bims-ovdlit 2026-04-19 papers

Nat Rev Cancer. 2026 Apr 13.

Rethinking ovarian cancer III: the past decade and future directions.

Approximately 80% of deaths from ovarian cancer are due to high-grade serous carcinoma (HGSC), which has the highest proportion of BRCA1 or BRCA2 (BRCA1/BRCA2) mutations of any cancer type and is a highly chromosomally unstable disease. Despite the introduction of targeted therapies benefitting some patients with HGSC as well as surgical advances, only 50% of patients will survive more than 5 years, and just 30% of patients who present with advanced disease without BRCA1/BRCA2 mutations will survive this long. This Expert Recommendation is based on discussions among emerging and leading ovarian cancer researchers at the 15th Helene Harris Memorial Trust International Forum on ovarian cancer hosted by Ovarian Cancer Action in October 2024. The meeting considered advances in HGSC research and treatment made over the last decade, current challenges, emerging technologies in prevention, early detection, and treatment, and research priorities for the years ahead.

DOI: https://doi.org/10.1038/s41568-026-00916-0

NPJ Breast Cancer. 2026 Apr 15.

Functional assays for BRCA1 and BRCA2 variant analysis: new tools and their applications.

Muthiah Bose, Elangoli Ebrahimkutty Faseela, Maria Rossing, Claus Storgaard Sørensen.

Genetic variants perturbing BRCA1 and BRCA2 function are linked to hereditary breast and ovarian cancers. As BRCA1 and BRCA2 are critical for homologous recombination-mediated DNA repair, interpretation of variants of uncertain significance is essential. Here, we review established and emerging assays used to functionally characterize BRCA1 and BRCA2 variants and highlight the strengths and limitations of each approach, as well as their general relevance to variant classification and clinical applications.

DOI: https://doi.org/10.1038/s41523-026-00949-6

Mol Oncol. 2026 Apr 18.

Molecular cancer prevention: Intercepting disease.

Charlotte Grieco, Tej Pandya, Charles Swanton.

Over several decades, therapeutic advances have transformed oncology, yet for many tumour types, survival improvements have been incremental, with substantial treatment-related morbidity. A decisive pivot in oncology, from treating established malignancy to intercepting and preventing carcinogenesis, could deliver far greater population impact. Delivering this shift requires further mechanistic understanding of tumour initiation, validated biomarkers of premalignant progression and redesigned prevention trials in at-risk populations. Regulatory and commercial frameworks must evolve to enable scalable molecular prevention. Such trials must deliver tolerable side effect profiles and rely on biologically validated surrogate endpoints rather than traditional survival outcomes. Cancer interception should be established as a core pillar of oncological management, alongside early detection and the therapeutic management of established disease, together creating an opportunity to reduce global disease burden at a scale that decades of therapeutic progress in advanced cancer have yet to achieve.

Keywords: cancer interception; chemoprevention; clinical trial design; inflammation; premalignant biomarkers; tumour initiation

DOI: https://doi.org/10.1002/1878-0261.70258

Nat Commun. 2026 Apr 15.

The genetic basis for DNA methylation variation across tissues and development.

Jonathan Rosenski, Ofra Sabag, Eitan Marcus, Netanel Loyfer, Yuval Dor, Howard Cedar, Tommy Kaplan.

The mechanisms by which genetic variation shapes the epigenome across cell types and developmental stages have remained elusive. Here, we define a unifying developmental framework for DNA methylation programming, grounded in genome-wide methylation and genetic variation data from both mouse and human. In mice, we identify thousands of differentially methylated regions (DMRs) linked to sequence polymorphisms that disrupt transcription factor binding. These DMRs are programmed either during implantation or later in organogenesis, revealing two distinct periods of epigenetic regulation. Extending this logic to humans, we analyze our atlas of over 200 WGBS samples from 39 purified cell types and map 33,574 regions where common SNPs control allele-specific methylation. These include both early-established and cell-type-specific loci, many of which colocalize with eQTLs, enhancers, silencers, and disease-associated variants. Our results uncover a widespread mechanism by which genetic variation influences the regulatory landscape, linking sequence, methylation, and transcription across tissues. This cross-species atlas of sequence-dependent methylation not only clarifies the logic and timing of epigenetic programming, but also provides a foundational resource for deciphering non-coding variants in development, complex disease, and regenerative medicine.

DOI: https://doi.org/10.1038/s41467-026-71693-5

Lancet. 2026 Apr 10. pii: S0140-6736(26)00462-9. [Epub ahead of print]

Overall survival with relacorilant and nab-paclitaxel in patients with platinum-resistant ovarian cancer (ROSELLA): a phase 3 randomised controlled trial.

BACKGROUND: Relacorilant is a selective glucocorticoid receptor antagonist that increases the sensitivity of many cancer cell types to chemotherapy. The efficacy and safety of relacorilant plus nab-paclitaxel were assessed in the phase 3 ROSELLA (GOG-3073, ENGOT-ov72, APGOT-Ov10, and LACOG-0223) trial; the combination showed significant improvement in progression-free survival among patients with platinum-resistant ovarian cancer compared with nab-paclitaxel monotherapy. Results of the final overall survival analysis are reported here.
METHODS: In this open-label phase 3 trial, patients were randomly assigned 1:1 to receive relacorilant (150 mg orally the day before, day of, and day after nab-paclitaxel infusion) plus nab-paclitaxel (80 mg/m2 intravenously on days 1, 8, and 15 of each 28-day cycle) or nab-paclitaxel monotherapy (100 mg/m2 intravenously on the aforementioned schedule). Patients, aged 18 years or older, with one to three lines of previous anticancer therapy and platinum-resistant disease (progression <6 months from their last dose of platinum) were eligible. The trial was conducted at 117 hospitals and community oncology centres in 14 countries across Australia, Europe, Latin America, North America, and South Korea. Progression-free survival, assessed by blinded independent central review, and overall survival (time from randomisation to death from any cause) were dual primary endpoints. Additional prespecified endpoints included safety, second progression-free survival (time from randomisation to disease progression on subsequent anticancer therapy or death due to any cause, whichever occurred first), and patient-reported outcomes. This trial is registered at ClinicalTrials.gov, NCT05257408, and is ongoing.
FINDINGS: Between Jan 5, 2023, and April 8, 2024, 381 patients were randomly assigned to the relacorilant combination group (n=188) or the nab-paclitaxel monotherapy group (n=193). All patients had received bevacizumab; 167 (44%) had received three previous lines of therapy, and 234 (61%) had received a poly(ADP-ribose) polymerase inhibitor. At a median follow-up of 24·8 months (95% CI 23·6-25·7), the addition of relacorilant to nab-paclitaxel resulted in a statistically and clinically significant improvement in overall survival compared with nab-paclitaxel monotherapy (hazard ratio for death 0·65 [95% CI 0·51-0·83]; p=0·0004); 18-month overall survival was 46% and 27%, respectively. The median overall survival in the relacorilant combination group was extended by 4·1 months compared with the nab-paclitaxel monotherapy group (16·0 [95% CI 13·0-18·3] vs 11·9 months [10·0-13·8]). Subsequent anticancer treatments were similar across study groups. Adverse events were similar in both groups when adjusted for duration of study treatment. Neutropenia (121 [64%]), anaemia (115 [61%]), fatigue (101 [54%]), and nausea (82 [44%]) were the most common adverse events in the relacorilant combination group. No new safety signals were observed with additional follow-up since the primary analysis.
INTERPRETATION: The addition of relacorilant to nab-paclitaxel led to significantly longer overall survival in patients with platinum-resistant ovarian cancer, without the need for biomarker selection. The findings support relacorilant plus nab-paclitaxel as a potential new standard treatment option for patients with platinum-resistant ovarian cancer.
FUNDING: Corcept Therapeutics.

DOI: https://doi.org/10.1016/S0140-6736(26)00462-9

NPJ Precis Oncol. 2026 Apr 15.

Integrative fragmentomic and mutational signature profile of plasma cfDNA for early lung cancer detection.

Jianxing He, Huiting Wang, Yi Feng, Jianfu Li, Peiling Chen, Xin Zheng, Wenhai Fu, Caichen Li, Hua Bao, Song Wang, Shuang Chang, Dongqin Zhu, Shanshan Yang, Yang Shao, Wen Zhong, Weisheng Guo, Rong Yin, Wenhua Liang.

Detecting lung cancer effectively in the general population is essential for optimizing treatment outcomes and improving the 5-year survival rate. While low-dose computed tomography (LDCT) is the current standard, it has limitations in broader populations. We developed a blood-based multi-omics model using whole-genome cell-free DNA (cfDNA) features to distinguish lung cancer from non-cancer individuals. This study included 1600 patients and an equal number of non-cancer controls, divided into training and validation cohorts. The model achieved an area under the curve (AUC) of 95.59% for the training cohort and 95.74% for the validation cohort. The model consistently performed well across various cancer stages and histological subtypes. To further validate the performance of the model, an external validation cohort was utilized. Notably, it also effectively differentiated non-cancer samples from cancer samples in the external validation cohort, with 85.9% sensitivity and 94.78% specificity. Importantly, in simulated population screenings, our ctDNA assay outperformed both LDCT and a previously established method. This suggests its potential utility in wider lung cancer screening programs, possibly complementing the LDCT approach. In conclusion, our ctDNA assay emerges as a promising and highly sensitive tool for the early detection and categorization of lung cancer.

DOI: https://doi.org/10.1038/s41698-026-01416-y