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Human papilloma virus (HPV) circulating tumor DNA (ctDNA) can be used to find residual disease after chemoradiation in cervical cancer, researchers reported.

HPV ctDNA may identify patients at highest risk of relapse. A previous pilot study showed that at the end of chemoradiation, which was associated with inferior progression-free survival (PFS). The study also found that a .

Kathy Han, MD, MSc, of the University of Toronto, and colleagues set out to prospectively validate HPV ctDNA as a tool for early detection of residual disease. The prospective, multicenter validation study, published in the , accrued patients with stages IB-IVA cervical cancer treated with chemoradiation between 2017 and 2022.

Han elaborated on the findings in the following interview.

What does this study add to the literature?

Han: This is the first study to prospectively validate HPV ctDNA as a tool for early detection of residual disease after definitive chemoradiation in stage IB-IVA cervical cancer. Persistent HPV ctDNA after chemoradiation was independently associated with inferior PFS in this prospective validation study at all timepoints, confirming our previous results.

There was no statistically significant difference between the performance of HPV-seq and digital PCR in molecular residual disease (MRD) detection nor between the timepoints that were evaluated, highlighting the benefit of early identification of patients with MRD at risk of relapse.

Persistent HPV ctDNA after chemoradiation is independently associated with inferior PFS. With a median follow-up of 2.2 years, there were 24 PFS events among the 70 patients with HPV-positive cervical cancer. Patients with detectable HPV ctDNA on digital PCR at the end of chemoradiation, 4-6 weeks post-chemoradiation, and 3 months post-chemoradiation had significantly worse 2-year PFS compared with those with undetectable HPV ctDNA (77% vs 51%, 82% vs 15%, and 82% vs 24%, respectively). The median lead time to recurrence was 5.9 months.

A sequencing-based assay enables highly sensitive detection and accurate HPV genotyping from baseline plasma cell-free DNA. HPV-seq showed similar results as digital PCR. On multivariable analyses, detectable HPV ctDNA on digital PCR and HPV-seq remained independently associated with inferior PFS.

What was the rationale for the study?

Han: There is no effective salvage treatment for patients with cervical cancer who develop recurrence. Accurate prognostication allows robust stratification in clinical trials and personalized treatment to improve outcomes. These results should be useful in selecting the highest-risk patients for the development of treatments to prevent clinical recurrence.

What is the next step in this research?

Han: The next step is to use this validated tool to select patients at high risk of recurrence -- that is, those with detectable HPV ctDNA -- after chemoradiation for treatment-intensification trials. Although we counted any detectable HPV ctDNA as a positive result, future studies could seek to optimize cutoff values that maximize either sensitivity or specificity depending on the clinical use case.

With the recent failure of large studies that included patients on the basis of the pretreatment stage/nodal status, a biomarker-enriched population with a high relapse rate would be an ideal population for future studies testing new approaches to improve outcomes.

Our study suggests that early post-treatment timepoints could be used to ensure timely trial enrollment and initiation of therapy. For example, patients with detectable HPV ctDNA at the end of chemoradiation could be randomly assigned to standard-of-care versus intensified systemic treatment starting within 4-6 weeks of chemoradiation completion. Alternatively, patients with detectable HPV ctDNA who on restaging are found to have localized nodal or distant oligometastases could be treated with ablative local therapy.

What is the potential of HPV ctDNA in selecting patients for intensified systemic treatment?

Han: HPV ctDNA can identify, as early as at the end of chemoradiation, patients at high risk of recurrence. Early post-chemoradiation timepoints -- that is, within the standard adjuvant treatment window while residual disease burdens are lower -- are likely of greater clinical utility.

To our knowledge, this is the largest prospective cervical cancer cohort with serial HPV ctDNA analysis. Digital PCR should become more widely available in lower-/middle-income countries where cervical cancer is most prevalent on the basis of guidance from the World Health Organization.

What's the bottom-line message for practicing oncologists?

Han: HPV-seq enables sensitive HPV detection and genotyping directly from plasma. HPV ctDNA can be useful in early identification of patients at high risk of recurrence.

Read the study here.