bims-tumhet 2025-11-09 papers

Issue of 2025–11–09
eight papers selected by
Sergio Marchini, Humanitas Research

Gynecol Oncol. 2025 Oct;pii: S0090-8258(25)01026-1. [Epub ahead of print]201 A1-A2

The 15th Biennial Rivkin Center ovarian cancer research symposium.

Kenneth P Nephew, Ronny Drapkin, Jackie Lang, Yelena Zhuravlev, Sagar Ghosh, Melanie Neagley, Christina Annunziata.

The 15th Biennial Ovarian Cancer Research Symposium was presented by the Rivkin Center for Ovarian Cancer Research and the American Association for Cancer Research in September 2024 in Seattle, WA, USA. The 2024 Symposium featured oral and poster presentations on five broad areas of ovarian cancer research: Biology of Ovarian Cancer; Prevention, Early Detection, and Interception; Novel Immunotherapies; Emerging Therapeutics; and Healthcare Disparities. Additionally, the Symposium began with a patient advocacy panel titled 'Research is Care: How patients and researchers can work together to bring the bedside back to the bench.' The presentations highlighted the patient's perspective, new advances in fundamentally important areas of ovarian cancer biology, immunotherapy, new therapeutic targets, and healthcare challenges facing the clinical and research community.

DOI: https://doi.org/10.1016/j.ygyno.2025.10.010

Thorax. 2025 Oct 31. pii: thorax-2024-222052. [Epub ahead of print]

Intratumour, anatomical and temporal heterogeneity in mesothelioma.

Maya Arnould, Mark D J Neilly, Kevin G Blyth, Didier Jean.

BACKGROUND: Pleural mesothelioma (PM) is characterised by marked heterogeneity, both clinically in terms of survival and response to treatment, and in terms of histology and molecular status. Development of novel therapies, stratified treatment pathways and a better understanding of resistance mechanisms are urgently needed. This requires an in-depth understanding of the multiple sources of heterogeneity affecting tumour cells and the tumour microenvironment.
METHODS AND RESULTS: This review, which synthesises the key studies available in the literature, provides a detailed description of the current state of the art regarding heterogeneity in PM. After an overview of the general molecular landscape and a summary of heterogeneity between patients (intertumour heterogeneity), we review sources of variation within an individual patient's tumour (intratumour heterogeneity). This section covers both the local heterogeneity classically reported in other tumours and the anatomical heterogeneity, which is more profound in PM given the large pleural surface area over which the disease develops and progresses. We also synthesise the available data on changes that develop over time (temporal heterogeneity). The various cellular and molecular sources of heterogeneity are also highlighted throughout each section, including histological variations, genomic and non-genomic molecular changes and variations in tumour, stromal and immune compartments.
CONCLUSIONS: The solid understanding of intertumour heterogeneity recently achieved has highlighted diverse molecular and cellular landscapes. However, this knowledge has yet to be effectively translated into clinical practice (eg, diagnostic classification, treatment allocation, trial design). Further research is needed for a better comprehension of intratumour heterogeneity, including characterisation of local tumour-immune-stromal interactions, including those based on anatomical position on the pleural surface. Efforts should also include dissection of intratumour heterogeneity in patients treated by immunotherapy, development of preclinical models that adequately capture heterogeneity and the investigation of clonality and tumour evolution over time.

Keywords: Asbestos Induced Lung Disease; Mesothelioma; Pleural Disease; Rare lung diseases

DOI: https://doi.org/10.1136/thorax-2024-222052

Genome Med. 2025 Nov 04. 17(1): 139

Genome instability and crosstalk with the immune response.

Roman M Chabanon, François-Xavier Danlos, Kaissa Ouali, Sophie Postel-Vinay.

Genome instability, tumour-promoting inflammation, and immune escape are three distinct hallmarks of cancer. However, accumulating scientific and clinical evidence over the past decade have uncovered a multifaceted interplay of complex dynamic network of interactions between genome instability, the DNA damage response (DDR), and tumour immunogenicity. Fuelled by the clinical successes of immune checkpoint blockers (ICB), growing interest for immuno-oncology and recent cancer biology discoveries have allowed a better understanding of the underlying biology and clinical opportunities brought by this interplay-which is yet, still only in its infancy. The cooperative nature of tumour cell-intrinsic and -extrinsic mechanisms involved suggests that harnessing genomic instability in cancer does not only hamper cancer cells fitness but also stimulate the anti-tumour immune response, thereby paving the way to the development of DDR-based immunomodulatory therapeutic strategies applicable to a variety of molecular and histological cancer types. Here, we review the various aspects of this crosstalk between genome instability and tumour immunogenicity, including feedforward and feedback mechanisms affecting either side of this interplay, as well as the specific consequences of chromosomal instability. We further discuss emerging DDR-based predictive biomarkers of response to ICB therapies, and finally examine the latest clinical developments of therapeutic combinations that exploit the DDR-immunity interplay in immuno-oncology.

Keywords: Aneuploidy; Anti-tumour immune response; Cytoplasmic nucleic acid; DNA damage response; Genomic instability; Replication stress; Tumour immunogenicity

DOI: https://doi.org/10.1186/s13073-025-01509-6

Nat Commun. 2025 Nov 05. 16(1): 9756

Olaparib, durvalumab, and cyclophosphamide, and a prognostic blood signature in platinum-sensitive ovarian cancer: the randomized phase 2 SOLACE2 trial.

SOLACE2 (ACTRN12618000686202) investigates whether 12-weeks of olaparib, or cyclophosphamide-olaparib priming, improves subsequent durvalumab-olaparib progression-free survival (PFS), and is superior to olaparib monotherapy without any priming, in platinum-sensitive recurrent ovarian cancer (n = 114). We also evaluate the utility of CUP-CC assay, an immune signature of C-C chemokine receptor type 4 up-regulation, chemokines, and cytokines. Priming with olaparib, or cyclophosphamide-olaparib, followed by durvalumab-olaparib, are both associated with longer PFS compared to olaparib monotherapy, but do not reach the pre-specified primary endpoint of 36-week trial threshold (PFS36). PFS36 rates are 47.4% (95% CI, 31.0-62.1; olaparib priming then olaparib-durvalumab), 48.7% (32.5-63.2; olaparib-cyclophosphamide then olaparib-durvalumab) and 35.1% (20.4-50.3; olaparib monotherapy). PFS is significantly longer for the homologous recombination deficient (N = 71) as compared to the proficient (HRP) (N = 29) subgroups (Hazard Ratio (HR) 0.55, 0.35-0.87). CUP-CC+ subgroup (N = 58) has a significantly longer PFS (HR 0.31, 0.19-0.49) than CUP-CC- (N = 46). Future studies should investigate whether CUP-CC has the potential to personalize poly (ADP-ribose) polymerase inhibitor therapies for patients who are BRCA wild-type, including HRP patients.

DOI: https://doi.org/10.1038/s41467-025-64130-6

ESMO Open. 2025 Nov 05. pii: S2059-7029(25)01757-0. [Epub ahead of print]10(11): 105888

Genomic actionability and matched targeted therapy in a decade-long institutional precision medicine program for solid tumors.

BACKGROUND: Precision oncology has evolved from concept to clinical reality, advancing cancer treatment and drug development in the last decade. However, disparities persist in patient access to comprehensive genomic profiling and matched therapies.
MATERIALS AND METHODS: This was a retrospective analysis of all patients enrolled in the Vall d'Hebron Institute of Oncology (VHIO) precision medicine program (PMP) between 2014 and 2024. Tumor profiling outcomes were reviewed, focusing on actionable alterations, classified by the European Society for Medical Oncology Scale for Clinical Actionability of Molecular Targets (ESCAT). Interpretation and therapy prioritization were standardized through regular multidisciplinary molecular tumor boards. Key performance indicators (KPIs) included the proportions of patients with ESCAT tier I-IV alterations and those receiving matched therapies, either via clinical trials or approved regimens. The analysis also considered advances in molecular diagnostics, such as liquid biopsies, and the evolving clinical trial portfolio requiring biomarkers.
RESULTS: From 2014 to 2024, 12 168 unique patients underwent 13 718 multi-gene molecular profiles at VHIO PMP. The detection rate of actionable alterations increased substantially over time, from 10.1% in 2014 to 53.1% in 2024, paralleling advances in drug biomarkers, sequencing technology, and broader use of assays. Overall, 10.1% of patients received molecularly matched therapies, rising from 1% in 2014 to 14.2% in 2024. Among patients with actionable alterations, 23.5% received targeted therapies, with annual rates ranging from 19.5% to 32.7%. Liquid biopsy integration notably enhanced actionable target detection and therapy access. The proportion of clinical trials with molecular inclusion criteria varied, starting at 40.2% in 2014 and dropping to 19.4% in 2020 before rising to 34.2% in 2024.
CONCLUSION: Over a decade, VHIO's institutionally integrated PMP has enabled robust actionable alteration detection and access to matched therapies. Standardized KPI monitoring enables ongoing evaluation and sustainability of program performance. Continued innovation in diagnostics and molecularly guided trials is essential for further progress in precision oncology.

Keywords: actionability; matched therapies; molecular trials; performance indicators; precision oncology

DOI: https://doi.org/10.1016/j.esmoop.2025.105888

Cancer Cell. 2025 Nov 06. pii: S1535-6108(25)00448-9. [Epub ahead of print]

Decoding the spatial dynamics of tumor and immune cell interactions in solid cancers.

Eleanor Minogue, Pilar Baldominos, Lauren Hsu, Marcia C Haigis, Judith Agudo.

The spatial landscape of the tumor immune microenvironment (TIME) is under significant investigation as a driver of immunotherapy resistance in solid tumors. Most work centers on constituent immune cells within intra-tumoral niches, overlooking tumor cell phenotypes. Yet cancer cells shape their milieu by multiple modalities, including secreting and depleting metabolites. Here, we argue that integrating cancer cell phenotypic heterogeneity into spatial analyses is essential to reveal the mechanisms that generate TIME diversity and to better address resistance to immunotherapy.

DOI: https://doi.org/10.1016/j.ccell.2025.10.007

Ann Oncol. 2025 Nov 05. pii: S0923-7534(25)06217-9. [Epub ahead of print]

Intratumoral heterogeneity and immunotherapy resistance: clinical implications.

imCORE Network

The impressive but incomplete clinical success of immunotherapy with immune checkpoint inhibitors makes it of paramount importance to understand and overcome immunotherapy resistance. The phenomenon of resistance to immunotherapy has been largely categorized as innate or acquired; however, many cellular and molecular mechanisms of resistance are remarkably common to both. This notion raises the possibility that resistance mechanisms develop during the coevolution of the tumor and the immune response, reflecting the multiple interactions between malignant cells and cells of the tumor immune microenvironment. This tumor-editing interaction selects for often preexisting adapted genetic or epigenetic variants, and results in intratumoral heterogeneity (ITH) within tumors and among metastatic lesions. Variants encompass both tumor-intrinsic genetically driven ("hardware") and tumor-extrinsic ("software") resistance mechanisms that dynamically coevolve under strong immune selection pressures in a Darwinian fashion. The level of ITH, which is shaped by the evolution of tumors in their immune microenvironment, may dictate the ability of tumors to adapt and evade attacks by the immune system. Standardized methods and metrics for measuring and addressing ITH and making use of this information in human cancer management remain limited, partly due to the lack of suitable models, technologies, and bioinformatic tools. Opportunities exist to design therapeutic approaches to overcome immunotherapy resistance, with an emphasis on interventions targeting intrinsic versus extrinsic resistance mechanisms in the context of ITH. These therapeutic approaches can be tailored according to the nature of the specific ongoing or predicted resistance mechanisms, as observed on a per-case basis, and may include a range of options, such as biomarker-driven rational immunotherapy combinations, novel immunoregulatory targets, and the suitable incorporation of cell-based adoptive therapies. In this review, we discuss the evidence for ITH driving immunotherapy resistance and provide a perspective on integrating ITH as a biomarker and when designing more efficacious therapeutic strategies.

Keywords: Intratumoral heterogeneity; cancer immunology; checkpoint inhibitors; immunotherapy; therapeutic resistance

DOI: https://doi.org/10.1016/j.annonc.2025.10.1239

JAMA Netw Open. 2025 Nov 03. 8(11): e2541648

PARP Inhibitor Maintenance After First-Line Chemotherapy in Advanced-Stage Epithelial Ovarian Cancer: A Systematic Review and Meta-Analysis.

Stamatios Petousis, Ilker Kahramanoglu, Christian Appenzeller-Herzog, Martina A Angeles, Chrysoula Margioula-Siarkou, Joanna Kacperczyk-Bartnik, Esra Bilir, Christos Chatzakis, Giuseppe Caruso, Nicolò Bizzarri, Konstantinos Dinas, David D L Bowtell, Dale W Garsed, Isabelle Ray-Coquard, Jonathan A Ledermann, Michael Friedlander, Alexandros Sotiriadis, Viola Heinzelmann-Schwarz, Tibor A Zwimpfer.

Importance: First-line maintenance therapy with poly(adenosine diphosphate-ribose) polymerase inhibitors (PARP inhibitors) after platinum-based chemotherapy improves progression-free survival (PFS) in advanced epithelial ovarian cancer (EOC), particularly in patients with BRCA-variant or homologous recombination-deficient tumors. However, overall survival (OS) benefits remain uncertain, and toxic effect profiles emphasize the need for optimized patient and agent selection.
Objective: To evaluate the efficacy and safety of first-line PARP inhibitor maintenance therapy compared with chemotherapy alone in advanced-stage EOC, with subgroup analyses by BRCA and HRD status, up-front or interval surgery, chemotherapy response, and residual disease.
Data sources: Medline, Embase, Web of Science, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched from database inception to August 19, 2024.
Study Selection: Randomized clinical trials and prospective 2-arm studies evaluating PARP inhibitor maintenance therapy in patients with advanced-stage EOC responding to first-line platinum-based chemotherapy were included.
Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline was followed in reporting this study. Data were independently extracted by 2 reviewers. Random-effects models were used for meta-analysis. Risk of bias was assessed with Cochrane risk of bias and certainty of evidence with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework.
Main Outcomes and Measures: Primary outcomes were PFS and OS; secondary outcomes included high-grade adverse events.
Results: A total of 7 randomized clinical trials with 4013 patients with advanced-stage epithelial ovarian cancer responding to first-line platinum-based chemotherapy were included. PARP inhibitor maintenance was associated with improved PFS in the overall population (hazard ratio [HR], 0.57; 95% CI, 0.46-0.70; high certainty) and in all molecular subgroups except the homologous recombination proficient group (BRCA variant: HR, 0.40; 95% CI, 0.35-0.45; BRCA wild type: HR, 0.62; 95% CI, 0.44-0.86; homologous recombination deficient: HR, 0.44; 95% CI, 0.39-0.50; all high certainty). PFS benefits were consistent across surgical timing, chemotherapy responses, and residual disease; for example, surgical timing had HRs of 0.51 (95% CI, 0.31-0.84) for neoadjuvant chemotherapy and 0.54 (95% CI, 0.36-0.81) for primary cytoreductive surgery (all high certainty). No molecular subgroup showed a statistically significant OS improvement (high to low certainty). High-grade adverse events were more common in the PARP inhibitor group (HR, 2.40; 95% CI, 1.16-4.93; high certainty). Observed treatment efficacy and toxic effects varied across PARP inhibitor regimens; for example, the risk ratio for any recurrence or death in the overall study group ranged from 0.53 (95% CI, 0.40-0.70) for senaparib to 0.83 (95% CI, 0.68-1.00) for olaparib, while the risk ratio for high-grade adverse events ranged from 1.15 (95% CI, 0.64-2.06) for veliparib to 4.73 (95% CI, 2.77-8.07) for niraparib.
Conclusions and Relevance: In this study, no subgroup showed an association between first-line PARP inhibitor maintenance therapy in advanced-stage EOC and improved OS, and findings suggest that the consistency of associated PFS benefits may vary, particularly in homologous recombination proficient and BRCA wild type tumors. Variability in efficacy and toxic effects across subgroups and PARP inhibitor regimens underscores the importance of individualized treatment decisions.

DOI: https://doi.org/10.1001/jamanetworkopen.2025.41648