Cell-Free HPV DNA Provides an Accurate and Rapid Diagnosis of HPV-Associated Head and Neck Cancer

Siravegna, Giulia; O'Boyle, Connor J.; Varmeh, Shohreh; Queenan, Natalia; Michel, Alexa; Stein, Jarrod; Thierauf, Julia; Sadow, Peter M.; Faquin, William C.; Perry, Simon K; Bard, Adam Z.; Wang, Wei; Deschler, Daniel G.; Emerick, Kevin S.; Varvares, Mark A.; Park, Jong C.; Clark, John R.; Chan, Annie W.; Arasa, Vanessa Carlota Andreu; Sakai, Osamu; Lennerz, Jochen K.; Corcoran, Ryan B.; Wirth, Lori J.; Lin, Derrick T.; Iafrate, A. John; Richmon, Jeremy D.; Faden, Daniel L.

doi:10.1158/1078-0432.ccr-21-3151

Cited by 66 publications

(82 citation statements)

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“…We found that POD 1 ctHPVDNA levels are associated with the risk of residual disease. These findings are the first to demonstrate the potential utility of ctHPVDNA as a tool for personalized treatment decision‐making in patients with HPV+OPSCC undergoing surgery and add to a growing body of literature which support ctHPVDNA use as a diagnostic test and a biomarker of treatment response and recurrence after CRT 20,21,26 …”

Section: Discussionmentioning

confidence: 66%

“…Five ddPCR assays were developed and optimized to detect conserved regions of E7 from HPV 16, 18, 33, 35, and 45 26 . Probes were confirmed to have no cross‐genotype reactivity, to be linear ( R 2 > 0.96 for all genotypes), and to have limits of detection ≤0.1% fractional abundance.…”

Section: Methodsmentioning

confidence: 99%

“…Probes were confirmed to have no cross‐genotype reactivity, to be linear ( R 2 > 0.96 for all genotypes), and to have limits of detection ≤0.1% fractional abundance. Detailed assay metrics and performance can be found in Siravegna et al 26 …”

Section: Methodsmentioning

confidence: 99%

“…Circulating tumor DNA (ctDNA) is released into the blood by cancer cells, contributing a small fraction of total cell‐free DNA 14 . HPV‐associated cancers also release ctHPVDNA 15‐26 . Most recently, droplet digital polymerase chain reaction (ddPCR)–based approaches, which have the benefit of high sensitivity and fidelity, have been used to demonstrate that 1) most patients have detectable ctHPVDNA at the time of diagnosis (sensitivity of 89%‐98% and specificity of 97%‐100% compared to p16 immunohistochemistry [IHC]), 2) ctHPVDNA levels trend down slowly during definitive CRT in responding patients, and 3) ctHPVDNA is a marker of recurrence in the post‐CRT setting with levels re‐elevating in patients who suffer recurrence 20‐24,26 .…”

Section: Introductionmentioning

confidence: 99%

“…14 HPV-associated cancers also release ctHPVDNA. [15][16][17][18][19][20][21][22][23][24][25][26] Most recently, droplet digital polymerase chain reaction (ddPCR)-based approaches, which have the benefit of high sensitivity and fidelity, have been used to demonstrate that 1) most patients have detectable ctHPVDNA at the time of diagnosis (sensitivity of 89%-98% and specificity of 97%-100% compared to p16 immunohistochemistry [IHC]), 2) ctHPVDNA levels trend down slowly during definitive CRT in responding patients, and 3) ctHPVDNA is a marker of recurrence in the post-CRT setting with levels re-elevating in patients who suffer recurrence. [20][21][22][23][24]26 Taken together, ctHPVDNA detection appears to be a promising noninvasive approach to determining the presence or absence of HPV+OPSCC.…”

Section: Introductionmentioning

confidence: 99%

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Cell‐free human papillomavirus DNA kinetics after surgery for human papillomavirus–associated oropharyngeal cancer

O'Boyle

Siravegna

Varmeh

et al. 2022

Cancer

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BACKGROUND: New ultrasensitive methods for detecting residual disease after surgery are needed in human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV+OPSCC). METHODS: To determine whether the clearance kinetics of circulating tumor human papillomavirus DNA (ctHPVDNA) is associated with postoperative disease status, a prospective observational study was conducted in 33 patients with HPV+OPSCC undergoing surgery. Blood was collected before surgery, postoperative days 1 (POD 1), 7, and 30 and with follow-up. A subcohort of 12 patients underwent frequent blood collections in the first 24 hours after surgery to define early clearance kinetics. Plasma was run on custom droplet digital polymerase chain reaction (ddPCR) assays for HPV genotypes 16, 18, 33, 35, and 45. RESULTS: In patients without pathologic risk factors for recurrence who were observed after surgery, ctHPVDNA rapidly decreased to <1 copy/mL by POD 1 (n = 8/8). In patients with risk factors for macroscopic residual disease, ctHPVDNA was markedly elevated on POD 1 (>350 copies/mL) and remained elevated until adjuvant treatment (n = 3/3). Patients with intermediate POD 1 ctH-PVDNA levels (1.2-58.4 copies/mL) all possessed pathologic risk factors for microscopic residual disease (n = 9/9). POD 1 ctHPVDNA levels were higher in patients with known adverse pathologic risk factors such as extranodal extension >1 mm (P = .0481) and with increasing lymph nodes involved (P = .0453) and were further associated with adjuvant treatment received (P = .0076). One of 33 patients had a recurrence that was detected by ctHPVDNA 2 months earlier than clinical detection. CONCLUSIONS: POD 1 ctHPVDNA levels are associated with the risk of residual disease in patients with HPV+OPSCC undergoing curative intent surgery and thus could be used as a personalized biomarker for selecting adjuvant treatment in the future.

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Section: Discussionmentioning

confidence: 66%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Cell‐free human papillomavirus DNA kinetics after surgery for human papillomavirus–associated oropharyngeal cancer

O'Boyle

Siravegna

Varmeh

et al. 2022

Cancer

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

Lang Kuhs,

Brenner,

Holsinger

et al. 2023

JAMA Oncol

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ImportanceHuman papillomavirus (HPV)–positive oropharyngeal squamous cell carcinoma has an overall favorable prognosis, yet a subset of patients will experience devastating disease recurrence. Current surveillance standards for detection of recurrent disease are imperfect. There is growing interest in improving detection of recurrent disease through the use of plasma-based assays able to detect circulating tumor HPV DNA.ObservationsAlthough most circulating tumor HPV DNA assays remain in the research domain, the circulating tumor tissue–modified viral HPV DNA assay became commercially available in the United States in early 2020 and has been increasingly used in the clinical setting. With the rapidly increasing incidence of HPV-positive oropharyngeal squamous cell carcinoma and concomitant expansion of biomarker capabilities for this disease, it is critical to reexamine current posttreatment surveillance practices and to determine whether emerging technologies may be used to improve outcomes for a growing survivor population. However, caution is advised; it is not yet known whether biomarker-based surveillance is truly beneficial, and as is true with any intervention, it has the capacity to cause harm.Conclusions and RelevanceUsing Margaret Pepe’s classic 5 phases of biomarker development for early detection of cancer as a framework, this article reviews the current state of knowledge, highlights existing knowledge gaps, and suggests research that should be prioritized to understand the association between biomarker-based surveillance and patient outcomes. Specific attention is paid to the commercially available tumor tissue–modified viral HPV DNA assay, given its increasing clinical use. This review may serve as a road map for future research and a guide for clinicians considering its adoption in practice. Enrollment of patients into clinical trials incorporating biomarker-based surveillance should be prioritized.

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

Rettig

Wang

Tran

et al. 2022

JAMA Otolaryngol Head Neck Surg

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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.

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Cell-Free HPV DNA Provides an Accurate and Rapid Diagnosis of HPV-Associated Head and Neck Cancer

Cited by 66 publications

References 42 publications

Cell‐free human papillomavirus DNA kinetics after surgery for human papillomavirus–associated oropharyngeal cancer

Cell‐free human papillomavirus DNA kinetics after surgery for human papillomavirus–associated oropharyngeal cancer

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

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

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