Circulating Cell-free DNA for Metastatic Cervical Cancer Detection, Genotyping, and Monitoring

Clin Cancer Res. 2017 Nov 15;23(22):6856-6862. doi: 10.1158/1078-0432.CCR-17-1553. Epub 2017 Sep 12.


Purpose: Circulating cell-free (ccf) human papillomavirus (HPV) DNA may serve as a unique tumor marker for HPV-associated malignancies, including cervical cancer. We developed a method to genotype and quantify circulating HPV DNA in patients with HPV16- or HPV18-positive metastatic cervical cancer for potential disease monitoring and treatment-related decision making.Experimental Design: In this retrospective study, HPV ccfDNA was measured in serum samples from 19 metastatic cervical cancer patients by duplex digital droplet PCR (ddPCR). Nine patients had received tumor-infiltrating lymphocyte (TIL) immunotherapy. ccfDNA data were aligned with the tumor HPV genotype, drug treatment, and clinical outcome.Results: In blinded tests, HPV ccfDNA was detected in 19 of 19 (100%) patients with HPV-positive metastatic cervical cancer but not in any of the 45 healthy blood donors. The HPV genotype harbored in the patients' tumors was correctly identified in 87 of 87 (100%) sequential patient serum samples from 9 patients who received TIL immunotherapy. In three patients who experienced objective cancer regression after TIL treatment, a transient HPV ccfDNA peak was detected 2-3 days after TIL infusion. Furthermore, persistent clearance of HPV ccfDNA was only observed in two patients who experienced complete response (CR) after TIL immunotherapy.Conclusions: HPV ccfDNA represents a promising tumor marker for noninvasive HPV genotyping and may be used in selecting patients for HPV type-specific T-cell-based immunotherapies. It may also have value in detecting antitumor activity of therapeutic agents and in the long-term follow-up of cervical cancer patients in remission. Clin Cancer Res; 23(22); 6856-62. ©2017 AACR.

MeSH terms

  • Cell-Free Nucleic Acids*
  • DNA, Viral
  • Early Detection of Cancer
  • Female
  • Genotyping Techniques
  • Humans
  • Immunotherapy, Adoptive
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Neoplasm Metastasis
  • Neoplasm Staging
  • Papillomaviridae / genetics
  • Papillomavirus Infections / complications
  • Papillomavirus Infections / virology
  • Retrospective Studies
  • Sensitivity and Specificity
  • Uterine Cervical Neoplasms / diagnosis*
  • Uterine Cervical Neoplasms / etiology
  • Uterine Cervical Neoplasms / genetics*
  • Uterine Cervical Neoplasms / therapy


  • Cell-Free Nucleic Acids
  • DNA, Viral