Immunotherapy time of infusion impacts survival in head and neck cancer: A propensity score matched analysis.

The adaptive immune response is physiologically regulated by the circadian rhythm. Data in lung and melanoma malignancies suggests immunotherapy infusions earlier in the day may be associated with improved response; however, the optimal time of administration for patients with head and neck squamous cell carcinoma (HNSCC) is not known. We aimed to evaluate the association of immunotherapy infusion time with overall survival (OS) and progression free survival (PFS) in patients with HNSCC in an Institutional Review Board-approved, retrospective cohort study. 113 patients met study inclusion criteria and 98 patients were included in a propensity score-matched cohort. In the full unmatched cohort (N = 113), each additional 20 % of infusions received after 1500 h conferred an OS hazard ratio (HR) of 1.35 (95 % C.I.1.2-1.6; p-value = 0.0003) and a PFS HR of 1.34 (95 % C.I.1.2-1.6; p-value < 0.0001). A propensity score-matched analysis of patients who did or did not receive ≥20 % of infusions after 1500 h showed that those who were administered ≥20 % of infusions after 1500 h trended towards a shorter OS (HR = 1.35; p-value = 0.26) and a shorter PFS (HR = 1.57, 95 % C.I. 1.02-2.42, p-value = 0.04). Each additional 20 % of infusions received after 1500 h remained robust in the matched cohort multivariable analysis and was associated with shorter OS (adjusted HR = 1.4 (95 % C.I.1.2-1.8), p-value < 0.001). Patients with advanced HNSCC who received more of their infusions in the afternoon were associated with shorter OS and PFS and scheduling immunotherapy infusions earlier in the day may be warranted.

Assessing the feasibility of a multimodal liquid biopsy for the diagnosis of HPV-associated oropharyngeal squamous cell carcinoma.

OBJECTIVES: In this feasibility study, we explored the combined use of circulating tumor human papillomavirus (HPV) DNA (ctHPVDNA) and HPV serology as diagnostic tests for HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). METHODS: Among patients with research-banked serum or plasma at diagnosis, IgG antibodies to oncoproteins from HPV types 16, 18, 31, 33, 35, 45, 52, and 58 were detected with multiplex serology. Positivity for HPV 16 was defined based on detection of combinations of anti-E6, E1, E2, and E7 and for other high-risk types on detection of anti-E6 and anti-E7. Circulating tumor HPV DNA was detected by custom digital droplet polymerase chain reaction (ddPCR) assays for HPV types 16, 18, 33, 35, and 45. p16 immunohistochemistry and high-risk HPV RNA in situ hybridization (ISH) using a cocktail of 18 high-risk HPV types were performed on tissue. RESULTS: Of 75 patients, 67 (89.3%) were HPV-associated (p16 and HPV RNA ISH positive) and 8 (10.7%) were HPV-independent. All 8 HPV-independent patients were seronegative and negative for ctHPVDNA (100% specificity). Serology was positive in 53 (79.1%) of 67 HPV-associated patients, while ddPCR was positive for ctHPVDNA in 59 (88.6%) of 67 HPV-associated patients. Requiring both tests to be positive resulted in a sensitivity of 50 (74.6%) of 67 while combining assays (either positive) improved sensitivity to 62 (92.6%) of 67. CONCLUSIONS: Compared to HPV RNA ISH, HPV serology and ctHPVDNA are sensitive and highly specific biomarkers for HPV-associated OPSCC at the time of presentation.

Blood-based screening for HPV-associated cancers.

Background: HPV-associated oropharyngeal cancer (HPV+OPSCC) is the most common HPV-associated cancer in the United States yet unlike cervical cancer lacks a screening test. HPV+OPSCCs are presumed to start developing 10-15 years prior to clinical diagnosis. Circulating tumor HPV DNA (ctHPVDNA) is a sensitive and specific biomarker for HPV+OPSCC. Taken together, blood-based screening for HPV+OPSCC may be feasible years prior to diagnosis. Methods: We developed an HPV whole genome sequencing assay, HPV-DeepSeek, with 99% sensitivity and specificity at clinical diagnosis. 28 plasma samples from HPV+OPSCC patients collected 1.3-10.8 years prior to diagnosis along with 1:1 age and gender-matched controls were run on HPV-DeepSeek and an HPV serology assay. Results: 22/28 (79%) of cases and 0/28 controls screened positive for HPV+OPSCC with 100% detection within four years of diagnosis and a maximum lead time of 7.8 years. We next applied a machine learning model classifying 27/28 cases (96%) with 100% detection within 10 years. Plasma-based PIK3CA gene mutations, viral genome integration events and HPV serology were used to orthogonally validate cancer detection with 68% (19/28) of the cohort having multiple cancer signals detected. Molecular fingerprinting of HPV genomes was performed across patients demonstrating that each viral genome was unique, ruling out contamination. In patients with tumor blocks from diagnosis (15/28), molecular fingerprinting was performed within patients confirming the same viral genome across time. Conclusions: We demonstrate accurate blood-based detection of HPV-associated cancers with lead times up to 10 years before clinical cancer diagnosis and in doing so, highlight the enormous potential of ctDNA-based cancer screening.

ctDNA predicts recurrence and survival in stage I and II HPV-associated head and neck cancer patients treated with surgery.

Human papillomavirus-associated oropharyngeal squamous cell carcinomas (HPV+OPSCC) release circulating tumor HPV DNA (ctHPVDNA) into the blood which we, and others, have shown is an accurate real-time biomarker of disease status. In a prior prospective observational trial of 34 patients with AJCC 8 stage I-II HPV+OPSCC treated with surgery, we reported that ctHPVDNA was rapidly cleared within hours of surgery in patients who underwent complete cancer extirpation, yet remained elevated in those with macroscopic residual disease. The primary outcomes of this study were to assess 2-year OS and RFS between patients with and without molecular residual disease (MRD) following completion of treatment in this prospective cohort. MRD was defined as persistent elevation of ctHPVDNA at two consecutive time points, without clinical evidence of disease. The secondary outcomes were 2-year OS and RFS between patients with and without detectable MRD after surgery. We observed that patients with MRD after treatment completion were more likely to recur compared to patients without MRD, while there was no difference in recurrence rates between patients with MRD and without MRD on postoperative day 1. OS did not significantly differ between patients with MRD after surgery or treatment completion compared to patients without MRD; however, time to death was significantly different between the groups in both settings, suggesting that with a larger sample size OS would differ significantly between the groups or that the impact of MRD detection on survival is time dependent.

Circulating Tumor DNA in the Immediate Postoperative Setting.

BACKGROUND: Circulating tumor DNA (ctDNA) has emerged as an accurate real-time biomarker of disease status across many solid tumor types. Most studies evaluating the utility of ctDNA have focused on time points weeks to months after surgery, which, for many cancer types, is significantly later than decision-making time points for adjuvant treatment. In this systematic review, we summarize the state of the literature on the feasibility of using ctDNA as a biomarker in the immediate postoperative period. METHODS: We performed a systematic review evaluating the early kinetics, defined here as 3 days of ctDNA in patients who underwent curative-intent surgery. RESULTS: Among the 2057 studies identified, eight cohort studies met the criteria for evaluation. Across six different cancer types, all studies showed an increased risk of cancer recurrence in patients with detectable ctDNA in the immediate postoperative period. CONCLUSION: While ctDNA clearance kinetics appear to vary based on tumor type, across all studies detectable ctDNA after surgery was predictive of recurrence, suggesting early postoperative time points could be feasibly used for determining minimal residual disease. However, larger studies need to be performed to better understand the precise kinetics of ctDNA clearance across different cancer types as well as to determine optimal postoperative time points.

Personal Social Networks and Care-Seeking for Head and Neck Cancer: A Qualitative Study.

OBJECTIVES: To investigate the role of patients' personal social networks (SNs) in accessing head and neck cancer (HNC) care through patients' and health care workers' (HCWs) perspectives. STUDY DESIGN: Qualitative study. SETTING: Tertiary HNC centers at 2 academic medical centers, including 1 safety net hospital. METHODS: Patients with newly diagnosed HNC, and HCWs caring for HNC patients, aged ≥18 years were recruited between June 2022 and July 2023. Semistructured interviews were conducted with both patients and HCWs. Inductive and deductive thematic analysis was performed with 2 coders (κ = 0.82) to analyze the data. RESULTS: The study included 72 participants: 42 patients (mean age 57 years, 64% female, 81% white), and 30 HCWs (mean age 42 years, 77% female, 83% white). Four themes emerged: (1) Patients' SNs facilitate care through various forms of support, (2) patients may hesitate to seek help from their networks, (3) obligations toward SNs may act as barriers to seeking care, and (4) the SN composition and dedication influence care-seeking. CONCLUSION: Personal SNs play a vital role in prompting early care-seeking among HNC patients. SN-based interventions could enhance care and improve outcomes for HNC patients.

Comparing the Diagnostic Performance of Quantitative PCR, Digital Droplet PCR, and Next-Generation Sequencing Liquid Biopsies for Human Papillomavirus-Associated Cancers.

Human papillomavirus (HPV)-associated cancers, including oropharyngeal squamous cell carcinoma (HPV + OPSCC), cervical cancer, and squamous cell carcinoma of the anus (HPV + SCCA), release circulating tumor HPV DNA (ctHPVDNA) into the blood. The diagnostic performance of ctHPVDNA detection depends on the approaches used and the individual assay metrics. A comparison of these approaches has not been systematically performed to inform expected performance, which in turn affects clinical interpretation. A meta-analysis was performed using Ovid MEDLINE, Embase, and Web of Science Core Collection databases to assess the diagnostic accuracy of ctHPVDNA detection across cancer anatomic sites, detection platforms, and blood components. The population included patients with HPV + OPSCC, HPV-associated cervical cancer, and HPV + SCCA with pretreatment samples analyzed by quantitative PCR (qPCR), digital droplet PCR (ddPCR), or next-generation sequencing (NGS). Thirty-six studies involving 2986 patients met the inclusion criteria. The sensitivity, specificity, and quality of each study were assessed and pooled for each analysis. The sensitivity of ctHPVDNA detection was greatest with NGS, followed by ddPCR and then qPCR when pooling all studies, whereas specificity was similar (sensitivity: ddPCR > qPCR, P < 0.001; NGS > ddPCR, P = 0.014). ctHPVDNA from OPSCC was more easily detected compared with cervical cancer and SCCA, overall (P = 0.044). In conclusion, detection platform, anatomic site of the cancer, and blood component used affects ctHPVDNA detection and must be considered when interpreting results. Plasma NGS-based testing may be the most sensitive approach for ctHPVDNA overall.

Determinants of the level of circulating-tumor HPV16 DNA in patients with HPV-associated oropharyngeal cancer at the time of diagnosis.

Circulating tumor HPV DNA (ctHPV16) assessed in liquid biopsy may be used as a marker of cancer in patients with HPV-associated oropharyngeal cancer (HPV + OPC). Factors influencing the initial ctHPV16 quantity are not well recognized. In this study we aimed to establish what factors are related to the level of ctHPV16 at the time of diagnosis. 51 patients (37 men and 14 women, median age of 57 years old) with HPV + OPC prior to definitive treatment were included. ctHPV16 was measured by qPCR. Tumor and nodal staging were assessed according to AJCC8. Blood derived factors included squamous cell carcinoma antigen (SCC-Ag), serum soluble fragment of cytokeratin 19 (CYFRA 21-1), C-reactive protein (CRP), albumin level (Alb), neutrophils (Neut), thrombocytes (Plt) and lymphocyte (Lym) count, Neut/Lym ratio were assessed. The volumes of the primary tumor (TV) and involved lymph nodes (NV) were calculated using MRI, CT or PET-CT scans. Data were analysed using parametric and nonparametric methods. Variables for multivariable linear regression analysis were chosen based on the results from univariable analysis (correlation, univariable regression and difference). There were 9 (18%), 10 (19%) and 32 (63%) patients who had TV and NV assessed in MRI, CT or PET respectively. Primary tumor neither as T-stage nor TV was related to ctHPV16 level. Significant differences in the ctHPV16 between patients with high vs low pain (P = 0.038), NV (P = 0.023), TV + NV (P = 0.018), CYFRA 21-1 (P = 0.002), CRP (P = 0.019), and N1 vs N3 (P = 0.044) were observed. ctHPV16 was significantly associated with CYFRA 21-1 (P = 0.017), N stage (P = 0.005), NV (P = 0.009), TV + NV (P = 0.002), CRP (P = 0.019), and pain (P = 0.038). In univariable linear regression analysis the same variables predicted ctHPV16 level. In multivariable analyses, CYFRA 21-1 and CRP (both as categorical variables) were predictors of ctHPV16 level even above NV. ctHPV16 at presentation is driven by tumor volume measured mostly by N. CYFRA 21-1 and CRP are additional factors related to ctHPV16 prior to the treatment.

circulating tumor DNA in the immediate post-operative setting.

Background: Circulating tumor DNA (ctDNA) has emerged as an accurate real-time biomarker of disease status across most solid tumor types. Most studies evaluating the utility of ctDNA have focused on time points weeks to months after surgery, which for many cancer types, is significantly later than decision-making time points for adjuvant treatment. In this systematic review, we summarize the state of the literature on the feasibility of using ctDNA as a biomarker in the immediate postoperative period. Methods: We performed a systematic review evaluating the early kinetics, defined here as three days, of ctDNA in patients who underwent curative-intent surgery across several cancer types. Results: Among the 2057 studies identified, we evaluated eight cohort studies with ctDNA levels measured within the first three days after surgery. Across six different cancer types, all studies showed an increased risk of cancer recurrence in patients with a positive early postoperative ctDNA level. Discussion: While ctDNA clearance kinetics appear to vary based on tumor type, across all studies- detectable ctDNA after surgery was predictive of recurrence, suggesting early postoperative timepoints could be feasibly used for determining minimal residual disease. However, larger studies need to be performed to better understand the precise kinetics of ctDNA clearance across different cancer types as well as to determine optimal postoperative time points. Synopsis: This systematic review analyzed the use of ctDNA as a biomarker for minimal residual disease detection in the early postoperative setting and found that ctDNA detection within three days after surgery is associated with an increased risk of recurrence.

Deciphering Knowledge and Opinions of Human Papillomavirus and Human Papillomavirus Vaccination for Facilitation of Point-of-Care Vaccination in Adults.

Importance: Human papillomavirus (HPV) vaccination rates remain significantly below rates for other common childhood vaccines, which has implications for future rates of HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). Objective: To assess whether individuals who were aware of the association between HPV and OPSCC would be more likely to have been previously vaccinated. Design, Setting, and Participants: This survey study included patients aged 18 to 45 years who sought routine outpatient care at the otolaryngology clinic at Boston Medical Center from September 1, 2020, to May 19, 2021. A survey (HPV-Associated Head and Neck Cancer Epidemiology, Awareness and Demographics) [HEAD]) composed of validated questions to assess patient knowledge of HPV and HPV vaccination and barriers to vaccination was delivered to participants. The survey was paired with a novel point-of-care vaccination program housed within an otolaryngology department. Main Outcomes and Measures: The main outcome was prevalence of knowledge of the relationship between HPV infection and OPSCC based on survey responses. The association of knowledge of HPV-associated OPSCC with likelihood of having been vaccinated was assessed in the overall cohort and by demographic characteristics using multivariate logistic regression. Results: Of 405 patients given the survey, 288 (71.1%) responded. Of these patients, 271 (94.1%) had surveys included; 158 (58.3%) were female, and median age was 29 years (IQR, 24-35 years). The baseline vaccination rate in the surveyed population was low (26.6%; n = 72) overall (10.6% among men [12 of 113]; 37.9% among women [60 of 158]). Few participants understood the relationship between HPV infection and OPSCC (63 of 271 [23.3%]) or that HPV-associated OPSCC is the most common HPV-associated cancer type (9 of 121 [7.4%]). Compared with men, women were more likely to have been previously vaccinated (odds ratio [OR], 6.5; 95% CI, 3.0-13.9), more aware that HPV causes cancer (OR, 3.7; 95% CI, 1.9-7.1), and more likely to have heard about HPV and HPV vaccination from their health care practitioner (OR, 2.6; 95% CI, 1.2-5.7). Knowledge of the relationship between HPV infection and cancer and between HPV and OPSCC was associated with increased likelihood of having been vaccinated (HPV and cancer: OR, 4.1 [95% CI, 1.8-9.5]; HPV and OPSCC: OR, 3.7 [95% CI, 1.8-7.6]). Among 156 unvaccinated participants, 12 of 98 men (12.2%) and 7 of 131 women (5.3%) received point-of-care vaccination. Conclusions: Most participants in this survey study were unaware that HPV causes OPSCC. Understanding that HPV causes OPSCC was associated with increased likelihood of having been vaccinated. However, most patients surveyed were not informed of this relationship by their health care practitioners. Targeted education aimed at unvaccinated adults establishing the relationship between HPV infection and OPSCC, paired with point-of-care vaccination, may be an innovative strategy for increasing HPV vaccination rates in adults.

Comparison of patient-reported upper extremity disability following free flaps in head and neck reconstruction: A systematic review and meta-analysis.

BACKGROUND: Comparisons of patient-reported donor site morbidity based on the Disabilities in Arm, Shoulder, and Hand (DASH) instrument across upper trunk free flaps in head and neck surgery, including radial forearm (RFFF), osteocutaneous radial forearm (OCRFF), scapular tip (STFF), and serratus anterior (SAFF) free flaps, may help inform donor tissue selection. METHODS: In this meta-analysis, 12 studies were included and the primary outcome was average DASH score. RESULTS: The pooled DASH scores were 12.14 (95% CI: 7.40-16.88) for RFFF (5 studies), 17.99 (11.87-24.12) for OCRFF (2 studies), 12.19 (8.74-15.64) for STFF (3 studies), and 16.49 (5.92-27.05) for SAFF (2 studies) and were not significantly different. CONCLUSIONS: Results suggest that patients generally function well, with minimal to mild donor site morbidity, when assessed at an average of 20 months after flap harvest. These results are based on few effects from primarily retrospective studies of fair quality, and further research is needed.

Double trouble: Synchronous and metachronous primaries confound ctHPVDNA monitoring.

BACKGROUND: Human papillomavirus-associated head and neck squamous cell carcinoma (HPV + HNSCC) occurs in the oropharynx (HPV + OPSCC), sinonasal cavity (HPV + SNSCC), and nasopharynx (HPV + NPC). Circulating tumor HPV DNA (ctHPVDNA) is an accurate tool for diagnosis, treatment monitoring, and recurrence detection. An emerging challenge with ctHPVDNA is that ~7.4% of HPV + HNSCC patients develop synchronous or metachronous HPV+ primaries, which could confound ctHPVDNA monitoring. METHODS: We describe a 65-year-old patient with T2N1M0 HPV16 + OPSCC and a 55-year-old patient with T2N2M0 HPV16 + OPSCC. Both patients were enrolled in our prospective observational ctHPVDNA study with longitudinal blood collections throughout treatment. Both patients developed multiple HPV+ primaries. RESULTS: Detailed discussion of the patients' treatment courses, the subsequent diagnoses of their second HPV+ primaries, and their ctHPVDNA monitoring is presented. CONCLUSIONS: As ctHPVDNA use becomes more prevalent, it is important to recognize that an increase in ctHPVDNA can come not only from the primary tumor or metastatic clones, but also from synchronous or metachronous second primaries.

Detection and Monitoring of Circulating Tumor HPV DNA in HPV-Associated Sinonasal and Nasopharyngeal Cancers.

This prospective observational study examines if circulating tumor human papillomavirus DNA can be used as an accurate measure of disease status at the time of diagnosis, throughout treatment, and during monitoring in human papillomavirus-associated sinonasal and nasopharyngeal squamous cell carcinomas.

Rate of atypical nodal metastases in surgically treated HPV-associated oropharyngeal squamous cell carcinoma.

BACKGROUND: Understanding of nodal metastasis in patients with HPV+ oropharyngeal squamous cell carcinoma (OPSCC) is warranted. METHODS: Patients with HPV+ OPSCC who underwent neck dissection (ND) between 2016 and 2021 were reviewed. Pathology reports were reviewed for lymph node (LN) metastases. Noncontiguous metastases were defined as pathologic evidence of level II disease with another involved LN in a noncontiguous neck level. Skip metastases were defined as pathologic lymph node(s) in the neck without disease in level II. RESULTS: One hundred and thirty-one patients underwent levels II-IV ND with a mean (SD) LN yield of 33.3 (±13.5). The rate of atypical metastases in both the therapeutic and elective ND cohort was 5%. The noncontiguous and skip metastases were in level IV (n = 2) and level III (n = 4), respectively. CONCLUSIONS: Skip and noncontiguous metastases were rare in patients with HPV+ OPSCC undergoing surgical treatment. Surgeons may consider a selective ND omitting Level IV in select patients with HPV+ OPSCC undergoing surgery.

Single-cell transcriptomic profiling for inferring tumor origin and mechanisms of therapeutic resistance.

Head and Neck Squamous Cell Carcinoma (HNSCC) is an aggressive epithelial cancer with poor overall response rates to checkpoint inhibitor therapy (CPI) despite CPI being the recommended treatment for recurrent or metastatic HNSCC. Mechanisms of resistance to CPI in HNSCC are poorly understood. To identify drivers of response and resistance to CPI in a unique patient who was believed to have developed three separate HNSCCs, we performed single-cell RNA-seq (scRNA-seq) profiling of two responding lesions and one progressive lesion that developed during CPI. Our results not only suggest interferon-induced APOBEC3-mediated acquired resistance as a mechanism of CPI resistance in the progressing lesion but further, that the lesion in question was actually a metastasis as opposed to a new primary tumor, highlighting the immense power of scRNA-seq as a clinical tool for inferring tumor origin and mechanisms of therapeutic resistance.

Detection of circulating tumor human papillomavirus DNA before diagnosis of HPV-positive head and neck cancer.

Human papillomavirus (HPV), most commonly HPV16, causes a growing subset of head and neck squamous cell carcinomas (HNSCCs), including the overwhelming majority of oropharynx squamous cell carcinomas in many developed countries. Circulating biomarkers for HPV-positive HNSCC may allow for earlier diagnosis, with potential to decrease morbidity and mortality. This case-control study evaluated whether circulating tumor HPV DNA (ctHPVDNA) is detectable in prediagnostic plasma from individuals later diagnosed with HPV-positive HNSCC. Cases were participants in a hospital-based research biobank with archived plasma collected ≥6 months before HNSCC diagnosis, and available archival tumor tissue for HPV testing. Controls were biobank participants without cancer or HPV-related diagnoses, matched 10:1 to cases by sex, race, age and year of plasma collection. HPV DNA was detected in plasma and tumor tissue using a previously validated digital droplet PCR-based assay that quantifies tumor-tissue-modified viral (TTMV) HPV DNA. Twelve HNSCC patients with median age of 68.5 years (range, 51-87 years) were included. Ten (83.3%) had HPV16 DNA-positive tumors. ctHPV16DNA was detected in prediagnostic plasma from 3 of 10 (30%) patients with HPV16-positive tumors, including 3 of 7 (43%) patients with HPV16-positive oropharynx tumors. The timing of the plasma collection was 19, 34 and 43 months before cancer diagnosis. None of the 100 matched controls had detectable ctHPV16DNA. This is the first report that ctHPV16 DNA is detectable at least several years before diagnosis of HPV16-positive HNSCC for a subset of patients. Further investigation of ctHPV16DNA as a biomarker for early diagnosis of HPV16-positive HNSCC is warranted.

Cell-free human papillomavirus DNA kinetics after surgery for human papillomavirus-associated oropharyngeal cancer.

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 ctHPVDNA 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. LAY SUMMARY: Human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV+OPSCC) is increasing at epidemic proportions and is commonly treated with surgery. This report describes results from a study examining the clearance kinetics of circulating tumor HPV DNA (circulating tumor human papillomavirus DNA [ctHPVDNA]) following surgical treatment of HPV+OPSCC. We found that ctHPVDNA levels 1 day after surgery are associated with the risk of residual disease in patients with HPV+OPSCC and thus could be used as a personalized biomarker for selecting adjuvant treatment in the future. These findings are the first to demonstrate the potential utility of ctHPVDNA in patients with HPV+OPSCC undergoing surgery.