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Clinical Cancer Research : An Official... Nov 2021Almost all cervical cancers are caused by human papillomavirus (HPV) and patients with advanced stage are at high risk for relapse. Circulating HPV DNA (HPV ctDNA) may...
PURPOSE
Almost all cervical cancers are caused by human papillomavirus (HPV) and patients with advanced stage are at high risk for relapse. Circulating HPV DNA (HPV ctDNA) may serve as a residual tumor marker at the end of chemoradiation or to predict relapse during the follow-up period.
EXPERIMENTAL DESIGN
We analyzed serum samples from 94 HPV16- or HPV18-related CCs from the BioRAIDs prospective cohort. Samples were collected before and after treatment and during an 18-month follow-up period. Using digital droplet PCR (ddPCR), we assessed the relevance of circulating HPV gene as a marker for residual disease compared to HPV integration site and mutations. Finally, the prognostic impact of circulating HPV gene was assessed with its prediction value of relapse.
RESULTS
HPV gene was the most sensitive tumor marker, superior to both HPV integration sites and mutations in serum. Circulating HPV DNA (HPV ctDNA) was detected in 63% (59/94) of patients, before treatment. HPV ctDNA detection in serum sample was associated with high FIGO stage ( = 0.02) and para-aortic lymph node involvement ( = 0.01). The level of HPV ctDNA was positively correlated with HPV copy number in the tumor ( = 0.39, < 0.001). Complete clearance of HPV ctDNA by the end of treatment was significantly associated with a longer PFS ( < 0.0001). Patients with persistent HPV ctDNA in serum relapsed with a median time of 10 months (range, 2-15) from HPV ctDNA detection.
CONCLUSIONS
HPV ctDNA detection is a useful marker to predict relapse in cervical cancer..
Topics: Adult; Aged; Aged, 80 and over; Alphapapillomavirus; Biomarkers, Tumor; Chemoradiotherapy; DNA, Viral; Early Detection of Cancer; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Neoplasm, Residual; Papillomavirus Infections; Prospective Studies; Uterine Cervical Neoplasms; Young Adult
PubMed: 34210686
DOI: 10.1158/1078-0432.CCR-21-0625 -
Cancer Discovery Dec 2017Identifying molecular residual disease (MRD) after treatment of localized lung cancer could facilitate early intervention and personalization of adjuvant therapies....
Identifying molecular residual disease (MRD) after treatment of localized lung cancer could facilitate early intervention and personalization of adjuvant therapies. Here, we apply cancer personalized profiling by deep sequencing (CAPP-seq) circulating tumor DNA (ctDNA) analysis to 255 samples from 40 patients treated with curative intent for stage I-III lung cancer and 54 healthy adults. In 94% of evaluable patients experiencing recurrence, ctDNA was detectable in the first posttreatment blood sample, indicating reliable identification of MRD. Posttreatment ctDNA detection preceded radiographic progression in 72% of patients by a median of 5.2 months, and 53% of patients harbored ctDNA mutation profiles associated with favorable responses to tyrosine kinase inhibitors or immune checkpoint blockade. Collectively, these results indicate that ctDNA MRD in patients with lung cancer can be accurately detected using CAPP-seq and may allow personalized adjuvant treatment while disease burden is lowest. This study shows that ctDNA analysis can robustly identify posttreatment MRD in patients with localized lung cancer, identifying residual/recurrent disease earlier than standard-of-care radiologic imaging, and thus could facilitate personalized adjuvant treatment at early time points when disease burden is lowest. .
Topics: Circulating Tumor DNA; Female; Humans; Lung Neoplasms; Male; Neoplasm, Residual
PubMed: 28899864
DOI: 10.1158/2159-8290.CD-17-0716 -
Signal Transduction and Targeted Therapy Sep 2021Surgery is the common treatment for early lung cancer with multiple pulmonary nodules, but it is often accompanied by the problem of significant malignancy of other... (Clinical Trial)
Clinical Trial
Surgery is the common treatment for early lung cancer with multiple pulmonary nodules, but it is often accompanied by the problem of significant malignancy of other nodules in non-therapeutic areas. In this study, we found that a combined treatment of local radiofrequency ablation (RFA) and melatonin (MLT) greatly improved clinical outcomes for early lung cancer patients with multiple pulmonary nodules by minimizing lung function injury and reducing the probability of malignant transformation or enlargement of nodules in non-ablated areas. Mechanically, as demonstrated in an associated mouse lung tumor model, RFA not only effectively remove treated tumors but also stimulate antitumor immunity, which could inhibit tumor growth in non-ablated areas. MLT enhanced RFA-stimulated NK activity and exerted synergistic antitumor effects with RFA. Transcriptomics and proteomics analyses of residual tumor tissues revealed enhanced oxidative phosphorylation and reduced acidification as well as hypoxia in the tumor microenvironment, which suggests reprogrammed tumor metabolism after combined treatment with RFA and MLT. Analysis of residual tumor further revealed the depressed activity of MAPK, NF-kappa B, Wnt, and Hedgehog pathways and upregulated P53 pathway in tumors, which was in line with the inhibited tumor growth. Combined RFA and MLT treatment also reversed the Warburg effect and decreased tumor malignancy. These findings thus demonstrated that combined treatment of RFA and MLT effectively inhibited the malignancy of non-ablated nodules and provided an innovative non-invasive strategy for treating early lung tumors with multiple pulmonary nodules. Trial registration: www.chictr.org.cn , identifier ChiCTR2100042695, http://www.chictr.org.cn/showproj.aspx?proj=120931 .
Topics: Adult; Aged; Aged, 80 and over; Animals; Cell Proliferation; Combined Modality Therapy; Female; Hedgehog Proteins; Heterografts; Humans; Kaplan-Meier Estimate; Killer Cells, Natural; Lung Neoplasms; Male; Melatonin; Mice; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Multiple Pulmonary Nodules; NF-kappa B; Neoplasm, Residual; Progression-Free Survival; Radiofrequency Ablation; Treatment Outcome; Wnt Signaling Pathway
PubMed: 34471091
DOI: 10.1038/s41392-021-00745-7 -
Cold Spring Harbor Perspectives in... Mar 2019Prostate cancer (PCa) prognosis and clinical outcome is directly dependent on metastatic occurrence. The bone microenvironment is a favorable metastatic niche. Different... (Review)
Review
Prostate cancer (PCa) prognosis and clinical outcome is directly dependent on metastatic occurrence. The bone microenvironment is a favorable metastatic niche. Different biological processes have been suggested to contribute to the osteotropism of PCa such as hemodynamics, bone-specific signaling interactions, and the "seed and soil" hypothesis. However, prevalence of disseminating tumor cells in the bone is not proportional to the actual occurrence of metastases, as not all patients will develop bone metastases. The fate and tumor-reforming ability of a metastatic cell is greatly influenced by the microenvironment. In this review, the molecular mechanisms of bone and soft-tissue metastasis in PCa are discussed. Specific attention is dedicated to the residual disease, novel approaches, and animal models used in oncological translational research are illustrated.
Topics: Animals; Bone Neoplasms; Disease Models, Animal; Humans; Male; Neoplasm Metastasis; Neoplasm, Residual; Neoplastic Cells, Circulating; Prostatic Neoplasms; Soft Tissue Neoplasms; Tumor Microenvironment
PubMed: 29661810
DOI: 10.1101/cshperspect.a033688 -
Clinical Cancer Research : An Official... Jun 2020Existing cell-free DNA (cfDNA) methods lack the sensitivity needed for detecting minimal residual disease (MRD) following therapy. We developed a test for tracking...
PURPOSE
Existing cell-free DNA (cfDNA) methods lack the sensitivity needed for detecting minimal residual disease (MRD) following therapy. We developed a test for tracking hundreds of patient-specific mutations to detect MRD with a 1,000-fold lower error rate than conventional sequencing.
EXPERIMENTAL DESIGN
We compared the sensitivity of our approach to digital droplet PCR (ddPCR) in a dilution series, then retrospectively identified two cohorts of patients who had undergone prospective plasma sampling and clinical data collection: 16 patients with ER+/HER2- metastatic breast cancer (MBC) sampled within 6 months following metastatic diagnosis and 142 patients with stage 0 to III breast cancer who received curative-intent treatment with most sampled at surgery and 1 year postoperative. We performed whole-exome sequencing of tumors and designed individualized MRD tests, which we applied to serial cfDNA samples.
RESULTS
Our approach was 100-fold more sensitive than ddPCR when tracking 488 mutations, but most patients had fewer identifiable tumor mutations to track in cfDNA (median = 57; range = 2-346). Clinical sensitivity was 81% ( = 13/16) in newly diagnosed MBC, 23% ( = 7/30) at postoperative and 19% ( = 6/32) at 1 year in early-stage disease, and highest in patients with the most tumor mutations available to track. MRD detection at 1 year was strongly associated with distant recurrence [HR = 20.8; 95% confidence interval, 7.3-58.9]. Median lead time from first positive sample to recurrence was 18.9 months (range = 3.4-39.2 months).
CONCLUSIONS
Tracking large numbers of individualized tumor mutations in cfDNA can improve MRD detection, but its sensitivity is driven by the number of tumor mutations available to track.
Topics: Adult; Breast Neoplasms; Circulating Tumor DNA; Combined Modality Therapy; Estrogen Receptor alpha; Female; Follow-Up Studies; Humans; Neoplasm Recurrence, Local; Neoplasm, Residual; Prognosis; Prospective Studies; Retrospective Studies; Survival Rate
PubMed: 32170028
DOI: 10.1158/1078-0432.CCR-19-3005 -
Cold Spring Harbor Perspectives in... Apr 2020Recurrent metastasis following extended periods of disease-free survival remains a common cause of morbidity and mortality for many cancer patients. Recurrence is... (Review)
Review
Recurrent metastasis following extended periods of disease-free survival remains a common cause of morbidity and mortality for many cancer patients. Recurrence is thought to be mediated by tumor cells that escaped the primary site early in the disease course and colonize distant organs. In these locations, cells adapt to the local environment, entering a state of long-term dormancy in which they can resist therapy. Then, through mechanisms that are poorly understood, a proportion of these cells are reactivated and become proliferative, forming lethal metastases. Here, we discuss disseminated tumor cell dormancy in recurrent metastasis. We discuss mechanisms known to control entrance of cells into dormancy, highlighting the relevant microenvironments or "niches" in which these cells reside and mechanisms known to be involved in dormant cell reactivation. Finally, we consider emerging therapeutic approaches aimed at eradicating residual disease and preventing metastatic relapse.
Topics: Animals; Disease Progression; Humans; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm, Residual; Neoplasms; Tumor Microenvironment
PubMed: 31548220
DOI: 10.1101/cshperspect.a037556 -
PLoS Medicine Oct 2021Beryne Odeny discusses PLOS Medicine's Special Issue on early cancer detection and minimal residual disease.
Beryne Odeny discusses PLOS Medicine's Special Issue on early cancer detection and minimal residual disease.
Topics: Cell-Free Nucleic Acids; Colorectal Neoplasms; DNA, Neoplasm; Early Detection of Cancer; Humans; Liquid Biopsy; Liver Neoplasms; Neoplasm Recurrence, Local; Neoplasm, Residual; Risk Factors
PubMed: 34637442
DOI: 10.1371/journal.pmed.1003794 -
EBioMedicine May 2023Liquid biopsy is a promising non-invasive alternative for cancer screening and minimal residual disease (MRD) detection, although there are some concerns regarding its...
Multi-omics integrated circulating cell-free DNA genomic signatures enhanced the diagnostic performance of early-stage lung cancer and postoperative minimal residual disease.
BACKGROUND
Liquid biopsy is a promising non-invasive alternative for cancer screening and minimal residual disease (MRD) detection, although there are some concerns regarding its clinical applications. We aimed to develop an accurate detection platform based on liquid biopsy for both cancer screening and MRD detection in patients with lung cancer (LC), which is also applicable to clinical use.
METHODS
We applied a modified whole-genome sequencing (WGS) -based High-performance Infrastructure For MultIomics (HIFI) method for LC screening and postoperative MRD detection by combining the hyper-co-methylated read approach and the circulating single-molecule amplification and resequencing technology (cSMART2.0).
FINDINGS
For early screening of LC, the LC score model was constructed using the support vector machine, which showed sensitivity (51.8%) at high specificity (96.3%) and achieved an AUC of 0.912 in the validation set prospectively enrolled from multiple centers. The screening model achieved detection efficiency with an AUC of 0.906 in patients with lung adenocarcinoma and outperformed other clinical models in solid nodule cohort. When applied the HIFI model to real social population, a negative predictive value (NPV) of 99.92% was achieved in Chinese population. Additionally, the MRD detection rate improved significantly by combining results from WGS and cSMART2.0, with sensitivity of 73.7% at specificity of 97.3%.
INTERPRETATION
In conclusion, the HIFI method is promising for diagnosis and postoperative monitoring of LC.
FUNDING
This study was supported by CAMS Innovation Fund for Medical Sciences, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, Beijing Natural Science Foundation and Peking University People's Hospital.
Topics: Humans; Multiomics; Neoplasm, Residual; Lung Neoplasms; Genomics; Cell-Free Nucleic Acids; Biomarkers, Tumor
PubMed: 37027928
DOI: 10.1016/j.ebiom.2023.104553 -
Biomolecules Jan 2021Progression from localized to metastatic disease requires cancer cells spreading to distant organs through the bloodstream. Only a small proportion of these circulating... (Review)
Review
Progression from localized to metastatic disease requires cancer cells spreading to distant organs through the bloodstream. Only a small proportion of these circulating tumor cells (CTCs) survives dissemination due to anoikis, shear forces and elimination by the immune system. However, all metastases originate from CTCs capable of surviving and extravasating into distant tissue to re-initiate a tumor. Metastasis initiation is not always immediate as disseminated tumor cells (DTCs) may enter a non-dividing state of cell dormancy. Cancer dormancy is a reversible condition that can be maintained for many years without being clinically detectable. Subsequently, late disease relapses are thought to be due to cancer cells ultimately escaping from dormant state. Cancer dormancy is usually associated with minimal residual disease (MRD), where DTCs persist after intended curative therapy. Thus, MRD is commonly regarded as an indicator of poor prognosis in all cancers. In this review, we examine the current understanding of MRD and immunity during cancer progression to metastasis and discuss clinical perspectives for oncology.
Topics: Animals; Apoptosis; Clinical Trials as Topic; Disease Progression; Gene Expression Regulation, Neoplastic; Humans; Immune System; Immunotherapy; Medical Oncology; Mice; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm, Residual; Neoplasms; Neoplastic Cells, Circulating; Prognosis; Signal Transduction
PubMed: 33498251
DOI: 10.3390/biom11020130 -
Neurosurgery Clinics of North America Jan 2021This article discusses intraoperative imaging techniques used during high-grade glioma surgery. Gliomas can be difficult to differentiate from surrounding tissue during... (Review)
Review
This article discusses intraoperative imaging techniques used during high-grade glioma surgery. Gliomas can be difficult to differentiate from surrounding tissue during surgery. Intraoperative imaging helps to alleviate problems encountered during glioma surgery, such as brain shift and residual tumor. There are a variety of modalities available all of which aim to give the surgeon more information, address brain shift, identify residual tumor, and increase the extent of surgical resection. The article starts with a brief introduction followed by a review of with the latest advances in intraoperative ultrasound, intraoperative MRI, and intraoperative computed tomography.
Topics: Brain Neoplasms; Glioma; Humans; Monitoring, Intraoperative; Neoplasm, Residual; Neuronavigation; Neurosurgical Procedures
PubMed: 33223025
DOI: 10.1016/j.nec.2020.09.003