bims-ovdlit 2025-01-19 papers

Issue of 2025–01–19
six papers selected by
Lara Paracchini, Humanitas Research

EBioMedicine. 2025 Jan 13. pii: S2352-3964(24)00590-5. [Epub ahead of print]112 105554

Estimating the ovarian cancer CA-125 preclinical detectable phase, in-vivo tumour doubling time, and window for detection in early stage: an exploratory analysis of UKCTOCS.

Jacob S Bedia, Ian J Jacobs, Andy Ryan, Aleksandra Gentry-Maharaj, Matthew Burnell, Naveena Singh, Ranjit Manchanda, Jatinderpal K Kalsi, Anne Dawnay, Lesley Fallowfield, Alistair J McGuire, Stuart Campbell, Mahesh K B Parmar, Usha Menon, Steven J Skates.

BACKGROUND: The ovarian cancer (OC) preclinical detectable phase (PCDP), defined as the interval during which cancer is detectable prior to clinical diagnosis, remains poorly characterised. We report exploratory analyses from the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS).
METHODS: In UKCTOCS between Apr-2001 and Sep-2005, 101,314 postmenopausal women were randomised to no screening (NS) and 50,625 to annual multimodal screening (MMS) (until Dec-2011) using serum CA-125 interpreted by the Risk of Ovarian Cancer Algorithm (ROCA). All provided a baseline blood sample. Women with invasive epithelial OC diagnosed between randomisation and trial censorship (Dec-2014) in the MMS and NS arms with two or more CA-125 measurements, including one within two years of diagnosis were included. OC-free women (2:1 to cases) from the MMS arm provided information on baseline CA-125 distribution. CA-125 measurements were obtained from MMS results, secondary analysis of baseline samples, and medical records. PCDP duration and in-vivo tumour doubling time were estimated using the change-point model underlying ROCA. Early-stage (Stage I and II) PCDP was estimated from a Bayesian model for the probability of early stage given a CA-125 measurement.
FINDINGS: Of 541 women (2371 CA-125 measurements) with high-grade serous cancer (HGSC), 93% (504/541) secreted CA-125 into the circulation. Median CA-125 PCDP duration for clinically-diagnosed HGSC was 15.2 (IQR 13.1-16.9, 95% IPR 9.6-21.8) months, of which 11.9 (IQR 10.5-13.1, 95% IPR 7.5-16.5) months was in early stage. The median HGSC in-vivo tumour doubling time for cancers secreting CA-125 was 2.9 (IQR 2.3-3.7, 95% IPR 1.5-7.6) months.
INTERPRETATION: We report a comprehensive characterisation of the OC CA-125 PCDP. The 12-month window for early-stage detection and short tumour doubling time of HGSC provide a benchmark for researchers evaluating novel screening approaches including need to reduce diagnostic workup interval. Equally the findings provide urgent impetus for clinicians to reduce intervals from presentation to treatment onset.
FUNDING: NCI Early Detection Research Network, Concord (MA) Detect Ovarian Cancer Early Fund, MRC Clinical Trials Unit at UCL Core Funding.

Keywords: Biomarker; Blood; CA-125 antigen; Carcinoma; Early detection of cancer∗; Early diagnosis; Epidemiology; Longitudinal studies; Mass screening; Natural history of cancer; Ovarian epithelial∗; Ovarian neoplasms∗; Preclinical detectable phase; Preclinical history of cancer; UKCTOCS

DOI: https://doi.org/10.1016/j.ebiom.2024.105554

APMIS. 2025 Jan;133(1): e13509

No Bacterial Biomass Detected in Tissue From Patients With Ovarian Cancer and Serous Tubal Intraepithelial Carcinomas Using 16S rDNA Sequencing.

Kasper Ingerslev, Tim Svenstrup Poulsen, Mikael Lenz Strube, Wojciech Skovrider-Ruminski, Doris Schledermann, Tine Henrichsen Schnack, Claus Høgdall, Jan Blaakær, Estrid Høgdall.

The ovarian oncobiome is subject to increasing scientific focus, but a potential link between bacterial dysbiosis and ovarian carcinogenesis remains controversial. Our primary aim was to characterize the bacterial microbiota in epithelial ovarian cancer samples. Secondarily, we aimed to compare results from the bacterial microbiota in formalin-fixed, paraffin-embedded ovarian tissue samples from 194 patients with epithelial ovarian cancer, fallopian tube tissue samples from 16 patients with serous tubal intraepithelial carcinomas and in benign fallopian tube tissue samples from 25 patients. Bacterial abundance was investigated by means of 16S rDNA Next Generation Sequencing. The 16S rDNA sequencing run produced a very low number of bacterial reads. Only seven samples displayed bacterial reads above 5000. Validation of detected bacterial reads by qPCR was negative and indicative of results being background amplification. Our results indicate no amount of bacterial biomass in the ovarian cancer, benign fallopian tube and in the samples with serous tubal intraepithelial carcinomas. The findings underline the importance of validating results from bacterial microbiota studies with additional technical assays before any conclusion may be drawn.

Keywords: 16s rDNA sequencing; microbiota; oncobiome; ovarian cancer; serous tubal intraepithelial carcinoma

DOI: https://doi.org/10.1111/apm.13509

BJOG. 2025 Jan 17.

Salpingectomy With Delayed Oophorectomy Versus Salpingo-Oophorectomy in BRCA1/2 Carriers: Three-Year Outcomes of a Prospective Preference Trial.

OBJECTIVE: To compare menopause-related quality of life (QoL) after risk-reducing salpingectomy (RRS) versus risk-reducing salpingo-oophorectomy (RRSO) until 3 years of post-surgery.
DESIGN: A prospective study (TUBA study) with treatment allocation based on patients' preference. Data were collected pre-surgery and at 3 months, 1 and 3 years of post-surgery.
SETTING: Multicentre prospective preference trial in thirteen hospitals in the Netherlands.
POPULATION: BRCA1/2 pathogenic variant (PV) carriers aged 25-40 (BRCA1) or 25-45 (BRCA2), who were premenopausal, without a future child wish and without current (treatment for) malignancy.
METHODS: Treatment allocation was based on patients' preference: either RRS from the age of 25 years with delayed oophorectomy at the maximum age of 45 (BRCA1) or 50 (BRCA2), or RRSO between the ages of 35-40 (BRCA1) or 40-45 (BRCA2). After RRSO, hormone replacement therapy (HRT) was recommended, if not contraindicated. Primarily, menopause-related QoL as measured with the Greene Climacteric Scale (GCS) was compared between the RRS and RRSO without HRT group. Secondarily, GSC-scores of the RRS group were compared with the scores of the RRSO with HRT after surgery group. A higher GSC-score reflects more climacteric symptoms.
RESULTS: Until April 2023, 410 participants had undergone RRS and 160 RRSO. The BRCA1/BRCA2 proportions were 51.4%/48.6%. The mean age at surgery (SD) was 37.9 (3.5) years. Participants 3 years after RRSO without HRT had a 4.3 (95% CI 2.1-6.5; p < 0.001) point higher increase in GCS-score from baseline compared to those after RRS, while the difference was 7.9 (95% CI 5.9-9.8) and 8.5 (95% CI 6.5-10.5) points at 3 and 12 months, respectively. Among participants with HRT after surgery, the RRSO group had a 2.4 (95% CI 0.8-3.9; p = 0.002) point higher increase in GCS-score from baseline compared to the RRS group.
CONCLUSIONS: In this multicentre preference trial, menopause-related QoL was better after RRS than after RRSO, even with HRT after RRSO. Differences between arms were most pronounced until one-year post-surgery.

Keywords: BRCA1; BRCA2; delayed oophorectomy; ovarian cancer; quality of life; salpingectomy; salpingo‐oophorectomy

DOI: https://doi.org/10.1111/1471-0528.18075

Lancet Oncol. 2025 Jan 13. pii: S1470-2045(24)00667-3. [Epub ahead of print]

The psychological impact of screening with a multicancer early detection test.

Jon Emery.

DOI: https://doi.org/10.1016/S1470-2045(24)00667-3

NPJ Genom Med. 2025 Jan 10. 10(1): 1

Assessment of candidate high-grade serous ovarian carcinoma predisposition genes through integrated germline and tumour sequencing.

Deepak N Subramanian, Maia Zethoven, Kathleen I Pishas, Evanny R Marinović, Simone McInerny, Simone M Rowley, Prue E Allan, Lisa Devereux, Dane Cheasley, Paul A James, Ian G Campbell.

High-grade serous ovarian carcinoma (HGSOC) has a significant hereditary component, only half of which is explained. Previously, we performed germline exome sequencing on BRCA1 and BRCA2-negative HGSOC patients, revealing three proposed and 43 novel candidate genes enriched with rare loss-of-function variants. For validation, we undertook case-control analyses using genomic data from disease-free controls. This confirms enrichment for nearly all previously identified genes. Additionally, one-hundred-and-eleven HGSOC tumours from variant carriers were sequenced alongside other complementary studies, seeking evidence of biallelic inactivation as supportive evidence. PALB2 and ATM validate as HGSOC predisposition genes, with 6/8 germline carrier tumours exhibiting biallelic inactivation accompanied by characteristic mutational signatures. Among candidate genes, only LLGL2 consistently shows biallelic inactivation and protein expression loss, supporting it as a novel HGSOC susceptibility gene. The remaining candidate genes fail to validate. Integrating case-control analyses with tumour sequencing is thus crucial for accurate gene discovery in familial cancer studies.

DOI: https://doi.org/10.1038/s41525-024-00447-3

Genome Res. 2025 Jan 13. pii: gr.279144.124. [Epub ahead of print]

Nanopore-based consensus sequencing enables accurate multimodal tumor cell-free DNA profiling.

Shallow genome-wide cell-free DNA (cfDNA) sequencing holds great promise for non-invasive cancer monitoring by providing reliable copy number alteration (CNA) and fragmentomic profiles. Single nucleotide variations (SNVs) are, however, much harder to identify with low sequencing depth due to sequencing errors. Here we present Nanopore Rolling Circle Amplification (RCA)-enhanced Consensus Sequencing (NanoRCS), which leverages RCA and consensus calling based on genome-wide long-read nanopore sequencing to enable simultaneous multimodal tumor fraction estimation through SNVs, CNAs, and fragmentomics. Efficacy of NanoRCS is tested on 18 cancer patient samples and seven healthy controls, demonstrating its ability to reliably detect tumor fractions as low as 0.24%. In vitro experiments confirm that SNV measurements are essential for detecting tumor fractions below 3%. NanoRCS provides the opportunity for cost-effective and rapid processing, which aligns well with clinical needs, particularly in settings where quick and accurate cancer monitoring is essential for personalized treatment strategies.

DOI: https://doi.org/10.1101/gr.279144.124