HPV Sequencing Facilitates Ultrasensitive Detection of HPV Circulating Tumor DNA

Clinical Cancer Research, Год журнала: 2021, Номер 27(21), С. 5857 - 5868

Опубликована: Сен. 27, 2021

Human papillomavirus (HPV) DNA offers a convenient circulating tumor (ctDNA) marker for HPV-associated malignancies, but current methods, such as digital PCR (dPCR), provide insufficient accuracy clinical applications in patients with low disease burden. We asked whether next-generation sequencing approach, HPV (HPV-seq), could quantitative and qualitative assessment of ctDNA burden settings.We conducted preclinical technical validation studies on HPV-seq applied it retrospectively to prospective multicenter cohort locally advanced cervix cancer (NCT02388698) oropharynx cancer. results were compared dPCR. The primary outcome was progression-free survival (PFS) according end-of-treatment detectability.HPV-seq achieved reproducible detection at levels less than 0.6 copies cell line data. dPCR highly correlated (R2 = 0.95, P 1.9 × 10-29) detecting down 0.03 copies/mL plasma dPCR-negative posttreatment samples. Detectable associated inferior PFS 100% sensitivity 67% specificity recurrence. Accurate genotyping successful from pretreatment fragment sizes consistently shorter non-cancer-derived cell-free (cfDNA) fragments, stereotyped cfDNA fragmentomic patterns observed across genomes.HPV-seq is method that outperforms reveals information about ctDNA. Our findings this proof-of-principle study have implications treatment monitoring HPV-related cancers. Future are needed confirm undetectable following chemoradiotherapy exceptionally high cure rates.

Язык: Английский

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Phase II Multi-institutional Clinical Trial Result of Concurrent Cetuximab and Nivolumab in Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma

Clinical Cancer Research, Год журнала: 2022, Номер 28(11), С. 2329 - 2338

Опубликована: Март 1, 2022

Abstract Purpose: A phase II multi-institutional clinical trial was conducted to determine overall survival (OS) in patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) treated a combination of cetuximab nivolumab. Patients Methods: R/M HNSCC were 500 mg/m2 i.v. on day 14 as lead-in followed by nivolumab 240 mg 1 15 each 28-day cycle. Expression p16 programmed death-ligand (PD-L1) archived tumors determined. Tumor-tissue–modified human papillomavirus (TTMV) DNA quantified plasma. Results: Ninety-five enrolled, 88 evaluable for OS median follow-up 15.9 months. Median the 45 who had prior therapy (cohort A) 11.4 months, year 50% [90% confidence interval (CI), 0.43–0.57]. 43 no B) 20.2 1-year 66% (90% CI, 0.59–0.71). In combined cohorts, p16-negative immunostaining associated higher response rate (RR; P = 0.02) but did not impact while PD-L1 positive score RR (P 0.03) longer (log-rank 0.04). p16-positive patients, lower (1,230 copies/mL) TTMV counts 0.01) compared 0.05). Conclusions: The is effective both previously untreated warrants further evaluation.

Язык: Английский

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Human papilloma virus circulating tumor DNA assay predicts treatment response in recurrent/metastatic head and neck squamous cell carcinoma

Oncotarget, Год журнала: 2021, Номер 12(13), С. 1214 - 1229

Опубликована: Июнь 16, 2021

Despite the rising incidence of human papillomavirus related (HPV+) oropharyngeal squamous cell carcinoma (OPSCC), treatment metastatic disease remains palliative. Even with new treatments such as immunotherapy, response rates are low and can be delayed, while even mild tumor progression in face an ineffective therapy lead to rapid death. Real-time biomarkers could improve outcomes by guiding early change setting. Herein, we developed analytically validated a droplet digital PCR (ddPCR)-based assay for HPV16 circulating DNA (ctDNA) evaluated plasma ctDNA predicting HPV+ OPSCC. We found that longitudinal changes correlate responses observed earlier than conventional imaging (average 70 days, range: 35-166). With additional validation multi-site studies, this may enable identification failure, allowing patients directed promptly toward clinical trials or alternative therapies.

Язык: Английский

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Detectable Postoperative Circulating Tumor Human Papillomavirus DNA and Association with Recurrence in Patients With HPV-Associated Oropharyngeal Squamous Cell Carcinoma

International Journal of Radiation Oncology*Biology*Physics, Год журнала: 2022, Номер 113(3), С. 530 - 538

Опубликована: Фев. 12, 2022

Язык: Английский

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

Cancer, Год журнала: 2022, Номер 128(11), С. 2193 - 2204

Опубликована: Фев. 9, 2022

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 papillomavirus DNA (ctHPVDNA) is associated with postoperative status, a prospective observational study was conducted 33 patients HPV+OPSCC undergoing surgery. Blood collected before surgery, days 1 (POD 1), 7, and 30 follow‐up. A subcohort 12 underwent frequent blood collections first 24 hours to define early kinetics. Plasma run on custom droplet digital polymerase chain reaction (ddPCR) assays HPV genotypes 16, 18, 33, 35, 45. Results In without pathologic risk factors recurrence who were observed ctHPVDNA rapidly decreased <1 copy/mL by POD (n = 8/8). macroscopic disease, markedly elevated (>350 copies/mL) remained until adjuvant treatment 3/3). Patients intermediate levels (1.2‐58.4 all possessed microscopic 9/9). higher known adverse such as extranodal extension >1 mm ( P .0481) increasing lymph nodes involved .0453) further received .0076). One had that detected 2 months earlier than clinical detection. Conclusions curative intent thus could be used personalized biomarker selecting future. Lay Summary Human (HPV+OPSCC) at epidemic proportions commonly treated This report describes results from examining (circulating [ctHPVDNA]) following surgical HPV+OPSCC. We found day These findings demonstrate potential utility

Язык: Английский

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

International Journal of Cancer, Год журнала: 2022, Номер 151(7), С. 1081 - 1085

Опубликована: Март 9, 2022

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

Язык: Английский

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Consensuses, controversies, and future directions in treatment deintensification for human papillomavirus‐associated oropharyngeal cancer

CA A Cancer Journal for Clinicians, Год журнала: 2022, Номер 73(2), С. 164 - 197

Опубликована: Окт. 28, 2022

Abstract The most common cancer caused by human papillomavirus (HPV) infection in the United States is oropharyngeal (OPC), and its incidence has been rising since turn of century. Because substantial long‐term morbidities with chemoradiation favorable prognosis HPV‐positive OPC, identifying optimal deintensification strategy for this group a keystone academic head‐and‐neck surgery, radiation oncology, medical oncology over past decade. However, first generation randomized chemotherapy trials failed to change standard care, triggering concern feasibility de‐escalation. National database studies estimate that up one third patients receive nonstandard de‐escalated treatments, which have subspecialty‐specific nuances. A synthesis multidisciplinary data current treatment standards important community reinforce best practices ensure patient outcomes. In review, authors present summary comparison prospective OPC de‐escalation trials. Chemotherapy attenuation compromises outcomes without reducing toxicity. Limited comparing transoral robotic surgery (TORS) raise toxicity TORS. There are promising support de‐escalating adjuvant therapy after TORS, but consensus on indications needed. Encouraging strategies reported (upfront dose reduction induction chemotherapy‐based selection), level I evidence years away. Ultimately, stage HPV status may be insufficient guide future lie incorporating intratreatment response assessments harness powers personalized medicine integrate real‐time surveillance.

Язык: Английский

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

JAMA Otolaryngology–Head & Neck Surgery, Год журнала: 2022, Номер 148(12), С. 1120 - 1120

Опубликована: Окт. 27, 2022

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

Язык: Английский

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Patterns of recurrence in head and neck squamous cell carcinoma to inform personalized surveillance protocols

Cancer, Год журнала: 2023, Номер 129(18), С. 2817 - 2827

Опубликована: Май 10, 2023

Development of evidence-based post-treatment surveillance guidelines in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) is limited by comprehensive documentation patterns recurrence metastatic spread.A retrospective analysis patients diagnosed with R/M HNSCC at a National Cancer Institute-designated cancer center between 1998- 2019 was performed (n = 447). Univariate multivariate identified predictors survival.Median overall survival (mOS) improved over time (6.7 months 1998-2007 to 11.8 2008-2019, p .006). Predictors worse mOS included human papillomavirus (HPV) negativity (hazard ratio [HR], 1.8; 95% confidence interval [CI], 1.2-2.6), high neutrophil/lymphocyte (HR, 2.1 [1.4-3.0], disease-free (DFI) ≤6 1.4 [1.02-2.0]), poor performance status (Eastern Cooperative Oncology Group, ≥2; HR, 1.91.1-3.4). In this cohort, 50.6% recurrences occurred within 6 treatment completion, 72.5% 1 year, 88.6% 2 years. Metachronous distant metastases were more likely occur HPV-positive disease (odds [OR], 2.3 [1.4-4.0]), DFI >6 (OR, 2.4 [1.5-4.0]), body mass index ≥30 [1.1-4.8]). Oligometastatic treated local ablative therapy associated polymetastatic 0.36; CI, 0.24-0.55).These data regarding metastasis support the clinical utility early detection recurrence. Patterns population can be used inform individualized programs as well risk-stratify eligible for trials.After (HNC), are risk prior sites or body. This study includes large group recurrent HNC examines factors outcomes patterns. Patients (HPV)-positive have good outcomes, but if they recur, may regions later than HPV-negative patients. These argue personalized follow-up schedules HNC, perhaps incorporating imaging studies novel blood tests.

Язык: Английский

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Prophylactic HPV vaccines in patients with HPV-associated diseases and cancer

Vaccine, Год журнала: 2023, Номер 41(42), С. 6194 - 6205

Опубликована: Сен. 12, 2023

Individuals with human papillomavirus (HPV)-related disease remain at risk for subsequent HPV infection and related after treatment of specific lesions. Prophylactic vaccines have shown benefits in preventing HPV-related when administered before or soon treatment. Based on our understanding the life cycle vaccine mechanism action, prophylactic vaccination is not expected to clear active persistent unresected HPV-associated dysplastic tissue remaining surgery. However, may reasonably be prevent new infections caused by a different type as well re-infection same type, whether from exposure an infected partner through autoinoculation adjacent distant productively site. In this review, we describe evidence using patients before, during, discuss potential mechanisms which individuals benefit vaccines. We also consider how precise terminology relating use population critical avoid incorrect implication that direct therapeutic potential, would counter vaccine's considered off-label. other words, observed effects occur known action vaccines, namely virus infecting patient procedure.

Язык: Английский

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