bims-tumhet 2026-08-30 papers

Issue of 2026–08–30
six papers selected by
Sergio Marchini, Humanitas Research

Front Oncol. 2026 ;16 1806868

Liquid biopsies for detection, characterization, and interception of therapy resistance in thoracic malignancies.

Ezgi Oner, Volga M Saini, Christina Cahill, Hannah O'Toole, Jennifer W Li, Kathy Gately, Valsamo Anagnostou.

Therapy resistance remains a leading cause of treatment failure and mortality in thoracic malignancies, despite major advances in targeted therapies and immunotherapies. Resistance evolves through heterogeneous, patient-specific mechanisms, including genetic alterations, epigenetic reprogramming, lineage plasticity, and tumor-microenvironment interactions, often emerging before radiographic progression or clinical relapse. Conventional tissue biopsies and imaging, while essential for diagnosis and treatment selection, are limited in their ability to capture spatial and temporal tumor heterogeneity or to support dynamic monitoring of tumor evolution. Liquid biopsy has therefore emerged as a minimally invasive approach for real-time assessment of tumor-derived biomarkers in circulation, enabling longitudinal tracking of resistance biology across the cancer care continuum. In this review, we highlight recent advances in liquid biopsy applications for thoracic malignancies, focusing on circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) as complementary analytes for baseline molecular profiling, detection of primary and acquired resistance to therapy, and identification of minimal residual disease and molecular relapse. Beyond mutation-based approaches, we highlight emerging non-genomic ctDNA features, including epigenomic and fragmentomic signatures, that capture treatment-induced adaptation and lineage plasticity not detectable by conventional plasma genomic profiling, and discuss advances in CTC technologies that preserve cellular and phenotypic context relevant to resistance and metastatic potential. Finally, we examine multimodal liquid biopsy strategies that integrate multiple circulating analytes with artificial intelligence-assisted methods to enhance sensitivity, provide a more comprehensive view of tumor biology, and inform adaptive therapy strategies. We also outline key analytical and clinical challenges that must be addressed through standardized, prospective trials to translate liquid biopsy-guided surveillance and early interception of resistance into improved patient outcomes.

Keywords: circulating tumor DNA (ctDNA); circulating tumor cells (CTCs); liquid biopsies; lung cancer; therapy resistance; thoracic malignancies

DOI: https://doi.org/10.3389/fonc.2026.1806868

J Clin Med. 2026 Aug 11. pii: 6222. [Epub ahead of print]15(16):

Circulating Tumor DNA for Minimal Residual Disease Detection and Recurrence Prediction in Upper Gastrointestinal Cancers: A Scoping Review.

Loizos Hadjigeorgiou, Melina Yerolatsite, Nanteznta Torounidou, George Zarkavelis, Dimitrios Schizas, Vasileios Tatsis, Stefano Rausei, Konstantinos Vlachos, Georgios D Lianos.

Circulating tumor DNA (ctDNA) is a promising non-invasive biomarker for detecting minimal residual disease (MRD) and predicting recurrence after curative treatment, yet evidence in esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAC), and gastric cancer has largely been examined within individual tumor types. In this scoping review, we mapped this evidence across all three malignancies and clarified key methodological and clinical considerations. Following the PRISMA-ScR guidelines, we searched PubMed, Scopus, and the Cochrane Library (3 April 2026) for studies linking ctDNA to disease-free, recurrence-free, or overall survival after curative-intent treatment. Twenty-seven studies (1746 patients; 10 ESCC, 4 EAC, 8 gastric, and 5 mixed) were included. Across every tumor type, postoperative ctDNA MRD was the most informative timepoint, with independent multivariable hazard ratios for disease-free, recurrence-free, or event-free survival of 2.8 to 21.8, whereas preoperative ctDNA was seldom prognostic. Serial monitoring further improved performance and flagged recurrence 78 to 278 days before imaging. Tumor-informed assays showed higher sensitivity than tumor-agnostic ones (80% vs. 35%), though direct comparisons were limited; correction for clonal hematopoiesis was essential for tumor-agnostic assays, and blood-based assays performed poorly in diffuse-type and peritoneal disease. Postoperative ctDNA MRD is a consistent, independent prognostic biomarker across upper gastrointestinal cancers that adds prognostic information beyond conventional staging and pathological response, supporting prospective interventional trials of ctDNA-guided management.

Keywords: circulating tumor DNA; ctDNA; esophageal cancer; gastric cancer; liquid biopsy; minimal residual disease; prognosis; recurrence

DOI: https://doi.org/10.3390/jcm15166222

Cell Rep Med. 2026 Aug 28. pii: S2666-3791(26)00430-1. [Epub ahead of print] 103013

Pan-tumor spatial transcriptomics reveals conserved properties of tumor organization.

Vivek Behera, Alexander Guzzetta, Hannah Giba, Ue-Yu Pen, Anna Di Lello, Bipul Pandey, Benjamin A Doran, Alessandra Esposito, Apameh Pezeshk, Aliya Husain, Christine M Bestvina, Justin Kline, Marina C Garassino, Arjun S Raman.

Tumor microenvironments (TMEs) are compositionally and functionally heterogeneous, making it challenging to discover organizing structural principles. Through a study of 262 solid tumors profiled by spatial transcriptomics, we identify a conserved architecture where TMEs are partitioned into discrete, hierarchically organized multicellular sub-regions, which we term "spatial groups" (SGs). As indicated by orthogonal spatial measurements and expert pathologist review, SGs associate with recognizable biological domains spanning global tissue context to local cellular neighborhoods. Comparing tumors through SGs reveals a pan-tumor classification where the dominant axis of variation is spatial heterogeneity of immune biology. In an independent, retrospective cohort of non-small cell lung cancer patients treated with immune checkpoint blockade (ICB; n = 16), pan-tumor spatial biology classification distinguishes clinical response and captures structural and biological hallmarks associated with ICB sensitivity. Together, these findings suggest that SGs may be important organizing domains of the TME that relate spatial structure, biological function, and response to therapy.

Keywords: computational biology; immunotherapy; machine learning; spatial transcriptomics; systems biology; tumor microenvironment

DOI: https://doi.org/10.1016/j.xcrm.2026.103013

Bioinformatics. 2026 Aug 01. pii: btag491. [Epub ahead of print]42(Supplement_2):

Liquid biopsies reveal dual compartments of cancer risk from tumor and host-derived mutations.

Federica Malighetti, Ivan Civettini, Andrea Aroldi, Alberto Maria Villa, Matteo Villa, Luca Sala, Nicoletta Cordani, Massimiliano Cadamuro, Diego Cortinovis, Rocco Piazza, Luca Mologni, Daniele Ramazzotti.

MOTIVATION: Circulating tumor DNA (ctDNA) and clonal hematopoiesis of indeterminate potential (CHIP) are two biologically distinct sources of somatic mutations detectable in blood. While ctDNA captures tumor-intrinsic alterations, CHIP arises from age-related hematopoietic clones and is often considered background noise. Here, we conduct a large-scale, tumor-type-resolved analysis of over 9000 patients with CHIP data and 1500 patients with ctDNA data across solid tumors profiled at Memorial Sloan Kettering Cancer Center.
RESULTS: Our results reveal that CHIP and ctDNA mutations exhibit non-overlapping, clinically meaningful signals. CHIP mutations, particularly in DNA damage response and epigenetic regulators (e.g. PPM1D, CHEK2, ATM, TP53, ASXL1), are associated with worse overall survival, increased metastatic potential, and site-specific dissemination. ctDNA mutations in canonical oncogenic drivers (e.g. TP53, EGFR, KRAS, STK11) reflect tumor aggressiveness and correlate with poor prognosis and metastasis across multiple cancer types. Joint modeling in lung adenocarcinoma confirms the independent prognostic contributions of both compartments. Additionally, longitudinal clonal analysis links specific CHIP mutations to the emergence of hematologic malignancies under therapeutic pressure. These findings support a dual-compartment model of liquid biopsy, in which tumor- and host-derived mutations jointly inform on cancer risk, progression, and metastatic behavior. Integrating both compartments may enhance the clinical utility of blood-based biomarkers in oncology.
AVAILABILITY: All genomic and clinical data used in this study are available through cBioPortal. Summarized outputs and processed results tables are provided in Supplementary Data.

DOI: https://doi.org/10.1093/bioinformatics/btag491

Curr Treat Options Oncol. 2026 Aug 27. pii: 44. [Epub ahead of print]27(1):

Current Treatment Options Guided by Molecular Classification in Endometrial Cancer.

Qingyu Zhou, Wenxiu Fu, Qianshuo Zhang, Xiaolu Tian, Zhengmao Zhang.

OPINION STATEMENT: In our view, molecular classification should guide, but not independently determine, treatment for endometrial cancer. The four major molecular subtypes-POLE-mutated (POLEmut), mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H), p53-abnormal/copy-number-high (p53abn/CNH), and no specific molecular profile/copy-number-low (NSMP/CNL)-should be interpreted together with histological type, tumor grade, stage, myometrial invasion, lymphovascular space invasion, comorbidities, fertility goals, treatment accessibility, and patient preferences. For advanced or recurrent dMMR/MSI-H disease, we favor immune checkpoint inhibition because this subtype has the clearest predictive evidence, with immunotherapy increasingly incorporated into first-line treatment. For tumors harboring a confirmed pathogenic POLE exonuclease-domain mutation, we support careful consideration of adjuvant treatment de-escalation, while avoiding de-escalation based on non-pathogenic variants, variants of uncertain significance, or molecular classification alone in advanced-stage disease. We regard p53abn/CNH tumors as a high-risk phenotype requiring appropriately intensive multimodality treatment; human epidermal growth factor receptor 2-targeted therapy, DNA damage response-directed strategies, WEE1 G2 checkpoint kinase inhibition, and antibody-drug conjugates should be considered according to tumor biomarkers, treatment setting, and evidence strength. NSMP/CNL should not be managed as a uniform residual category. Secondary stratification using estrogen receptor/progesterone receptor status, L1 cell adhesion molecule expression, catenin beta 1 alterations, and phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin pathway alterations may identify hormone-sensitive, high-risk, and potentially targetable subgroups. In fertility-sparing management, molecular findings may refine counseling and surveillance but should not replace established eligibility criteria. At recurrence or progression, repeat biopsy and biomarker reassessment should be considered when clinically feasible and likely to alter treatment.

Keywords: Eendometrial cancer; Fertility-sparing treatment; Immunotherapy; Molecular classification; Targeted therapy

DOI: https://doi.org/10.1007/s11864-026-01409-w

J Liq Biopsy. 2026 Sep;13 100489

Liquid biopsy in oncology practice: A global survey by the Young Committee of the International Society of Liquid Biopsy (ISLB).

Background: Liquid biopsy is a transformative tool for precision oncology, yet its clinical use remains variable across healthcare systems, and barriers to its implementation are poorly characterized. This survey aims to assess perceptions and practices related to liquid biopsy in oncology practice worldwide.
Methods: A cross sectional, web-based survey was distributed to oncology providers worldwide from November 2024 to December 2025. The survey captured clinical practice characteristics, liquid biopsy uses and workflows, interpretation practices, reimbursement patterns, molecular tumor board (MTB) access, and perceived clinical- and system-level barriers. Descriptive statistics and subgroup comparisons were performed across geographic region, country income level, work setting, years in independent practice, and practice type.
Results: Responses from 393 participants across 59 countries were analyzed, with 53% practicing in Europe. Most were medical oncologists (90%) self-identified as specialists (68%), practicing in academic centers (78%), and in high-income countries (70%). Liquid biopsy use was variable: 83% of respondents used it in ≤50% of patients, with pronounced differences across all subgroups (all p < 0.01). Circulating tumor DNA (ctDNA) testing predominated (77%), while circulating tumor cell (CTC) use was uncommon (4% alone; 18% in combination with ctDNA). Clinicians in high-income countries, academic settings, and specialists were more likely to have structured workflows and institutional support for test-ordering. Interpretation practices varied, with most respondents relying on self-interpretation (36%) or vendor reports (30%); MTB-based primary interpretation was rare overall (4%), except in Northwestern Europe (23%). MTB availability and use varied substantially across regions and settings. Payment mechanisms differed markedly: government coverage predominated in Europe, private insurance in North America, and patient self-pay in Africa, Asia, and South/Central America-Caribbean. Cost (67%), test availability (55%), difficulty interpreting results (48%), and turnaround time (47%) were the most frequently cited barriers, with cost demonstrating the greatest regional variability (p < 0.001). Most clinicians rated liquid biopsy as important (88%) and felt confident applying results (80%), though both varied significantly by region.
Conclusions: These results highlight the high perceived value of liquid biopsy testing, while informing region- and setting-specific differences and challenges, which could be used to guide strategies to implement liquid biopsy in cancer care worldwide.

Keywords: CTCs; Clinical use; Disparities; Implementation barriers; Liquid biopsy; Molecular tumor board; Reimbursement; Solid tumors; ctDNA

DOI: https://doi.org/10.1016/j.jlb.2026.100489