bims-tumhet 2025-12-28 papers

Gynecol Oncol. 2025 Dec 19. pii: S0090-8258(25)01133-3. [Epub ahead of print]205 1-8

Prognostic value of perioperative circulating tumor DNA in endometrial cancer: systematic review & meta-analysis.

Amna Ahmed, Gagandeep Saini, Sarah E Ferguson, Rouhi Fazelzad, Qixuan Li, Kathy Han, Trevor Pugh, Derek Wong, Raymond H Kim, Anjelica Hodgson, Samuel Leung, Amy Jamieson, Jessica N McAlpine, Kristina Lindemann, Franziska Siegenthaler, Soyoun Rachel Kim.

IMPORTANCE: Decisions regarding endometrial cancer (EC) adjuvant therapy can be challenging due to the need to balance the benefits of recurrence reduction with treatment toxicity. Circulating tumor DNA (ctDNA) has the potential to guide adjuvant therapy decisions by stratifying patients based on their risk of recurrence.
OBJECTIVE: To determine the association between perioperative ctDNA positivity and survival outcomes in patients with EC.
METHODS: An electronic search was performed in MEDLINE, Embase, Cochrane Central, Cochrane Database of Systematic Reviews, and Web of Science and included all articles up to July 23rd, 2025. Studies were included if they assessed patients with EC who had ctDNA assessment before and/or after surgery and reported on survival outcomes. Meta-analysis was done to explore the association between ctDNA levels and survival.
MAIN OUTCOME AND MEASURES: The primary outcome was the association between ctDNA positivity pre- or post-operatively and progression-free survival (PFS).
RESULTS: Of 2862 articles reviewed, 11 met inclusion criteria, which led to reporting on 1298 patients. Pre-operative as well as post-operative ctDNA positivity was significantly associated with worse PFS (HR 3.69 [95 % confidence interval (CI), 2.58-5.26], HR 12.61 [95 % CI, 8.78-18.13] respectively), with no significant heterogeneity.
CONCLUSIONS AND RELEVANCE: This systematic review and meta-analysis demonstrates that perioperative detection of ctDNA positivity is significantly associated with worse PFS and could serve as a valuable tool for EC prognostication and guidance for adjuvant therapy decision-making. Prospective studies that evaluate the role of ctDNA in EC are needed for this to be implemented in clinical practice.

Keywords: Circulating tumor DNA; Endometrial cancer; Tumor biomarker

DOI: https://doi.org/10.1016/j.ygyno.2025.12.008

Cancer Cell. 2025 Dec 24. pii: S1535-6108(25)00536-7. [Epub ahead of print]

Targeting STING to generate therapeutic anti-tumor immunity.

Caroline G Fahey, Anthony F Cordova, Patrick C Gedeon, David A Barbie.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway bridges cytosolic DNA sensing with type I interferon activation in cancer. Despite promising preclinical results, generating clinically meaningful anti-tumor immunity with STING agonists has faced substantial challenges, highlighting gaps in model systems and the biologic complexity of STING signaling. In the tumor microenvironment (TME), STING activation elicits highly context- and cell type-dependent outcomes, with divergent effects on tumor cells, myeloid cells, T cells, and other cell types. Furthermore, the downstream induction of type I interferon and other cytokines in the TME can have both pro- and anti-tumorigenic consequences, with emerging interferon-independent functions of STING signaling adding further complexity. In this review, we chart the diverse impact of STING activation across the TME and discuss how recent insights can inform the design of next-generation therapeutic strategies that more effectively harness STING-driven innate immunity to promote durable anti-tumor activity in humans.

Keywords: STING; anti-tumor immunity; cGAS; innate immunity; interferon; tumor microenvironment

DOI: https://doi.org/10.1016/j.ccell.2025.12.002

Clin Chim Acta. 2025 Dec 19. pii: S0009-8981(25)00676-X. [Epub ahead of print]582 120797

Recent advances in the early detection of ovarian Cancer.

Anahita Soleimani, Akbar Amirfiroozy, Mohammad M Pourseif, Mahmoud Shekari Khaniani.

Ovarian cancer (OC), predominantly epithelial OC, remains the most lethal gynecological malignancy. Owing to its often asymptomatic or non-specific clinical presentation, approximately 70 % of patients are diagnosed at advanced stages (FIGO III-IV), typically characterized by extensive peritoneal dissemination. Although early detection is critical for improving survival outcomes, current standard diagnostic modalities, including serum CA125 and transvaginal ultrasound, lack sufficient sensitivity and specificity for population-level screening of early-stage disease. This review comprehensively evaluates emerging biomarkers and advanced diagnostic technologies, with a particular focus on liquid biopsy analytes, including circulating tumor DNA, microRNAs, and uterine liquid biopsies. We further discuss the clinical utility of multi-biomarker panels and artificial intelligence (AI)-driven models that integrate genomic, proteomic, and radiomic data, while highlighting their current performance limitations and stage-dependent diagnostic accuracy. Despite the considerable potential of liquid biopsies and AI-based approaches, challenges related to assay standardization and the need for large-scale prospective validation remain major barriers to widespread clinical implementation. Overall, this review underscores the need for robust, multimodal diagnostic strategies that may enable earlier detection and ultimately reduce OC-associated mortality.

Keywords: Artificial intelligence; CA125; Circulating tumor DNA; Early detection; HE4; Liquid biopsy; Multi-omics; Ovarian Cancer

DOI: https://doi.org/10.1016/j.cca.2025.120797

Mol Oncol. 2025 Dec 23.

Crucial parameters for precise copy number variation detection in formalin-fixed paraffin-embedded solid cancer samples.

Hanne Goris, Vasiliki Siozopoulou, Léon C van Kempen, Anne Sieben, Ella Roelant, Stig Hellemans, Elyne Backx, Laure Sorber, Koen De Winne, Senada Koljenović, Karen Zwaenepoel.

Copy number variations (CNVs) play a crucial role in cancer diagnostics and prognostics, potentially impacting treatment decisions. Ultra-low-pass whole-genome sequencing (ULP-WGS) has emerged as a promising alternative to array-based methods for CNV detection, especially in formalin-fixed paraffin-embedded (FFPE) samples. However, sequencing biases and sample heterogeneity necessitate the optimization of CNV detection tools for FFPE sample-derived data. This study evaluates three open-source CNV callers (CNVpytor, ichorCNA, and WisecondorX) using ULP-WGS and compares their performance against a single nucleotide polymorphism (SNP) array. Our results demonstrate that under optimal experimental conditions, ichorCNA and WisecondorX achieved equal detection of true positive results, with reduced false positive results compared to the SNP array. The SNP array detection pattern differed somewhat from that of the CNV callers, while ichorCNA and WisecondorX had the most comparable detection pattern. We highlight the importance of (pre-)analytical parameters such as neoplastic cell content, sequencing coverage, and bin size selection on CNV detection accuracy. Our findings support the adoption of ULP-WGS-based CNV detection as a robust alternative to SNP arrays, with WisecondorX emerging as the most suitable tool for clinical implementation.

Keywords: FFPE tissue; SNP array; ULP‐WGS; cancer diagnostics; copy number variations

DOI: https://doi.org/10.1002/1878-0261.70192

Lancet Oncol. 2026 Jan;pii: S1470-2045(25)00680-1. [Epub ahead of print]27(1): 2-3

Is PORTEC-4a the tipping point in endometrial cancer management?

Ilaria Betella, Lucia Ribero.

DOI: https://doi.org/10.1016/S1470-2045(25)00680-1

Lancet Oncol. 2026 Jan;pii: S1470-2045(25)00566-2. [Epub ahead of print]27(1): 68-78

Nivolumab plus docetaxel versus placebo plus docetaxel for androgen receptor pathway inhibitor-pretreated and chemotherapy-naive metastatic castration-resistant prostate cancer (CheckMate 7DX): a double-blind, randomised, phase 3 trial.

BACKGROUND: Androgen receptor pathway inhibitors (ARPIs) and docetaxel are established standards of care for chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC). We aimed to assess the efficacy and safety of adding nivolumab to docetaxel versus docetaxel alone in ARPI-pretreated, chemotherapy-naive mCRPC.
METHODS: CheckMate 7DX was a double-blind, randomised, phase 3 trial that enrolled adult patients (aged ≥18 years) with histologically confirmed, ARPI-pretreated, and chemotherapy-naive mCRPC at 291 hospitals and cancer centres across 27 countries. Patients had documented progression within 6 months of screening and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) to nivolumab (360 mg), or equivalent placebo, and docetaxel (75 mg/m2) intravenously every 3 weeks for up to ten doses, followed by nivolumab (480 mg) or equivalent placebo every 4 weeks. Randomisation, stratified by previous ARPI therapy and visceral disease, was done using interactive response technology in permuted blocks with a block size of six. Patients, investigators, and the trial sponsor were masked to individual patient treatment assignment. The primary endpoints were radiographic progression-free survival by blinded independent central review and overall survival, assessed in all randomly assigned patients. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT04100018, and is completed.
FINDINGS: Between March 11, 2020, and Aug 2, 2022, 1414 patients were screened for eligibility, 1030 of whom were randomly assigned to nivolumab plus docetaxel (n=514) or placebo plus docetaxel (n=516). All participants were male, median age was 70 years (range 34-91), 662 (64%) were White, 240 (23%) were Asian, and 35 (3%) were Black or African American. With a median follow-up of 17·2 months (IQR 13·2-22·0), median radiographic progression-free survival was 9·4 months (95% CI 8·5-10·3) in the nivolumab plus docetaxel group versus 8·7 months (95% CI 8·4-10·0) in the placebo plus docetaxel group (hazard ratio [HR] 0·96 [99% CI 0·77-1·19]; p=0·59) and median overall survival was 18·7 months (95% CI 17·0-21·0) versus 18·9 months (95% CI 17·3-22·0, HR 1·09 [99·41% CI 0·84-1·43]; p=0·36). Grade 3-4 treatment-related adverse events occurred in 223 (44%) of 510 patients in the nivolumab plus docetaxel group and 187 (37%) of 510 in the placebo plus docetaxel group. The most common grade 3-4 events in both treatment groups were neutropenia (37 [7%] in the nivolumab plus docetaxel group and 50 [10%] in the placebo plus docetaxel group) and decreased neutrophil count (41 [8%] and 39 [8%]). Any-grade treatment-related serious adverse events occurred in 107 (21%) patients in the nivolumab plus docetaxel group and 77 (15%) in the placebo plus docetaxel group. 12 deaths were attributed to nivolumab plus docetaxel (three due to sepsis; one each due to Guillain-Barré syndrome, diverticulitis, myocarditis, liver injury, peritonitis, pneumonitis, pneumonia, and diarrhoea; and one due to unknown causes) and one was attributed to placebo plus docetaxel (due to pneumocystis).
INTERPRETATION: Nivolumab plus docetaxel did not improve progression-free survival or overall survival versus placebo plus docetaxel in patients with ARPI-pretreated, chemotherapy-naive mCRPC. These findings do not support the use of combinations of anti-PD-1 immune checkpoint inhibitors and docetaxel in the treatment of unselected populations of patients with ARPI-pretreated, chemotherapy-naive mCRPC.
FUNDING: Bristol Myers Squibb.

DOI: https://doi.org/10.1016/S1470-2045(25)00566-2

Clin Transl Sci. 2026 Jan;19(1): e70463

Lexicon for Clonal Hematopoiesis in Liquid Biopsy.

Historically, clonal hematopoiesis (CH) has been recognized as a confounder of cell-free DNA (cfDNA) testing. Recent evidence now demonstrates the role of CH as a risk factor in health, generating distinct sources of cfDNA that can be leveraged for liquid biopsy diagnostics. Nonetheless, gaps in standardization challenge the advancement of such diagnostics from development to regulatory approval, through clinical trials, and ultimately, to routine implementation. In 2024, the Blood Profiling Atlas in Cancer (BLOODPAC) Consortium, a collaborative infrastructure for developing standards and best practices for liquid biopsy assays, established the CH/clonal hematopoiesis of indeterminate potential (CHIP) Working Group to address the need for accurate identification and removal of CH from liquid biopsy results. As a first step to support the interpretability of CH/CHIP results, the Working Group developed this lexicon to standardize terms and provide a unified vocabulary related to CH and liquid biopsy, DNA sequencing tests, biomarkers, and clinical use cases, facilitating communication within the field. BLOODPAC's CH/CHIP Working Group believes that terminology agreement across these various stakeholders can improve communication in the field and unify future data collection efforts across studies.

Keywords: CH; CHIP; liquid biopsy

DOI: https://doi.org/10.1111/cts.70463

Nat Commun. 2025 Dec 23. 16(1): 11339

Prostate cancer cells converge to an inflammatory-like state upon metastatic dissemination.

Identifying drivers of cancer progression to guide treatment selection is hindered by our limited understanding of tumor heterogeneity and its impact on tumor evolution. Here, we delineate the phenotypic variability across ~300,000 cells collected from multiple tumor loci in primary prostate and matched locoregional metastases using single-cell chromatin accessibility and gene expression sequencing. We find inter-patient heterogeneity to be confined to malignant populations. Within individual tumor loci, we see phenotypic heterogeneity among malignant cell populations despite a shared clonal genotypic architecture. We also observe that malignant cell populations disseminating to locoregional lymph nodes mirror the clonal architecture and phenotypic heterogeneity across primary tumor loci, while shifting from canonical prostate-cancer states to non-canonical inflammatory-like states. Our findings suggest a bottleneck imposed during the dissemination process, funneling prostate cancer cells toward an inflammatory-like cell state. These insights into the interplay between phenotypic identity and clonal architecture refine our understanding of prostate cancer progression and suggest that convergence of cancer cells towards an inflammatory-like state underlies dissemination to lymph nodes, offering a critical framework for future studies into prostate cancer metastatic potential.

DOI: https://doi.org/10.1038/s41467-025-67856-5

Clin Cancer Res. 2025 Dec 22.

CtDNA detection with low-pass whole genome bisulfite sequencing in RAS wild-type metastatic colorectal cancer: an exploratory objective of the VALENTINO trial.

PURPOSE: Longitudinal measuring of circulating tumor DNA (ctDNA) during systemic treatment of metastatic colorectal cancer (mCRC) is promising for disease monitoring, but it is hampered by high costs and lacks formal demonstration of clinical usefulness.
PATIENTS AND METHODS: We leveraged METER, a novel, highly reproducible, computational workflow that infers ctDNA presence and fraction from low-pass whole genome bisulfite sequencing to investigate baseline and 8-week ctDNA dynamics in patients with RAS wild-type mCRC undergoing first-line treatment with panitumumab/FOLFOX in the VALENTINO randomized phase 2 trial. IchorCNA was used to provide a benchmark for METER.
RESULTS: A total of 154 patients were evaluable. Baseline ctDNA was detected in 72.7% of patients and was associated with significantly higher risk of progression (1.65, 95%CI: 1.13-2.42; p=0.010) and death (HR: 2.24, 95%CI: 1.37-3.66; p<0.001). CtDNA clearance at 8 weeks was observed in 80.2% of patients with baseline detectable ctDNA; persistence of ctDNA was associated with significantly higher risk of progression (2.70, 95%CI: 1.63-4.49; p<0.001) and death (HR: 3.37, 95%CI: 2.00-5.69; p<0.001). CtDNA clearance was associated with a more profound depth of response (DoR) (median -48.4% vs -41.2%; p=0.023) but not with a higher frequency of early tumor shrinkage (72.0% vs 73.7%, p=1.00). METER expanded the number of ctDNA-positive patients relative to a copy number alteration- and a variant allele frequency-based methods.
CONCLUSION: CtDNA detection and quantification with METER is a promising tool for cost-effective treatment monitoring in mCRC and can complement radiological assessment of response dynamics.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-2773