bims-ovdlit Biomed News
on Ovarian cancer: early diagnosis, liquid biopsy and therapy
Issue of 2025–03–30
seven papers selected by
Lara Paracchini, Humanitas Research
  1. Impact of BRCA mutations, age, surgical indication, and hormone status on the molecular phenotype of the human Fallopian tube.
  2. Copy-number alterations in cell-free DNA can be transient or harbingers of clonal hematopoiesis.
  3. Integrating Plasma Cell-Free DNA Fragment End Motif and Size with Genomic Features Enables Lung Cancer Detection.
  4. Screening and prevention of gynecologic malignancies in patients with lynch syndrome: following the guidelines.
  5. Ovarian Aging and Fertility.
  6. ENGOT-OV16/NOVA trial of niraparib in recurrent ovarian cancer: Survival and long-term safety.
  7. Detection of minimal residual disease and prediction of recurrence in breast cancer using a plasma-only circulating tumor DNA assay.
  1. Nat Commun. 2025 Mar 26. 16(1): 2981
    Impact of BRCA mutations, age, surgical indication, and hormone status on the molecular phenotype of the human Fallopian tube.
    Ian Beddows, Svetlana Djirackor, Dalia K Omran, Euihye Jung, Natalie Nc Shih, Ritu Roy, Aaron Hechmer, Adam Olshen, Guillaume Adelmant, Ann Tom, Jacob Morrison, Marie Adams, Daniel C Rohrer, Lauren E Schwartz, Celeste Leigh Pearce, Heidi Auman, Jarrod A Marto, Charles W Drescher, Ronny Drapkin, Hui Shen.
      The human Fallopian tube (FT) is an important organ in the female reproductive system and has been implicated as a site of origin for pelvic serous cancers, including high-grade serous tubo-ovarian carcinoma (HGSC). We have generated comprehensive whole-genome bisulfite sequencing, RNA-seq, and proteomic data of over 100 human FTs, with detailed clinical covariate annotations. Our results challenge existing paradigms that extensive epigenetic, transcriptomic and proteomic alterations exist in the FTs from women carrying heterozygous germline BRCA1/2 pathogenic variants. We find minimal differences between BRCA1/2 carriers and non-carriers prior to loss of heterozygosity. Covariates such as age and surgical indication can confound BRCA1/2-related differences reported in the literature, mainly through their impact on cell composition. We systematically document and highlight the degree of variations across normal human FT, defining five groups capturing major cellular and molecular changes across various reproductive stages, pregnancy, and aging. We are able to associate gene, protein, and epigenetic changes with these and other clinical covariates, but not heterozygous BRCA1/2 mutation status. This sheds new light into prevention and early detection of tumorigenesis in populations at high-risk for ovarian cancer.
    DOI:  https://doi.org/10.1038/s41467-025-58145-2
  2. NPJ Precis Oncol. 2025 Mar 25. 9(1): 88
    Copy-number alterations in cell-free DNA can be transient or harbingers of clonal hematopoiesis.
    Stefania Tuveri, Nathalie Brison, Tatjana Jatsenko, Barbara Dewaele, Cindy Melotte, Charlotte Maggen, Vincent Vandecaveye, Peter Vandenberghe, Frederic Amant, Liesbeth Lenaerts, Joris R Vermeesch.
      Genome-wide plasma cfDNA pan-cancer screening of 1002 healthy elderly identified 15 individuals with CNAs of unknown origin. Nine participants were reassessed over 3-5 years through health questionnaires, WB-MRI, and cfDNA and blood analyses. CNAs resolved in two cases but persisted in seven mainly associated with low-grade clonal mosaicism. These findings suggest cfDNA CNAs may be transient or serve as early markers of clonal mosaicism, preceding clinical detection by years.
    DOI:  https://doi.org/10.1038/s41698-025-00877-x
  3. Cancer Res. 2025 Mar 26. OF1-OF12
    Integrating Plasma Cell-Free DNA Fragment End Motif and Size with Genomic Features Enables Lung Cancer Detection.
    Tae-Rim Lee, Jin Mo Ahn, Junnam Lee, Dasom Kim, Juntae Park, Byeong-Ho Jeong, Dongryul Oh, Sang Man Kim, Gyou-Chul Jung, Beom Hee Choi, Min-Jung Kwon, Mengchi Wang, Michael Salmans, Andrew Carson, Bryan Leatham, Kristin Fathe, Byung In Lee, Byoungsok Jung, Chang-Seok Ki, Young Sik Park, Eun-Hae Cho.
      Early detection of lung cancer is important for improving patient survival rates. Liquid biopsy using whole-genome sequencing of cell-free DNA (cfDNA) offers a promising avenue for lung cancer screening, providing a potential alternative or complementary approach to current screening modalities. Here, we aimed to develop and validate an approach by integrating fragment and genomic features of cfDNA to enhance lung cancer detection accuracy across diverse populations. Deep learning-based classifiers were trained using comprehensive cfDNA fragmentomic features from participants in multi-institutional studies, including a Korean discovery dataset (218 patients with lung cancer and 2,559 controls), a Korean validation dataset (111 patients with lung cancer and 1,136 controls), and an independent Caucasian validation cohort (50 patients with lung cancer and 50 controls). In the discovery dataset, classifiers using fragment end motif by size, a feature that captures both fragment end motif and size profiles, outperformed standalone fragment end motif and fragment size classifiers, achieving an area under the curve (AUC) of 0.917. The ensemble classifier integrating fragment end motif by size and genomic coverage achieved an improved performance, with an AUC of 0.937. This performance extended to the Korean validation dataset and demonstrated ethnic generalizability in the Caucasian validation cohort. Overall, the development of a deep learning-based classifier integrating cfDNA fragmentomic and genomic features in this study highlights the potential for accurate lung cancer detection across diverse populations. Significance: Evaluating fragment-based features and genomic coverage in cell-free DNA offers an accurate lung cancer screening method, promising improvements in early cancer detection and addressing challenges associated with current screening methods.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-1517
  4. Front Oncol. 2025 ;15 1563022
    Screening and prevention of gynecologic malignancies in patients with lynch syndrome: following the guidelines.
    Chen Ben David, Yoav Siegler, Revital Linder, Amnon Amit, Emad Matanes.
      Lynch syndrome (LS), a hereditary condition caused by germline mutations in mismatch repair (MMR) genes, significantly elevates the lifetime risk of endometrial cancer (EC) (40-60%) and ovarian cancer (8-10%) in affected women. Despite advances in colorectal cancer screening for LS patients, optimal strategies for gynecologic cancer prevention remain under debate. Current recommendations for EC surveillance, including annual transvaginal ultrasound and endometrial biopsy starting at age 30-35, lack robust evidence for effectiveness. Risk-reducing hysterectomy with bilateral salpingo-oophorectomy (BSO) is frequently advised after childbearing to mitigate cancer risk. Emerging data suggest that hormonal interventions, such as oral contraceptives and progestin-based therapies, may reduce EC risk by up to 50%, offering non-surgical preventive options. Lifestyle modifications, including weight management and physical activity, further complement risk reduction strategies. Molecular diagnostic advancements, including immunohistochemistry and microsatellite instability testing, enhance early identification of LS-associated gynecologic malignancies. For patients with advanced or recurrent EC, the integration of immunotherapy into treatment regimens has demonstrated significant efficacy. Agents such as pembrolizumab and dostarlimab, particularly in combination with carboplatin and paclitaxel, have improved progression-free and overall survival rates for patients with MMR-deficient tumors. This review highlights the need for personalized, evidence-based approaches to gynecologic cancer screening and prevention in LS, emphasizing the importance of integrating genetic testing, patient education, and novel therapeutic options. Future research should focus on refining screening protocols and expanding non-invasive preventive strategies to improve outcomes for this high-risk population.
    Keywords:  MIS; endometrial cancer; gynecologic cancer diagnosis; lynch syndrome; ovaria cancer
    DOI:  https://doi.org/10.3389/fonc.2025.1563022
  5. JAMA. 2025 Mar 27.
    Ovarian Aging and Fertility.
    Kristin L Walter.
      
    DOI:  https://doi.org/10.1001/jama.2025.2361
  6. Gynecol Oncol. 2025 Mar 25. pii: S0090-8258(25)00087-3. [Epub ahead of print]195 192-199
    ENGOT-OV16/NOVA trial of niraparib in recurrent ovarian cancer: Survival and long-term safety.
    Ursula A Matulonis, Jørn Herrstedt, Amit Oza, Sven Mahner, Andrés Redondo, Dominique Berton, Jonathan S Berek, Charlotte A Haslund, Frederik Marmé, Antonio González-Martín, Stéphanie Bécourt, Anna V Tinker, Jonathan A Ledermann, Benedict Benigno, Gabriel Lindahl, Nicoletta Colombo, Izabela A Malinowska, Wenlei Liu, Manjinder Bains, Bradley J Monk, Mansoor R Mirza.
       OBJECTIVE: To evaluate secondary efficacy endpoints and safety for the ENGOT-OV16/NOVA (NCT01847274) trial of niraparib maintenance therapy after extended follow-up and vital-status-data retrieval. Previously reported analyses (data cutoff, October 1, 2020) indicated benefit of niraparib maintenance therapy beyond first progression, but overall survival (OS) analyses were limited by missing data.
    METHODS: Patients were randomized 2:1 to niraparib (300 mg once daily) or placebo. A vital status check was extended to retrieve last-known-alive status for patients with missing survival data. Prespecified secondary efficacy outcomes (OS, chemotherapy-free interval [CFI], time to first subsequent therapy [TFST], PFS2, time to second subsequent therapy [TSST]) and safety are reported based on the extended data cutoff (March 31, 2021).
    RESULTS: Survival status was available for 97.6% (540/553) of randomized patients (germline BRCA [gBRCA]-mutated, 203; non-gBRCA-mutated, 350). Median OS with niraparib and placebo was 40.9 and 38.1 months, respectively, in the gBRCA-mutated cohort (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.61-1.20) and 31.0 and 34.8 months, respectively, in the non-gBRCA-mutated cohort (HR, 1.06; 95% CI, 0.81-1.37). Medians for CFI, TFST, PFS2, and TSST numerically favored niraparib in both cohorts. No new safety signals were detected.
    CONCLUSIONS: OS did not significantly differ between treatment arms. Prespecified secondary efficacy endpoints numerically favored niraparib. Long-term safety remained consistent with the established niraparib safety profile. Taken together with the significant improvements in PFS observed in the primary analysis, these data support a favorable overall benefit-risk profile for niraparib in the recurrent OC maintenance setting.
    Keywords:  Maintenance; Niraparib; Ovarian cancer; Platinum sensitive recurrence
    DOI:  https://doi.org/10.1016/j.ygyno.2025.03.018
  7. ESMO Open. 2025 Mar 21. pii: S2059-7029(25)00164-4. [Epub ahead of print]10(4): 104296
    Detection of minimal residual disease and prediction of recurrence in breast cancer using a plasma-only circulating tumor DNA assay.
    W Janni, B Rack, T W P Friedl, A D Hartkopf, L Wiesmüller, K Pfister, F Mergel, A Fink, T Braun, F Mehmeti, N Uhl, A De Gregorio, J Huober, T Fehm, V Müller, T A Rich, D J Dustin, S Zhang, S T Huesmann.
       BACKGROUND: Detection of minimal residual disease (MRD) in early breast cancer (EBC) after curative-intent treatment may identify patients at risk for recurrence. Most circulating tumor DNA (ctDNA)-based MRD assays require knowledge of genomic alterations from tumor tissue. However, tissue availability may be limited in some patients. Here, we evaluated sensitivity and specificity for recurrence detection, using a plasma-only ctDNA MRD assay.
    MATERIALS AND METHODS: For this pilot study, 47 plasma samples from 38 EBC patients were collected at 12 or 36 months post-diagnosis or at clinical recurrence. ctDNA presence was determined by a custom bioinformatics classifier that identifies tumor-derived somatic variants and methylation profiles specific to individual cancer types using a 5-Mb next-generation sequencing panel.
    RESULTS: ctDNA was detected at or before distant recurrence in 11/14 (79%) patients [sensitivity was 85% (11/13) among samples collected within 2 years from recurrence]. Lead time was evaluable in 4/6 (67%) samples collected before distant recurrence with detectable ctDNA and ranged from 3.4 to 18.5 months. ctDNA was not detected in samples from patients without recurrence (n = 13).
    CONCLUSIONS: This study demonstrates the feasibility of MRD detection in EBC using a plasma-only multiomic ctDNA-based approach. Larger studies are ongoing to further validate the clinical performance of the assay and demonstrate its applications.
    Keywords:  MRD; breast cancer recurrence; circulating tumor DNA; ctDNA; early breast cancer; minimal residual disease
    DOI:  https://doi.org/10.1016/j.esmoop.2025.104296
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