bims-ovdlit 2024-09-15 papers

bims-ovdlit

Biomed News

on Ovarian cancer: early diagnosis, liquid biopsy and therapy

Issue of 2024–09–15
nine papers selected by
Lara Paracchini, Humanitas Research

The Impact of Liquid Biopsy in Advanced Ovarian Cancer Care.
The Feasibility for Screening for Ovarian Cancer.
Timely targeted testing for hereditary cancer syndromes - Importance of clinician-facilitated cascade testing in the first year post-diagnosis.
Economic Evaluation of Population-Based BRCA1 and BRCA2 Testing in Canada.
HPV-YAP1 oncogenic alliance drives malignant transformation of fallopian tube epithelial cells.
Navigating the landscape of HPV-associated cancers: From epidemiology to prevention.
Establishment and validation of circulating cell-free DNA signatures for nasopharyngeal carcinoma detection.
Does circulating tumor DNA apply as a reliable biomarker for the diagnosis and prognosis of head and neck squamous cell carcinoma?
Plasma ctDNA as a treatment response biomarker in metastatic cancers: evaluation by the RECIST working group.

Diagnostics (Basel). 2024 Aug 26. pii: 1868. [Epub ahead of print]14(17):

The Impact of Liquid Biopsy in Advanced Ovarian Cancer Care.

Antoni Llueca, Sarai Canete-Mota, Anna Jaureguí, Manuela Barneo, Maria Victoria Ibañez, Alexander Neef, Enrique Ochoa, Sarai Tomas-Perez, Josep Mari-Alexandre, Juan Gilabert-Estelles, Anna Serra, Maria Teresa Climent, Carla Bellido, Nuria Ruiz, Blanca Segarra-Vidal, Maria Llueca.

   INTRODUCTION: Ovarian cancer is the third most common gynaecological cancer and has a very high mortality rate. The cornerstone of treatment is complete debulking surgery plus chemotherapy. Even with treatment, 80% of patients have a recurrence. Circulating tumour DNA (ctDNA) has been shown to be useful in the control and follow-up of some tumours. It could be an option to define complete cytoreduction and for the early diagnosis of recurrence.
OBJECTIVE: We aimed to demonstrate the usefulness of ctDNA and cell-free DNA (cfDNA) as a marker of complete cytoreduction and during follow-up in patients with advanced ovarian cancer.
MATERIAL AND METHODS: We selected 22 women diagnosed with advanced high-grade serous ovarian cancer, of which only 4 had complete records. We detected cfDNA by polymerase chain reaction (PCR), presented as ng/mL, and detected ctDNA with droplet digital PCR (ddPCR). We calculated Pearson correlation coefficients to evaluate correlations among cfDNA, ctDNA, and cancer antigen 125 (CA125), a biomarker.
RESULTS: The results obtained in the evaluation of cfDNA and ctDNA and their correlation with tumour markers and the radiology of patients with complete follow-up show disease progression during the disease, stable disease, or signs of recurrence. cfDNA and ctDNA correlated significantly with CA125. Following cfDNA and ctDNA over time indicated a recurrence several months earlier than computed tomography and CA125 changes.
CONCLUSION: An analysis of cfDNA and ctDNA offers a non-invasive clinical tool for monitoring the primary tumour to establish a complete cytoreduction and to diagnose recurrence early.

Keywords:  advanced ovarian cancer; cancer care; liquid biopsy; translational research

DOI:  https://doi.org/10.3390/diagnostics14171868
EJIFCC. 2024 Aug;35(2): 132-135

The Feasibility for Screening for Ovarian Cancer.

Miyo K Chatanaka, Eleftherios P Diamandis.

Introduction: The majority of the high-grade serous ovarian cancer (HGSOC) cases are diagnosed late, preventing effective treatment and therapy. We examine the feasibility of using EVA (Early oVArian cancer), a new molecular test for early HGSOC detection.
Methods: Comparison of the advantages and disadvantages of EVA with previously reported ovarian cancer tests, including CA125, was made, and the positive and negative predictive values of the tests were calculated as a measure of usefulness in the clinic.
Results: The positive predictive value of EVA and CA125 was 8.6% and 6.8% respectively, which was calculated based on the disease prevalence of 0.5%. The negative predictive value was 99.9% in both cases.
Conclusions: EVA and CA125 are unlikely to provide a meaningful population screening method for HGSOC in women at risk, since the predictive values would drive women not to perform these tests.

Keywords: EVA test; Ovarian Cancer; detection; molecular test; screening
Gynecol Oncol. 2024 Sep 09. pii: S0090-8258(24)01108-9. [Epub ahead of print]190 250-254

Timely targeted testing for hereditary cancer syndromes - Importance of clinician-facilitated cascade testing in the first year post-diagnosis.

Benjamin Grant, Alex Raghunandan, Emily Epstein, Jesse T Brewer, Isabelle Chandler, Taylor Larosa, Alissa Kalyan, Sarah Schulman, Ashley Llenas, Eloise Chapman-Davis, Charlene Thomas, Paul Christos, Steven M Lipkin, Ravi N Sharaf, Melissa K Frey.

   OBJECTIVE: Cascade testing for hereditary cancer syndromes allows relatives to estimate cancer risk and pursue prevention and early detection strategies. The current paradigm relies on patient coordinated care, resulting in only one-third of relatives successfully completing testing. Studies suggest that team-based approaches, where clinicians facilitate testing, can increase uptake. As institutions consider implementing such programs, understanding patient characteristics associated with interest is crucial for resource allocation. We aim to assess interest in clinician-facilitated testing and evaluate barriers.
METHODS: Patients with cancer-associated pathogenic variants seen at a gynecologic oncology clinic were offered clinician-facilitated cascade testing. Patient interest and demographic variables were recorded and patients that declined were interviewed regarding the decision.
RESULTS: From 11/2023-4/2024, 139 patients were offered clinician-facilitated cascade testing. Median patient age was 43 years (IQR 17), 97 (69.8 %) self-identified as White and 101 (72.7 %) as non-Hispanic. Fifty-six (40.3 %) patients harbored a BRCA1 pathogenic variant, 37 (26.6 %) BRCA2, and 46 (33.1 %) other cancer-associated genes. Fifty-seven (41.0 %) patients expressed interest in the intervention. Interested patients were more likely to have been diagnosed in the prior year vs. patients who were not interested on univariate (OR 4.6, 95 % CI 2.0-10.2, P = 0.0002) and multivariable analyses (adjusted OR 3.8, 95 % CI 1.622-9.009, P = 0.0022).
CONCLUSIONS: Our study demonstrates that patients are almost five time more likely to be interested in cascade genetic testing within the first year of diagnosis of a pathogenic variant. Given the utility of such programs and their resource requirements, targeting this population could maximize effectiveness and uptake of cascade services.

Keywords:  Cascade testing; Genetics; Hereditary cancer syndromes; Pathogenic variant

DOI:  https://doi.org/10.1016/j.ygyno.2024.09.001
JAMA Netw Open. 2024 Sep 03. 7(9): e2432725

Economic Evaluation of Population-Based BRCA1 and BRCA2 Testing in Canada.

Li Sun, Xia Wei, Caitlin T Fierheller, Lesa Dawson, Samuel Oxley, Ashwin Kalra, Jacqueline Sia, Fabio Feldman, Stuart Peacock, Kasmintan A Schrader, Rosa Legood, Janice S Kwon, Ranjit Manchanda.

Importance: Population-based BRCA testing can identify many more BRCA carriers who will be missed by the current practice of BRCA testing based on family history (FH) and clinical criteria. These carriers can benefit from screening and prevention, potentially preventing many more breast and ovarian cancers and deaths than the current practice.
Objective: To estimate the incremental lifetime health outcomes, costs, and cost-effectiveness associated with population-based BRCA testing compared with FH-based testing in Canada.
Design, Setting, and Participants: For this economic evaluation, a Markov model was developed to compare the lifetime costs and outcomes of BRCA1/BRCA2 testing for all general population women aged 30 years compared with FH-based testing. BRCA carriers are offered risk-reducing salpingo-oophorectomy to reduce their ovarian cancer risk and magnetic resonance imaging (MRI) and mammography screening, medical prevention, and risk-reducing mastectomy to reduce their breast cancer risk. The analyses were conducted from both payer and societal perspectives. This study was conducted from October 1, 2022, to February 20, 2024.
Main Outcomes and Measures: Outcomes of interest were ovarian cancer, breast cancer, additional heart disease deaths, and incremental cost-effectiveness ratio ICER per quality-adjusted life-year (QALY). One-way and probabilistic-sensitivity-analyses (PSA) were undertaken to explore the uncertainty.
Results: In the simulated cohort of 1 000 000 women aged 30 years in Canada, the base case ICERs of population-based BRCA testing were CAD $32 276 (US $23 402.84) per QALY from the payer perspective or CAD $16 416 (US $11 903.00) per QALY from the societal perspective compared with FH-based testing, well below the established Canadian cost-effectiveness thresholds. Population testing remained cost-effective for ages 40 to 60 years but not at age 70 years. The results were robust for multiple scenarios, 1-way sensitivity, and PSA. More than 99% of simulations from payer and societal perspectives were cost-effective on PSA (5000 simulations) at the CAD $50 000 (US $36 254.25) per QALY willingness-to-pay threshold. Population-based BRCA testing could potentially prevent an additional 2555 breast cancers and 485 ovarian cancers in the Canadian population, corresponding to averting 196 breast cancer deaths and 163 ovarian cancer deaths per 1 000 000 population.
Conclusions and Relevance: In this economic evaluation, population-based BRCA testing was cost-effective compared with FH-based testing in Canada from payer and societal perspectives. These findings suggest that changing the genetic testing paradigm to population-based testing could prevent thousands of breast and ovarian cancers.

DOI: https://doi.org/10.1001/jamanetworkopen.2024.32725
EMBO Rep. 2024 Sep 13.

HPV-YAP1 oncogenic alliance drives malignant transformation of fallopian tube epithelial cells.

Chunbo He, Xiangmin Lv, Jiyuan Liu, Jinpeng Ruan, Peichao Chen, Cong Huang, Peter C Angeletti, Guohua Hua, Madelyn Leigh Moness, Davie Shi, Anjali Dhar, Siyi Yang, Savannah Murphy, Isabelle Montoute, Xingcheng Chen, Kazi Nazrul Islam, Sophia George, Tan A Ince, Ronny Drapkin, Chittibabu Guda, John S Davis, Cheng Wang.

  High grade serous ovarian carcinoma (HGSOC) is the most common and aggressive ovarian malignancy. Accumulating evidence indicates that HGSOC may originate from human fallopian tube epithelial cells (FTECs), although the exact pathogen(s) and/or molecular mechanism underlying the malignant transformation of FTECs is unclear. Here we show that human papillomavirus (HPV), which could reach FTECs via retrograde menstruation or sperm-carrying, interacts with the yes-associated protein 1 (YAP1) to drive the malignant transformation of FTECs. HPV prevents FTECs from natural replicative and YAP1-induced senescence, thereby promoting YAP1-induced malignant transformation of FTECs. HPV also stimulates proliferation and drives metastasis of YAP1-transformed FTECs. YAP1, in turn, stimulates the expression of the putative HPV receptors and suppresses the innate immune system to facilitate HPV acquisition. These findings provide critical clues for developing new strategies to prevent and treat HGSOC.

Keywords:  Fallopian Tube; HGSOC; HPV Infection; Hippo Pathway; Innate Immunity

DOI:  https://doi.org/10.1038/s44319-024-00233-3
Pathol Res Pract. 2024 Aug 31. pii: S0344-0338(24)00485-0. [Epub ahead of print]263 155574

Navigating the landscape of HPV-associated cancers: From epidemiology to prevention.

Durre Aden, Sufian Zaheer, Sabina Khan, Zeeba S Jairajpuri, Sujata Jetley.

  Human Papillomavirus (HPV) is a widespread infection associated with various cancers, including cervical, oropharyngeal, anal, and genital cancers. This infection contributes to 5 % of global cancer cases annually, affecting approximately 625,600 women and 69,400 men. Cervical cancer remains the most prevalent HPV-linked cancer among females, with the highest incidence seen in low and middle-income countries (LMICs). While most HPV infections are transient, factors such as HPV variants, age, gender, and socioeconomic status influence transmission risks. HPV is categorized into high-risk (HR-HPV) and low-risk types, with strains like HPV 16 and 18 displaying distinct demographic patterns. The intricate pathogenesis of HPV involves genetic and epigenetic interactions, with HPV oncogenes (E6 and E7) and integration into host DNA playing a pivotal role in driving malignancies. Early diagnostics, utilizing HPV DNA testing with surrogate markers such as p16, and advanced molecular techniques like PCR, liquid biopsy, and NGS, significantly impact the management of HPV-induced cancers. Effectively managing HPV-related cancers demands a multidisciplinary approach, including immunotherapy, integrating current therapies, ongoing trials, and evolving treatments. Prevention via HPV vaccination and the inclusion of cervical cancer screening in national immunization programs by conventional Pap smear examination and HPV DNA testing remains fundamental.Despite the preventability of HPV-related cancers, uncertainties persist in testing, vaccination, and treatment. This review article covers epidemiology, pathogenesis, diagnostics, management, prevention strategies, challenges, and future directions. Addressing issues like vaccine hesitancy, healthcare disparities, and advancing therapies requires collaboration among researchers, healthcare providers, policymakers, and the public. Advancements in understanding the disease's molecular basis and clinical progression are crucial for early detection, proper management, and improved outcomes.

Keywords:  Epidemiology; HPV; HPV-associated cancers; Pathogenesis; Prevention

DOI:  https://doi.org/10.1016/j.prp.2024.155574
EBioMedicine. 2024 Sep 11. pii: S2352-3964(24)00357-8. [Epub ahead of print]108 105321

Establishment and validation of circulating cell-free DNA signatures for nasopharyngeal carcinoma detection.

Su-Fang Qiu, Qing-Zheng Zhang, Zi-Yi Wu, Ming-Zhu Liu, Qin Ding, Fu-Ming Sun, Yin Wang, Han-Xuan Yang, Lu Zheng, Xin Chen, Lin Wu, Jian Bai, Jing-Feng Liu, Chuan-Ben Chen.

   BACKGROUND: Early detection of nasopharyngeal carcinoma (NPC) poses a significant challenge. The absence of highly sensitive and specific diagnostic biomarkers for nasopharyngeal carcinoma contributes to the unfavourable prognosis of NPC patients. Here, we aimed to establish a non-invasive approach for detecting NPC using circulating cell-free DNA (cfDNA).
METHODS: We investigated the potential of next-generation sequencing (NGS) of peripheral blood cells as a diagnostic tool for NPC. We collected data on genome-wide nucleosome footprint (NF), 5'-end motifs, fragmentation patterns, CNV information, and EBV content from 553 Chinese subjects, including 234 NPC patients and 319 healthy individuals. Through case-control analysis, we developed a diagnostic model for NPC, and validated its detection capability.
FINDINGS: Our findings revealed that the frequencies of NF, fragmentation, and motifs were significantly higher in NPC patients compared to healthy controls. We developed an NPC score based on these parameters that accurately distinguished NPC from non-NPC cases according to the American Joint Committee on Cancer staging system from non-NPC (validation set: area under curve (AUC) = 99.9% (95% CI: 99.8%-100%), se: 98.15%, sp: 100%). This model showed superior performance over plasma EBV DNA. Additionally, the NPC score effectively differentiated between NPC patients and healthy controls, even after clinical treatment. Furthermore, the NPC score was found to be independent of potential confounders such as age, sex, or TNM stage.
INTERPRETATION: We have developed and verified a non-invasive approach with substantial potential for clinical application in detecting NPC.
FUNDING: A full list of funding bodies that contributed to this study can be found in Funding section.

Keywords:  Biomarkers; Cancer detection; Nasopharyngeal carcinoma; cfDNA

DOI:  https://doi.org/10.1016/j.ebiom.2024.105321
Discov Oncol. 2024 Sep 11. 15(1): 427

Does circulating tumor DNA apply as a reliable biomarker for the diagnosis and prognosis of head and neck squamous cell carcinoma?

Negin Ghiyasimoghaddam, Navidreza Shayan, Hanieh Alsadat Mirkatuli, Mohammadhasan Baghbani, Nima Ameli, Zeynab Ashari, Nooshin Mohtasham.

  Oral cavity cancer is the most common type of head and neck cancer. There is no definitive standard diagnosis, prognosis, or treatment response biomarker panel based on simple, specific, non-invasive, and reliable methods for head and neck squamous cell carcinoma (HNSCC) patients. On the other hand, the frequent post-treatment biopsies make it challenging to discriminate residual disease or recurrent tumors following postoperative reparative and post-radiation changes. Saliva, blood plasma, and serum samples were commonly used to monitor HNSCC through liquid biopsies. Based on the evidence, the most prominent molecular-based fluid biomarker, such as circulating tumor DNA (ctDNA), has potential applications for early cancer diagnosis, screening, patient management, and surveillance. ctDNA showed genomic and epigenomic changes and the status of human papillomavirus (HPV) with the real-time monitoring of tumor status through cancer therapy. Due to the intra and inter-tumor heterogeneity of tumor cells like cancer stem cells (CSCs) and tumor microenvironment (TME) in HNSCC, the tiny tissue biopsy cannot reflect all genomic and transcriptomic abnormality. Most liquid biopsies are applied to detect circulating molecular biomarkers consisting of cell-free DNA (cfDNA), ctDNA, microRNA, mRNA, and exosome for monitoring tumor progression. Based on the results of previous studies, liquid biopsy can be applied for comprehensive multi-omic discovery by assessing the predictive value of ctDNA in both early and advanced cancers. Liquid biopsy can be used to evaluate molecular signature profiles in HNSCC patients, with great potential to help in early diagnosis, prognosis, surveillance, and treatment monitoring of tumors. These happen by designing longitudinal extensive cohort studies and the utility of organoid technology that promotes the context of personalized and precision cancer medicine.

Keywords:  Biomarkers; Cell-free nucleic acids; Circulating tumor DNA; Squamous cell carcinoma of head and neck

DOI:  https://doi.org/10.1007/s12672-024-01308-2
Clin Cancer Res. 2024 Sep 13.

Plasma ctDNA as a treatment response biomarker in metastatic cancers: evaluation by the RECIST working group.

Alexander W Wyatt, Saskia Litière, Francois-Clement Bidard, Luc Cabel, Lars Dyrskjøt, Chris A Karlovich, Klaus Pantel, Joan Petrie, Reena Philip, Hillary S Andrews, Paz J Vellanki, Sofie H Tolmeijer, Xenia Villalobos Alberu, Christian Alfano, Jan Bogaerts, Emiliano Calvo, Alice P Chen, Rodrigo A Toledo, Elisabeth G E de Vries, Lesley Seymour, Scott A Laurie, Elena Garralda.

Early indicators of metastatic cancer response to therapy are important for evaluating new drugs and stopping ineffective treatment. The Response Evaluation Criteria in Solid Tumors (RECIST) based on repeat cancer imaging are widely adopted in clinical trials, are used to identify active regimens that may change practice, and contribute to regulatory approvals. However, these criteria do not provide insight before 6 - 12 weeks of treatment and typically require that patients have measurable disease. Recent data suggests that measuring on-treatment changes in the amount or proportion of circulating tumor DNA (ctDNA) in peripheral blood plasma may accurately identify responding and non-responding cancers at earlier time points. Over the past year, the RECIST working group has evaluated current evidence for plasma ctDNA kinetics as a treatment response biomarker in metastatic cancers and early endpoint in clinical trials, to identify areas of focus for future research and validation. Here, we outline the requirement for large standardized trial datasets, greater scrutiny of optimal ctDNA collection time points and assay thresholds, and consideration of regulatory body guidelines and patient opinions. In particular, clinically-meaningful changes in plasma ctDNA abundance are likely to differ by cancer type and therapy class, and must be assessed before ctDNA can be considered as a potential pan-cancer response evaluation biomarker. Despite the need for additional data, minimally-invasive on-treatment ctDNA measurements hold promise to build upon existing response assessments such as RECIST, and offer opportunities for developing novel early endpoints for modern clinical trials.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-1883