG-0218, ICON-8, ICON-8B, VELIA, and IMagyn050), patients with poorly chemosensitive disease may have derived greater benefit from intensification strategies. Weekly dose-dense paclitaxel was associated with improved survival in the 2 red flags subgroup of ICON-8. Bevacizumab, added either to standard postoperative chemotherapy or to neoadjuvant dose-dense chemotherapy, showed signals of greater benefit on both progression-free and overall survival in high-risk and poorly chemosensitive subsets. In contrast, poly(ADP-ribose) polymerase inhibitor and immune checkpoint inhibitor combinations showed meaningful activity only in selected subgroups, supporting further evaluation of innovative DNA repair-targeting agents and immunotherapeutic approaches in these populations.
Conclusions and Relevance: Early identification of poorly chemosensitive advanced high-grade serous ovarian cancer enables a response-adapted first-line strategy in which treatment intensification is selectively offered to patients most likely to benefit-an approach now being prospectively evaluated in the phase 3 SALVOVAR and phase 1/2 RegeNovar trials. This framework provides a clinically actionable platform to test novel therapies aimed at increasing complete interval cytoreduction rates and improving survival in a population with otherwise limited options.

DOI: https://doi.org/10.1001/jamaoncol.2026.3875

Int J Womens Health. 2026 ;18 571328

Biomarker-Driven Treatments for Ovarian Cancer: Moving Beyond HRD?

Liz Joseph, Michael Flynn, Jonathan A Ledermann.

Ovarian cancer is a biologically heterogeneous disease, yet for more than two decades its standard treatment of surgery and platinum-taxane chemotherapy changed little. Only a modest additional benefit was seen with the addition of bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor A (VEGF-A) in selected patients. The recognition that BRCA1/2 mutations impair the repair of DNA double-strand breaks by homologous recombination, and that inhibitors of PARP are highly active in this setting, established the first widely adopted biomarker-driven treatment in this disease. Homologous recombination deficiency (HRD) therefore remains the established predictive biomarker for first-line maintenance therapy, but it is imperfect: benefit is not confined to HRD-positive tumours, assays report historical genomic scars, and most patients ultimately relapse with platinum-resistant disease. This review examines how biomarker-driven treatment in ovarian cancer is developing beyond HRD. We appraise the evidence for strategies that are already clinically established, principally PARP inhibitors, the folate receptor α-directed antibody-drug conjugate mirvetuximab soravtansine, and, more recently, PD-L1-selected immune checkpoint inhibition in platinum-resistant disease and distinguish these from approaches that remain investigational, including antibody-drug conjugates directed at HER2, TROP2, CLDN6, B7-H3/H4 and CDH6, and agents exploiting cell cycle dysregulation and replication stress such as CCNE1-associated, WEE1 and ATR-directed therapies. We also consider the practical obstacles to implementation: tumour heterogeneity and evolution, the complementary roles of tissue and liquid biopsy, when molecular profiling should be repeated, assay standardisation and access, and the limitations of basket trial designs. Progress will depend on expanding the development of practical frameworks for biomarker testing, treatment selection and sequencing.

Keywords: HRD; PARP inhibitors; antibody-drug conjugates; biomarkers; folate-receptor; ovarian cancer; platinum resistant ovarian cancer; targeted therapy

DOI: https://doi.org/10.2147/IJWH.S571328