Detection of Occult Recurrence Using Circulating Tumor Tissue Modified Viral HPV DNA among Patients Treated for HPV-Driven Oropharyngeal Carcinoma

Abstract

Purpose: Despite generally favorable outcomes, 15-25% of patients with HPV-driven oropharyngeal squamous cell carcinoma (OPSCC) will recur. Current post-treatment surveillance practices rely on physical exams and imaging and are inconsistently applied. We assessed circulating tumor tissue modified viral (TTMV)-HPV DNA obtained during routine post-treatment surveillance among a large population of real-world patients. Experimental Design: This retrospective clinical case series included 1076 consecutive patients across 108 U.S. sites who were >=3 months post-treatment for HPV-driven OPSCC and who had 1 or more TTMV-HPV DNA tests (NavDx®, Naveris Laboratories, Natick, MA) obtained during surveillance. between 2/6/2020 and 6/29/2021. Test results were compared to subsequent clinical evaluations. Results: Circulating TTMV-HPV DNA was positive in 80/1076 (7.4%) patients, with follow-up available on all. At first positive surveillance testing, 21/80 (26%) patients had known recurrence while 59/80 (74%) patients were not known to have recurrent disease. Among these 59 patients, 55 (93%) subsequently had a confirmed recurrence, two patients have clinically suspicious lesions and two are clinically NED at last follow-up. To date, the overall positive predictive value of TTMV-HPV DNA testing for recurrent disease is 95% (N=76/80). Additionally, the point-in-time negative predictive value is 95% (N=1198/1256). Conclusions: These findings highlight the clinical potential for circulating TTMV-HPV DNA testing in routine practice. As a surveillance tool, TTMV-HPV DNA positivity was the first indication of recurrence in the majority of cases, pre-dating identification by routine clinical and imaging exams. These data may inform future clinical and guideline-endorsed strategies for HPV-driven malignancy surveillance.

Surgical clinical trials for HPV-positive oropharyngeal carcinoma

“…Finally, circulating tumor HPV (ctHPV) DNA shows promise in both detection and surveillance of HPV-positive oropharyngeal cancer ( 59 – 61 ). By targeting E6 and/or E7 oncogenes, plasma ctHPV DNA can be measured with PCR or next generation sequencing.…”

“…with two consecutive positive tests strongly predicting disease recurrence ( 60 ). Clearance kinetics suggest that in low risk patients, ctHPV DNA rapidly decreases to <1 copy/mL by the first postoperative day ( 61 , 62 ). Therefore, elevated levels are associated with risk of residual disease and could be used as a biomarker for selecting adjuvant therapy in future surgical clinical trial design.…”

Oligometastatic Head and Neck Cancer: Challenges and Perspectives

“…In a recent study on 93 patients with HPV-positive oropharynx carcinoma, the presence of combined salivary and plasma HPV DNA after radical treatment was 91% specific and 70% sensitive in predicting recurrence within 3 years [ 80 ]. A multicenter study of 1076 HPV-positive oropharyngeal carcinoma from 108 institutions in the United States showed that ct-HPV DNA was able to identify 96% cases with occult recurrence [ 90 ]. Therefore, emerging evidence supports the promising role of these biomarkers for early cancer detection, tumor mutational burden evaluation and post-treatment surveillance, and are currently being investigated [ 80 , 91 ].…”

Clinical Utility of Human Papillomavirus Circulating Tumour DNA in Human Papillomavirus-positive Head and Neck Squamous Cell Carcinomas

“…15 Studies to date have primarily evaluated the utility of qPCR or ddPCR in analysing HPV ctDNA in the plasma, serum and saliva of patients with head and neck cancers (Table 1). [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] Over the years, numerous assays have been developed to measure HPV ctDNA in patients with HPV-positive head and neck carcinoma with varying sensitivity and specificity. One of the early studies using qPCR, Cao et al, found detectable HPV ctDNA in 65% of the pretreatment plasma samples of 40 patients with HPV-positive oropharyngeal carcinoma.…”

“…45 HPV ctDNA analysis is sensitive in detecting recurrence with promise for clinical application in surveillance. 29,30 One retrospective study by Berger et al evaluated the utility of HPV ctDNA as a biomarker of recurrent disease in 1,076 patients with HPV-positive OPSCC. 30 Eighty patients (7.4%) had at least one positive HPV ctDNA.…”