Clinical Uncertainties of Circulating Tumor DNA in Human Papillomavirus–Related Oropharyngeal Squamous Cell Carcinoma in the Absence of National Comprehensive Cancer Network Guidelines

Xie, Deborah X.; Kut, Carmen; Quon, Harry; Seiwert, Tanguy Y.; D’Souza, Gypsyamber; Fakhry, Carole

doi:10.1200/jco.22.00264

Cited by 10 publications

(9 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The multitude of assays, ranging from institutional assays to proprietary commercial assays, vary in substrate used for analysis (ie, saliva, plasma/blood, urine) and molecular detection technique used (ie, quantitative PCR, droplet digital PCR, next generation sequencing). 18,19 Combining these different meth- ods, a recent systematic review and meta-analysis found that in 10 studies, including 457 patients, ctDNA-based assays had a pooled sensitivity of 65% and a specificity of 99% in detecting disease. 20 While the specificity is quite good across assays, the sensitivity is more highly variable.…”

Section: Discussionmentioning

confidence: 99%

“…This unique tumor biology coupled with advances in molecular diagnostic techniques has led to the development of multiple assays to detect HPV ctDNA. The multitude of assays, ranging from institutional assays to proprietary commercial assays, vary in substrate used for analysis (ie, saliva, plasma/blood, urine) and molecular detection technique used (ie, quantitative PCR, droplet digital PCR, next generation sequencing) . Combining these different methods, a recent systematic review and meta-analysis found that in 10 studies, including 457 patients, ctDNA-based assays had a pooled sensitivity of 65% and a specificity of 99% in detecting disease .…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Performance of Liquid Biopsy for Diagnosis and Surveillance of Human Papillomavirus–Associated Oropharyngeal Cancer

Ferrandino

Chen

Kappauf

et al. 2023

JAMA Otolaryngol Head Neck Surg

View full text Add to dashboard Cite

ImportanceThere is growing interest in the use of circulating plasma tumor human papillomavirus (HPV) DNA for diagnosis and surveillance of patients with HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). Recent advances in the assays, combining the identification of circulating HPV tumor DNA and tumor DNA fragment analysis (tumor tissue–modified viral [TTMV]-HPV DNA), have been shown to be highly accurate. However, use of these newer techniques has been limited to small cohort studies and clinical trials.ObjectiveTo establish the clinical efficacy of plasma TTMV-HPV DNA testing in the diagnosis and surveillance of HPV-associated OPSCC in a contemporary clinical setting.Design, Setting, and ParticipantsThis retrospective observational cohort study included patients with OPSCC who underwent TTMV-HPV DNA testing between April 2020 and September 2022 during the course of routine clinical care. For the diagnosis cohort, patients with at least 1 TTMV-HPV DNA measurement prior to initiation of primary therapy were included. Patients were included in the surveillance cohort if they had at least 1 TTMV-HPV DNA test performed after completion of definitive or salvage therapy.Main Outcomes and MeasuresPer-test performance metrics, including sensitivity, specificity, positive predictive value, and negative predictive value, for TTMV-HPV DNA testing.ResultsOf 399 patients included in the analysis, 163 were in the diagnostic cohort (median [IQR] age, 63 [56-68.5] years; 142 [87.1%] male), and 290 were in the surveillance cohort (median [IQR] age, 63 [57-70] years; 237 [81.7%] male). Of the 163 patients in the diagnostic cohort, 152 (93.3%) had HPV-associated OPSCC while 11 (6.7%) had HPV-negative OPSCC. The TTMV-HPV DNA sensitivity in pretreatment diagnosis was 91.5% (95% CI, 85.8%-95.4% [139 of 152 tests]), and the specificity was 100% (95% CI, 71.5%-100% [11 of 11 tests]). In the surveillance cohort, 591 tests conducted in 290 patients were evaluated. A total of 23 patients had molecularly confirmed pathologic recurrences. The TTMV-HPV DNA test demonstrated sensitivity of 88.4% (95% CI, 74.9%-96.1% [38 of 43 tests]) and specificity of 100% (95% CI, 99.3%-100% [548 of 548 tests]) in detecting the recurrences. Positive predictive value was 100% (95% CI, 90.7%-100% [38 of 38 tests]), and negative predictive value was 99.1% (95% CI, 97.9%-99.7% [548 of 553 tests]). The median (range) lead time from positive TTMV-HPV DNA test to pathologic confirmation was 47 (0-507) days.Conclusions and RelevanceThis cohort study demonstrated that when evaluated in a clinical setting, the TTMV-HPV DNA assay demonstrated 100% specificity in both diagnosis and surveillance. However, the sensitivity was 91.5% for the diagnosis cohort and 88.4% for the surveillance cohort, signifying that nearly 1 in 10 negative tests among patients with HPV-associated OPSCC was a false negative. Additional research is required to validate the assay’s performance and, if validated, then further research into the implementation of this assay into standard clinical practice guidelines will be required.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Performance of Liquid Biopsy for Diagnosis and Surveillance of Human Papillomavirus–Associated Oropharyngeal Cancer

Ferrandino

Chen

Kappauf

et al. 2023

JAMA Otolaryngol Head Neck Surg

View full text Add to dashboard Cite

show abstract

“…Second, cost-effectiveness and insurance reimbursement for routine clinical use without Food and Drug Administration authorization remain unresolved 31 . Finally, it remains unclear how best to incorporate plasma ctDNA into routine surveillance paradigms for HPV + OPSCC established by the National Comprehensive Cancer Network 32 . These areas require clarification before the widespread implementation of ctDNA as a biomarker in clinical practice.…”

Section: Current State Of Liquid Biopsies In Hpv+ Opsccmentioning

confidence: 99%

“…31 Finally, it remains unclear how best to incorporate plasma ctDNA into routine surveillance paradigms for HPV + OPSCC established by the National Comprehensive Cancer Network. 32 These areas require clarification before the widespread implementation of ctDNA as a biomarker in clinical practice.…”

Section: Current State Of Liquid Biopsies In Hpv + Opsccmentioning

confidence: 99%

Tumor-Derived Exosomes and the Role of Liquid Biopsy in Human Papillomavirus Oropharyngeal Squamous Cell Carcinoma

et al. 2023

View full text Add to dashboard Cite

The global incidence of human papillomavirus–positive (HPV+) head and neck squamous cell carcinoma (HNSCC) has surged in recent decades, with HPV+ HNSCC accounting for >70% of oropharynx cancers in the United States. Its incidence in men has surpassed that of HPV+ cervical cancer in women, and reliable assays are needed for early detection and to monitor response to therapy. Human papillomavirus–positive OPSCC has a more favorable response to therapy and prognosis than HPV-negative (HPV−) HNSCC, motivating regimens to deintensify curative surgery or chemoradiotherapy protocols. A barrier to deintensifying and personalizing therapy is lack of reliable predictive biomarkers. Furthermore, HPV− HNSCC survival rates are static without reliable surveillance biomarkers available. The emergence of circulating plasma-based biomarkers reflecting the tumor-immune microenvironment heralds a new era in HNSCC diagnosis and therapy. We review evidence on tumor-derived extracellular vesicles (exosomes) as biomarkers for diagnosis, prognostication, and treatment in HPV+ and HPV− HNSCC.

show abstract

“…To the Editor Ferrandino et al report clinical performance of plasma tumor tissue–modified viral (TTMV)-human papillomavirus (HPV) DNA in diagnosis and surveillance of HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). The findings highlight the promise of liquid biopsies for improving patient care and the uncertainties around how to integrate these assays with imaging, clinical examinations, and conventional biopsy . The variable time points for plasma TTMV-HPV DNA monitoring limited estimates of lead time detection, suggesting an opportunity for further standardizing timing of liquid biopsy testing protocols.…”

mentioning

confidence: 99%

Liquid Biopsies for Head and Neck Cancers—Any Hope for Human Papillomavirus–Negative Disease?

Smith,

Brenner,

Chinn

2024

JAMA Otolaryngol Head Neck Surg

View full text Add to dashboard Cite

To the Editor Ferrandino et al 1 report clinical performance of plasma tumor tissue-modified viral (TTMV)-human papillomavirus (HPV) DNA in diagnosis and surveillance of HPVassociated oropharyngeal squamous cell carcinoma (OPSCC). The findings highlight the promise of liquid biopsies for improving patient care and the uncertainties around how to integrate these assays with imaging, clinical examinations, and conventional biopsy. 2 The variable time points for plasma TTMV-HPV DNA monitoring limited estimates of lead time detection, suggesting an opportunity for further standardizing timing of liquid biopsy testing protocols. A key question is whether liquid biopsies have a role in HPV-negative OPSCC.Whereas plasma TTMV-HPV DNA assays detect viral DNA shed from the primary tumor or metastatic deposits, HPVnegative head and neck squamous cell carcinoma (HNSCC) lacks this viral fingerprint. Biomarkers for HPV-negative HNSCC are thus more nuanced, relying on detection of genomic and/or proteomic signatures of the parent tumor. These assays can use saliva, urine, or plasma-based biomarkers to improve diagnosis, treatment, and surveillance paradigms, but progress in developing robust and reliable liquid biopsy techniques for patients with HPV-negative HNSCC is more arduous. Nonetheless, preclinical and translational efforts are advancing liquid biopsy techniques for patients with HPV-negative tumors. 3 Recently, plasma tumor-derived extracellular vesicles (TDEVs), also known as exosomes, have emerged as a promising alternative to the circulating tumor DNA techniques. TDEVs are small (30 nm-200 nm), lipid-bilayer bound particles that are constitutively released by malignant cells harboring diverse DNA, RNA, and protein cargo. These particles are abundant in saliva, urine, and plasma of patients with HPVnegative HNSCC and can be readily isolated before, during, and after treatment. TDEVs have been studied in multiple cancers, including HPV-negative HNSCC. 4 Plasma TDEV kinetics and protein cargo (eg, surface programmed cell death ligand 1 [PD-L1] expression) can predict disease recurrence and treatment response in certain HPV-negative HNSCC populations. 5 The study by Ferrandino et al 1 underscores the need for further investigation of liquid biopsy, encompassing the implications for de-escalating therapy and improving patient out-

show abstract

Clinical Uncertainties of Circulating Tumor DNA in Human Papillomavirus–Related Oropharyngeal Squamous Cell Carcinoma in the Absence of National Comprehensive Cancer Network Guidelines

Abstract: Author affiliations and support information (if applicable) appear at the end of this article.

Cited by 10 publications

References 40 publications

Performance of Liquid Biopsy for Diagnosis and Surveillance of Human Papillomavirus–Associated Oropharyngeal Cancer

Performance of Liquid Biopsy for Diagnosis and Surveillance of Human Papillomavirus–Associated Oropharyngeal Cancer

Tumor-Derived Exosomes and the Role of Liquid Biopsy in Human Papillomavirus Oropharyngeal Squamous Cell Carcinoma

Liquid Biopsies for Head and Neck Cancers—Any Hope for Human Papillomavirus–Negative Disease?

Contact Info

Product

Resources

About