Blood Test Outperforms Tissue Biopsy in Detecting HPV+ Head and Neck Cancer

A novel, investigational blood test for human papillomavirus-positive (HPV+) head and neck squamous cell carcinoma (HNSCC) was superior to tissue biopsy with 99% sensitivity and specificity. The study data, published in Clinical Cancer Research, highlight the promise of HPV whole genome sequencing testing (WGS) liquid biopsy as a more cost-effective screening method with early detection capabilities.¹

Gloved hand holding blood test sample | Image Credit: © StudioLaMagica - stock.adobe.com

According to the CDC, HPV causes approximately 60% to 70% of oropharyngeal cancers in the United States, and incidence is increasing. There are currently no methods for HPV+ HNSCC early detection. Circulating tumor HPV DNA (ctHPVDNA) and HPV early protein antibodies (HPV Ab), 2 blood-based analytes for the early detection and identification of HPV+ HNSCC, exhibit promise. However, existing methods do not provide sufficient diagnostic accuracy for widespread clinical use, and performance metrics across various assays alone or in combination have not been compared head-to-head.^1,2

"The major advantage of this approach would be in settings like minimal residual disease [MRD] after surgery, and we're very interested in applying the test in a screening setting," Daniel L. Faden, MD, of Massachusetts Eye and Ear in Boston told MedPage Today. "We don't have a screening test for HPV-associated oropharynx cancer, unlike cervical cancer. We've done some preliminary studies using ddPCR [digital droplet PCR], showing that in some patients you can detect circulating tumor DNA, but not in most patients, suggesting the need for a more sensitive test."³

To overcome these restrictions, the study authors created a multifeatured HPV WGS liquid biopsy for enhanced low-level ctHPVDNA detection. In order to identify the best single or combinatorial biomarker method for future prospective research on HPV+ HNSCC early detection, they outlined the performance characteristics of this WGS-based approach and conducted a head-to-head comparison with existing blood-based HPV detection approaches.¹

The authors tested blood samples from 304 participants, of whom 152 had untreated incident HPV+ HNSCC (stage I: 77%) and 152 were control patients. They compared various assays against gold-standard HPV + HNSCC tissue diagnosis, including WGS-based ctHPVDNA detection, single-plex ddPCR–based ctHPVDNA detection, multiplex ddPCR-based ctHPVDNA detection, multiplex HPV Ab detection, and clinical standard-of-care tissue biopsy. Then, they modeled the operational feasibility of these approaches.¹

The results showed that HPV WGS achieved both sensitivity and specificity of 98.7%. In comparison, single-plex ddPCR demonstrated a sensitivity of 94.2% and specificity of 98.6%, whereas multiplex ddPCR showed sensitivity and specificity of 90.6% and 96.3%, respectively. HPV Ab testing yielded sensitivity of 86.4% and specificity of 96.3%. When combining HPV WGS with HPV Ab, the approach produced a sensitivity of 87.4% and specificity of 98.8%.¹

HPV WGS significantly outperformed other diagnostic approaches. The Youden index for HPV WGS was about 0.99, compared with 0.90 for ddPCR (P < .001), 0.83 for HPV Ab (P < .001), and 0.82 for standard clinical workup (P < .001). This superior diagnostic accuracy remained consistent even when analyzing only early-stage cases. Among men aged 55 to 74, HPV WGS had the lowest number needed to screen (n = 2,903) and the highest positive predictive value.¹

"I do foresee a time when we would have so much faith in these types of tests that we would treat or act based on the results," Neil Gross, MD, of the University of Texas MD Anderson Cancer Center, said in an interview with MedPage Today. "Right now, it's still exploratory, so we still use imaging and traditional biopsies the most and then decide how to treat. So, it's not disruptive to what we're currently doing, as it stands now, but it's easy to imagine how it could really augment what we're doing in terms of screening patients and populations and early disease detection."

REFERENCES

1. Bryan M, Aye L, Das D, et al. Direct comparison of alternative blood-based approaches for early detection and diagnosis of HPV-associated head and neck cancers. Clin Cancer Res. May 20, 2025. doi:10.1158/1078-0432.CCR-24-2525

2. HPV and oropharyngeal cancer. CDC. September 17, 2024. Accessed June 12, 2025. https://www.cdc.gov/cancer/hpv/oropharyngeal-cancer.html

3. New blood test for HPV+ Head and neck cancer tops existing tests, tissue biopsy. MedPage Today. May 28, 2025. Accessed June 12, 2025. https://www.medpagetoday.com/hematologyoncology/othercancers/115793?xid=nl_mpt_morningbreak2025-05-29&mh=6d2b5f4f91352444bdf817a9c17750bc&zdee=gAAAAABm4uL9FCoIf1N83nrcwYYqnQUvN6Iw4dbaY-dGva4sOp57nSM2Ew3wD87ohRuoseQBDbCp1MG30J6ETpHXK1wNpp0NgnGTMFXrtFaNfWUoL5ekf-Y%3D&utm_source=Sailthru&utm_medium=email&utm_campaign=MorningBreak_052925&utm_term=NL_Gen_Int_Daily_News_Update_active