Monitoring circulating cell-free HPV DNA in metastatic or recurrent cervical cancer: clinical significance and treatment implications
- Department of Gynecologic Radiation Oncology, (Zhejiang Key Laboratory of Radiation Oncology), Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, China
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, China
Figures
Figure 1
CONSORT flow diagram showing the enrollment of an observational cohort of patients diagnosed with recurrent or metastatic human papillomavirus (HPV)-positive cervical cancer undergoing serum HPV cell-free DNA surveillance.
Figure 2
Comparison of baseline copy numbers of HPV cfDNA among different HPV genotypes and recurrence/metastasis pattern groups (n=28).
(A) Serum CONSORT (HPV) cell-free DNA (cfDNA) copy number for six HPV genotypes at baseline. (B) Baseline HPV cfDNA copy numbers for five recurrence/metastasis subgroups. Statistical significance was determined using a two-sided Kruskal-Wallis test. Abbreviations: LR, local recurrence; LNM, lymph node metastasis; HM, hematogenous metastasis; LN + HM, lymph node + hematogenous metastasis; LN + H + DSM, lymph node + hematogenous + diffuse serosal metastasis. (C) Relationship between HPV cfDNA copy number and metastatic pattern. Statistical significance was determined using a two-sided Mann-Whitney U test. All plots show the median and interquartile range on a log10 scale.
Figure 3
Paired plots for serum human papillomavirus (HPV) cell-free DNA (cfDNA) (copies/mL) and squamous cell carcinoma antigen (SCC-Ag) (ng/mL) levels were measured longitudinally in patients with metastatic or recurrent HPV-positive cervical cancer (each patient is represented by a line of the same color).
HPV cfDNA levels in serum were scaled using log10. (A1, A2) Patients whose disease progressed during treatment. (B1, B2) Selected patients who showed a response to cytotoxic chemotherapy. (C1, C2) Response to immune therapy in a patient with stage IVB cervical cancer positive for HPV genotypes 33 and 16, treated with paclitaxel + cisplatin, concurrent chemoradiotherapy, brachytherapy, and bevacizumab. (D1, D2) Selected patients with a response to radiotherapy. (E1, E2) HPV cfDNA levels were significantly higher than normal at some of the longitudinal time points in five patients, but SCC-Ag levels were within the normal range (<1.5 ng/mL) at all time points. (F1, F2) HPV cfDNA levels for all patients with longitudinal samples (n=21) and matched SCC-Ag levels for the patients with squamous cell cancer (n=20). Each colored line corresponds to one patient, except in C. Horizontal dashed lines indicate the days between plasma HPV cfDNA levels suggestive of a response or progression (rise or fall in levels) and imaging-confirmed changes in disease status. The associated number of days (D) is listed adjacent to the horizontal dashed line for comparison. It should be noted that not all HPV cfDNA data points are plotted for each patient.
Figure 4
Comparison of overall survival (OS) in the entire cohort of patients (n=28) grouped by different HPV genotypes, and in stage IVB patients (n=21) grouped by different baseline serum HPV cfDNA copy numbers.
(A) Overall survival for patients stratified by human papillomavirus (HPV) subtype (HPV 16+ versus non-HPV16+). (B) Overall survival for patients stratified by baseline serum HPV cell-free DNA (cfDNA) copy number, using a cutoff of 3.9 × 104 copies/mL. P-values were calculated using a two-sided log-rank test.
Tables
Table 1
Characteristics of patients with metastatic or recurrent cervical cancer.
| N | All patients (n=28) | Primary IVB stage (n=21) | Recurrence or metastasis (n=7) |
|---|---|---|---|
| Age (years) | |||
| Median age (range) | 52(34-67) | 51(34-66) | 53(37-67) |
| Pathological types (n) | |||
| Squamous cell carcinoma | 26 | 20 | 6 |
| Adenocarcinoma | 1 | 0 | 1 |
| Large cell neuroendocrine carcinoma | 1 | 1 | 0 |
| HPV subtype | |||
| 16 | 20 | 14 | 6 |
| 58 | 3 | 3 | 0 |
| 18 | 2 | 2 | 0 |
| 31 | 1 | 0 | 1 |
| 66 | 1 | 1 | 0 |
| 16,33 | 1 | 1 | 0 |
| Baseline serum sampling time | |||
| Treatment initiation | 25 | 20 | 5 |
| During treatment | 3 | 1 | 2 |
| Pattern of metastasis | |||
| Local recurrence | 1 | 0 | 1 |
| Lymphatic node metastasis | 11 | 10 | 1 |
| Hematogenous metastasis | 4 | 2 | 2 |
| Lymph node +hematogenous metastasis | 9 | 8 | 1 |
| Lymph node +hematogenous + diffuse serosal metastasis | 3 | 1 | 2 |
| Treatment modality | |||
| Neoadjuvant chemotherapy | 18 | 18 | 0 |
| Surgeries | 2 | 0 | 2 |
| Adjuvant chemotherapy | 25 | 18 | 7 |
| Radiotherapy/concurrent chemoradiotherapy | 25 | 18 | 7 |
| Targeted therapy | 12 | 7 | 5 |
| Immunotherapy | 16 | 9 | 7 |
Additional files
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Supplementary file 1
Primer and probe sequences for ddPCR, fragment sizes, and annealing.
- https://cdn.elifesciences.org/articles/101887/elife-101887-supp1-v1.docx
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Supplementary file 2
HPV cfDNA Levels and Clinical Treatment and Outcomes in the Whole Group of Patients.
- https://cdn.elifesciences.org/articles/101887/elife-101887-supp2-v1.docx
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Supplementary file 3
Univariate analysis of prognostic factors for overall survival (n=28).
- https://cdn.elifesciences.org/articles/101887/elife-101887-supp3-v1.docx
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MDAR checklist
- https://cdn.elifesciences.org/articles/101887/elife-101887-mdarchecklist1-v1.docx
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Reporting standard 1
STROBE checklist.
- https://cdn.elifesciences.org/articles/101887/elife-101887-repstand1-v1.docx
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Monitoring circulating cell-free HPV DNA in metastatic or recurrent cervical cancer: clinical significance and treatment implications
eLife 13:RP101887.
https://doi.org/10.7554/eLife.101887.3
