bims-tumhet 2026-09-20 papers

Issue of 2026–09–20
eight papers selected by
Sergio Marchini, Humanitas Research

Annu Rev Pathol. 2026 Sep 17.

The Pathogenesis of Epithelial Ovarian Cancer.

Epithelial ovarian cancer is not a single disease but a group of biologically distinct malignancies that include serous (high-grade and low-grade), endometrioid, clear cell, and mucinous carcinomas, along with other rare subtypes. Integrating clinicopathological analyses, genomic and multiomic data, and experimental investigations in model systems has revealed the pathogenesis of the various histologic subtypes. A unique feature of epithelial ovarian cancer is that most of these tumors are now recognized to arise not from ovarian tissue but from the fallopian tube or endometrium, the latter in the context of ovarian endometriosis. Studies of precursor lesions have revealed complex evolutionary trajectories and the earliest molecular events in their development. Recent single-cell and spatial technologies further elucidate the roles of intratumoral heterogeneity and the tumor microenvironment in disease progression. This review summarizes these advances from the perspective of tissue of origin and highlights their implications for prevention, early detection, and therapeutic development.

DOI: https://doi.org/10.1146/annurev-pathmechdis-032025-021500

Cancer Cell. 2026 Sep 14. pii: S1535-6108(26)00357-0. [Epub ahead of print]44(9): 1715-1720

Molecular residual disease: Charting a new path for treating resectable solid tumors.

Shin Kobayashi, Tadayoshi Hashimoto, Hideaki Bando, Yoshiaki Nakamura, Aparna Parikh, Jeanne Tie, Qian Shi, Eiji Oki, Takayuki Yoshino.

Molecular residual disease (MRD), detected via circulating tumor DNA (ctDNA) after curative-intent surgery, identifies resectable solid tumor patients at high recurrence risk, thereby enabling enriched trials with larger effect sizes and smaller samples. Yet enrichment narrows the eligible population and thus challenges conventional randomized designs. We propose an MRD Registry as an external control cohort that integrates quantitative ctDNA data with outcomes to validate ctDNA dynamics as response indicators-facilitating efficient MRD-based trial design and accelerating novel therapy development.

DOI: https://doi.org/10.1016/j.ccell.2026.08.001

Int J Mol Sci. 2026 Aug 28. pii: 7697. [Epub ahead of print]27(17):

Liquid Biopsy for Molecular Residual Disease Detection and Postoperative Surveillance in Gastric Cancer: Current Evidence and Future Directions.

Lydia Lazaridou, Kalliopi Vakalou, Alexandra Dimaki, Konstantinos Eleftherios Koumarelas, Konstantinos Zachos, Dimitrios Schizas, Grigorios Christodoulidis.

Gastric cancer remains a major cause of cancer mortality worldwide, mainly due to its frequent diagnosis at advanced stages and the high probability of recurrence even after curative treatment. Conventional postoperative follow-up is mainly based on imaging studies, endoscopy and serological tumor markers, such as carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and carbohydrate antigen 72-4 (CA72-4)This narrative review was based on a structured literature search of PubMed, Scopus, Web of Science, MEDLINE, the Cochrane Library, and ClinicalTrials.gov from database inception through June 2026, with 75 studies included in the final narrative synthesis. Among these analytes, circulating tumor DNA (ctDNA)currently provides the most mature data for the detection of molecular residual disease and postoperative risk stratification. Although it allows for the early detection of recurrent or residual disease prior to imaging confirmation, postoperative ctDNA has shown significant prognostic value in many studies; however, routine use as a basis for decision-making in treatment planning is still considered investigational and will require future prospective clinical validation. Tumor-informed ctDNA approaches offer high analytical specificity and sensitivity in low-burden disease settings. In contrast, tumor-agnostic approaches, such as methylation analysis and fragmentomics, may improve the scalability of the method. However, they require further validation in the postoperative setting. At the same time, emerging data indicate that extracellular vesicles, exosomal RNA and peritoneal lavage analytes can provide complementary biological information, especially in cases of peritoneal dissemination. Despite the significant prospects, the use of liquid biopsy in guiding the treatment of gastric cancer remains under investigation. This is because even today there are limitations. Characteristic are the low ctDNA excretion and the anatomical heterogeneity of the disease, as well as clonal hematopoiesis. Limitations also include the lack of standardization as well as the cost and the need for prospective clinical studies. This review summarizes the biological basis of molecular residual disease, liquid biopsy technologies, ctDNA data, the concept of molecular recurrence, and the future prospects of multi-analytic and artificial intelligence (AI)-assisted surveillance models in gastric cancer.

Keywords: cell-free RNA; circulating tumor DNA; circulating tumor cells; exosomes; extracellular vesicles; gastric cancer; liquid biopsy; minimal residual disease; molecular relapse; molecular residual disease; postoperative surveillance

DOI: https://doi.org/10.3390/ijms27177697

Nat Cancer. 2026 Sep 14.

Circulating tumor DNA-guided de-escalation or escalation of adjuvant therapy in high-risk stage II and stage III colon cancer: the phase 2 PEGASUS trial.

Oxaliplatin-fluoropyrimidine combinations are standard adjuvant therapy after radical resection of high-risk stage II and stage III colon cancer but expose many patients to toxicity while failing to prevent relapse in others. PEGASUS was a multicenter, single-arm, phase 2 trial evaluating the feasibility of an adaptive circulating tumor DNA (ctDNA)-guided treatment strategy in patients with resected microsatellite-stable, T4N0 or stage III colon cancer. Postsurgery ctDNA-positive patients received 3 months of CAPOX, escalating to 6 months of FOLFIRI if persistently positive, whereas confirmed ctDNA-negative patients received 6 months of capecitabine. The primary endpoint was the 2-year relapse-free rate among ctDNA-negative patients at 2 subsequent postsurgery liquid biopsies. Among the 135 enrolled patients, 26% (n = 35) were ctDNA positive at the postsurgery landmark, with a 3-year disease-free survival rate of 58% for ctDNA positive versus 83% for ctDNA negative (hazard ratio = 2.71; 95% CI = 1.35-5.45; P = 0.0036). With 100 rather than 134 ctDNA-negative cases, the observed 2-year relapse-free rate (88%, 90% CI = 81-93%) was below the predefined threshold (≥92%); the primary endpoint was not met. Versus a matched TOSCA ( NCT00646607 ) control cohort, ctDNA-guided strategy showed similar disease-free survival and substantially less neurotoxicity. Transcriptomic profiling linked the relapse to consensus molecular subtype 4, stroma-rich biology. These findings suggest that dynamic ctDNA-guided management can be leveraged operationally in clinical practice, highlighting the needs for randomized trials and more effective strategies for ctDNA-positive disease. ClinicalTrials.gov identifier: NCT04259944 .

DOI: https://doi.org/10.1038/s43018-026-01237-9

Front Oncol. 2026 ;16 1907210

Clonal evolution in gastrointestinal cancers: multi-omics insights into tumor heterogeneity, microenvironmental selection, and translational biomarkers.

Wenyi Fan, Chunhong Zheng.

Clonal evolution in hepatocellular carcinoma (HCC), esophageal squamous cell carcinoma (ESCC), and gastric cancer (GC) reflects the interaction of genetic diversification, cell-state plasticity, and tissue-specific selection. Multi-region and single-cell DNA sequencing resolve truncal and subclonal lineages, whereas single-cell and spatial transcriptomics, proteomics, and serial liquid biopsy characterize cellular states, ecological niches, and temporal dynamics. The three cancers differ in dissemination timing, dominant selective pressures, and biomarker maturity: early seeding is best supported in selected HCC cohorts, ESCC is strongly influenced by field cancerization and epithelial-stromal crosstalk, and GC follows subtype- and ecotype-dependent trajectories. We discuss the assumptions and sampling biases that constrain phylogenetic inference, the causal limits of cross-sectional tumor atlases, clonal hematopoiesis, and the incremental value of broad multi-omics over focused assays. Liquid-biopsy detection of minimal residual disease is prognostic, but treatment benefit from marker-guided intervention remains context dependent. Near-term translation requires standardized, decision-linked assays; adaptive therapy and evolutionary steering remain investigational.

Keywords: clonal evolution; esophageal squamous cell carcinoma; gastric cancer; hepatocellular carcinoma; liquid biopsy; multi-omics; single-cell DNA sequencing; tumor microenvironment

DOI: https://doi.org/10.3389/fonc.2026.1907210

Cancers (Basel). 2026 Aug 24. pii: 2748. [Epub ahead of print]18(17):

Clinical Implications of Incorporating Molecular Profiles into the Staging of Endometrial Cancer: A Critical Review of the 2023 FIGO System on the Wave of 2025 ESGO/ESTRO/ESP Guidelines.

Angela Santoro, Giuseppe Angelico, Antonio d'Amati, Livia Maccio, Emma Bragantini, Francesco Fanfani, Anna Fagotti, Gian Franco Zannoni.

This review examines the clinical and practical implications of embedding molecular profiles directly into the 2023 FIGO staging system for endometrial carcinoma, in the context of the 2025 ESGO/ESTRO/ESP guidelines. The primary purpose is to navigate a central conflict in modern oncology: how to deliver increasingly personalized care while maintaining a globally accessible, equitable, and standardized cancer classification system. The 2023 FIGO update represents a paradigm shift from the traditional dualistic model (Type I versus Type II) by allowing molecular findings to redefine stage itself. While this integration offers clear benefits, it introduces significant challenges. First, the system depends on advanced molecular testing, creating a "rich-poor" divide where patients in resource-limited settings are systematically overtreated because testing is unavailable. Second, stage becomes unstable, changing with sequential histologic and molecular re-review, which causes confusion for patients and clinicians. Third, the system lumps prognostically distinct histotypes (Serous, Clear Cell, Carcinosarcoma, and Grade 3 Endometrioid) into a single aggressive stage, obscuring meaningful differences in survival. Fourth, it relies on subjective parameters such as "substantial" lymphovascular space invasion, for which no standardized definition exists, leading to high inter-observer variability. After analyzing these controversies, the review proposes a pragmatic solution: decouple anatomical staging from molecular risk stratification. Staging should remain a purely anatomical, universally applicable descriptor of tumor extent, while molecular and histologic data are used separately within a dynamic risk assessment model, as suggested by the European guidelines. This dual-track approach preserves global comparability, reduces inequity, and maintains diagnostic stability, while still enabling personalized treatment where advanced diagnostics are available.

Keywords: TCGA; clear cell carcinoma; endometrial carcinoma; serous carcinoma; undifferentiated carcinoma

DOI: https://doi.org/10.3390/cancers18172748

Lancet. 2026 Sep 19. pii: S0140-6736(26)01543-6. [Epub ahead of print]408(10560): 1088-1089

Unmasking inequity: emergency presentations in ovarian cancer care - Authors' reply.

Lancet Ovarian Cancer Commission

DOI: https://doi.org/10.1016/S0140-6736(26)01543-6