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Chantre-Justino M, Alves G, Delmonico L. Clinical applications of liquid biopsy in HPV‐negative and HPV‐positive head and neck squamous cell carcinoma: advances and challenges. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2022; 3:533-552. [PMID: 36071985 PMCID: PMC9446158 DOI: 10.37349/etat.2022.00099] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 06/22/2022] [Indexed: 12/02/2022] Open
Abstract
Head and neck squamous cell carcinomas (HNSCCs) represent the most common epithelial tumors that arise from mucosa of the oral cavity, pharynx, and larynx. The development of HNSCCs is usually associated with tobacco use, alcohol consumption, and human papillomavirus (HPV) infection. Most HNSCCs are diagnosed in advanced states, leading to a worse clinical outcome. Screening tests based on potential biomarkers associated with HNSCCs could improve this scenario. Liquid biopsy has emerged as a promising area of cancer investigation, offering a minimally invasive approach to track circulating biomarkers in body fluids that could potentially contribute to the diagnosis, predict prognosis, and monitor response to treatment. This review will discuss translational studies describing the clinical applications of liquid biopsy in HPV-negative and HPV-positive HNSCCs focused on circulating nucleic acids [cell-free DNA (cfDNA) and cell-free RNA (cfRNA)], circulating tumor cells (CTCs), and extracellular vesicles (EVs), which can be found in plasma, serum, and saliva.
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Affiliation(s)
- Mariana Chantre-Justino
- 1Research Division, National Institute of Traumatology and Orthopaedics (INTO), Rio de Janeiro 20940-070, Brazil 2Circulating Biomarkers Laboratory, Pathology Department, Faculty of Medical Sciences, Rio de Janeiro State University, Rio de Janeiro 20550-170, Brazil
| | - Gilda Alves
- 2Circulating Biomarkers Laboratory, Pathology Department, Faculty of Medical Sciences, Rio de Janeiro State University, Rio de Janeiro 20550-170, Brazil
| | - Lucas Delmonico
- 3Oncoclínicas Precision Medicine, Vila Nova Conceição, São Paulo 04513-020, Brazil
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Bueno de Oliveira T, Camila Braun A, Ribaldo Nicolau U, Ali Abdallah E, da Silva Alves V, Hugo Fonseca de Jesus V, Fernando Calsavara V, Paulo Kowaslki L, Domingos Chinen LT. Prognostic impact and potential predictive role of baseline circulating tumor cells in locally advanced head and neck squamous cell carcinoma. Oral Oncol 2021; 121:105480. [PMID: 34403888 DOI: 10.1016/j.oraloncology.2021.105480] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 07/28/2021] [Accepted: 08/02/2021] [Indexed: 12/24/2022]
Abstract
OBJECTIVES The prognostic impact of circulating tumor cells (CTCs) or circulating tumor microemboli (CTM) in locally advanced head and neck squamous cell carcinoma (LA-HNSCC) is yet to be determined, with conflicting results in previous trials. The role of induction chemotherapy (ICT) in the management of LA-HNSCC is controversial with no predictive biomarkers to guide treatment strategy in this scenario. The aim of this trial is to determine the prognostic impact of CTCs and CTM, their biomarkers expression by immunocytochemistry (ICC), and its potential role as predictors of ICT benefit in LA-HNSCC. MATERIALS AND METHODS Prospective study, with newly diagnosed stage III/IV non-metastatic LA-HNSCC patients treated with curative intent. Blood samples analyzed for CTCs and CTM before treatment using the ISET method. RESULTS A total of 83 patients were included. CTCs counts were an independent prognostic factor for overall survival (OS; HR: 1.17; 95 %CI: 1.05-1.31; p = 0.005) and progression free survival (PFS; HR:1.14; 95 %CI: 1.03-1.26; p = 0.007). Using the Lausen and Schumacher technique, 2.8 CTCs/mL for OS and 3.8 CTCs/mL for PFS were defined as the best cut-offs. CTM were detected in 27.7% of patients, correlating with worse PFS (HR = 2.70; IC95%: 1.30-5.58; p = 0.007). MRP-7 expression in CTM correlated with worse OS (HR = 3.49; 95 %CI: 1.01-12.04; p = 0.047) and PFS (HR = 3.62; 95 %CI: 1.08-12.13; p = 0.037). CTCs counts were predictive of complete response to treatment (OR = 0.74; 95 %CI: 0.58-0.95; p = 0.022) and high counts (cut-off 3.8/mL) and CTM were potential predictors of ICT benefit. CONCLUSION CTCs/CTM had significant prognostic impact and potential role as predictors of ICT benefit in LA-HNSCC.
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Affiliation(s)
| | | | | | | | | | | | | | - Luiz Paulo Kowaslki
- Head and Neck Surgery and Otorhinolaryngology Department - AC Camargo Cancer Center, Brazil
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Tinhofer I, Staudte S. Circulating tumor cells as biomarkers in head and neck cancer: recent advances and future outlook. Expert Rev Mol Diagn 2018; 18:897-906. [DOI: 10.1080/14737159.2018.1522251] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Affiliation(s)
- Ingeborg Tinhofer
- Department of Radiooncology and Radiotherapy, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
- German Cancer Research Center (DKFZ), Heidelberg, and German Cancer Consortium (DKTK) partner site Berlin, Berlin, Germany
| | - Stephanie Staudte
- Department of Radiooncology and Radiotherapy, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
- German Cancer Research Center (DKFZ), Heidelberg, and German Cancer Consortium (DKTK) partner site Berlin, Berlin, Germany
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McMullen KP, Chalmers JJ, Lang JC, Kumar P, Jatana KR. Circulating tumor cells in head and neck cancer: A review. World J Otorhinolaryngol Head Neck Surg 2016; 2:109-116. [PMID: 29204555 PMCID: PMC5698518 DOI: 10.1016/j.wjorl.2016.05.003] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Accepted: 05/12/2016] [Indexed: 11/25/2022] Open
Abstract
Carcinoma of the head and neck represents 3.5% of all cancers, and the vast majority of these tumors are squamous cell carcinoma (HNSCC). With a stable overall survival rate of 50% among all stages, there is continued interested in developing measures for early detection and disease aggressiveness. Circulating tumor cells (CTCs) have been identified as a potential marker for early metastatic disease, response to treatment, and surveillance in head and neck squamous cell carcinoma. In this article, techniques of CTC detection, applications of CTC technology, and outcomes of HNSCC patients will be discussed.
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Affiliation(s)
- Kyle P McMullen
- Department of Otolaryngology-Head and Neck Surgery, Wexner Medical Center at Ohio State University, Columbus, OH, USA
| | - Jeffrey J Chalmers
- William G. Lowrie Department of Chemical and Biomolecular Engineering, Ohio State University, Columbus, OH, USA
| | - Jas C Lang
- Department of Otolaryngology-Head and Neck Surgery, Wexner Medical Center at Ohio State University, Columbus, OH, USA
| | - Pawan Kumar
- Department of Otolaryngology-Head and Neck Surgery, Wexner Medical Center at Ohio State University, Columbus, OH, USA
| | - Kris R Jatana
- Department of Otolaryngology-Head and Neck Surgery, Wexner Medical Center at Ohio State University, Columbus, OH, USA.,Department of Pediatric Otolaryngology-Head & Neck Surgery, Nationwide Children's Hospital, Columbus, OH, USA
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Wikner J, Gröbe A, Pantel K, Riethdorf S. Squamous cell carcinoma of the oral cavity and circulating tumour cells. World J Clin Oncol 2014; 5:114-124. [PMID: 24829858 PMCID: PMC4014783 DOI: 10.5306/wjco.v5.i2.114] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2013] [Revised: 02/10/2014] [Accepted: 03/17/2014] [Indexed: 02/06/2023] Open
Abstract
Due to a lack of substantial improvement in the outcome of patients suffering from oral squamous cell carcinoma (OSCC) during the past decades, current staging methods need to be revised. This disease is associated with poor survival rates despite considerable advances in diagnosis and treatment. The early detection of metastases is an important indicator of survival, prognosis and relapse. Therefore, a better understanding of the mechanisms underlying metastasis is crucial. Exploring alternative measures apart from common procedures is needed to identify new prognostic markers. Similar to previous findings predominantly for other solid tumours, recently published studies demonstrate that circulating tumour cells (CTCs) and disseminated tumour cells (DTCs) might serve as prognostic markers and could supplement routine staging in OSCC. Thus, the detection of CTCs/DTCs is a promising tool to determine the individual need for therapeutic intervention. Encouraging results and new approaches point to the future use of targeted therapies for OSCC, an exceedingly heterogeneous subgroup of head and neck cancer. This review focuses on summarising technologies currently used to detect CTCs/DTCs. The translational relevance for OSCC is highlighted. The inherent challenges in detecting CTCs/DTCs will be emphasised.
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Langevin SM, Houseman EA, Accomando WP, Koestler DC, Christensen BC, Nelson HH, Karagas MR, Marsit CJ, Wiencke JK, Kelsey KT. Leukocyte-adjusted epigenome-wide association studies of blood from solid tumor patients. Epigenetics 2014; 9:884-95. [PMID: 24671036 DOI: 10.4161/epi.28575] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Epigenome-wide studies of DNA methylation using blood-derived DNA from cancer patients are complicated by the heterogeneity of cell types within blood and the associated cell lineage specification of DNA methylation signatures. Here, we applied a novel set of analytic approaches to assess the association between cancer case-status and DNA methylation adjusted for leukocyte variation using blood specimens from three case-control cancer studies (bladder: 223 cases, 205 controls; head and neck: 92 cases, 92 controls; and ovarian: 131 cases, 274 controls). Using previously published data on leukocyte-specific CpG loci and a recently described approach to deconvolute subject-specific blood composition, we performed an epigenome-wide analysis to examine the association between blood-based DNA methylation patterns and each of the three aforementioned solid tumor types adjusted for cellular heterogeneity in blood. After adjusting for leukocyte profile in our epigenome-wide analysis, the omnibus association between case-status and methylation was significant for all three studies (bladder cancer: P = 0.047; HNSCC: P = 0.013; ovarian cancer: P = 0.0002). Subsequent analyses revealed that CpG sites associated with cancer were enriched for transcription factor binding motifs involved with cancer-associated pathways. These results support the existence of cancer-associated DNA methylation profiles in the blood of solid tumor patients that are independent of alterations in normal leukocyte distributions. Adoption of the methods developed here will make it feasible to rigorously assess the influence of variability of normal leukocyte profiles when investigating cancer related changes in blood-based epigenome-wide association studies.
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Affiliation(s)
- Scott M Langevin
- Department of Environmental Health; University of Cincinnati College of Medicine; Cincinnati, OH USA; Department of Epidemiology; Brown University; Providence, RI USA
| | - E Andres Houseman
- Department of Biostatistics; Oregon State University College of Public Health and Human Sciences; Corvallis, OR USA
| | - William P Accomando
- Department of Pathology & Laboratory Medicine; Brown University; Providence, RI USA
| | - Devin C Koestler
- Department of Community and Family Medicine; Section of Biostatistics and Epidemiology; Dartmouth Medical School; Lebanon, NH USA
| | - Brock C Christensen
- Department of Community and Family Medicine; Section of Biostatistics and Epidemiology; Dartmouth Medical School; Lebanon, NH USA; Department of Pharmacology and Toxicology; Dartmouth Medical School; Lebanon, NH USA
| | - Heather H Nelson
- Division of Epidemiology and Community Health; University of Minnesota Masonic Cancer Center; Minneapolis, MN USA
| | - Margaret R Karagas
- Department of Community and Family Medicine; Section of Biostatistics and Epidemiology; Dartmouth Medical School; Lebanon, NH USA
| | - Carmen J Marsit
- Department of Community and Family Medicine; Section of Biostatistics and Epidemiology; Dartmouth Medical School; Lebanon, NH USA; Department of Pharmacology and Toxicology; Dartmouth Medical School; Lebanon, NH USA
| | - John K Wiencke
- Department of Neurological Surgery; University of California San Francisco; San Francisco, CA USA
| | - Karl T Kelsey
- Department of Epidemiology; Brown University; Providence, RI USA; Department of Pathology & Laboratory Medicine; Brown University; Providence, RI USA
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Gröbe A, Blessmann M, Hanken H, Friedrich RE, Schön G, Wikner J, Effenberger KE, Kluwe L, Heiland M, Pantel K, Riethdorf S. Prognostic Relevance of Circulating Tumor Cells in Blood and Disseminated Tumor Cells in Bone Marrow of Patients with Squamous Cell Carcinoma of the Oral Cavity. Clin Cancer Res 2013; 20:425-33. [DOI: 10.1158/1078-0432.ccr-13-1101] [Citation(s) in RCA: 94] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Circulating tumor cells in head and neck cancer: clinical impact in diagnosis and follow-up. Eur Arch Otorhinolaryngol 2013; 271:15-21. [DOI: 10.1007/s00405-013-2391-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2012] [Accepted: 01/29/2013] [Indexed: 01/30/2023]
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Tsai JH, Donaher JL, Murphy DA, Chau S, Yang J. Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell 2012; 22. [PMID: 23201165 PMCID: PMC3522773 DOI: 10.1016/j.ccr.2012.09.022] [Citation(s) in RCA: 850] [Impact Index Per Article: 65.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Epithelial-mesenchymal transition (EMT) is implicated in converting stationary epithelial tumor cells into motile mesenchymal cells during metastasis. However, the involvement of EMT in metastasis is still controversial, due to the lack of a mesenchymal phenotype in human carcinoma metastases. Using a spontaneous squamous cell carcinoma mouse model, we show that activation of the EMT-inducing transcription factor Twist1 is sufficient to promote carcinoma cells to undergo EMT and disseminate into blood circulation. Importantly, in distant sites, turning off Twist1 to allow reversion of EMT is essential for disseminated tumor cells to proliferate and form metastases. Our study demonstrates in vivo the requirement of "reversible EMT" in tumor metastasis and may resolve the controversy on the importance of EMT in carcinoma metastasis.
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Affiliation(s)
- Jeff H. Tsai
- Department of Pharmacology, University of California, San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, CA, 92093-0636
| | - Joana Liu Donaher
- Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA, 02142
| | | | - Sandra Chau
- Department of Pharmacology, University of California, San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, CA, 92093-0636
| | - Jing Yang
- Department of Pharmacology, University of California, San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, CA, 92093-0636
- Department of Pediatrics, University of California, San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, CA, 92093-0636
- To whom correspondence should be addressed:
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Xu Y, Zhao X, Guan M, Li B, Zhou Y, Zhou F. Determination of lymph node micrometastases in patients with supraglottic carcinoma. Acta Otolaryngol 2007; 127:1188-95. [PMID: 17851895 DOI: 10.1080/00016480701200327] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
CONCLUSIONS The frequency of loss of heterozygosity (LOH) at D9S 171 microsatellite locus on 9p21 may serve as an available method to evaluate occult micrometastases in laryngeal squamous cell carcinoma. High frequency of LOH was associated with a decreased probability of survival time. OBJECTIVE To explore an available and sensitive method to detect cervical lymph node micrometastases in patients with laryngeal squamous cell carcinoma, the frequency of LOH at D9S171 microsatellite locus on 9p21 was studied. PATIENTS AND METHODS Twenty samples from supraglottic cancer and 182 lymph nodes from neck dissections were examined by LOH comparing immunohistochemical (IHC) staining using cytokeratin 19 (CK19), and hematoxylin and eosin (H&E) staining. The frequency of lymph node metastasis and the clinical relevance were analysed. RESULTS The frequency of LOH was 37.4% of lymph nodes and all of the primary tumors. Occult micrometastases were present in 9 of 20 cases; 23.6% of lymph nodes were positive for CK19 by IHC; 16.5% of lymph nodes were positive by H&E. There was a highly significant difference among the three methods. The highest rate of positive lymph nodes was at level II of the neck. There was a highly significant difference between overall survival time and lymph node metastasis with LOH and CK19 analysis.
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Affiliation(s)
- Yaping Xu
- Department of Otorhinolaryngology, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, 88# Jie Fang Road, Hangzhou, 310009, Zhejiang, China.
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