International Journal of Radiation Oncology*Biology*Physics
Biology ContributionMonitoring of Circulating Tumor Cells and Their Expression of EGFR/Phospho-EGFR During Combined Radiotherapy Regimens in Locally Advanced Squamous Cell Carcinoma of the Head and Neck
Introduction
The presence of circulating tumor cells (CTCs) in peripheral blood of patients with solid tumors has previously been associated with a more aggressive disease, an increased risk of local or distant metastasis and reduced disease-free and overall survival 1, 2, 3. In a recent study using a multicolor flow cytometry protocol for detection and molecular characterization of CTCs their presence was detected in 43% of locally advanced, inoperable squamous cell carcinoma of the head and neck (SCCHN) cases (4). Their detection was independent from T stage and tumor volume but was significantly associated with nodal disease (4).
Beside the prognostic value of CTC detection before treatment, monitoring of CTCs during and after therapy has also been proposed as a potential diagnostic tool allowing adjustment of treatment in cases of inadequate treatment and nonresponding tumors. Indeed, a significant correlation between treatment-related changes in CTC numbers or their persistence after treatment with PFS and OS in metastatic colorectal (3) and prostate cancer (5) and with relapse-free survival in nonmetastatic breast cancer (6) has been demonstrated. The previous analysis of blood samples from SCCHN patients collected before treatment and during the course of concurrent chemoradiation revealed that despite a reduction in their frequency, CTCs persisted during treatment in 20% of cases (4). We extended the analysis of CTCs in SCCHN in the current study and evaluated their response to different treatment schedules: induction chemotherapy followed by radiotherapy plus cetuximab treatment or concurrent chemoradiation. The integration of the CTC analysis in a multicenter clinical trial performed under the leadership of our clinical department allowed us to collect blood samples at predefined time points: before therapy and after completion of the individual treatment regimens (induction chemotherapy, radiotherapy plus cetuximab, concurrent chemoradiation).
Taking into account the important role of EGFR signaling in metastasis and for treatment efficacy (7) and its relevance as therapeutic target for increasing the efficacy of radiotherapy and chemotherapy in SCCHN 8, 9, we assessed the influence of treatment on the detection rate of CTCs and also determined the changes in expression of EGFR and its phosphorylated form (pEGFR) in CTCs during the course of treatment.
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Patients
This study was approved by the local ethics committee. Patients with locally advanced stage IVA/B SCCHN (n=38) participating in an ongoing multicenter randomized phase II clinical trial were included in this translational research program. The clinical trial is evaluating the feasibility and efficacy of induction chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (TPF) followed by radiotherapy plus cetuximab compared with concurrent chemoradiation with cisplatin and 5-FU. Of the 38
Basal CTC numbers and their changes during treatment
For detection of CTCs in blood samples from SCCHN patients the previously described multicolor flow cytometry protocol for detection of EpCAM+cytokeratin+CD45− cells was used (4). Before treatment, ≥1 CTC per 3.75 mL blood were detected in 9 of 31 samples (29%, Figure 1A). The frequency of CTC detection was not dependent on tumor localization (data not shown). The gating strategy for detection of EpCAM+cytokeratin+CD45− CTCs and a representative result for a CTC+ sample with 2 CTCs detected in
Discussion
Although the benefit of radiotherapy in tumor therapy is well established, a relevant number of previous studies also suggest that radiation of the primary tumor might not only lead to growth inhibition and tumor cell killing but also increase the migratory and invasive potential of surviving radioresistant tumor cell subclones 10, 11. Indeed, a significant increase in the formation of lung metastases has been reported for mice bearing lung carcinoma xenografts that were treated with
References (20)
- et al.
Circulating tumor cells, disease progression, and survival in metastatic breast cancer
N Engl J Med
(2004) - et al.
Circulating tumor cell number and prognosis in progressive castration-resistant prostate cancer
Clin Cancer Res
(2007) - Cohen SJ PC, Iannotti N, Saidman BH, et al. Relationship of circulating tumor cells to tumor response, progression-free...
- et al.
The presence of circulating tumor cells (CTCs) correlates with lymph node metastasis in nonresectable squamous cell carcinoma of the head and neck region (SCCHN)
Ann Oncol
(2011) - et al.
Circulating tumour cells as prognostic markers in progressive, castration-resistant prostate cancer: a reanalysis of IMMC38 trial data
Lancet Oncol
(2009) - et al.
An increase in cell number at completion of therapy may develop as an indicator of early relapse: quantification of circulating epithelial tumor cells (CETC) for monitoring of adjuvant therapy in breast cancer
J Cancer Res Clin Oncol
(2008) - et al.
Targeting epidermal growth factor receptor and SRC pathways in head and neck cancer
Semin Oncol
(2008) - et al.
Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck
N Engl J Med
(2006) - et al.
Platinum-based chemotherapy plus cetuximab in head and neck cancer
N Engl J Med
(2008) - et al.
Radiation therapy to a primary tumor accelerates metastatic growth in mice
Cancer Res
(2001)
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Oral squamous cell carcinoma
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2022, International Journal of Oral and Maxillofacial SurgeryCitation Excerpt :Metabolic analysis of CTCs holds promise as a tool to monitor treatment efficacy and as a guide to direct cancer therapies towards individualized metabolic targets71,84. Changes in CTC numbers and CTC expression of EGFR and PD-L1 on CTCs have been used to measure treatment effects in HNSCC73,85. In an exploratory multicentre trial, early changes in EGFR expression by CTCs was predictive of the response to chemotherapy86.
Clinicopathological and prognostic significance of circulating tumor cells in head and neck squamous cell carcinoma: A systematic review and meta-analysis
2020, Oral OncologyCitation Excerpt :Wang et al also pointed that CTCs count changes could be an independent prognostic factor in patients with locally advanced HNSCC during concurrent chemoradiotherapy [47]. Moreover, the increased number of CTCs and the increased expression of epidermal growth factor receptor (EGFR)/ phosphorylated EGFR (pEGFR) can promote the systemic spread of tumor cells in HNSCC patients [48]. There also are some limitations in our meta-analysis.
Circulating Tumor Cells and Implications of the Epithelial-to-Mesenchymal Transition
2018, Advances in Clinical ChemistryA FACS-based novel isolation technique identifies heterogeneous CTCs in oral squamous cell carcinoma
2024, Frontiers in Oncology
This study was supported by a research grant from Merck Pharma GmbH, Germany (to IT and UK) and the Berliner Krebsgesellschaft (to IT).
Merck Serono has reviewed the publication. The views and opinions described in the publication do not necessarily reflect those of Merck Serono.
Conflict of interest: Dr Tinhofer has received a research grant and support for travel to meetings from Merck Pharma GmbH. Dr Keilholz has received a research grant and support for travel to meetings, for consultancy and lectures from Merck Serono and Sanofi-Aventis. Dr Stromberger was supported for travels to meetings by Merck Pharma GmbH. Dr Budach has received honorarium and support for travel to meetings from Merck Serono and Sanofi-Aventis.