Oropharyngeal squamous cell carcinoma (OPSCC), a relatively new disease, is growing in incidence and changing in its demographics. Two decades ago, OPSCC was largely associated with patients with a history of heavy tobacco and alcohol use. Today it is primarily seen in patients with human papillomavirus (HPV).

“HPV-positive OPSCC has become an epidemic and is more common today than cervical cancer,” says Eleni M. Rettig, MD, associate surgeon, Division of Otolaryngology-Head and Neck Surgery, Brigham and Women’s Hospital. “Although most cases have a favorable prognosis, some patients experience recurrence. As we learn more about this disease, we understand that we need to develop better surveillance standards for detecting recurrence.”

Dr. Rettig says she’s particularly excited about the emergence of plasma-based assays to detect circulating tumor HPV DNA (ctHPVDNA) post-treatment. She recently published a review of biomarker-based cancer surveillance, including the use of a recently commercialized ctHPVDNA assay, in JAMA Oncology.

Identifying Knowledge Gaps and Research Priorities

Using Margaret Pepe’s classic five phases of biomarker development for early detection of cancer as a framework, the JAMA Oncology review covers the current state of knowledge, highlights existing knowledge gaps, and suggests research that should be prioritized to understand the association between biomarker-based surveillance and patient outcomes. The review focuses on the commercially available ctHPVDNA assay because of its increasing clinical use across the United States.

According to the review, work for Phase 1, preclinical exploratory studies is largely complete. However, the marker is not anatomically site-specific because ctHPVDNA may also derive from HPV-associated anogenital cancer. As noted in the review, current Phase 2 evidence for clinical assay development and validation suggests ctHPVDNA assays have consistently high sensitivity and specificity. However, questions remain around the factors that affect assay sensitivity, the specificity of the assay, and the ability to reproduce the assay.

The review establishes that current evidence for Phase 3, the biomarker’s capability to detect preclinical disease as a function of time, is based on just four published studies and raises questions around what constitutes a positive test result, the test’s sensitivity for recurrence, and how sensitivity is associated with patient- and disease-related factors.

Neither Phase 4 prospective surveillance studies nor Phase 5 cancer control studies existed at the time of the review, leading Dr. Rettig and co-authors to call for rigorous, timely, and epidemiologically sound research to prudently implement ctHPVDNA testing for surveillance in a way that maximizes its potential benefits while mitigating unintended harms.

“The review can serve as a roadmap for future research and a guide for clinicians considering its adoption in practice,” Dr. Rettig says. “However, because the clinical use of this surveillance method is so new, there is still a lot we don’t know, and caution should be urged as we work to define how best to use these biomarkers.

“One of the key takeaways is the test’s sensitivity levels, which appear to be around 90% for newly diagnosed disease and 85% for recurrent disease. This should guide clinicians to understand that absence of a positive blood test does not necessarily mean absence of disease. Therefore, it remains sensible to biopsy imaged lesions and pay attention to concerning symptoms like throat pain and neck lumps.”

Pushing to Incorporate ctHPVDNA Testing in Surveillance Paradigms

Physician-scientists at the Brigham are actively working to fill in the knowledge gaps that remain before ctHPVDNA testing is incorporated as a standard of care in surveillance paradigms. In April 2023, Dr. Rettig completed accruing data in a three-year, first-of-its-kind prospective clinical trial of over 150 patients and plans to publish her findings in 2024. She is using the same assay in studies of oral markers to see if they are useful as a complement to plasma markers.

Dana-Farber Brigham Cancer Center colleagues in Radiation Oncology and Medical Oncology are currently conducting the ReACT study, in which they are evaluating radiation treatment modifications based on real-time changes in ctHPVDNA. According to Dr. Rettig, the ctHPVDNA assay may also prove useful in disease diagnosis, including in early diagnosis. She recently published a study in Oral Oncology indicating that the test is feasible and holds the potential as a diagnostic aid alongside standard clinical workup.

“The Brigham is one of the first academic medical centers to start studying and using this potentially powerful tool,” Dr. Rettig says. “Our work will be influential in terms of how biomarker-guided surveillance is approached in this disease. We take seriously our responsibility to study it thoroughly, make sure it is being used appropriately, and share evidence with the wider otolaryngology field.”