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Journal of Clinical Oncology : Official... Feb 2024Most cervical cancers are caused by human papilloma virus (HPV), and HPV circulating tumor DNA (ctDNA) may identify patients at highest risk of relapse. Our pilot study...
PURPOSE
Most cervical cancers are caused by human papilloma virus (HPV), and HPV circulating tumor DNA (ctDNA) may identify patients at highest risk of relapse. Our pilot study using digital polymerase chain reaction (dPCR) showed that detectable HPV ctDNA at the end of chemoradiation (CRT) is associated with inferior progression-free survival (PFS) and that a next-generation sequencing approach (HPV-seq) may outperform dPCR. We aimed to prospectively validate HPV ctDNA as a tool for early detection of residual disease.
METHODS
This prospective, multicenter validation study accrued patients with stage IB-IVA cervical cancer treated with CRT between 2017 and 2022. Participants underwent phlebotomy at baseline, end of CRT, 4-6 weeks post-CRT, and 3 months post-CRT for HPV ctDNA levels. Plasma HPV genotype-specific DNA levels were quantified using both dPCR and HPV-seq. The primary end point was 2-year PFS.
RESULTS
With a median follow-up of 2.2 (range, 0.5-5.5) years, there were 24 PFS events among the 70 patients with HPV+ cervical cancer. Patients with detectable HPV ctDNA on dPCR at the end of CRT, 4-6 weeks post-CRT, and 3 months post-CRT had significantly worse 2-year PFS compared with those with undetectable HPV ctDNA (77% 51%, = .03; 82% 15%, < .001; and 82% 24%, < .001, respectively); the median lead time to recurrence was 5.9 months. HPV-seq showed similar results as dPCR. On multivariable analyses, detectable HPV ctDNA on dPCR and HPV-seq remained independently associated with inferior PFS.
CONCLUSION
Persistent HPV ctDNA after CRT is independently associated with inferior PFS. HPV ctDNA testing can identify, as early as at the end of CRT, patients at high risk of recurrence for future treatment intensification trials.
Topics: Female; Humans; Circulating Tumor DNA; Uterine Cervical Neoplasms; Human Papillomavirus Viruses; Prospective Studies; Papillomavirus Infections; Pilot Projects; Neoplasm Recurrence, Local; Biomarkers, Tumor
PubMed: 37972346
DOI: 10.1200/JCO.23.00954 -
Cancers Dec 2023The oncogenic and persistent Epstein Barr virus (EBV) is carried by more than 95% of the human adult population. While asymptomatic in most of these, EBV can cause a... (Review)
Review
The oncogenic and persistent Epstein Barr virus (EBV) is carried by more than 95% of the human adult population. While asymptomatic in most of these, EBV can cause a wide variety of malignancies of lymphoid or epithelial cell origin. Some of these are also associated with co-infections that either increase EBV-induced tumorigenesis or weaken its immune control. The respective pathogens include Kaposi-sarcoma-associated herpesvirus (KSHV), and human immunodeficiency virus (HIV). In this review, I will discuss the respective tumor entities and possible mechanisms by which co-infections increase the EBV-associated cancer burden. A better understanding of the underlying mechanisms could allow us to identify crucial features of EBV-associated malignancies and defects in their immune control. These could then be explored to develop therapies against the respective cancers by targeting EBV and/or the respective co-infections with pathogen-specific therapies or vaccinations.
PubMed: 38136285
DOI: 10.3390/cancers15245739 -
Frontiers in Reproductive Health 2023
PubMed: 38023533
DOI: 10.3389/frph.2023.1287513 -
Journal of Clinical Medicine Sep 2023Cervical cancer is an international public health crisis, affecting several hundred thousand women annually. While not universally protective due to other risk factors,... (Review)
Review
Cervical cancer is an international public health crisis, affecting several hundred thousand women annually. While not universally protective due to other risk factors, many such cases are preventable with vaccination against high-risk serotypes of the human papilloma virus (HPV 6, 11, 16, 18, 31, 33, 45, 53, 58). Advanced-stage and recurrent cervical cancers are typically lethal and have been the focus in recent years of the integration of immune checkpoint inhibitors (CPIs) to improve survival. We have consolidated information regarding the role of the immune system in both disease progression and disease clearance with the aid of targeted therapies and immunotherapeutic agents. Additionally, we have characterized the treatment modalities currently indicated as the standard of care-such as bevacizumab and the immune CPIs-and those recently approved or in development, including Tivdak, Vigil, and chimeric antigen receptor (CAR) T-cells.
PubMed: 37762931
DOI: 10.3390/jcm12185992 -
Molecular & Cellular Proteomics : MCP Nov 2023The NFE2L2 (NRF2) oncogene and transcription factor drives a gene expression program that promotes cancer progression, metabolic reprogramming, immune evasion, and...
The NFE2L2 (NRF2) oncogene and transcription factor drives a gene expression program that promotes cancer progression, metabolic reprogramming, immune evasion, and chemoradiation resistance. Patient stratification by NRF2 activity may guide treatment decisions to improve outcome. Here, we developed a mass spectrometry-based targeted proteomics assay based on internal standard-triggered parallel reaction monitoring to quantify 69 NRF2 pathway components and targets, as well as 21 proteins of broad clinical significance in head and neck squamous cell carcinoma (HNSCC). We improved an existing internal standard-triggered parallel reaction monitoring acquisition algorithm, called SureQuant, to increase throughput, sensitivity, and precision. Testing the optimized platform on 27 lung and upper aerodigestive cancer cell models revealed 35 NRF2 responsive proteins. In formalin-fixed paraffin-embedded HNSCCs, NRF2 signaling intensity positively correlated with NRF2-activating mutations and with SOX2 protein expression. Protein markers of T-cell infiltration correlated positively with one another and with human papilloma virus infection status. CDKN2A (p16) protein expression positively correlated with the human papilloma virus oncogenic E7 protein and confirmed the presence of translationally active virus. This work establishes a clinically actionable HNSCC protein biomarker assay capable of quantifying over 600 peptides from frozen or formalin-fixed paraffin-embedded archived tissues in under 90 min.
Topics: Humans; Squamous Cell Carcinoma of Head and Neck; Carcinoma, Squamous Cell; NF-E2-Related Factor 2; Head and Neck Neoplasms; Proteomics; Papillomavirus Infections; Biomarkers, Tumor; Cyclin-Dependent Kinase Inhibitor p16; Formaldehyde
PubMed: 37716475
DOI: 10.1016/j.mcpro.2023.100647