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Multicenter Study
. 2024 Feb 1;42(4):431-440.
doi: 10.1200/JCO.23.00954. Epub 2023 Nov 16.

Clinical Validation of Human Papilloma Virus Circulating Tumor DNA for Early Detection of Residual Disease After Chemoradiation in Cervical Cancer

Kathy Han  1   2 , Jinfeng Zou  1 , Zhen Zhao  1 , Zeynep Baskurt  3 , Yangqiao Zheng  1 , Elizabeth Barnes  2   4 , Jennifer Croke  1   2 , Sarah E Ferguson  1   5 , Anthony Fyles  1   2 , Lilian Gien  4   5 , Adam Gladwish  2 , Magali Lecavalier-Barsoum  6 , Stephanie Lheureux  7 , Jelena Lukovic  1   2 , Helen Mackay  4   7 , Eve-Lyne Marchand  8 , Ur Metser  1   9 , Michael Milosevic  1   2 , Amandeep S Taggar  2   4 , Scott V Bratman  1   2 , Eric Leung  2   4
Affiliations
Multicenter Study

Clinical Validation of Human Papilloma Virus Circulating Tumor DNA for Early Detection of Residual Disease After Chemoradiation in Cervical Cancer

Kathy Han et al. J Clin Oncol. .

Abstract

Purpose: Most cervical cancers are caused by human papilloma virus (HPV), and HPV circulating tumor DNA (ctDNA) may identify patients at highest risk of relapse. Our pilot study using digital polymerase chain reaction (dPCR) showed that detectable HPV ctDNA at the end of chemoradiation (CRT) is associated with inferior progression-free survival (PFS) and that a next-generation sequencing approach (HPV-seq) may outperform dPCR. We aimed to prospectively validate HPV ctDNA as a tool for early detection of residual disease.

Methods: This prospective, multicenter validation study accrued patients with stage IB-IVA cervical cancer treated with CRT between 2017 and 2022. Participants underwent phlebotomy at baseline, end of CRT, 4-6 weeks post-CRT, and 3 months post-CRT for HPV ctDNA levels. Plasma HPV genotype-specific DNA levels were quantified using both dPCR and HPV-seq. The primary end point was 2-year PFS.

Results: With a median follow-up of 2.2 (range, 0.5-5.5) years, there were 24 PFS events among the 70 patients with HPV+ cervical cancer. Patients with detectable HPV ctDNA on dPCR at the end of CRT, 4-6 weeks post-CRT, and 3 months post-CRT had significantly worse 2-year PFS compared with those with undetectable HPV ctDNA (77% v 51%, P = .03; 82% v 15%, P < .001; and 82% v 24%, P < .001, respectively); the median lead time to recurrence was 5.9 months. HPV-seq showed similar results as dPCR. On multivariable analyses, detectable HPV ctDNA on dPCR and HPV-seq remained independently associated with inferior PFS.

Conclusion: Persistent HPV ctDNA after CRT is independently associated with inferior PFS. HPV ctDNA testing can identify, as early as at the end of CRT, patients at high risk of recurrence for future treatment intensification trials.

Trial registration: ClinicalTrials.gov NCT03853915 NCT03702309.

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Conflict of interest statement

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Figures

FIG 1.
FIG 1.
Flow diagram. CRT, chemoradiation; CT, computed tomography; HPV, human papilloma virus; MRI, magnetic resonance imaging; PET, positron emission tomography.
FIG 2.
FIG 2.
HPV ctDNA burden over time on the basis of (A) dPCR and (B) HPV-seq. Patients who are disease-free are depicted in gray; those who relapsed are depicted in red. The change in HPV ctDNA burden was determined using adjacent timepoints. Patients had (1) rapid clearance of HPV ctDNA at all three nonbaseline timepoints (end of CRT, 4-6 weeks post-CRT, and 3 months post-CRT); (2) a gradual decrease in HPV ctDNA; (3) an increase in HPV ctDNA level relative to an earlier adjacent timepoint; or (4) missing adjacent timepoints. PFS by HPV ctDNA kinetic patterns (1)-(3), on the basis of (C) dPCR and (D) HPV-seq. CRT, chemoradiation; dPCR, digital polymerase chain reaction; HPV ctDNA, human papilloma virus circulating tumor DNA; PFS, progression-free survival.
FIG 3.
FIG 3.
PFS by HPV DNA copy number in plasma on dPCR at (A) end of CRT, (B) 4-6 weeks post-CRT, and (C) 3 months post-CRT. CRT, chemoradiation; ctDNA, circulating tumor DNA; dPCR, digital polymerase chain reaction; HPV, human papilloma virus; HR, hazard ratio; PFS, progression-free survival.
FIG 4.
FIG 4.
PFS by HPV DNA copy number in plasma on HPV-seq at (A) end of CRT, (B) 4-6 weeks post-CRT, and (C) 3 months post-CRT. CRT, chemoradiation; ctDNA, circulating tumor DNA; HPV, human papilloma virus; HR, hazard ratio; PFS, progression-free survival.
See this image and copyright information in PMC

References

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