Association of Pretreatment Circulating Tumor Tissue–Modified Viral HPV DNA With Clinicopathologic Factors in HPV-Positive Oropharyngeal Cancer

Abstract

ImportanceCirculating tumor tissue–modified viral (TTMV) human papillomavirus (HPV) DNA is a dynamic, clinically relevant biomarker for HPV-positive oropharyngeal squamous cell carcinoma. Reasons for its wide pretreatment interpatient variability are not well understood.ObjectiveTo characterize clinicopathologic factors associated with TTMV HPV DNA.Design, Setting, and ParticipantsThis cross-sectional study included patients evaluated for HPV-positive oropharyngeal squamous cell carcinoma at Dana-Farber Cancer Institute in Boston, Massachusetts, between December 2019 and January 2022 and who were undergoing curative-intent treatment.ExposuresClinicopathologic characteristics including demographic variables, tumor and nodal staging, HPV genotype, and imaging findings.Main Outcomes and MeasuresPretreatment circulating TTMV HPV DNA from 5 genotypes (16, 18, 31, 33, and 35) assessed using a commercially available digital droplet polymerase chain reaction–based assay, considered as either detectable/undetectable or a continuous score (fragments/mL).ResultsAmong 110 included patients, 96 were men (87%) and 104 were White (95%), with a mean (SD) age of 62.2 (9.4) years. Circulating TTMV HPV DNA was detected in 98 patients (89%), with a median (IQR) score of 315 (47-2686) fragments/mL (range, 0-60 061 fragments/mL). Most detectable TTMV HPV DNA was genotype 16 (n = 86 [88%]), while 12 patients (12%) harbored other genotypes. Circulating TTMV HPV DNA detection was most strongly associated with clinical N stage. Although few patients had clinical stage N0 disease, only 4 of these 11 patients (36%) had detectable DNA compared with 94 of 99 patients (95%) with clinical stage N1 to N3 disease (proportion difference, 59%; 95% CI, 30%-87%). Among patients with undetectable TTMV HPV DNA, more than half (7 of 12 [58%]) had clinical stage N0 disease. The TTMV HPV DNA prevalence and score increased with progressively higher clinical nodal stage, diameter of largest lymph node, and higher nodal maximum standardized uptake value on positron emission tomography/computed tomography. In multivariable analysis, clinical nodal stage and nodal maximum standardized uptake value were each strongly associated with TTMV HPV DNA score. Among 27 surgically treated patients, more patients with than without lymphovascular invasion had detectable TTMV HPV DNA (12 of 12 [100%] vs 9 of 15 [60%]).Conclusions and RelevanceIn this cross-sectional study, circulating TTMV HPV DNA was statistically significantly associated with nodal disease at HPV-positive OPSCC diagnosis. The few patients with undetectable levels had predominantly clinical stage N0 disease, suggesting assay sensitivity for diagnostic purposes may be lower among patients without cervical lymphadenopathy. Mechanisms underlying this association, and the use of this biomarker for surveillance of patients with undetectable baseline values, warrant further investigation.

Liquid biopsy in head neck cancer: ready for clinical routine diagnostics?

“…A strong association was recently demonstrated for baseline ctHPVDNA detection with measures of nodal disease in a cross-sectional study of 110 HPV-positive OPSCC patients [23 ▪ ]. Associations of ctHPVDNA with other clinicopathological characteristics including primary tumour features were notably weaker [23 ▪ ]. Though interesting with respect to the biology of HPV-driven disease, the prognostic significance of this observation remains to be determined, especially in light of the fact that nodal metastases in HPV-positive disease have a weaker association with prognosis than in HPV-negative HNSCC [24].…”

“…While pretreatment circulating tumour EBV DNA levels have been shown to be an independent prognostic factor for patients with nasopharyngeal carcinoma (NPC) and will probably be incorporated into future staging criteria for NPC [22], ctHPVDNA levels in patients with treatment-naïve OPSCC have not been correlated as reliably with prognosis [9]. A strong association was recently demonstrated for baseline ctHPVDNA detection with measures of nodal disease in a cross-sectional study of 110 HPV-positive OPSCC patients [23 ▪ ]. Associations of ctHPVDNA with other clinicopathological characteristics including primary tumour features were notably weaker [23 ▪ ].…”

ctHPV-DNA-basierte Präzisionsonkologie für Patienten mit Oropharynxkarzinom – wo stehen wir?

“…bei geringer Tumorlast zu detektieren, konnte bereits gezeigt werden. Ein Zusammenhang zwischen TNM-Stadium und der Kopienzahl der ctHPV-DNA im Plasma wurde in mehreren Studien bestätigt [18,24,26,29,30,31,32,33]. Chera fand heraus, dass der Plasmaspiegel der ctHPV16-DNA bei Patienten mit einem T2-Tumor höher lag als bei Patienten mit T0/T1-Tumoren [33].…”

“…Ein Zusammenhang zwischen TNM-Stadium und der Kopienzahl der ctHPV-DNA im Plasma wurde in mehreren Studien bestätigt [18,24,26,29,30,31,32,33]. Chera fand heraus, dass der Plasmaspiegel der ctHPV16-DNA bei Patienten mit einem T2-Tumor höher lag als bei Patienten mit T0/T1-Tumoren [33]. Jedoch war die Zahl der ctHPV16-DNA-Kopien bei Patienten mit T3/T4-Tumoren im Vergleich zu T2-Tumoren erniedrigt [34].…”

Circulating Tumor DNA in Human Papillomavirus–Mediated Oropharynx Cancer

“…In HPV-mediated head and neck cancer, there is evidence that HPV ctDNA is detectable several years before diagnosis of cancer while there are no detectable levels in negative controls 13–15 . At the time of diagnosis, ctDNA has been shown to correlate with numerous clinicopathologic characteristics of disease, including total tumor burden, nodal stage, HPV16 copy number, and integration status 16–19 …”