Can HPV ctDNA Guide the Adjuvant Treatment of Oropharyngeal Cancer?

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Although liquid biopsies are now helping determine the need for adjuvant therapy in a number of malignancies, they have yet to prove useful in the setting of oropharyngeal carcinoma, according to a prospective pilot study presented at the 2024 Multidisciplinary Head and Neck Cancers Symposium that evaluated the use of human papillomavirus cell-free tumor DNA to select patients for active surveillance (Abstract LBA 01).

“Our pilot study approach of using HPV ctDNA–based selection of [patients with] oropharyngeal cancer for postoperative active surveillance closed early due to a high rate of gross disease recurrence—25%—and we failed to meet our primary endpoint,” said Linda Chen, MD, of the Department of Radiation Oncology at Memorial Sloan Kettering Cancer Center, who reported the findings at the meeting. She noted that the three radiographic recurrences that occurred in the study were not preceded by an emergence of detectable HPV ctDNA—therefore, the assay failed to provide an early signal of disease progression. “Additional data are needed to select patients for active surveillance,” she concluded.

The concept of using HPV ctDNA is based on its potential for identifying measurable residual disease (MRD) prior to clinically apparent recurrences. Dr. Chen and colleagues hypothesized that undetectable postoperative HPV ctDNA—as a biomarker for undetectable MRD—could help select patients for whom omission or delay of adjuvant radiation would be a safe option. Radiation would be instituted should HPV ctDNA become detectable.

Study Details

HPV ctDNA was assessed in patients using the NavDx assay, a liquid biopsy test that quantifies circulating tumor tissue modified viral (TTMV)-HPV DNA. Investigators screened 53 HPV-positive surgical candidates, finding 12 (mostly with tonsillar cancer) who met the criteria for active surveillance: preoperative TTMV-HPV DNA Score of ≥ 50 fragments/mL, surgical resection of all gross disease, at least one pathologic risk factor that warranted adjuvant therapy, no signs of disease on magnetic resonance imaging (MRI), and negative postoperative HPV ctDNA at two time points (2 and 6 weeks after surgery).  

During active surveillance, patients were monitored with TTMV-HPV DNA testing, imaging, and a physical exam every 3 months, with delayed adjuvant radiation begun on study only if they developed detectable TTMV-HPV DNA without evidence of gross disease. Patients who were found to have developed gross disease during surveillance were taken off study, regardless of HPV ctDNA status. This active surveillance approach would be considered worthy of further study if ≥ 85% of evaluable patients were without evidence of gross disease at 1 year, Dr. Chen explained. 

The median preoperative TTMV-HPV DNA score of the 12 patients was 448 fragments/mL, and median follow-up was 12.5 months.

Primary Endpoint Not Met

Of the 12 patients, 8 (67%) successfully underwent active surveillance, having shown no evidence of HPV ctDNA over the 6 months of the study. Among the other four, one (8%) had detectable HPV ctDNA that emerged 6 months after surgery, without evidence of gross disease, and was treated with 60 Gy of radiation on study. The three (25%) other patients developed radiographic-detected disease progression by the 6-month surveillance time point; two of these recurrences were synchronous with the detection of TTMV-HPV DNA and the other was detected radiographically before TTMV-HPV DNA was detected.

“As 3 of the 12 patients developed gross recurrent disease, this cohort was closed due to failure to meet our primary endpoint,” Dr. Chen said. “Additional clinical factors are needed to select patients for active surveillance and initiation of delayed adjuvant therapy prior to recurrence.”

In a second cohort, the study is evaluating de-escalation of radiotherapy and chemotherapy in patients with positive margins (< 3 mm) or extracapsular extension. This part of the study remains open. 

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