bims-ovdlit 2025-06-29 papers

Nat Genet. 2025 Jun 23.

Predicting resistance to chemotherapy using chromosomal instability signatures.

Chemotherapies are often given without precision biomarkers, exposing patients to toxic side effects without guaranteed benefit. Here we present chromosomal instability signature biomarkers that identify resistance to platinum-, taxane- and anthracycline-based treatments using a single genomic test. In retrospectively emulated randomized-control biomarker clinical trials using real-world cohorts (n = 840), predicted resistant patients had elevated treatment failure risk for taxane (hazard ratio (HR) of 7.44) and anthracycline (HR of 1.88) in ovarian, taxane (HR of 3.98) and anthracycline (HR of 3.69) in metastatic breast and taxane (HR of 5.46) in metastatic prostate. Nonrandomized emulations showed predictive capacity for platinum resistance in ovarian (HR of 1.46) and anthracycline in sarcoma (HR of 3.59). We demonstrate feasibility using whole-genome sequencing, capture-panel sequencing and cell-free DNA. Our findings highlight the clinical value of chromosomal instability signatures in predicting resistance to chemotherapies across multiple cancer types, with the potential to transform the one-size-fits-all chemotherapy approach into precise, tailored treatment.

DOI: https://doi.org/10.1038/s41588-025-02233-y

Cancers (Basel). 2025 Jun 17. pii: 2026. [Epub ahead of print]17(12):

Genome-Wide cfDNA Methylation Profiling Reveals Robust Hypermethylation Signatures in Ovarian Cancer.

Simone Karlsson Terp, Karen Guldbrandsen, Malene Pontoppidan Stoico, Lasse Ringsted Mark, Anna Poulsgaard Frandsen, Karen Dybkær, Inge Søkilde Pedersen.

Background: Ovarian cancer remains the most lethal gynecological cancer, primarily due to its asymptomatic nature in early stages and consequent late diagnosis. Early detection improves survival, but current biomarkers lack sensitivity and specificity. Cell-free DNA (cfDNA) released from tumor cells captures tumor-associated epigenetic alterations and represents a promising source for minimally invasive biomarkers. Among these, aberrant DNA methylation occurs early in tumorigenesis and may reflect underlying disease biology. This study aimed to investigate genome-wide cfDNA methylation profiles in patients with ovarian cancer, benign ovarian conditions, and healthy controls to identify cancer-associated methylation patterns that may inform future biomarker development. Results: We performed genome-wide cfDNA methylation profiling using cell-free methylated DNA immunoprecipitation sequencing (cfMeDIP-seq) on plasma samples from 40 patients with high-grade serous ovarian carcinoma, 38 patients with benign ovarian conditions, and 38 healthy postmenopausal women. A total of 536 differentially methylated regions (DMRs) were identified between ovarian cancer and controls (n = 76), with 97% showing hypermethylation in ovarian cancer. DMRs were enriched in CpG islands and gene bodies and depleted in repetitive elements, consistent with known cancer-associated methylation patterns. Fifteen genes showed robust hypermethylation across analyses. These genes exhibited methylation across intronic, exonic, and upstream regulatory regions. Separate comparisons of ovarian cancer to each control group (benign and healthy) supported the reproducibility of these findings. Gene Ontology enrichment analysis revealed enrichment in gland development, embryonic morphogenesis, and endocrine regulation, suggesting biological relevance to ovarian tumorigenesis. Conclusions: This study identifies consistent cfDNA hypermethylation patterns in ovarian cancer, affecting genes involved in developmental regulation and hormone-related processes. Our findings underscore the potential of cfMeDIP-seq for detecting tumor-specific methylation signatures in plasma and highlight these 15 hypermethylated genes as biologically relevant targets for future studies on cfDNA methylation in ovarian cancer.

Keywords: Cell-free DNA; DNA methylation; biomarkers; epigenetics; ovarian cancer

DOI: https://doi.org/10.3390/cancers17122026

Nat Med. 2025 Jun 26.

AI-powered fragmentomics of cell-free DNA for early detection of multiple cancers.

DOI: https://doi.org/10.1038/s41591-025-03810-8

J Clin Med. 2025 Jun 06. pii: 4018. [Epub ahead of print]14(12):

Vaginal Natural Orifice Transluminal Endoscopic Surgery (vNOTES) in Risk-Reducing Gynecologic Cancer Surgery: A New Frontier in Hereditary Cancer Prevention.

Victor Bogdan Buciu, Denis Mihai Șerban, Dorin Novacescu, Larisa Tomescu, Sebastian Ciurescu, Nicoleta Nicolae, Adrian Ratiu, Elena Lavinia Rusu, Sebastian Olariu, Mihai Ionac, Ioan Sas.

Background: Hereditary cancer syndromes such as BRCA1/2 and Lynch syndrome significantly increase the lifetime risk of ovarian, fallopian tube, and endometrial cancers. Risk-reducing salpingo-oophorectomy (RRSO) and hysterectomy are standard preventive strategies. Vaginal natural orifice transluminal endoscopic surgery (vNOTES) has recently emerged as a minimally invasive, scarless alternative that may enhance patient acceptance while maintaining oncologic safety. Objective: This narrative review aims to synthesize the current evidence regarding the role of vNOTES in risk-reducing gynecologic surgery for women with hereditary cancer syndromes, focusing on surgical feasibility, technical considerations, oncologic safety, and patient-reported outcomes. Methods: A structured literature search was conducted in PubMed and Web of Science for studies published between January 2000 and April 2025, using terms related to vNOTES, prophylactic gynecologic surgery, BRCA mutations, and Lynch syndrome. Inclusion criteria focused on studies reporting outcomes of vNOTES in risk-reducing or oncologic contexts. A total of eight studies were included for qualitative synthesis. Results: vNOTES has demonstrated technical feasibility and favorable surgical outcomes in risk-reducing procedures such as RRSO and hysterectomy in BRCA and Lynch syndrome carriers. Comparative studies report lower postoperative pain, faster recovery, and high patient satisfaction, with oncologic standards maintained through specimen containment, peritoneal inspection, and adherence to the SEE-FIM protocol. Limitations include the learning curve and restricted access to the upper abdomen, which may necessitate hybrid approaches in selected cases. Conclusions: vNOTES offers a promising, patient-centered surgical approach for hereditary cancer prevention, combining oncologic safety with enhanced recovery and cosmetic benefits. Further research is needed to standardize protocols, evaluate long-term outcomes, and define its role within broader personalized cancer prevention strategies.

Keywords: BRCA; Lynch syndrome; SEE-FIM protocol; hereditary cancer syndromes; hysterectomy; minimally invasive surgery; prophylactic surgery; salpingo-oophorectomy; vNOTES

DOI: https://doi.org/10.3390/jcm14124018

Eur J Cancer. 2025 Jun 17. pii: S0959-8049(25)00369-7. [Epub ahead of print]225 115587

Veliparib concomitant with first-line chemotherapy and as maintenance therapy in ovarian cancer: Final overall survival and disease-related symptoms results.

Robert L Coleman, Gini F Fleming, Mark F Brady, Elizabeth M Swisher, Karina D Steffensen, Michael Friedlander, Aikou Okamoto, Kathleen N Moore, Charles A Leath, David Cella, Zhaowen Sun, Shilpen Patel, Zequn Tang, Christine K Ratajczak, Carol Aghajanian, Michael A Bookman.

INTRODUCTION: In the VELIA trial, the addition of veliparib to standard first-line platinum-based chemotherapy and continued as maintenance resulted in significantly longer median progression-free survival (PFS) compared with carboplatin plus paclitaxel induction therapy alone (23.5 vs 17.3 months; p < 0.001) in patients with ovarian cancer. We now report final overall survival (OS) and updated safety and disease-related symptoms (DRS) from patient-reported outcomes of the trial.
METHODS: This randomized, placebo-controlled, double-blind, multicenter, phase 3 study enrolled adult women with an initial diagnosis of stage III/IV high-grade serous ovarian cancer undergoing primary or interval cytoreductive surgery. Patients were randomized 1:1:1 to chemotherapy plus veliparib followed by veliparib maintenance (veliparib-throughout), chemotherapy plus veliparib followed by placebo maintenance (veliparib-combination-only), or chemotherapy plus placebo followed by placebo maintenance (placebo-throughout). PFS was the primary endpoint; OS and DRS were secondary endpoints.
RESULTS: In the intention-to-treat population (N = 1140), median OS was 59.2 months (95 % confidence interval: 52.1, 68.2) for the veliparib-throughout group, 58.0 (50.6, 64.1) months for veliparib-combination-only, and 57.8 (52.3, 63.8) months for placebo-throughout. OS outcomes were not significantly different between arms overall or in the BRCA-deficient and homologous recombination-deficient cohorts. No new safety signals were identified during the longer follow-up period and DRS analyses indicated there was no significant additional symptom-related burden overall when veliparib was added to chemotherapy or used for maintenance.
CONCLUSION: No OS or DRS benefit of addition of veliparib to platinum-based chemotherapy and continued as maintenance therapy was detected in this study, despite an observed benefit over chemotherapy alone in PFS.

Keywords: Maintenance; Ovarian cancer; Overall survival; PARP inhibitor; Phase 3 trial; Veliparib

DOI: https://doi.org/10.1016/j.ejca.2025.115587

Lancet Oncol. 2025 Jun 19. pii: S1470-2045(25)00372-9. [Epub ahead of print]

England changes cervical cancer screening to every 5 years.

Tony Kirby.

DOI: https://doi.org/10.1016/S1470-2045(25)00372-9

JCO Precis Oncol. 2025 Jun;9 e2400589

Epithelial Abnormalities in the High-Risk Fallopian Tube of a Rare TP53/BRCA2 Li-Fraumeni Syndrome Patient With Multiple Tumors.

Megan L Ritting, Simrit K Warring, Manuel M Bettencourt, Syed Mohammed Musheer Aalam, Maryam Shahi, Fergus J Couch, Jamie N Bakkum-Gamez, Nagarajan Kannan.

DOI: https://doi.org/10.1200/PO-24-00589

J Natl Cancer Inst. 2025 Jun 25. pii: djaf150. [Epub ahead of print]

A Cancer Predisposition Screening Tool for Young Adults with Cancer.

Tim Ripperger, Christian P Kratz.

One in twelve malignancies is diagnosed in a young adult between 20 and 39 years of age. One of the most relevant known causes of cancer in this age group, which is present in approximately 10% of cancer patients, is genetic cancer predisposition that originates from constitutional or postzygotic somatic (epi-)genetic variants leading to an increased cancer risk compared to the general population. The diagnosis of a cancer predisposition syndrome is important as it can affect cancer surveillance, prevention, and therapy. Universal gene-panel germline sequencing is offered by some centers, however, in clinical settings with limited resources, cancer predisposition syndrome screening tools can support the identification of those cancer patients who may benefit from genetic counselling and/or testing regarding underlying genetic diseases. Effective screening tools have been developed for children with cancer, but comparable cancer predisposition syndrome screening algorithms are lacking for young adults with cancer. We present here an easy-to-use cancer predisposition syndrome screening tool designed specifically for young adults with cancer. By combining available recommendations and disease-specific criteria, the algorithm is focusing on somatic genetic findings in malignant cells, specific cancer types strongly associated with cancer predisposition syndromes, and the personal and family past medical history. This tool may increase clinical awareness among oncologists and facilitate the diagnoses of cancer predisposition syndromes in young adults with cancer.

DOI: https://doi.org/10.1093/jnci/djaf150