Importance: Human papillomavirus (HPV)–positive oropharyngeal squamous cell carcinoma has an overall favorable prognosis, yet a subset of patients will experience devastating disease recurrence. Current surveillance standards for detection of recurrent disease are imperfect. There is growing interest in improving detection of recurrent disease through the use of plasma-based assays able to detect circulating tumor HPV DNA.Observations: Although most circulating tumor HPV DNA assays remain in the research domain, the circulating tumor tissue–modified viral HPV DNA assay became commercially available in the United States in early 2020 and has been increasingly used in the clinical setting. With the rapidly increasing incidence of HPV-positive oropharyngeal squamous cell carcinoma and concomitant expansion of biomarker capabilities for this disease, it is critical to reexamine current posttreatment surveillance practices and to determine whether emerging technologies may be used to improve outcomes for a growing survivor population. However, caution is advised; it is not yet known whether biomarker-based surveillance is truly beneficial, and as is true with any intervention, it has the capacity to cause harm.Conclusions and Relevance: Using Margaret Pepe’s classic 5 phases of biomarker development for early detection of cancer as a framework, this article reviews 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. Specific attention is paid to the commercially available tumor tissue–modified viral HPV DNA assay, given its increasing clinical use. This review may serve as a road map for future research and a guide for clinicians considering its adoption in practice. Enrollment of patients into clinical trials incorporating biomarker-based surveillance should be prioritized.

The discovery of the SARS-CoV-2 virus in 2019 and the ensuing global COVID-19 pandemic led to unprecedented disruptions across all parts of society. Yet while the world focused on the threat posed by a novel respiratory virus, the threat of cancer remained ever present, and any associated reduction in observed cancer incidence during this period is of particular concern. Unlike other population health outcomes studied, a decline in new cancer diagnoses in 2020 does not indicate that cancer occurrence in the US decreased, but rather that new cancers were undetected.^1-3 The longer cancer exists undetected, the greater the risk of tumor progression and the lower the chances of survival and other positive outcomes for patients.⁴

The association of COVID-19 pandemic–related disruptions with the timely diagnosis of US cancer cases in 2020 has been well documented.^1-5 In a previous study, we estimated that rates of all-sites cancer incidence were 13.0% lower than expected during the first 10 months of the pandemic (March-December 2020), with even greater differences seen among certain cancer sites, stages at diagnosis, and population subgroups.¹ If, and to what extent, cancer rates recovered in 2021 is still unknown. In this study, we used observed cancer incidence rates from an authoritative collection of US cancer registries to assess the state of cancer diagnoses during the second year of the COVID-19 pandemic and better understand the lasting association of COVID-19 with cancer burden in the US.

APOBEC is a mutagenic source in human papillomavirus (HPV)-mediated malignancies, including HPV+ oropharyngeal squamous cell carcinoma (HPV + OPSCC), and in HPV genomes. It is unknown why APOBEC mutations predominate in HPV + OPSCC, or if the APOBEC-induced mutations observed in both human cancers and HPV genomes are directly linked. We performed sequencing of host somatic exomes, transcriptomes, and HPV16 genomes from 79 HPV + OPSCC samples, quantifying APOBEC mutational burden and activity in both host and virus. APOBEC was the dominant mutational signature in somatic exomes. In viral genomes, there was a mean of five (range 0–29) mutations per genome. The mean of APOBEC mutations in viral genomes was one (range 0–5). Viral APOBEC mutations, compared to non-APOBEC mutations, were more likely to be low-variant allele fraction mutations, suggesting that APOBEC mutagenesis actively occurrs in viral genomes during infection. HPV16 APOBEC-induced mutation patterns in OPSCC were similar to those previously observed in cervical samples. Paired host and viral analyses revealed that APOBEC-enriched tumor samples had higher viral APOBEC mutation rates (p = 0.028), and APOBEC-associated RNA editing (p = 0.008), supporting the concept that APOBEC mutagenesis in host and viral genomes is directly linked and occurrs during infection. Using paired sequencing of host somatic exomes, transcriptomes, and viral genomes, we demonstrated for the first-time definitive evidence of concordance between tumor and viral APOBEC mutagenesis. This finding provides a missing link connecting APOBEC mutagenesis in host and virus and supports a common mechanism driving APOBEC dysregulation.