Negative Predictive Value of Circulating Tumor Tissue Modified Viral (TTMV)-HPV DNA for HPV-driven Oropharyngeal Cancer Surveillance

Abstract

Background: Human papillomavirus (HPV) is causally linked to oropharyngeal squamous cell carcinoma (OPSCC). Consensus guidelines recommend clinical exams and imaging in decreasing frequency as part of post-treatment surveillance for recurrence. Plasma tumor tissue modified viral (TTMV)-HPV DNA testing has emerged as a biomarker which can inform disease status during surveillance. Methods: This retrospective observational cohort study involved 543 patients who completed curative-intent therapy for HPV-associated OPSCC between February 2020 and January 2022 at 8 U.S. cancer care institutions. We determined the negative predictive value (NPV) of TTMV-HPV DNA for recurrence when matched to physician-reported clinical outcome data (median follow-up time: 27.9 months; range: 4.5-154). Results: The cohort included mostly men with a median age of 61 who had locoregionally advanced disease. HPV status was determined by p16 positivity in 87% of patients, with a positive HPV PCR/ISH among 55%; while pre-treatment TTMV-HPV DNA status was unknown for most (79%) patients. Patients had a mean of 2.6 tests and almost half had 3 or more TTMV-HPV DNA results during surveillance. The per-test and per-patient sensitivity of the assay was 92.5% (95%CI: 87.5-97.5) and 87.3% (95%CI: 79.1-95.5), respectively. The NPV for the assay was 99.4% (95%CI: 98.9-99.8) and 98.4% (95%CI: 97.3-99.5), respectively. Conclusions: TTMV-HPV DNA surveillance testing yields few false negative results and few missed recurrences. These data could inform decisions on when to pursue re-imaging following first disease restaging and could inform future surveillance practice. Additional study of how pre-treatment TTMV-HPV DNA status impacts sensitivity for recurrence is needed.

Circulating Tumor HPV DNA for Surveillance of HPV-Positive Oropharyngeal Squamous Cell Carcinoma

“…21,23,44 Several recent studies using the commercial TTMV-HPV DNA assay, which was developed based on work by Chera et al, 45 reported high positive predictive values for recurrence of 95% to 100%. 19,33,34 However, despite the promise-and, pragmatically, the availability-of ctHPVDNA testing, rigorous evidence to support its widespread clinical use is still developing. The remainder of this review applies Margaret Pepe's classic 5 phases of biomarker development for early detection of cancer 46 as a framework to review the current evidence, highlight outstanding questions, and suggest research to be prioritized (Table 2).…”

“…This group conducted a follow-up study of 543 patients with commercial TTMV-HPV DNA testing. 33 Among 63 patients with recurrent disease, 55 had detectable TTMV-HPV DNA, yielding a sensitivity of 87.3%. TTMV-HPV DNA testing was the first sign of recurrence for 38 of these 55 patients (69%) with a median lead time of 53 days (range, 7-610 days).…”

“…Our current knowledge of TTMV-HPV DNA assay sensitivity is based on 6 peer-reviewed studies representing 559 HPV-positive patients, whereas specificity is based on 4 studies and 226 controls . Although test sensitivity and specificity have been reassuringly consistent and high, important questions remain:…”

“…Considering only TTMV-HPV DNA testing, 4 studies have evaluated the assay for detection of preclinical recurrent disease (Table 1). In a study of 115 patients with HPV-positive OPSCC (median follow-up, 23 months; range, 6.1-54.7 months), 0 of 87 patients with undetectable TTMV-HPV DNA had disease recurrence (100% negative predictive value) compared with 15 of 28 patients with any positive test results (54% positive predictive value) and 15 of 16 patients with 2 consecutive positive test results (94% positive predictive value) .…”

“…Our current knowledge of the TTMV-HPV DNA assay’s performance for detecting preclinical recurrence in surveillance is from 4 studies and approximately 220 HPV-positive OPSCC recurrences.…”