HPV16 DNA and Recurrence of Oropharyngeal Cancer

7–10 minutes

Could a simple mouth rinse help detect cancer recurrence? A groundbreaking study published in JAMA Oncology suggests that persistent HPV16 DNA found in oral rinses after treatment may be a strong predictor of oropharyngeal cancer recurrence.

Scientists are increasingly exploring the role of human papillomavirus (HPV) in predicting cancer outcomes. Now, a new study finds that detecting HPV16 DNA in oral rinse samples after treatment may signal a higher risk of cancer recurrence in patients with oropharyngeal carcinoma.

Persistent human papillomavirus type 16 (HPV16) DNA in posttreatment oral rinses is associated with a higher risk of recurrence of oropharyngeal carcinoma and worse survival, according to findings from four academic tertiary referral cancer centers in the U.S.

“We were happy to see that HPV16 DNA was rare after treatment for HPV-related oropharyngeal cancer,” Dr. Gypsyamber D’Souza from Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, told Reuters Health by email. “There are very few patients who recur after treatment for HPV-related oropharyngeal cancer, but we were surprised that all of the patients with persistent HPV16 DNA detected after treatment in our study recurred. The survival difference was dramatic.”

HPV infection underlies most oropharyngeal carcinomas in the U.S., with HPV16 DNA detected in up to two-thirds of HPV-associated oropharyngeal carcinoma (HPV-OPC) cases. Earlier studies suggested that HPV16 DNA detection in posttreatment oral rinses might be associated with disease recurrence.

Dr. D’Souza and colleagues evaluated the prognostic and diagnostic implications of HPV16 DNA detection in serially collected posttreatment oral rinses in a prospective multicenter study of 124 patients with HPV-OPC.

About half the patients (67/124, 54%) had HPV16 DNA detected in oral rinses at diagnosis, but only six (5%) had detectable HPV16 DNA in any posttreatment oral rinse (4% at nine to 12 months and 3% at 18 to 24 months after diagnosis), according to the July 30 JAMA Oncology online report.

Four patients had persistent detection of oral HPV16 DNA; one had oral HPV16 DNA detected at diagnosis that cleared temporarily but was again detected at 18 and 24 months, and one patient had no HPV16 DNA detected at diagnosis but had oral HPV16 DNA at 12 months that subsequently cleared.

Other high-risk-HPV DNA was detected in 27 patients at diagnosis and in 12 patients after treatment.

Persistent HPV16 DNA was associated with a 29.7-fold increased risk of recurrence and a 23.5-fold increased risk of death, compared with not having persistent HPV16 DNA.

All five patients with persistent HPV16 DNA developed recurrent disease (including local recurrence in three), and three of these patients died of disease. The patient with newly detected oral HPV16 DNA that subsequently cleared was alive without disease at last follow-up, 23 months after diagnosis.

Only four of 108 patients without persistent oral HPV16 DNA at 9 to 12 months experienced recurrence.

Persistent detection of other high-risk HPV types other than HPV16 was not associated with survival.

Coauthor Dr. Eleni Rettig, from Johns Hopkins Medical Institutions, told Reuters Health by email, “Testing for HPV16 DNA in oral rinses may soon become a part of routine surveillance after treatment for HPV-positive oropharyngeal cancers, in addition to clinical examination and imaging. However, more studies are needed before this test can be recommended.”

“For example, we need to understand when and how frequently to administer the test and what exactly we should do with a positive result,” Dr. Rettig explained. “We also cannot yet say for sure that all of the HPV16 DNA comes from tumor cells, and in some cases it might even come from a newly acquired oral HPV16 infection. For all of these reasons, right now this test should only be used in the research setting until we have more information from additional studies.”

“HPV-positive oropharyngeal cancer is a distinct clinical entity from other HPV-negative head and neck cancers,” Dr. Rettig concluded. “Although recommendations for management of HPV-positive disease do not currently differ, our understanding of this cancer is rapidly evolving so physicians should be on the look-out for changes to national treatment and surveillance guidelines in the future.”

“Human papillomavirus-specific biomarkers in oropharyngeal squamous cell carcinoma (OPSCC) may be used to improve clinical outcomes, and this pioneering study demonstrates an association between persistent oral HPV16 DNA detection and recurrence,” Dr. Julie E. Bauman and Dr. Robert L. Ferris, from the University of Pittsburgh, Pennsylvania, wrote in a related editorial. “Operating characteristics, including low sensitivity, low confidence in the (positive predictive value), and high (number needed to treat), preclude immediate clinical adoption.”

“Incorporation of an HPV-specific biomarker in future surveillance guidelines will require improved sensitivity, perhaps realized in combination with serologic markers such as HPV16 DNA or E6 antibodies; narrowing of the confidence interval for PPV by study of larger populations; and confirmation of significant lead time increasing the rate of successful surgical salvage,” they suggested.

“Important answers may be provided by Eastern Cooperative Oncology Group 3311 (NCT01898494), an ongoing prospective trial investigating transoral surgery followed by risk-adapted adjuvant therapy in HPV-positive OPSCC, in which serial oral rinse samples and serologic analyses are being collected in the context of standardized surveillance for the purpose of answering this question,” the editorial concluded. “Meanwhile, the high negative predictive value of oral rinse HPV16 DNA detection raises the promise of deintensifying surveillance visits and/or costly imaging, particularly if on a prospective trial.”

Dr. Michael Baumann, from the German Cancer Research Center, Heidelberg, Germany, recently confirmed that HPV16 DNA status strongly predicts locoregional control after treatment of locally advanced oropharyngeal carcinoma. He told Reuters Health by email that it’s too early to incorporate HPV16 DNA testing into the routine management of these patients.

“We need to compare this in the same patients with the value of standard follow-up investigation, including mirror exams and imaging,” he said. “From these data we have to ask ourselves the question which added value can we expect compared to what can be done today. As a further step we then have to find out whether we can salvage patients earlier and more efficiently with this information compared to without — which would be the ultimate predictive value.”

“Research is needed to find out what is the underlying mechanism of persistence, and can we make predictions already before we start treatment,” Dr. Baumann said. “This research may potentially further personalize treatment.”

The Johns Hopkins Richard Gelb Cancer Prevention Award, the Oral Cancer Foundation, and the National Institutes of Health supported this research. Five coauthors reported a number of disclosures.

What the Study Found

Researchers from Johns Hopkins Bloomberg School of Public Health, along with three other U.S. cancer centers, followed 124 patients with HPV-positive oropharyngeal carcinoma (HPV-OPC). They were particularly focused on the presence of HPV16 DNA—a strain responsible for most HPV-related oral cancers.

At diagnosis, about half the patients had detectable HPV16 DNA in their oral rinses. However, after treatment, only 5% had any detectable HPV16 DNA. Of those few patients, the outcomes were alarming: every single one experienced cancer recurrence, and most had significantly poorer survival outcomes.

Dr. Gypsyamber D’Souza, the study’s lead author, stated, “The survival difference was dramatic.” All five patients with persistent HPV16 DNA eventually developed recurrent disease—three of them died from it.

Why It Matters

HPV16 is a high-risk strain of the human papillomavirus, commonly known for causing cervical and other genital cancers. In recent years, it’s also been linked to a growing number of head and neck cancers, particularly in younger adults.

This study is significant because it shows that the continued presence of HPV16 DNA in oral rinses may act as an early warning system. Patients who had persistent HPV16 DNA were 29.7 times more likely to experience recurrence and 23.5 times more likely to die than those who didn’t.

That makes this simple rinse-and-test method a potentially powerful surveillance tool.

How It Could Change Cancer Follow-Up Care

Dr. Eleni Rettig, coauthor of the study, believes this test could eventually be part of routine post-treatment follow-up. However, she cautions that more research is needed before it’s adopted widely.

“For example, we need to understand when and how frequently to administer the test and what exactly we should do with a positive result,” Rettig explained.

The findings raise several important questions:

Should persistent HPV16 DNA always signal recurrence?
Could a new HPV16 infection be mistaken for residual cancer?
How might this affect current surveillance protocols?

For now, the test should remain within research settings.

A Promising but Not Yet Perfect Tool

Experts including Dr. Julie Bauman and Dr. Robert Ferris of the University of Pittsburgh emphasized in a related editorial that while the results are promising, the test has limitations. Its sensitivity and positive predictive value need improvement before it can be used in everyday practice.

The hope is that combining oral rinse testing with other biomarkers—like HPV E6 antibodies—could increase accuracy and allow doctors to detect recurrences earlier and more reliably.

The Bigger Picture

Oropharyngeal cancer linked to HPV behaves differently from other head and neck cancers. Most patients respond well to treatment, and recurrence is relatively rare. But when it does happen, it’s often aggressive and deadly.

That’s why developing low-cost, accessible tools like this one is critical for improving patient outcomes and personalizing treatment plans.

As Dr. Michael Baumann from the German Cancer Research Center put it, “We need to find out whether we can salvage patients earlier and more efficiently with this information.”

Final Thoughts

This study points to a future where cancer surveillance may be as simple as a rinse and spit—offering patients peace of mind or an early heads-up. But for now, it’s a tool to watch, not yet a tool to use.