@article{pmid38829114,

title = {Quantification of human papillomavirus cell-free DNA from low-volume blood plasma samples by digital PCR},

author = {Fabian Rosing and Matthias Meier and Lea Schroeder and Simon Laban and Thomas Hoffmann and Andreas Kaufmann and Oliver Siefer and Nora Wuerdemann and Jens Peter Klußmann and Thorsten Rieckmann and Yvonne Alt and Daniel L Faden and Tim Waterboer and Daniela Höfler},

doi = {10.1128/spectrum.00024-24},

issn = {2165-0497},

year  = {2024},

date = {2024-06-01},

journal = {Microbiol Spectr},

pages = {e0002424},

abstract = {The incidence rate of human papillomavirus-driven oropharyngeal cancer (HPV-OPC) is increasing in countries with high human development index. HPV cell-free DNA (cfDNA) isolated from 3 to 4 mL blood plasma has been successfully used for therapy surveillance. A highly discussed application of HPV-cfDNA is early detection of HPV-OPC. This requires sensitive and specific cfDNA detection as cfDNA levels can be very low. To study the predictive power of pre-diagnostic HPV-cfDNA, archived samples from epidemiological cohorts with limited plasma volume are an important source. To establish a cfDNA detection workflow for low plasma volumes, we compared cfDNA purification methods [MagNA Pure 96 (MP96) and QIAamp ccfDNA/RNA] and digital PCR systems (Biorad QX200 and QIAGEN QIAcuity One). Final assay validation included 65 low-volume plasma samples from oropharyngeal cancer (OPC) patients with defined HPV status stored for 2-9 years. MP96 yielded a 28% higher cfDNA isolation efficiency in comparison to QIAamp. Both digital PCR systems showed comparable analytical sensitivity (6-17 copies for HPV16 and HPV33), but QIAcuity detected both types in the same assay. In the validation set, the assay had 80% sensitivity ( = 28/35) for HPV16 and HPV33 and a specificity of 97% ( = 29/30). In samples with ≥750 µL plasma, the sensitivity was 85% ( = 17/20), while in samples with <750 µL plasma, it was 73% ( = 11/15). Despite the expected drop in sensitivity with decreased plasma volume, the assay is sensitive and highly specific even in low-volume samples and thus suited for studies exploring HPV-cfDNA as an early HPV-OPC detection marker in low-volume archival material.IMPORTANCEHPV-OPC has a favorable prognosis compared to HPV-negative OPC. However, the majority of tumors is diagnosed after regional spread, thus making intensive treatment necessary. This can cause lasting morbidity with a large impact on quality of life. One potential method to decrease treatment-related morbidity is early detection of the cancer. HPV cfDNA has been successfully used for therapy surveillance and has also been detected in pre-diagnostic samples of HPV-OPC patients. These pre-diagnostic samples are only commonly available from biobanks, which usually only have small volumes of blood plasma available. Hence, we have developed a workflow optimized for small-volume archival samples. With this method, a high sensitivity can be achieved despite sample limitations, making it suitable to conduct further large-scale biobank studies of HPV-cfDNA as a prognostic biomarker for HPV-OPC.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38662357,

title = {Circulating Tumor HPV DNA in Patients With Stage I and II HPV-Associated Head and Neck Cancer After Surgery},

author = {Saskia Naegele and Dipon Das and Shun Hirayama and Sophia Z Shalhout and Hang Lee and Jeremy D Richmon and Daniel L Faden},

doi = {10.1001/jamaoto.2024.0740},

issn = {2168-619X},

year  = {2024},

date = {2024-06-01},

urldate = {2024-06-01},

journal = {JAMA Otolaryngol Head Neck Surg},

volume = {150},

number = {6},

pages = {521--523},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38349613,

title = {Assessing the feasibility of a multimodal liquid biopsy for the diagnosis of HPV-associated oropharyngeal squamous cell carcinoma},

author = {James S Lewis and Saskia Naegele and Vasileios Efthymiou and Mitra Mehrad and Kim A Ely and Tim Waterboer and Krystle A Lang Kuhs and Seth J Davis and Kelsey Richard and Dipon Das and Daniel L Faden},

doi = {10.1093/ajcp/aqad185},

issn = {1943-7722},

year  = {2024},

date = {2024-06-01},

urldate = {2024-06-01},

journal = {Am J Clin Pathol},

volume = {161},

number = {6},

pages = {570--578},

abstract = {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).nnMETHODS: 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.nnRESULTS: 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.nnCONCLUSIONS: Compared to HPV RNA ISH, HPV serology and ctHPVDNA are sensitive and highly specific biomarkers for HPV-associated OPSCC at the time of presentation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38507992,

title = {Immunotherapy time of infusion impacts survival in head and neck cancer: A propensity score matched analysis},

author = {Daniel A Ruiz-Torres and Saskia Naegele and Archana Podury and Lori Wirth and Sophia Z Shalhout and Daniel L Faden},

doi = {10.1016/j.oraloncology.2024.106761},

issn = {1879-0593},

year  = {2024},

date = {2024-04-01},

urldate = {2024-04-01},

journal = {Oral Oncol},

volume = {151},

pages = {106761},

abstract = {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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38328243,

title = {Blood-based screening for HPV-associated cancers},

author = {Dipon Das and Shun Hirayama and Ling Aye and Michael E Bryan and Saskia Naegele and Brian Zhao and Vasileios Efthymiou and Julia Mendel and Adam S Fisch and Lea Kröller and Birgitta E Michels and Tim Waterboer and Jeremy D Richmon and Viktor Adalsteinsson and Michael S Lawrence and Matthew G Crowson and A John Iafrate and 

Daniel L Faden},

year  = {2024},

date = {2024-02-02},

urldate = {2024-02-02},

journal = {medRxiv},

keywords = {},

pubstate = {forthcoming},

tppubtype = {article}

}

@article{pmid38190058,

title = {Circulating Tumor DNA in the Immediate Postoperative Setting},

author = {Vasileios Efthymiou and Natalia Queenan and Markus Haas and Saskia Naegele and Deborah Goss and Daniel L Faden},

doi = {10.1245/s10434-023-14860-y},

issn = {1534-4681},

year  = {2024},

date = {2024-01-01},

journal = {Ann Surg Oncol},

abstract = {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.nnMETHODS: We performed a systematic review evaluating the early kinetics, defined here as 3 days of ctDNA in patients who underwent curative-intent surgery.nnRESULTS: 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.nnCONCLUSION: 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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38040848,

title = {Determinants of the level of circulating-tumor HPV16 DNA in patients with HPV-associated oropharyngeal cancer at the time of diagnosis},

author = {Marek Kentnowski and Alexander J Cortez and Agnieszka M Mazurek and Jolanta Mrochem-Kwarciak and Anna Hebda and Urszula Kacorzyk and Katarzyna Drosik-Rutowicz and Ewa Chmielik and Piotr Paul and Karolina Gajda and Izabela Łasińska and Barbara Bobek-Billewicz and Andrea d'Amico and Krzysztof Składowski and Mirosław Śnietura and Daniel L Faden and Tomasz W Rutkowski},

doi = {10.1038/s41598-023-48506-6},

issn = {2045-2322},

year  = {2023},

date = {2023-12-01},

journal = {Sci Rep},

volume = {13},

number = {1},

pages = {21226},

abstract = {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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38103593,

title = {Comparing the Diagnostic Performance of qPCR, ddPCR, and NGS Liquid Biopsies for HPV-Associated Cancers},

author = {Saskia Naegele and Daniel A Ruiz-Torres and Yan Zhao and Deborah Goss and Daniel L Faden},

doi = {10.1016/j.jmoldx.2023.11.007},

issn = {1943-7811},

year  = {2023},

date = {2023-12-01},

journal = {J Mol Diagn},

abstract = {HPV-associated cancers, including oropharyngeal squamous cell carcinoma(HPV+OPSCC), cervical cancer(HPV+CC), 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 utilized and the individual assay metrics. A comparison of these approaches has not been systematically performed to inform expected performance, which in turn impacts 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 HPV+OPSCC, HPV+CC, and HPV+SCCA patients with pre-treatment samples analyzed by quantitative PCR(qPCR), digital droplet PCR(ddPCR), or next generation sequencing(NGS). 36 studies involving 2,986 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 lastly qPCR when pooling all studies, while specificity was similar(sensitivity: ddPCR>qPCR, p<0.001; NGS>ddPCR, p=0.014). ctHPVDNA from OPSCC was more easily detected compared to CC and SCCA, overall(p=0.044). In conclusion, detection platform, anatomic site of the cancer and blood component utilized impacts ctHPVDNA detection and must be considered when interpreting results. Plasma NGS-based testing should be considered the most sensitive approach for ctHPVDNA overall.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37651109,

title = {Deciphering Knowledge and Opinions of Human Papillomavirus and Human Papillomavirus Vaccination for Facilitation of Point-of-Care Vaccination in Adults},

author = {Jacob C Bloom and Nicole Kaufmann and Shirley Koss and Heather A Edwards and Rebecca B Perkins and Daniel L Faden},

doi = {10.1001/jamaoto.2023.2073},

issn = {2168-619X},

year  = {2023},

date = {2023-10-01},

urldate = {2023-10-01},

journal = {JAMA Otolaryngol Head Neck Surg},

volume = {149},

number = {10},

pages = {870--877},

abstract = {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).nnOBJECTIVE: To assess whether individuals who were aware of the association between HPV and OPSCC would be more likely to have been previously vaccinated.nnDESIGN, 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.nnMAIN 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.nnRESULTS: 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.nnCONCLUSIONS: 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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37384999,

title = {Atypical metastases highlight the true potential of ctDNA liquid biopsies for cancer monitoring},

author = {Brian Y Zhao and Saskia Naegele and Vasileios Efthymiou and Shun Hirayama and Julia Mendel and Derrick T Lin and Dipon Das and Daniel L Faden},

doi = {10.1016/j.oraloncology.2023.106464},

issn = {1879-0593},

year  = {2023},

date = {2023-09-01},

urldate = {2023-09-01},

journal = {Oral Oncol},

volume = {144},

pages = {106464},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37148655,

title = {Relationship of HPV16 E6 seropositivity with circulating tumor tissue modified HPV16 DNA before head and neck cancer diagnosis},

author = {Eleni M Rettig and Tim Waterboer and Edward Sim and Daniel L Faden and Julia Butt and Glenn J Hanna and Catherine Del Vecchio Fitz and Charlotte Kuperwasser and Herve Sroussi},

doi = {10.1016/j.oraloncology.2023.106417},

issn = {1879-0593},

year  = {2023},

date = {2023-06-01},

urldate = {2023-06-01},

journal = {Oral Oncol},

volume = {141},

pages = {106417},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37080924,

title = {Double trouble: Synchronous and metachronous primaries confound ctHPVDNA monitoring},

author = {Saskia Naegele and Vasileios Efthymiou and Shun Hirayama and Brian Y Zhao and Dipon Das and Annie W Chan and Jeremy D Richmon and A John Iafrate and Daniel L Faden},

doi = {10.1002/hed.27378},

issn = {1097-0347},

year  = {2023},

date = {2023-06-01},

urldate = {2023-06-01},

journal = {Head Neck},

volume = {45},

number = {6},

pages = {E25--E30},

abstract = {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.nnMETHODS: 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.nnRESULTS: Detailed discussion of the patients' treatment courses, the subsequent diagnoses of their second HPV+ primaries, and their ctHPVDNA monitoring is presented.nnCONCLUSIONS: 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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36520425,

title = {Detection and Monitoring of Circulating Tumor HPV DNA in HPV-Associated Sinonasal and Nasopharyngeal Cancers},

author = {Saskia Naegele and Vasileios Efthymiou and Dipon Das and Peter M Sadow and Jeremy D Richmon and A John Iafrate and Daniel L Faden},

doi = {10.1001/jamaoto.2022.4107},

issn = {2168-619X},

year  = {2023},

date = {2023-02-01},

urldate = {2023-02-01},

journal = {JAMA Otolaryngol Head Neck Surg},

volume = {149},

number = {2},

pages = {179--181},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36416254,

title = {Rate of atypical nodal metastases in surgically treated HPV-associated oropharyngeal squamous cell carcinoma},

author = {Lauren E Miller and Vivienne H Au and Shanmugappiriya Sivarajah and Derrick T Lin and Daniel G Deschler and Mark A Varvares and Daniel L Faden and Allen L Feng and Peter M Sadow and Jeremy D Richmon},

doi = {10.1002/hed.27256},

issn = {1097-0347},

year  = {2023},

date = {2023-02-01},

urldate = {2023-02-01},

journal = {Head Neck},

volume = {45},

number = {2},

pages = {409--416},

abstract = {BACKGROUND: Understanding of nodal metastasis in patients with HPV+ oropharyngeal squamous cell carcinoma (OPSCC) is warranted.nnMETHODS: 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.nnRESULTS: 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.nnCONCLUSIONS: 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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36210388,

title = {Single-cell transcriptomic profiling for inferring tumor origin and mechanisms of therapeutic resistance},

author = {Maoxuan Lin and Moshe Sade-Feldman and Lori Wirth and Michael S Lawrence and Daniel L Faden},

doi = {10.1038/s41698-022-00314-3},

issn = {2397-768X},

year  = {2022},

date = {2022-10-01},

urldate = {2022-10-01},

journal = {NPJ Precis Oncol},

volume = {6},

number = {1},

pages = {71},

abstract = {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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35262203,

title = {Detection of circulating tumor human papillomavirus DNA before diagnosis of HPV-positive head and neck cancer},

author = {Eleni M Rettig and Daniel L Faden and Shaiba Sandhu and Kristine Wong and William C Faquin and Chloe Warinner and Phil Stephens and Sunil Kumar and Charlotte Kuperwasser and Jeremy D Richmon and Ravindra Uppaluri and Mark Varvares and Rosh Sethi and Glenn J Hanna and Herve Sroussi},

doi = {10.1002/ijc.33996},

issn = {1097-0215},

year  = {2022},

date = {2022-10-01},

urldate = {2022-10-01},

journal = {Int J Cancer},

volume = {151},

number = {7},

pages = {1081--1085},

abstract = {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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35131987,

title = {Is it Time for a Molecular-based Classification System for Sinonasal Squamous Cell Carcinoma?},

author = {Markus Haas and Elisabeth E Hansen and James S Lewis and Daniel L Faden},

doi = {10.1097/PAS.0000000000001871},

issn = {1532-0979},

year  = {2022},

date = {2022-07-01},

urldate = {2022-07-01},

journal = {Am J Surg Pathol},

volume = {46},

number = {7},

pages = {873--877},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35306154,

title = {Genetic variation within the human papillomavirus type 16 genome is associated with oropharyngeal cancer prognosis},

author = {K A Lang Kuhs and D L Faden and L Chen and D K Smith and M Pinheiro and C B Wood and S Davis and M Yeager and J F Boland and M Cullen and M Steinberg and S Bass and X Wang and P Liu and M Mehrad and T Tucker and J S Lewis and R L Ferris and L Mirabello},

doi = {10.1016/j.annonc.2022.03.005},

issn = {1569-8041},

year  = {2022},

date = {2022-06-01},

urldate = {2022-06-01},

journal = {Ann Oncol},

volume = {33},

number = {6},

pages = {638--648},

abstract = {PURPOSE: A significant barrier to adoption of de-escalated treatment protocols for human papillomavirus-driven oropharyngeal cancer (HPV-OPC) is that few predictors of poor prognosis exist. We conducted the first large whole-genome sequencing (WGS) study to characterize the genetic variation of the HPV type 16 (HPV16) genome and to evaluate its association with HPV-OPC patient survival.nnPATIENTS AND METHODS: A total of 460 OPC tumor specimens from two large United States medical centers (1980-2017) underwent HPV16 whole-genome sequencing. Site-specific variable positions [single nucleotide polymorphisms (SNPs)] across the HPV16 genome were identified. Cox proportional hazards model estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival by HPV16 SNPs. Harrell C-index and time-dependent positive predictive value (PPV) curves and areas under the PPV curves were used to evaluate the predictive accuracy of HPV16 SNPs for overall survival.nnRESULTS: A total of 384 OPC tumor specimens (83.48%) passed quality control filters with sufficient depth and coverage of HPV16 genome sequencing to be analyzed. Some 284 HPV16 SNPs with a minor allele frequency ≥1% were identified. Eight HPV16 SNPs were significantly associated with worse survival after false discovery rate correction (individual prevalence: 1.0%-5.5%; combined prevalence: 15.10%); E1 gene position 1053 [HR for overall survival (HR): 3.75, 95% CI 1.77-7.95; P = 0.0099]; L2 gene positions 4410 (HR: 5.32, 95% CI 1.91-14.81; P = 0.0120), 4539 (HR: 6.54, 95% CI 2.03-21.08; P = 0.0117); 5050 (HR: 6.53, 95% CI 2.34-18.24; P = 0.0030), and 5254 (HR: 7.76, 95% CI 2.41-24.98; P = 0.0030); and L1 gene positions 5962 (HR: 4.40, 95% CI 1.88-10.31; P = 0.0110) and 6025 (HR: 5.71, 95% CI 2.43-13.41; P = 0.0008) and position 7173 within the upstream regulatory region (HR: 9.90, 95% CI 3.05-32.12; P = 0.0007). Median survival time for patients with ≥1 high-risk HPV16 SNPs was 3.96 years compared with 18.67 years for patients without a high-risk SNP; log-rank test P < 0.001. HPV16 SNPs significantly improved the predictive accuracy for overall survival above traditional factors (age, smoking, stage, treatment); increase in C-index was 0.069 (95% CI 0.019-0.119, P < 0.001); increase in area under the PPV curve for predicting 5-year survival was 0.068 (95% CI 0.015-0.111, P = 0.008).nnCONCLUSIONS: HPV16 genetic variation is associated with HPV-OPC prognosis and can improve prognostic accuracy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35139236,

title = {Cell-free human papillomavirus DNA kinetics after surgery for human papillomavirus-associated oropharyngeal cancer},

author = {Connor J O'Boyle and Giulia Siravegna and Shohreh Varmeh and Natalia Queenan and Alexa Michel and Kim Chang Sing Pang and Jarrod Stein and Julia C Thierauf and Peter M Sadow and William C Faquin and Wei Wang and Daniel G Deschler and Kevin S Emerick and Mark A Varvares and Jong C Park and John R Clark and Annie W Chan and Paul M Busse and Ryan B Corcoran and Lori J Wirth and Derrick T Lin and A John Iafrate and Jeremy D Richmon and Daniel L Faden},

doi = {10.1002/cncr.34109},

issn = {1097-0142},

year  = {2022},

date = {2022-06-01},

urldate = {2022-06-01},

journal = {Cancer},

volume = {128},

number = {11},

pages = {2193--2204},

abstract = {BACKGROUND: New ultrasensitive methods for detecting residual disease after surgery are needed in human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV+OPSCC).nnMETHODS: 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.nnRESULTS: 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.nnCONCLUSIONS: 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.nnLAY 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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34857594,

title = {Cell-Free HPV DNA Provides an Accurate and Rapid Diagnosis of HPV-Associated Head and Neck Cancer},

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

doi = {10.1158/1078-0432.CCR-21-3151},

issn = {1557-3265},

year  = {2022},

date = {2022-02-01},

urldate = {2022-02-01},

journal = {Clin Cancer Res},

volume = {28},

number = {4},

pages = {719--727},

abstract = {PURPOSE: HPV-associated head and neck squamous cell carcinoma (HPV+HNSCC) is the most common HPV-associated malignancy in the United States and continues to increase in incidence. Current diagnostic approaches for HPV+HNSCC rely on tissue biopsy followed by histomorphologic assessment and detection of HPV indirectly by p16 IHC. Such approaches are invasive and have variable sensitivity.nnEXPERIMENTAL DESIGN: We conducted a prospective observational study in 140 subjects (70 cases and 70 controls) to test the hypothesis that a noninvasive diagnostic approach for HPV+HNSCC would have improved diagnostic accuracy, lower cost, and shorter diagnostic interval compared with standard approaches. Blood was collected, processed for circulating tumor HPV DNA (ctHPVDNA), and analyzed with custom ddPCR assays for HPV genotypes 16, 18, 33, 35, and 45. Diagnostic performance, cost, and diagnostic interval were calculated for standard clinical workup and compared with a noninvasive approach using ctHPVDNA combined with cross-sectional imaging and physical examination findings.nnRESULTS: Sensitivity and specificity of ctHPVDNA for detecting HPV+HNSCC were 98.4% and 98.6%, respectively. Sensitivity and specificity of a composite noninvasive diagnostic using ctHPVDNA and imaging/physical examination were 95.1% and 98.6%, respectively. Diagnostic accuracy of this noninvasive approach was significantly higher than standard of care (Youden index 0.937 vs. 0.707, P = 0.0006). Costs of noninvasive diagnostic were 36% to 38% less than standard clinical workup and the median diagnostic interval was 26 days less.nnCONCLUSIONS: A noninvasive diagnostic approach for HPV+HNSCC demonstrated improved accuracy, reduced cost, and a shorter time to diagnosis compared with standard clinical workup and could be a viable alternative in the future.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34375020,

title = {Liquid biopsy for the diagnosis of HPV-associated head and neck cancer},

author = {Daniel L Faden},

doi = {10.1002/cncy.22497},

issn = {1934-6638},

year  = {2022},

date = {2022-01-01},

urldate = {2022-01-01},

journal = {Cancer Cytopathol},

volume = {130},

number = {1},

pages = {12--15},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33797697,

title = {Oropharyngeal Squamous Cell Carcinoma Morphology and Subtypes by Human Papillomavirus Type and by 16 Lineages and Sublineages},

author = {James S Lewis and Lisa Mirabello and Ping Liu and Xiaowei Wang and William D Dupont and W Dale Plummer and Maisa Pinheiro and Meredith Yeager and Joseph F Boland and Michael Cullen and Mia Steinberg and Sara Bass and Mitra Mehrad and Connor O'Boyle and Maoxuan Lin and Daniel L Faden and Krystle A Lang-Kuhs},

doi = {10.1007/s12105-021-01318-4},

issn = {1936-0568},

year  = {2021},

date = {2021-12-01},

urldate = {2021-12-01},

journal = {Head Neck Pathol},

volume = {15},

number = {4},

pages = {1089--1098},

abstract = {Oropharyngeal squamous cell carcinoma (SCC) is increasing in incidence and, in Western countries, strongly associated with transcriptionally-active high-risk human papillomavirus (HPV). Within HPV-positive tumors, there is wide morphologic diversity with numerous histologic subtypes of SCC. There are also variable degrees of keratinization, anaplasia, stromal fibrosis, and maturing squamous differentiation. Unlike in the uterine cervix, where associations between HPV types and lineages/sublineages within types have been investigated with some clear correlations identified, little to no data exists for oropharyngeal SCC. In this study, for a large cohort of oropharyngeal SCC patients, we performed RTPCR for high-risk HPV. For the HPV positive patients, we sequenced the DNA of the entire HPV16 genome and determined lineages and sublineages, correlating HPV status, genotype, and HPV16 lineages/sublineages with SCC subtype and various histologic features. Of the 259 patients, 224 (86.5%) were high-risk HPV positive, of which 210/224 (93.8%) were HPV type 16 and 6/224 (2.7%) HPV type 33. Of the four HPV16 lineages, A was the most frequent (192/214 or 89.8%) and of the HPV16 A sublineages, A1 was the most frequent (112/210 or 53.3%). Patients with HPV negative tumors were more often keratinizing vs other types (23/35 or 65.7%) and thus more likely to have more maturing squamous differentiation and stromal desmoplasia. There was no significant correlation between HPV type (16 versus other), between HPV16 lineage (A versus others), or HPV16 A sublineages (A1 or A2 versus others) and morphologic type of SCC nor the various morphologic features of anaplasia/multinucleation, degree of keratinization, nor amount of stromal desmoplasia. In summary, in our cohort, there was no correlation between the type of HPV, the HPV 16 lineage or sublineage, and any of the histologic features or morphologic SCC subtypes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34407971,

title = {Recurrent Human Papillomavirus-Related Head and Neck Cancer Undergoes Metabolic Reprogramming and Is Driven by Oxidative Phosphorylation},

author = {Avani Vyas and R Alex Harbison and Daniel L Faden and Mark Kubik and Drake Palmer and Qing Zhang and Hatice U Osmanbeyoglu and Kirill Kiselyov and Eduardo Méndez and Umamaheswar Duvvuri},

doi = {10.1158/1078-0432.CCR-20-4789},

issn = {1557-3265},

year  = {2021},

date = {2021-11-01},

journal = {Clin Cancer Res},

volume = {27},

number = {22},

pages = {6250--6264},

abstract = {PURPOSE: Human papillomavirus (HPV) infection drives the development of some head and neck squamous cell carcinomas (HNSCC). This disease is rapidly increasing in incidence worldwide. Although these tumors are sensitive to treatment, approximately 10% of patients fail therapy. However, the mechanisms that underlie treatment failure remain unclear.nnEXPERIMENTAL DESIGN: We performed RNA sequencing (RNA-seq) on tissues from matched primary- (pHNSCC) and metachronous-recurrent cancers (rHNSCC) to identify transcriptional differences to gain mechanistic insight into the evolutionary adaptations of metachronous-recurrent tumors. We used HPV-related HNSCC cells lines to investigate the effect of (i) NRF2 overexpression on growth  and , (ii) oxidative phosphorylation (OXPHOS) inhibition using IACS-010759 on NRF2-dependent cells, and (iii) combination of cisplatin and OXPHOS inhibition.nnRESULTS: The OXPHOS pathway is enriched in recurrent HPV-associated HNSCC and may contribute to treatment failure. NRF2-enriched HNSCC samples from The Cancer Genome Atlas (TCGA) with enrichment in OXPHOS, fatty-acid metabolism, Myc, Mtor, reactive oxygen species (ROS), and glycolytic signaling networks exhibited worse survival. HPV-positive HNSCC cells demonstrated sensitivity to the OXPHOS inhibitor, in a NRF2-dependent manner. Further, using murine xenograft models, we identified NRF2 as a driver of tumor growth. Mechanistically, NRF2 drives ROS and mitochondrial respiration, and NRF2 is a critical regulator of redox homeostasis that can be crippled by disruption of OXPHOS. NRF2 also mediated cisplatin sensitivity in endogenously overexpressing primary HPV-related HNSCC cells.nnCONCLUSIONS: These results unveil a paradigm-shifting translational target harnessing NRF2-mediated metabolic reprogramming in HPV-related HNSCC.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid34452530,

title = {APOBEC Mutagenesis Is Concordant between Tumor and Viral Genomes in HPV-Positive Head and Neck Squamous Cell Carcinoma},

author = {Daniel L Faden and Krystle A Lang Kuhs and Maoxuan Lin and Adam Langenbucher and Maisa Pinheiro and Meredith Yeager and Michael Cullen and Joseph F Boland and Mia Steinberg and Sara Bass and James S Lewis and Michael S Lawrence and Robert L Ferris and Lisa Mirabello},

doi = {10.3390/v13081666},

issn = {1999-4915},

year  = {2021},

date = {2021-08-01},

journal = {Viruses},

volume = {13},

number = {8},

abstract = {APOBEC is a mutagenic source in human papillomavirus (HPV)-mediated malignancies, including HPV+ oropharyngeal squamous cell carcinoma (HPV + OPSCC), and in HPV genomes. It is unknown why APOBEC mutations predominate in HPV + OPSCC, or if the APOBEC-induced mutations observed in both human cancers and HPV genomes are directly linked. We performed sequencing of host somatic exomes, transcriptomes, and HPV16 genomes from 79 HPV + OPSCC samples, quantifying APOBEC mutational burden and activity in both host and virus. APOBEC was the dominant mutational signature in somatic exomes. In viral genomes, there was a mean of five (range 0-29) mutations per genome. The mean of APOBEC mutations in viral genomes was one (range 0-5). Viral APOBEC mutations, compared to non-APOBEC mutations, were more likely to be low-variant allele fraction mutations, suggesting that APOBEC mutagenesis actively occurrs in viral genomes during infection. HPV16 APOBEC-induced mutation patterns in OPSCC were similar to those previously observed in cervical samples. Paired host and viral analyses revealed that APOBEC-enriched tumor samples had higher viral APOBEC mutation rates ( = 0.028), and APOBEC-associated RNA editing ( = 0.008), supporting the concept that APOBEC mutagenesis in host and viral genomes is directly linked and occurrs during infection. Using paired sequencing of host somatic exomes, transcriptomes, and viral genomes, we demonstrated for the first-time definitive evidence of concordance between tumor and viral APOBEC mutagenesis. This finding provides a missing link connecting APOBEC mutagenesis in host and virus and supports a common mechanism driving APOBEC dysregulation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33602576,

title = {Prospective assessment of multiple HPV-positive oropharyngeal squamous cell carcinomas},

author = {Daniel L Faden and Connor J O'Boyle and Derrick T Lin and Daniel G Deschler and Kevin S Emerick and Mark A Varvares and William C Faquin and Peter M Sadow and Jeremy D Richmon},

doi = {10.1016/j.oraloncology.2021.105212},

issn = {1879-0593},

year  = {2021},

date = {2021-06-01},

urldate = {2021-06-01},

journal = {Oral Oncol},

volume = {117},

pages = {105212},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33075810,

title = {HPV+ oropharyngeal squamous cell carcinomas from patients with two tumors display synchrony of viral genomes yet discordant mutational profiles and signatures},

author = {Daniel L Faden and Adam Langenbucher and Krystle Kuhs and James S Lewis and Lisa Mirabello and Meredith Yeager and Joseph F Boland and Sara Bass and Mia Steinberg and Michael Cullen and Michael S Lawrence and Robert L Ferris},

doi = {10.1093/carcin/bgaa111},

issn = {1460-2180},

year  = {2021},

date = {2021-02-01},

journal = {Carcinogenesis},

volume = {42},

number = {1},

pages = {14--20},

abstract = {Human papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma (HPV + OPSCC) is increasing in prevalence in the USA, as are cases of patients with multiple HPV + OPSCCs (mHPV + OPSCC). mHPV + OPSCCs present a unique opportunity to examine HPV + OPSCC mutation acquisition and evolution. We performed sequencing of the viral genome, somatic exome and somatic transcriptome from 8 patients each with 2 spatially distinct HPV + OPSCCs, and 37 'traditional' HPV + OPSCCs to first address if paired tumors are caused by the same viral isolate and next, if acquired alterations, and the underlying processes driving mutagenesis, are shared within pairs. All tumor pairs contained viral genomes from the same HPV type 16 sublineage and differed by 0-2 clonal single nucleotide polymorphisms (SNPs), suggesting infection with the same viral isolate. Despite this, there was significant discordance in expression profiles, mutational burden and mutational profiles between tumors in a pair, with only two pairs sharing any overlapping mutations (3/3343 variants). Within tumor pairs there was a striking discrepancy of mutational signatures, exemplified by no paired tumors sharing high APOBEC mutational burden. Here, leveraging mHPV + OPSCCs as a model system to study mutation acquisition in virally mediated tumors, in which the germline, environmental exposures, immune surveillance and tissue/organ type were internally controlled, we demonstrate that despite infection by the same viral isolate, paired mHPV + OPSCCs develop drastically different somatic alterations and even more strikingly, appear to be driven by disparate underlying mutational processes. Thus, despite a common starting point, HPV + OPSCCs evolve through variable mutational processes with resultant stochastic mutational profiles.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33146897,

title = {The mutational landscape of early- and typical-onset oral tongue squamous cell carcinoma},

author = {Benjamin R Campbell and Zhishan Chen and Daniel L Faden and Nishant Agrawal and Ryan J Li and Glenn J Hanna and N Gopalakrishna Iyer and Arnoud Boot and Steven G Rozen and Andre L Vettore and Binay Panda and Neeraja M Krishnan and Curtis R Pickering and Jeffrey N Myers and Xingyi Guo and Krystle A Lang Kuhs},

doi = {10.1002/cncr.33309},

issn = {1097-0142},

year  = {2021},

date = {2021-02-01},

journal = {Cancer},

volume = {127},

number = {4},

pages = {544--553},

abstract = {BACKGROUND: The incidence of oral tongue squamous cell carcinoma (OTSCC) is increasing among younger birth cohorts. The etiology of early-onset OTSCC (diagnosed before the age of 50 years) and cancer driver genes remain largely unknown.nnMETHODS: The Sequencing Consortium of Oral Tongue Cancer was established through the pooling of somatic mutation data of oral tongue cancer specimens (n = 227 [107 early-onset cases]) from 7 studies and The Cancer Genome Atlas. Somatic mutations at microsatellite loci and Catalog of Somatic Mutations in Cancer mutation signatures were identified. Cancer driver genes were identified with the MutSigCV and WITER algorithms. Mutation comparisons between early- and typical-onset OTSCC were evaluated via linear regression with adjustments for patient-related factors.nnRESULTS: Two novel driver genes (ATXN1 and CDC42EP1) and 5 previously reported driver genes (TP53, CDKN2A, CASP8, NOTCH1, and FAT1) were identified. Six recurrent mutations were identified, with 4 occurring in TP53. Early-onset OTSCC had significantly fewer nonsilent mutations even after adjustments for tobacco use. No associations of microsatellite locus mutations and mutation signatures with the age of OTSCC onset were observed.nnCONCLUSIONS: This international, multicenter consortium is the largest study to characterize the somatic mutational landscape of OTSCC and the first to suggest differences by age of onset. This study validates multiple previously identified OTSCC driver genes and proposes 2 novel cancer driver genes. In analyses by age, early-onset OTSCC had a significantly smaller somatic mutational burden that was not explained by differences in tobacco use.nnLAY SUMMARY: This study identifies 7 specific areas in the human genetic code that could be responsible for promoting the development of tongue cancer. Tongue cancer in young patients (under the age of 50 years) has fewer overall changes to the genetic code in comparison with tongue cancer in older patients, but the authors do not think that this is due to differences in smoking rates between the 2 groups. The cause of increasing cases of tongue cancer in young patients remains unclear.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33561073,

title = {Human Papillomavirus in Sinonasal Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis},

author = {Kim J W Chang Sing Pang and Taha Mur and Louise Collins and Sowmya R Rao and Daniel L Faden},

doi = {10.3390/cancers13010045},

issn = {2072-6694},

year  = {2020},

date = {2020-12-01},

journal = {Cancers (Basel)},

volume = {13},

number = {1},

abstract = {Human papillomavirus (HPV) drives tumorigenesis in a subset of oropharyngeal squamous cell carcinomas (OPSCC) and is increasing in prevalence across the world. Mounting evidence suggests HPV is also involved in a subset of sinonasal squamous cell carcinomas (SNSCC), yet small sample sizes and variability of HPV detection techniques in existing literature hinder definitive conclusions. A systematic review was performed by searching literature through March 29th 2020 using PubMed, Embase, and Web of Science Core Collection databases. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed by two authors independently. A meta-analysis was performed using the random-effects model. Sixty studies ( = 1449) were eligible for statistical analysis estimating an overall HPV prevalence of 25.5% (95% CI 20.7-31.0). When stratified by HPV detection method, prevalence with multiple substrate testing (20.5%, 95% CI 14.5-28.2) was lower than with single substrate testing (31.7%, 95% CI 23.6-41.1), highest in high-exposure anatomic subsites (nasal cavity and ethmoids) (37.6%, 95% CI 26.5-50.2) vs. low-exposure (15.1%, 95% CI 7.3-28.6) and highest in high HPV+ OPSCC prevalence geographic regions (North America) (30.9%, 95% CI 21.9-41.5) vs. low (Africa) (13.1, 95% CI 6.5-24.5)). While small sample sizes and variability in data cloud firm conclusions, here, we provide a new reference point prevalence for HPV in SNSCC along with orthogonal data supporting a causative role for virally driven tumorigenesis, including that HPV is more commonly found in sinonasal subsites with increased exposure to refluxed oropharyngeal secretions and in geographic regions where HPV+ OPSCC is more prevalent.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33065374,

title = {Treatment sequence of cetuximab and immune checkpoint inhibitor in head and neck squamous cell carcinoma differentially affects outcomes},

author = {Jong Chul Park and Julia Durbeck and John R Clark and Daniel L Faden},

doi = {10.1016/j.oraloncology.2020.105024},

issn = {1879-0593},

year  = {2020},

date = {2020-12-01},

journal = {Oral Oncol},

volume = {111},

pages = {105024},

abstract = {OBJECTIVES: To examine the impact of treatment sequences of Immune checkpoint inhibitor (ICI) and cetuximab on clinical outcomes in patients with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).nnMATERIALS AND METHODS: Clinicopathologic data were retrospectively collected on patients with R/M HNSCC who received ICI treatment. Association between treatment sequence and clinical outcomes were assessed.nnRESULTS: A total of 113 patients with R/M HNSCC were analyzed. Patients who had cetuximab prior to ICI had worse overall (HR, 1.83) and progression-free survival (HR, 1.76) compare to those without prior cetuximab. Among patients who had subsequent therapy after ICI, cetuximab-based therapy was associated with a trend toward higher response rate and longer survival than non-cetuximab regimen.nnCONCLUSION: Our single institution analysis showed that treatment sequence of cetuximab and ICI in R/M HNSCC may affect clinical outcomes. Cetuximab prior to ICI was associated with worse outcomes while the efficacy of cetuximab may be enhanced after ICI therapy.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32414645,

title = {Immune checkpoint inhibitors in sinonasal squamous cell carcinoma},

author = {Jong Chul Park and William C Faquin and Julia Durbeck and Daniel L Faden},

doi = {10.1016/j.oraloncology.2020.104776},

issn = {1879-0593},

year  = {2020},

date = {2020-10-01},

urldate = {2020-10-01},

journal = {Oral Oncol},

volume = {109},

pages = {104776},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32582473,

title = {Sinonasal Squamous Cell Carcinoma: Etiology, Pathogenesis, and the Role of Human Papilloma Virus},

author = {Katya Elgart and Daniel L Faden},

doi = {10.1007/s40136-020-00279-6},

issn = {2167-583X},

year  = {2020},

date = {2020-06-01},

journal = {Curr Otorhinolaryngol Rep},

volume = {8},

number = {2},

pages = {111--119},

abstract = {PURPOSE OF REVIEW: Sinonasal squamous cell carcinoma (SNSCC) is a rare disease with considerable histologic diversity. Currently, there is a poor understanding of the etiology and pathogenesis of SNSCC. Here, we review recent literature to summarize what is known regarding (1) the etiology of SNSCC, (2) the role of Human Papilloma Virus (HPV) in SNSCC, and (2) the molecular underpinnings of SNSCC.nnRECENT FINDINGS: 1. High risk HPVappears to play a role in the pathogenesis of a subset of SNSCCs. SNSCCs with high risk HPV have improved survival compared with those without HPV and occur in patients who are younger, similar to HPV mediated oropharyngeal cancer. 2. A subset of inverted papillomas have transcriptionally active low-risk HPV and have a higher risk of transformation, while low risk HPV negative inverted papillomas frequently have EGFR mutations.nnSUMMARY: SNSCC is a diverse disease with likely multiple etiologies including carcinogen, irritant exposure, and HPV. While not definitively proven, evidence supports a role for high-risk HPV in a subset of SNSCC, and low-risk HPV in a subset of inverted papillomas which transform to SNSCC. In-depth molecular and genomic studies are needed in SNSCC to better understand the genomic underpinnings and oncogenic drivers.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31765835,

title = {Two for the price of one: Prevalence, demographics and treatment implications of multiple HPV mediated Head and Neck Cancers},

author = {William Strober and Sachie Shishido and Burton Wood and James S Lewis and Krystle Kuhs and Robert L Ferris and Daniel L Faden},

doi = {10.1016/j.oraloncology.2019.104475},

issn = {1879-0593},

year  = {2020},

date = {2020-01-01},

journal = {Oral Oncol},

volume = {100},

pages = {104475},

abstract = {OBJECTIVES: HPV mediated head and neck squamous cell carcinoma (HPVmHNSCC) is increasing in prevalence in the United States, as are reports of patients with multiple HPVmHNSCCs. The prevalence, demographics, and treatment implications of this emerging clinical entity are poorly understood.nnMATERIALS AND METHODS: We performed a multitiered assessment of patients with multiple HPVmHNSCC including: 1. systematic review of the literature, 2. query of the 2017 Surveillance, Epidemiology and End Results (SEER) database and 3. institutional level reporting at two high volume academic centers.nnRESULTS: Systematic literature review: 13 articles met inclusion criteria (48 patients with multiple HPVmHNSCC). Pooled prevalence rate of multiple HPVmHNSCC was 2.64%. SEER database: 60(0.95%) patients with HPVmHNSCC had two tumors. Patients with multiple HPVmHNSCC were more likely to be younger and present with a lower T and N stage (p < 0.025 for all). The second identified tumor was more likely to be contralateral, found synchronously, of smaller size, and to occur in the tonsil (p < 0.05 for all). Institutional reporting: 17(1.69%) patients with HPVmHNSCC had two primary tumors. Similar to the SEER database, patients with multiple HPVmHNSCC were more likely to present with a low T stage and tonsil location (p < 0.007 for both).nnCONCLUSION: Multiple HPVmHNSCCs occur in a subset of HPVmHNSCC cases with distinct characteristics. Thorough interrogation of all oropharyngeal subsites should be performed as part of the initial workup for HPVmHNSCC, with consideration given to contralateral tonsillectomy at the time of surgical resection for HPV mediated tonsil cancers due to the prevalence of contralateral tonsil primaries.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}