bims-ovdlit 2025-06-08 papers

Issue of 2025–06–08
five papers selected by
Lara Paracchini, Humanitas Research

Nat Commun. 2025 May 25. 16(1): 4852

Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification.

NBCS Collaborators

Clinical genetic testing identifies variants causal for hereditary cancer, information that is used for risk assessment and clinical management. Unfortunately, some variants identified are of uncertain clinical significance (VUS), complicating patient management. Case-control data is one evidence type used to classify VUS. As an initiative of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Analytical Working Group we analyze germline sequencing data of BRCA1 and BRCA2 from 96,691 female breast cancer cases and 302,116 controls from three studies: the BRIDGES study of the Breast Cancer Association Consortium, the Cancer Risk Estimates Related to Susceptibility consortium, and the UK Biobank. We observe 11,207 BRCA1 and BRCA2 variants, with 6909 being coding, covering 23.4% of BRCA1 and BRCA2 VUS in ClinVar and 19.2% of ClinVar curated (likely) benign or pathogenic variants. Case-control likelihood ratio (ccLR) evidence is highly consistent with ClinVar assertions for (likely) benign or pathogenic variants; exhibiting 99.1% sensitivity and 95.3% specificity for BRCA1 and 93.3% sensitivity and 86.6% specificity for BRCA2. This approach provides case-control evidence for 787 unclassified variants; these include 579 with strong or moderate benign evidence and 10 with strong pathogenic evidence for which ccLR evidence is sufficient to alter clinical classification.

DOI: https://doi.org/10.1038/s41467-025-59979-6

Acta Obstet Gynecol Scand. 2025 Jun 05.

Implementation of opportunistic salpingectomy for ovarian cancer prevention: Analyzing clinical practice and key characteristics.

Charlotte Fisch, Malou E Gelderblom, Brigitte Slangen, Angèle L M Oei, Alexandra A van Ginkel, Huy Ngo, Joanne de Hullu, Jurgen Piek, Rosella Hermens.

INTRODUCTION: Ovarian cancer (OC) is the most lethal gynecologic cancer, often diagnosed at an advanced stage due to nonspecific symptoms and lack of effective screening. Over 90% of all ovarian cancer cases are epithelial in origin, which is thought to originate from the fallopian tubes in approximately 70% of cases. Opportunistic salpingectomy (OS), the additional removal of fallopian tubes during abdominal surgery, has emerged as a preventive strategy. Despite growing evidence, the implementation of OS varies widely. This study examines OS counseling and performance trends in the Netherlands from 2019 to 2022 and identifies associated patient, surgical, physician, and institutional characteristics.
MATERIAL AND METHODS: A historical cohort study was performed, analyzing electronic medical records from six Dutch hospitals, including two academic, two teaching, and two nonteaching hospitals. Patients undergoing elective gynecologic surgery from January 2019 to December 2022 were considered eligible. Multilevel logistic regression analyses identified characteristics associated with counseling and performance of OS.
RESULTS: Out of 2716 eligible patients, 51% were counseled about OS, of whom 92% opted for the procedure. The counseling rate increased from 38% in 2019 to 57% in 2022, while the performance rate rose from 39% to 56%. OS was more common among patients undergoing hysterectomy, laparoscopic surgery, and treatment at teaching hospitals. OS was less common during vaginal surgery. Physician characteristics accounted for 18% of counseling and 12% of performance variations.
CONCLUSIONS: Although OS implementation improved, substantial variability remains in counseling and performance, largely driven by surgical approach and type of surgery. Targeted interventions to enhance uptake among underutilized surgical types, including vaginal procedures, are necessary to standardize OS practice and ensure wider adoption across all eligible patients.

Keywords: counseling; fallopian tube; female sterilization; opportunistic salpingectomy; ovarian cancer; performance; prevention

DOI: https://doi.org/10.1111/aogs.15128

Ann Oncol. 2025 May 30. pii: S0923-7534(25)00201-7. [Epub ahead of print]

Dostarlimab and niraparib in primary advanced ovarian cancer.

BACKGROUND: The combination of immunotherapies and poly (ADP-ribose) polymerase inhibitors (PARPis) has been hypothesized to improve outcomes in advanced ovarian cancer (aOC). The FIRST/ENGOT-OV44 trial evaluated adding dostarlimab to first-line platinum-based chemotherapy (PBCT) and niraparib maintenance ± bevacizumab in patients with aOC.
PATIENTS AND METHODS: In this randomized, double-blind, phase III trial, patients with newly diagnosed stage III-IV epithelial OC were randomized (1:2) to arm 2 (PBCT-placebo with niraparib maintenance) or arm 3 (PBCT-dostarlimab with dostarlimab-niraparib maintenance); arm 1 (PBCT-placebo with placebo maintenance) enrollment terminated following PARPi approvals. Efficacy was assessed in arms 2 and 3 (intention-to-treat population). The primary endpoint was investigator-assessed progression-free survival (PFS) as per RECIST v1.1. The key secondary endpoint was overall survival (OS). Safety was assessed in patients who received one or more doses of study treatment (arms 1-3; analyzed as per treatment received).
RESULTS: From 14 November 2018 to 5 January 2021, 1138 patients were randomized to arms 2 (n = 385) and 3 (n = 753) and included in efficacy analyses. Median follow-up was 53.1 (interquartile range 47.5-59.7) months. There was a statistically significant difference in PFS in arm 3 versus arm 2 (median 20.6 versus 19.2 months; hazard ratio [HR] 0.85, 95% confidence interval [CI] 0.73-0.99, P = 0.0351). OS had reached 57% maturity and was not statistically significant (median 44.4 versus 45.4 months; HR 1.01, 95% CI 0.86-1.19, P = 0.9060). Toxicities observed were consistent with known safety profiles of the agents used in the study.
CONCLUSIONS: In the first-line treatment of patients with aOC, the addition of dostarlimab to PBCT and niraparib maintenance was associated with a statistically significant, but clinically modest, PFS improvement, with no difference in OS.

Keywords: PD-(L)1 inhibition; advanced ovarian cancer; dostarlimab; first line; immunotherapy; niraparib

DOI: https://doi.org/10.1016/j.annonc.2025.05.009

Nat Genet. 2025 Jun 02.

Longitudinal and multisite sampling reveals mutational and copy number evolution in tumors during metastatic dissemination.

Karena Zhao, Joris Vos, Stanley Lam, Lillian A Boe, Daniel Muldoon, Catherine Y Han, Cristina Valero, Mark Lee, Conall Fitzgerald, Andrew S Lee, Manu Prasad, Swati Jain, Xinzhu Deng, Timothy A Chan, Michael F Berger, Chaitanya Bandlamudi, Xi Kathy Zhou, Luc G T Morris.

To understand genetic evolution in cancer during metastasis, we analyzed genomic profiles of 3,732 cancer patients in whom several tumor sites were longitudinally biopsied. During distant metastasis, tumors were observed to accumulate copy number alterations (CNAs) to a much greater degree than mutations. In particular, the development of whole genome duplication was a common event during metastasis, emerging de novo in 28% of patients. Loss of 9p (including CDKN2A) developed during metastasis in 11% of patients. To a lesser degree, mutations and allelic loss in human leukocyte antigen class I and other genes associated with antigen presentation also emerged. Increasing CNA, but not increasing mutational load, was associated with immune evasion in patients treated with immunotherapy. Taken together, these data suggest that CNA, rather than mutational accumulation, is enriched during cancer metastasis, perhaps due to a more favorable balance of enhanced cellular fitness versus immunogenicity.

DOI: https://doi.org/10.1038/s41588-025-02204-3