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Persistent HPV16 DNA in oral rinses predicts oropharyngeal cancer recurrence
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The presence of HPV type 16 DNA in oral rinses following treatment for HPV-related oropharyngeal cancer corresponded with poor prognosis and may serve as a potential biomarker for long-term tumor surveillance and local recurrence, according to results of a prospective cohort study.
The incidence of HPV-related oropharyngeal carcinoma (HPV-OPC) has increased in the U.S. and despite its favorable prognosis, recurrence occurs in 10% to 25% of cases. Gypsyamber D’Souza, PhD, MS, associate professor of cancer epidemiology at Johns Hopkins Bloomberg School of Public Health, and colleagues sought to determine whether HPV DNA detection in oral rinses following treatment for HPV-OPC served as a prognostic biomarker for recurrence and survival.
The analysis included data from 124 patients (90% men) with incident HPV-OPC diagnosed between 2009 and 2013 who had one or more post-treatment oral rinses. The researchers collected rinse samples at diagnosis and at 9, 12, 18 and 24 months following treatment.
DFS, OS and the association of HPV DNA detection in oral rinses with survival rates served as the primary endpoints.
Median follow-up was 33 months (interquartile range, 24-41).
Sixty-seven patients (54%) had oral HPV type 16 (HPV16) at diagnosis. However, only six patients (5%) had detectable oral HPV16 following treatment, which included five patients who had persistent oral HPV16 since diagnosis.
Overall, 92% (95% CI, 94-100) of patients achieved 2-year DFS and 98% (95% CI, 93-99) achieved 2-year OS. Fourteen recurrences occurred in the population, resulting in six deaths.
The researchers associated persistent oral HPV16 DNA with worse DFS (HR = 29.7; 95% CI, 9-98.2) and OS (HR = 23.5; 95% CI, 4.7-116.9).
All five patients with persistent oral HPV16 DNA developed recurrent disease, including three cases of local disease involvement. Only nine patients (8%) without persistent oral HPV16 DNA experienced disease recurrence, with one case of local disease involvement.
The median time from earliest post-treatment oral HPV16 DNA detection to recurrence was 7 months (range, 3.7-10.9).
The researchers acknowledged the low number of deaths and recurrences and the infrequency of persistent oral HPV16 DNA detection as limitations to these findings. They also noted that the majority of patients in their study exhibited characteristics associated with improved prognosis, including higher incomes, higher likelihood of marriage and fewer pack-years of smoking.
“Our data suggest that persistent HPV16 DNA detection in post-treatment oral rinses, although uncommon, is associated with poor prognosis and may be predictive of disease recurrence, in particular local recurrence,” D’Souza and colleagues wrote. “Therefore, HPV16 DNA detection in oral rinses is a potentially useful tool for long-term tumor surveillance for the growing population of HPV-OPC survivors.”
A recurrence biomarker needs high sensitivity, high positive predictive value, accuracy for subclinical locoregional recurrence and a low number needed to treat, Julie E. Bauman, MD, MPH, director of the head and neck cancer section and thyroid cancer section in the division of hematology-oncology at the University of Pittsburgh School of Medicine, and Robert L. Ferris, MD, PhD, chief of the division of head and neck cancer surgery at the University of Pittsburgh Cancer Institute, wrote in an accompanying editorial.
“This pioneering study demonstrates an association between persistent oral HPV16 DNA detection and recurrence,” Bauman and Ferris wrote. “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 CI for positive predictive value by the study of larger populations; and confirmation of significant lead time increasing the rate of successful surgical salvage. … 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.” – by Cameron Kelsall
Disclosure: D’Souza reports prior institutional research funding from Merck. Please see the full study for a list of all other researchers’ relevant financial disclosures. Bauman and Ferris report no financial disclosures.
Perspective
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Miriam N. Lango, MD
Human papilloma virus (HPV) causes both cervical cancer and oropharyngeal cancer. The use of Pap smear for cervical cancer screening has been shown to decrease the number of new cases and save lives. The Pap test was supplanted by molecular testing for HPV DNA. In contrast to cervical cancer, the incidence of oropharyngeal cancer also caused by HPV has been increasing, but there are no non-invasive, molecular-based tests available to screen for disease or monitor response to therapy in patients treated for oropharyngeal cancer caused by HPV.
In the journal article by Rettig and colleagues, the investigators try to address this deficiency. In this study, researchers collected saliva specimens from 157 patients with oropharyngeal cancer caused by HPV who were treated at one of four institutions. Saliva samples in oral rinses were obtained before and after cancer treatment. Oral rinses were tested for HPV type 16, which is the type of HPV most commonly associated with the development of oropharyngeal cancer. The investigators observed several interesting findings. First of all, although all patients in the study had oropharyngeal cancers caused by HPV, only a little more than half produced oral rinses that tested positive for HPV. It’s possible that some oropharynx cancers caused by HPV are buried under the surface, and therefore do not shed cells into the saliva, or maybe the cancers are so small that the amount of HPV DNA shed into saliva is below the level of detection for this test.
Of patients with HPV 16 in the oral rinse prior to treatment, 93% had no detectable HPV 16 after treatment. However, those with persistent HPV 16 after treatment — five patients in all — all developed recurrence, and three have died from their cancer. This suggests that the HPV testing of oral rinses may be an effective, non-invasive method to determine a patient’s response to treatment.
Some important limitations should be noted, however. Although this test was very effective in predicting recurrence of cancer in the lining of the throat, it was ineffective in detecting or predicting recurrences in other parts of the body. Thus, the test is far less effective than a standard test such as a PET CT scan, which surveys the entire body for abnormal metabolic activity. It seems unlikely that an oral rinse will supplant the PET CT scan, which is the gold-standard test to determine the response to oropharynx cancer treatment.
Additionally, other types of HPV that are associated with the development of oropharyngeal cancer were also found in the oral rinses of patients treated for cancer, and in one patient, HPV type 16 was found only after treatment but not before treatment. This finding highlights the limitation of the test in being able to distinguish between oral infection and cancer caused by HPV. Patients may acquire new HPV infections after successful treatment for cancer, and these infections don’t necessarily mean that the cancer has returned. A false-positive test has the potential to cause substantial worry. Patients may fear placing themselves at risk by engaging in normal sexual activity after cancer treatment.
Nevertheless, the findings in this study are exciting, and may be a first step in devising a non-invasive screening test for oropharyngeal cancer.
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