bims-tumhet 2025-12-14 papers

bims-tumhet

Biomed News

on Tumor heterogeneity

Issue of 2025–12–14
twelve papers selected by
Sergio Marchini, Humanitas Research

The technology landscape for detection of DNA methylation in cancer liquid biopsies.
Durvalumab with carboplatin/paclitaxel and bevacizumab followed by durvalumab and bevacizumab with or without olaparib maintenance in newly diagnosed non-BRCA-mutated advanced ovarian cancer.
Homologous recombination repair status in advanced endometrial cancer: an exploratory biomarker analysis from the randomized, phase II MITOEND 3 trial.
Liquid biopsies across the cancer care continuum.
Exploring the Pivotal Functions of Tertiary Lymphoid Structures in Cancer Prognosis and Immunotherapy Outcomes.
Genomics of ovarian cancers and the potential of precision medicine.
Incidental Diagnosis of Serous Tubal Intraepithelial Carcinoma During Infertility Treatment: A Case Report.
The evolving landscape of RAS-targeted therapies.
Liquid biopsy.
Tumor Genomic and Transcriptomic Analysis Integrated With Liquid Biopsy ctDNA Monitoring: Analytical Validation and Clinical Insights.
Teclistamab plus Daratumumab in Relapsed or Refractory Multiple Myeloma.
Cancer screening must become more precise.

Epigenetics. 2025 Dec;20(1): 2453273

The technology landscape for detection of DNA methylation in cancer liquid biopsies.

Isabelle Neefs, Joe Ibrahim, Marc Peeters, Guy Van Camp, Ken Op de Beeck.

  DNA methylation is a well-studied epigenetic factor and has become a powerful player in the cancer biomarker research field. Together with the rising interest in methylation biomarkers, the technological advances for the detection of DNA methylation have been immense. This has led to a plethora of different methods. The first methods were established for DNA methylation detection in genomic DNA, while new methods have focused more on compatibility with the emerging interest of cell-free DNA (cfDNA) from liquid biopsies. As DNA methylation detection in cfDNA brings its own challenges, a shift from the gold standard bisulfite conversion towards enzymatic conversion methods can be observed in recent years. In this review, we aim to summarize the classic and more recent DNA methylation detection methods for liquid biopsies. Importantly, the few existing European Certified In Vitro Diagnostics (CE-IVD) clinical applications for liquid biopsies are also described, underlining the potential of DNA methylation as a detection biomarker in cfDNA. Furthermore, we provide some insights into how the field might evolve in the future, where we believe enzymatic conversion might become a new gold standard and direct sequencing methods, such as ONT-sequencing, will get an important place in the epigenetic research field. Lastly, we believe that multi-omics technologies, which can combine diverse types of biomarkers, will most likely become more important in future clinical applications. Moreover, novel recent technologies are being developed and show promising clinical applications. Taken together, methylation biomarkers are becoming more important for clinical implementation.

Keywords:  DNA methylation; cancer; detection

DOI:  https://doi.org/10.1080/15592294.2025.2453273
Ann Oncol. 2025 Dec 09. pii: S0923-7534(25)06315-X. [Epub ahead of print]

Durvalumab with carboplatin/paclitaxel and bevacizumab followed by durvalumab and bevacizumab with or without olaparib maintenance in newly diagnosed non-BRCA-mutated advanced ovarian cancer.

DUO-O Investigators

   BACKGROUND: Despite treatment advances in newly diagnosed advanced stage ovarian cancer (aOC), improved outcomes are needed.
PATIENTS AND METHODS: DUO-O (NCT03737643) a phase III placebo-controlled trial, enrolled patients with newly diagnosed aOC. Following one cycle of carboplatin/paclitaxel ± bevacizumab, patients without a tumor BRCA mutation (non-tBRCAm) were randomized (1:1:1) at Cycle 2 to carboplatin/paclitaxel plus bevacizumab followed by bevacizumab (control); carboplatin/paclitaxel, bevacizumab plus durvalumab followed by bevacizumab plus durvalumab (durvalumab arm); or carboplatin/paclitaxel, bevacizumab plus durvalumab followed by bevacizumab, durvalumab plus olaparib (durvalumab+olaparib arm). Investigator-assessed progression-free survival (PFS; primary endpoint) was tested for the durvalumab+olaparib arm versus control in the non-tBRCAm homologous recombination deficiency (HRD)-positive and non-tBRCAm intention-to-treat (ITT) populations.
RESULTS: 1130 patients were randomized. The prespecified interim PFS analysis (DCO: 5 December 2022) qualified as the primary analysis; PFS hazard ratio (HR) for the durvalumab+olaparib arm versus control was 0.49 (95%CI 0.34-0.69; P<0.0001; median [m]PFS 37.3 versus 23.0 months) in the non-tBRCAm HRD-positive and 0.63 (0.52-0.76; P<0.0001; mPFS 24.2 versus 19.3 months) in the non-tBRCAm ITT population. For the durvalumab arm versus control, PFS HR was 0.87 (0.73-1.04; P=0.13; mPFS 20.6 versus 19.3 months) in the non-tBRCAm ITT population. At final PFS and interim overall survival (OS) analysis (DCO: 18 September 2023), PFS results were consistent with primary analysis; interim OS HR for the durvalumab+olaparib arm versus control was 0.95 (95% CI 0.76-1.20; P=0.68; 39.0% maturity) in the non-tBRCAm ITT population. Safety was generally consistent with the profiles of the individual agents.
CONCLUSIONS: DUO-O met its primary PFS endpoints for first-line durvalumab plus carboplatin/paclitaxel and bevacizumab followed by durvalumab, bevacizumab plus olaparib maintenance versus carboplatin/paclitaxel and bevacizumab followed by bevacizumab in the non-tBRCAm HRD-positive and non-tBRCAm ITT populations. Further insight into long-term benefit is anticipated with additional follow-up.

Keywords:  Olaparib; advanced ovarian cancer; bevacizumab; carboplatin/paclitaxel; durvalumab; non-tumor BRCA mutation

DOI:  https://doi.org/10.1016/j.annonc.2025.11.020
ESMO Open. 2025 Dec 05. pii: S2059-7029(25)01789-2. [Epub ahead of print]10(12): 105919

Homologous recombination repair status in advanced endometrial cancer: an exploratory biomarker analysis from the randomized, phase II MITOEND 3 trial.

M Bartoletti, A Passarelli, A Fagotti, C Andreetta, S Tamberi, D Lorusso, C Pisano, D Califano, A Spina, C De Angelis, F Greco, R De Cecio, G L Scaglione, D Russo, V Ghizzoni, S Cinieri, S D Sisoudiya, E S Sokol, L Arenare, C Schettino, F Perrone, A Farolfi, S Pignata.

   BACKGROUND: Poly (ADP-ribose) polymerase (PARP) inhibitor use in endometrial cancer (EC) requires predictive biomarkers, currently lacking in clinical practice. This study assessed the incidence of homologous recombination deficiency (HRD) using genomic loss of heterozygosity (gLOH) and a machine learning-based HRD scar signature (HRDsig).
PATIENTS AND METHODS: MITO END 3 was a multicenter, phase II trial of advanced EC patients randomly assigned to receive platinum-based chemotherapy ± avelumab. Of 125 patients, 102 had tumor samples available for sequencing with FoundationOne®CDx. HRD was evaluated using gLOH (cut-off ≥16%, based on ARIEL3) and HRDsig (cut-off ≥0.7, validated pan-cancer).
RESULTS: Among 102 evaluable samples, 5 were HRDsig-positive, 90 HRDsig-negative, and 7 HRDsig unknown. gLOH was high in 10 cases, low in 53, and not assessable in 39. Most HRDsig-positive (4/5) and gLOH-high (8/10) tumors were of endometrioid histology and carried TP53 mutations. None were microsatellite instability-high.
CONCLUSIONS: A small subgroup of advanced EC patients shows HRD positivity by gLOH or HRDsig, potentially identifying those most likely to benefit from PARP inhibitors. These tumors are typically endometrioid with TP53 mutations.

Keywords:  HRD; PARPi; endometrial cancer; immunotherapy; precision medicine

DOI:  https://doi.org/10.1016/j.esmoop.2025.105919
Nat Med. 2025 Dec 10.

Liquid biopsies across the cancer care continuum.

Blair V Landon, Akshaya V Annapragada, Noushin Niknafs, Victor E Velculescu, Valsamo Anagnostou.

Liquid biopsies have the potential to transform precision oncology by enabling the sensitive and timely detection of cancer across various clinical settings. Minimally invasive analyses of circulating cell-free DNA (cfDNA) have emerged as cutting-edge approaches for cancer detection, characterization and monitoring. Early efforts focused on mutation-based targeted sequencing, whereas newer methods use whole-genome and epigenome sequencing combined with artificial intelligence to broaden the range of alterations that can be assessed in cfDNA. Despite these advances, substantial technical and clinical challenges prevent widespread adoption. Key areas for improvement include achieving clinically meaningful detection sensitivities, enhancing assay accessibility and prospectively evaluating the clinical sensitivity of circulating tumor DNA burden in early and metastatic settings, to support the integration of liquid biopsies into therapeutic decision-making. Here we discuss technologies and analytical methodologies in cfDNA detection, together with their clinical validity and utility. We highlight opportunities to address key challenges and to support the implementation of liquid biopsies throughout the cancer care continuum.

DOI: https://doi.org/10.1038/s41591-025-04093-9
Cancers (Basel). 2025 Nov 24. pii: 3754. [Epub ahead of print]17(23):

Exploring the Pivotal Functions of Tertiary Lymphoid Structures in Cancer Prognosis and Immunotherapy Outcomes.

Constantin N Baxevanis, Michael Sofopoulos, Ourania E Tsitsilonis, Angelos D Gritzapis.

  Tertiary lymphoid structures (TLS) arise from lymphoid neogenesis in non-lymphoid organs and are driven by persistent inflammation mediated by chemokines and cytokines. In cancer, TLS orchestrate immune mechanisms relevant to tumor growth and thereby influence clinical outcomes. Observations of a correlation between the presence of TLS and clinical benefits in cancer patients, which suggests that TLS may serve as prognostic and predictive biomarkers, have prompted increased investigation of TLS in tumors. Accumulating evidence indicates that the prognostic and predictive value of TLS is context-dependent and relevant to their cellular composition and functional state. Combining assessments of tumor-infiltrating lymphocytes (TILs) with TLS features yields a more refined prognostic tool by capturing both local immune activity and aspects of the broader tumor immune microenvironment. Improved understanding of TLS biology and of their interactions with TILs can enhance predictions of therapeutic response. Furthermore, therapeutic modulation of TLS composition or function to favor antitumor immunity represents a promising strategy to improve treatment outcomes.

Keywords:  antitumor immunity; chemokines; immune checkpoint inhibitors; immunotherapy; tertiary lymphoid structures; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3390/cancers17233754
Ther Adv Med Oncol. 2025 ;17 17588359251396651

Genomics of ovarian cancers and the potential of precision medicine.

Andrew Jarratt, Joseph Polidano, Clare L Scott, Holly E Barker.

  Epithelial ovarian cancer (OC) comprises molecularly distinct disease types, with high-grade serous ovarian cancer (HGSOC) accounting for ~75% of OC diagnoses; ovarian clear cell carcinoma (OCCC) and endometrioid ovarian carcinoma (EnOC) at ~10% each; mucinous ovarian carcinoma (MOC) and low-grade serous ovarian carcinoma (LGSOC) at ⩽5% each; and ovarian carcinosarcoma (OCS), the rarest type of OC at 1%-4% of OC diagnoses. LGSOC has the best prognosis, followed by EnOC, MOC and OCCC, with HGSOC then OCS being the most aggressive. For all types of OC, diagnosis at the advanced-stage results in dramatically reduced survival. Initial treatment consists of debulking surgery and platinum-based chemotherapy, usually in combination with a taxane; however, response rates vary depending on the OC type. Treatments specific to the OC type may improve treatment outcomes. For HGSOC, poly(ADP-ribose) polymerase inhibitor (PARPi) therapy has improved survival for women with DNA homologous recombination repair (HRR) defects; however, acquired resistance remains an issue and more effective treatments are needed. Next-generation sequencing of distinct types of OC has revealed the complexity of genetic variants and larger-scale genomic and epigenomic alterations harboured, including proven and putative biomarkers of drug response. A predominance of distinct gene classes is altered in specific OC types: HRR genes (e.g. BRCA1 and BRCA2) in HGSOC; ARID1A and PIK3CA in OCCC; PIK3CA and KRAS in EnOC; CDKN2A and KRAS in MOC and MAPK pathway genes (e.g. BRAF and KRAS) in LGSOC. Generating evidence for effective drug combination therapies targeting relevant aberrations in each OC type is urgently needed. The effects of long-term drug treatment on OC genomes, acquired drug-resistance and OC relapse require clarification, especially in women with HGSOC with acquired resistance to PARPi. This article provides an overview of the main types of OC and their genomic profiles. It highlights recent encouraging clinical trials, with an emphasis on the future of genomically-targeted combination therapies, for both first-line and subsequent treatment of OC. We focus on PARPi combinations for HGSOC, MAPK pathway inhibitors for LGSOC, cell cycle checkpoint inhibitors for OC with CCNE1 amplification, the potential of immune checkpoint inhibitors in OCCC and encouraging, as yet preliminary, responses for antibody-drug conjugate-based therapy. Thus, OC type-specific genomic susceptibilities provide direction for personalised therapy in OC.

Keywords:  clinical trials; epithelial ovarian cancer; homologous recombination deficiency (HRD); molecular profiling; molecular therapeutics; targeted therapy

DOI:  https://doi.org/10.1177/17588359251396651
Cureus. 2025 Nov;17(11): e96355

Incidental Diagnosis of Serous Tubal Intraepithelial Carcinoma During Infertility Treatment: A Case Report.

Keisuke Doi, Yasuhiro Ohara, Tsuyoshi Takiuchi, Tomomoto Ishikawa.

  Serous tubal intraepithelial carcinoma (STIC) represents a precursor lesion to high-grade serous ovarian carcinoma and is typically identified during prophylactic surgery in BRCA mutation carriers. To the best of our knowledge, we report the first case of STIC incidentally diagnosed during infertility treatment. A 43-year-old nulligravid woman with four years of primary infertility underwent laparoscopic left salpingectomy for hydrosalpinx prior to embryo transfer. Histopathological examination unexpectedly revealed STIC, confirmed by characteristic morphological features and immunohistochemical markers, including strong nuclear p53 expression and elevated Ki-67 index. The patient declined BRCA genetic testing and prophylactic surgical interventions, opting to continue fertility treatment under enhanced surveillance. This unprecedented case emphasizes the critical importance of comprehensive histopathological evaluation of surgically resected fallopian tubes, even when removed for benign reproductive indications, and highlights the complex decision-making process regarding genetic counseling, surveillance strategies, and fertility preservation in reproductive-aged women with incidentally diagnosed STIC.

Keywords:  assisted reproductive technology (art); brca; hydrosalpinx; laparoscopic salpingectomy; serous tubal intraepithelial carcinoma

DOI:  https://doi.org/10.7759/cureus.96355
Nat Cancer. 2025 Dec 10.

The evolving landscape of RAS-targeted therapies.

Sandra Misale.

DOI: https://doi.org/10.1038/s43018-025-01077-z
Nat Biotechnol. 2025 Dec;43(12): 1929

Liquid biopsy.

DOI: https://doi.org/10.1038/s41587-025-02940-1
Cancer Med. 2025 Dec;14(23): e71465

Tumor Genomic and Transcriptomic Analysis Integrated With Liquid Biopsy ctDNA Monitoring: Analytical Validation and Clinical Insights.

Nam H B Tran, Thien-Phuc Hoang Nguyen, Vinh Quang Bui, Vu Thuong Le, Trong Khoa Mai, Van-Anh Nguyen Hoang, Tien Anh Nguyen, Minh-Duc Nguyen, Ha-Hieu Pham, Tho Thi Le Vo, My T T Ngo, Du Quyen Nguyen, Duy Sinh Nguyen, Hoai-Nghia Nguyen, Minh-Duy Phan, Hoa Giang, Lan N Tu.

   BACKGROUND: Comprehensive genomic profiling (CGP) is a time- and tissue- efficient method to help guide precision oncology. To enhance the clinical utility of CGP, we investigated the performance of a novel strategy integrating tumor DNA and mRNA profiling, together with liquid biopsy ctDNA monitoring.
METHODS: Genomic DNA and mRNA simultaneously extracted from 604 archived tissue samples of 12 cancer types were used. Tumor DNA was subjected to targeted sequencing using a 504-gene panel with high-density probes (HDP), and shallow whole genome sequencing to profile genomic biomarkers. mRNA transcriptome profiling was performed to further capture fusion variants, and to predict tissue of origin (TOO) using our ensemble model OriCUP, an algorithm trained on 9889 samples and independently validated on 731 samples. In a cohort of 55 metastatic lung cancer patients, longitudinal plasma ctDNA was analyzed using a hybrid tumor-informed and tumor-agnostic approach to predict progression-free survival (PFS).
RESULTS: Among all biomarkers, DNA sequencing using HDP achieved higher sensitivity than the standard panel design to identify copy number variations at chromosome-, gene-, and exon- levels. The detection rate of fusion variants using DNA sequencing alone was 20% lower than mRNA sequencing in reference samples, while the combination of both methods was essential to maximize fusion detection in clinical FFPE samples. For TOO, our OriCup model achieved prediction accuracy of 87.7% for primary tumors and 81.4% for metastatic tumors. In 55 lung cancer patients, ctDNA profiling identified additional 11.5% tumor-agnostic actionable and resistance mutations. Patients having more than 50% ctDNA decrease from baseline were classified as molecular responders and showed significantly longer PFS than those classified as molecular non-responders (HR = 9.42, 95% CI: 3.33-26.67, p < 0.0001, 12-month PFS: 95.5% vs. 31.7%).
CONCLUSIONS: Comprehensive genomic and transcriptomic profiling could reliably unveil genetic details not provided by DNA-only CGP. The integration of ctDNA detection further helped detect tumor-agnostic mutations and monitor treatment response.

Keywords:  cancer of unknown primary; cancer tissue of origin; circulating tumor DNA; comprehensive genomic profiling; copy number variation; fusion; mRNA sequencing

DOI:  https://doi.org/10.1002/cam4.71465
N Engl J Med. 2025 Dec 09.

Teclistamab plus Daratumumab in Relapsed or Refractory Multiple Myeloma.

MajesTEC-3 Trial Investigators

BACKGROUND: In a phase 1-2 trial, teclistamab, a bispecific antibody targeting CD3 on T-cell surfaces and B-cell maturation antigen on myeloma cells, showed durable responses in heavily pretreated patients with relapsed or refractory multiple myeloma. Daratumumab, a monoclonal antibody targeting CD38 protein, has shown survival benefit in patients with multiple myeloma.
METHODS: In this phase 3 trial, we randomly assigned patients with one to three previous lines of therapy to receive combination therapy with teclistamab-daratumumab or daratumumab combined with dexamethasone plus the investigator's choice of pomalidomide (DPd) or bortezomib (DVd) - the DPd or DVd group. The primary end point was progression-free survival, as assessed by an independent review committee.
RESULTS: A total of 587 patients underwent randomization (291 to receive teclistamab-daratumumab and 296 to receive DPd or DVd). At a median of 34.5 months, progression-free survival was significantly longer with teclistamab-daratumumab than with DPd or DVd. The estimated 36-month progression-free survival was 83.4% in the teclistamab-daratumumab group and 29.7% in the DPd or DVd group (hazard ratio, 0.17; 95% confidence interval, 0.12 to 0.23; P<0.001). More patients in the teclistamab-daratumumab group than in the DPd or DVd group had a complete response or better (81.8% vs. 32.1%), an overall response (89.0% vs. 75.3%), and minimal residual disease negativity (10-5; 58.4% vs. 17.1%) (P<0.001 for all comparisons). Serious adverse events occurred in 70.7% of the patients in the teclistamab-daratumumab group and in 62.4% of those in the DPd or DVd group; death from adverse events occurred in 7.1% and 5.9%, respectively.
CONCLUSIONS: In patients with multiple myeloma who had received one to three previous lines of therapy, those in the teclistamab-daratumumab group had significantly longer progression-free survival than those in the DPd or DVd group. (Funded by Johnson & Johnson; ClinicalTrials.gov number, NCT05083169.).

DOI: https://doi.org/10.1056/NEJMoa2514663
Nat Med. 2025 Dec 12.

Cancer screening must become more precise.

DOI: https://doi.org/10.1038/s41591-025-04148-x