Abstract
Despite the rising incidence of human papillomavirus related (HPV+) oropharyngeal squamous cell carcinoma (OPSCC), treatment of metastatic disease remains palliative. Even with new treatments such as immunotherapy, response rates are low and can be delayed, while even mild tumor progression in the face of an ineffective therapy can lead to rapid death. Real-time biomarkers of response to therapy could improve outcomes by guiding early change of therapy in the metastatic setting. Herein, we developed and analytically validated a new droplet digital PCR (ddPCR)-based assay for HPV16 circulating tumor DNA (ctDNA) and evaluated plasma HPV16 ctDNA for predicting treatment response in metastatic HPV+ OPSCC. We found that longitudinal changes HPV16 ctDNA correlate with treatment response and that ctDNA responses are observed earlier than conventional imaging (average 70 days, range: 35–166). With additional validation in multi-site studies, this assay may enable early identification of treatment failure, allowing patients to be directed promptly toward clinical trials or alternative therapies.
Highlights
Head and neck squamous cell carcinomas (HNSCC) constitute 3–5% of all malignancies worldwide and there are approximately 600,000 newly diagnosed cases annually [1, 2]
We described our development and detailed analytical validation of a high-precision droplet digital PCR (ddPCR) assay to quantify plasma HPV16 circulating tumor DNA (ctDNA) and demonstrated through a prospective study that results of radiographic assessment and simultaneously collected HPV16 ctDNA were highly concordant
PCRbased ctDNA assays for EGFR genotyping in non-small cell lung cancer, and for KRAS genotyping in colorectal cancer have demonstrated clinical validity and have received regulatory approval in the United States and Europe [36,37,38]
Summary
Head and neck squamous cell carcinomas (HNSCC) constitute 3–5% of all malignancies worldwide and there are approximately 600,000 newly diagnosed cases annually [1, 2]. The only validated predictive biomarker is PD-L1, allowing for identification of patients who will have survival benefit with pembrolizumab versus chemotherapy as a first line treatment. Treatment response rates with currently available therapeutics remain low and no biomarker has been validated for dynamic response assessment or prediction of treatment benefit including PD-L1 [9,10,11]. As a result of the limited response rate, many patients experience significant progression leading to airway compromise and impaired functional status, rendering them unsuitable for further cancer directed therapy. A clear need exists for treatment individualization in R/M HNSCC, which necessitates identification of predictive biomarkers that can inform about response to therapy in real-time. A promising new biomarker that could meet these challenges, identifying patients not benefiting from therapy prior to traditional imaging, is circulating tumor DNA (ctDNA)
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