Abstract
ObjectivesHuman papillomavirus-related oropharyngeal squamous cell carcinoma (HPV+ OPSCC) is increasing in incidence. Although HPV+ OPSCC has favorable prognosis, 10 to 25% of HPV+ OPSCCs eventually recur. We sought to evaluate the feasibility of detection of HPV16 E6/E7 expression in Circulating Tumor Cells (CTCs) and its utility as a prognostic tool in HPV16-associated OPSCC.Materials and methodsWe developed a highly sensitive RT-qPCR assay for HPV mRNA expression in EpCAM(+) CTCs. In 22 patients with early stage and locally advanced OPSCC we evaluated HPV16 E6/E7 expression in the EpCAM(+) CTC fraction at baseline and at the end of concurrent chemoradiotherapy. HPV status in pre-therapy formalin-fixed paraffin-embedded (FFPE) tumor biopsies was assessed by p16 immunohistochemistry and polymerase chain reaction (PCR) and double positives were subjected to Real-time qPCR assay for detection of HPV16, 18 and 31 types.ResultsFourteen of 22 OPSCC (63.6%) were HPV DNA+/p16+. Among HPV+/p16+ patients, 10 patients (71.4%) were HPV16 DNA+. HPV16 E6/E7(+) CTCs were detected in 3 of 10 patients (30%) at baseline and 4 of 9 patients (44.4%) at the end-of-treatment, all of which were p16+/HPV16 DNA+. Survival analysis showed a significantly higher risk for disease relapse (p = 0.001) and death (p = 0.005) in patients with HPV16 E6/E7(+) baseline CTCs.ConclusionDetection of HPV E6/E7(+) CTCs might be a useful noninvasive test in liquid biopsy samples for determination of a clinically relevant HPV infection in HPV+ OPSCC. Combined interpretation of HPV E6/E7(+) CTCs with UICC staging data may lead to alteration of risk definition of patient subsets, with improved risk discrimination in early-stage disease.
Highlights
Human papillomavirus (HPV) is a well-recognized etiologic factor in oropharyngeal squamous cell carcinoma (OPSCC), and it has been demonstrated that seropositivity for antibodies against HPV16 oncogenic proteins E6 /E7 is present in prediagnostic samples of patients with OPSCC many years before diagnosis [1]
We developed a highly sensitive RT-qPCR assay for HPV mRNA expression in EpCAM(+) Circulating Tumor Cells (CTCs)
HPV status in pre-therapy formalin-fixed paraffin-embedded (FFPE) tumor biopsies was assessed by p16 immunohistochemistry and polymerase chain reaction (PCR) and double positives were subjected to Real-time qPCR assay for detection of HPV16, 18 and 31 types
Summary
Human papillomavirus (HPV) is a well-recognized etiologic factor in oropharyngeal squamous cell carcinoma (OPSCC), and it has been demonstrated that seropositivity for antibodies against HPV16 oncogenic proteins E6 /E7 is present in prediagnostic samples of patients with OPSCC many years before diagnosis [1]. It is commonly accepted that HPV-associated oropharyngeal tumors (HPV+ OPSCC) comprise a distinct disease entity, showing a distinct clinical behavior and better survival outcomes [1]. Studies have shown that CTCs in the peripheral blood could be a valuable tool for real-time monitoring of tumor status, predicting potential metastasis and recurrence, monitoring treatment efficacy and predicting survival of cancer patients [6]. HPV-E6/E7 oncogene expressing CTCs could be chosen as a unique biomarker for detection of viable tumor cells in the peripheral blood of OPSCC patients with transcriptionally active HPV infection
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