Sensitive MRD Detection from Lymphatic Fluid after Surgery in HPV-Associated Oropharyngeal Cancer.

PURPOSE: Our goal was to demonstrate that lymphatic drainage fluid (lymph) has improved sensitivity in quantifying postoperative minimal residual disease (MRD) in locally advanced human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) compared with plasma, and leverage this novel biofluid for patient risk stratification. EXPERIMENTAL DESIGN: We prospectively collected lymph samples from neck drains of 106 patients with HPV (+) OPSCC, along with 67 matched plasma samples, 24 hours after surgery. PCR and next-generation sequencing were used to quantify cancer-associated cell-free HPV (cf-HPV) and tumor-informed variants in lymph and plasma. Next, lymph cf-HPV and variants were compared with TNM stage, extranodal extension (ENE), and composite definitions of high-risk pathology. We then created a machine learning model, informed by lymph MRD and clinicopathologic features, to compare with progression-free survival (PFS). RESULTS: Postoperative lymph was enriched with cf-HPV compared with plasma (P < 0.0001) and correlated with pN2 stage (P = 0.003), ENE (P < 0.0001), and trial-defined pathologic risk criteria (mean AUC = 0.78). In addition, the lymph mutation number and variant allele frequency were higher in pN2 ENE (+) necks than in pN1 ENE (+) (P = 0.03, P = 0.02) or pN0-N1 ENE (-) (P = 0.04, P = 0.03, respectively). The lymph MRD-informed risk model demonstrated inferior PFS in high-risk patients (AUC = 0.96, P < 0.0001). CONCLUSIONS: Variant and cf-HPV quantification, performed in 24-hour postoperative lymph samples, reflects single- and multifeature high-risk pathologic criteria. Incorporating lymphatic MRD and clinicopathologic feature analysis can stratify PFS early after surgery in patients with HPV (+) head and neck cancer. See related commentary by Shannon and Iyer, p. 1223.

Targeted Proteomic Quantitation of NRF2 Signaling and Predictive Biomarkers in HNSCC.

The NFE2L2 (NRF2) oncogene and transcription factor drives a gene expression program that promotes cancer progression, metabolic reprogramming, immune evasion, and chemoradiation resistance. Patient stratification by NRF2 activity may guide treatment decisions to improve outcome. Here, we developed a mass spectrometry-based targeted proteomics assay based on internal standard-triggered parallel reaction monitoring to quantify 69 NRF2 pathway components and targets, as well as 21 proteins of broad clinical significance in head and neck squamous cell carcinoma (HNSCC). We improved an existing internal standard-triggered parallel reaction monitoring acquisition algorithm, called SureQuant, to increase throughput, sensitivity, and precision. Testing the optimized platform on 27 lung and upper aerodigestive cancer cell models revealed 35 NRF2 responsive proteins. In formalin-fixed paraffin-embedded HNSCCs, NRF2 signaling intensity positively correlated with NRF2-activating mutations and with SOX2 protein expression. Protein markers of T-cell infiltration correlated positively with one another and with human papilloma virus infection status. CDKN2A (p16) protein expression positively correlated with the human papilloma virus oncogenic E7 protein and confirmed the presence of translationally active virus. This work establishes a clinically actionable HNSCC protein biomarker assay capable of quantifying over 600 peptides from frozen or formalin-fixed paraffin-embedded archived tissues in under 90 min.

Patients' Views of Shared Decision-making and Decisional Conflict in Otolaryngologic Surgery During the COVID-19 Pandemic.

Importance: A patient's decision to undergo surgery may be fraught with uncertainty and decisional conflict. The unpredictable nature of the COVID-19 pandemic warrants further study into factors associated with patient decision-making. Objective: To assess decisional conflict and patient-specific concerns for people undergoing otolaryngologic surgery during the pandemic. Design, Setting, Participants: This prospective cross-sectional survey study was conducted via telephone from April 22 to August 31, 2020. English-speaking adults scheduled for surgery from a single academic surgical center were invited to participate. Individuals who were non-English speaking, lacked autonomous medical decision-making capacity, scheduled for emergent surgery, or had a communication disability were excluded. For race and ethnicity reporting, participants were classified dichotomously as White according to the Behavioral Risk Factor Surveillance System from the Centers for Disease Control and Prevention or non-White as a collective term including Black or African American, American Indian or Alaska Native, Asian, or Pacific Islander race and ethnicity. Exposures: The SURE Questionnaire (sure of myself, understand information, risks/benefits ratio, and encouragement) was used to screen for decisional conflict, with a total score greater than or equal to 3 indicating clinically significant decisional conflict. Participants were asked to share their specific concerns about having surgery. Main Outcome and Measures: Decisional conflict and patient demographic data were assessed via bivariate analyses, multivariable logistic regression and conjunctive consolidation. Patient-specific concerns were qualitatively analyzed for summative themes. Results: Of 444 patients screened for eligibility, 182 (40.9%) respondents participated. The median age was 60.5 years (interquartile range, 48-70 years). The racial and ethnic identity of the participants was classified as binary White (84% [153 of 182]) and non-White (16% [29 of 182]). The overall prevalence of decisional conflict was 19% (34 of 182). Decisional conflict was more prevalent among non-White than White participants (proportion difference 18.8%, 95% CI, 0.6%-37.0% and adjusted odds ratio 3.0; 95% CI, 1.2-7.4). Combining information from multiple variables through conjunctive consolidation, the group with the highest rate of decisional conflict was non-White patients with no college education receiving urgent surgery (odds ratio, 10.8; 95% CI, 2.6-45.0). Intraoperative and postoperative concerns were the most common themes expressed by participants. There was a clinically significant difference in the proportion of participants who screened positive for decisional conflict (30%) and expressed postoperative concerns than those who screened negative for decisional conflict (17%) (proportion difference, 13%; 95% CI, 1%-25%). Among patients reporting concerns about COVID-19, most screened positive for decisional conflict. Conclusions and Relevance: Results of this cross-sectional survey study suggest that the COVID-19 pandemic was associated with decisional conflict in patients undergoing otolaryngologic surgery. Consistent discussion of risks and benefits is essential. The role of race and ethnicity in decisional conflict warrants further study.

National trends in oropharyngeal cancer incidence and survival within the Veterans Affairs Health Care System.

BACKGROUND: Oropharyngeal squamous cell carcinoma (OPSCC) epidemiology has not been examined previously in the nationwide Veterans Affairs (VA) population. METHODS: Joinpoint regression analysis was applied to OPSCC cases identified from VA administrative data from 2000 to 2012. RESULTS: We identified 12 125 OPSCC cases (incidence: 12.2 of 100 000 persons). OPSCC incidence declined between 2000 and 2006 (annual percent change [APC] = -4.27, P < .05), then increased between 2006 and 2012 (APC = 7.02, P < .05). Significant incidence increases occurred among white (APC = 7.19, P < .05) and African American (APC = 4.87, P < .05) Veterans and across all age cohorts. The percentage of never-smokers increased from 8% in 2000 to 15.7% in 2012 (P < .001), and 2-year overall survival improved from 31.2% (95% confidence interval (CI) [30-33.4]) to 55.7% (95% CI [54.4-57.1]). CONCLUSIONS: OPSCC incidence is increasing across all racial and age cohorts in the VA population. Smoking rates remain high among Veterans with OPSCC and gains in survival lag those reported in the general population.