Researchers from Mass General Brigham Cancer Institute have shown that HPV-DeepSeek, an ultrasensitive blood test that detects human papillomavirus (HPV) DNA, could predict which patients with HPV-associated head and neck cancer are most likely to benefit from adjuvant treatment after surgery.
“Right now, the decision to give adjuvant radiation or chemoradiation after surgery hinges almost entirely on TNM staging and surgical pathology,” explained senior author Daniel Faden, MD, director of the Head and Neck Cancer Genomics and Liquid Biopsy Program at Mass General Brigham Cancer Institute.
This means that surgeons and oncologists look at features like the number of involved lymph nodes, whether there’s extranodal extension, surgical margin status, and perineural invasion or lymphovascular invasion.
“The problem is, these are static, backward-looking variables,” Faden told Inside Precision Medicine. “They tell us what was in the tumor specimen, but they don’t tell us whether the patient has microscopic disease left behind after surgery.”
This can result in some patients receiving more treatment than they need, with potential unnecessary side effects, and others receiving less treatment than they should and later having their cancer come back.
Previous work has shown that circulating tumor (ct)HPV DNA is a promising biomarker for predicting head and neck cancer recurrence, but current assays, using droplet digital polymerase chain reaction (ddPCR), lack the sensitivity needed for detecting minimal residual disease (MRD) after surgery.
Faden and team therefore used their experience of studying HPV to build HPV-DeepSeek, a whole genome sequencing (WGS) assay that detects ctHPV DNA in blood samples.
He noted that the assay differs from most currently available MRD assays as it is not tumor-informed and does not require building a bespoke panel from each patient’s tumor. This makes HPV-DeepSeek tissue agnostic, and means the assay has a lower cost and faster turnaround times than tumor-informed WGS approaches.
Faden and team evaluated the performance of HPV-DeepSeek in the Clear-HPVca study, which included 103 patients (mean age 62 years, 89% men) with stage I to IV HPV-positive head and neck cancer who were treated with surgery.
The authors report in Science Translational Medicine that among 74 patients with ctHPV DNA status available during the postsurgery period (four days to six months after surgery, before adjuvant therapy), 23% were MRD-positive.
After a median follow-up of 27 months, patients with ctHPV DNA detected had worse outcomes than those with no ctHPV DNA. Specifically, the two-year disease-free survival rate was 60% among the patients who were MRD-positive, compared with 100% for those who were MRD-negative, and the two-year overall survival rates were 73% and 98%, respectively.
The researchers also found that HPV-DeepSeek could predict which patients benefit from adjuvant treatment; the recurrence rate was 27% among 15 MRD-positive patients who received adjuvant treatment compared with 100% among the two MRD positive patients who did not receive adjuvant treatment.
Conversely, there was no benefit of adjuvant treatment among MRD-negative patients; in this group, the recurrence rate was 3% among the 37 MRD-negative patients who received adjuvant therapy and 0% among the 21 MRD-negative patients who did not receive adjuvant therapy.
Furthermore, the assay identified molecular recurrence an average of seven months, and up to 17.5 months, earlier than clinical recurrence. With ddPCR, molecular recurrence was only detected four months earlier than clinical recurrence.
Although the team knew that HPV-DeepSeek was more sensitive than ddPCR, Faden described the size of the lead-time as striking.
“It tells us we’re detecting recurrence at a disease burden that’s genuinely clinically meaningful and actionable,” he said. “We had some patients where molecular detection preceded clinical detection by over a year. That kind of window creates real opportunities—time to discuss salvage surgery or systemic therapy before a patient ever develops symptomatic recurrence.”
Faden and team are now planning interventional trials that will investigate whether using HPV-DeepSeek to guide adjuvant therapy decisions improves outcomes and reduces toxicity.
Faden hopes that the assay will eventually be used to guide personalized treatment decisions.
“As a surgeon who treats this disease, not just a scientist who studies it, this is where I get genuinely excited—because it’s a shift in philosophy, not just methodology,” he said. “What HPV-DeepSeek does is make disease biology—specifically, whether there’s residual disease—visible in real time.”
He added: “If you can accurately detect MRD early after surgery, you can make treatment decisions based on that biology [and] the downstream implications are significant. You reduce unnecessary toxicity in patients who don’t need more treatment. You potentially intensify treatment in patients with residual disease. And you can rethink surveillance—if a patient remains MRD-negative after treatment, can we move to less frequent imaging and potentially spare them years of follow-up CT scans?”
“We’re not there yet clinically, but this is a first step—a research finding with real promise. It’s the beginning of a conversation about how to personalize care.”
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