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. 2021 Nov 1;27(21):5869-5877.
doi: 10.1158/1078-0432.CCR-21-0625. Epub 2021 Jul 1.

Circulating HPV DNA as a Marker for Early Detection of Relapse in Patients with Cervical Cancer

Emmanuelle Jeannot  1   2 , Aurélien Latouche  3   4 , Claire Bonneau  3   5 , Marie-Ange Calméjane  1 , Corine Beaufort  6 , Kirsten Ruigrok-Ritstier  6 , Guillaume Bataillon  1 , Linda Larbi Chérif  7 , Célia Dupain  7 , Charlotte Lecerf  7 , Marina Popovic  8 , Anne de la Rochefordière  9 , Fabrice Lecuru  5 , Virginie Fourchotte  5 , Ekaterina S Jordanova  10 , Heiko von der Leyen  11 , Carine Tran-Perennou  1 , Marie-Emmanuelle Legrier  12 , Sylvain Dureau  13 , Laurence Raizonville  13 , Diana Bello Roufai  7 , Christophe Le Tourneau  3   7   14 , Ivan Bièche  2 , Roman Rouzier  3   5 , Els M J J Berns  6 , Maud Kamal #  7 , Suzy Scholl #  7
Affiliations

Circulating HPV DNA as a Marker for Early Detection of Relapse in Patients with Cervical Cancer

Emmanuelle Jeannot et al. Clin Cancer Res. .

Abstract

Purpose: Almost all cervical cancers are caused by human papillomavirus (HPV) and patients with advanced stage are at high risk for relapse. Circulating HPV DNA (HPV ctDNA) may serve as a residual tumor marker at the end of chemoradiation or to predict relapse during the follow-up period.

Experimental design: We analyzed serum samples from 94 HPV16- or HPV18-related CCs from the BioRAIDs prospective cohort. Samples were collected before and after treatment and during an 18-month follow-up period. Using digital droplet PCR (ddPCR), we assessed the relevance of circulating HPV E7 gene as a marker for residual disease compared to HPV integration site and PIK3CA mutations. Finally, the prognostic impact of circulating HPV E7 gene was assessed with its prediction value of relapse.

Results: HPV E7 gene was the most sensitive tumor marker, superior to both HPV integration sites and PIK3CA mutations in serum. Circulating HPV DNA (HPV ctDNA) was detected in 63% (59/94) of patients, before treatment. HPV ctDNA detection in serum sample was associated with high FIGO stage (P = 0.02) and para-aortic lymph node involvement (P = 0.01). The level of HPV ctDNA was positively correlated with HPV copy number in the tumor (R = 0.39, P < 0.001). Complete clearance of HPV ctDNA by the end of treatment was significantly associated with a longer PFS (P < 0.0001). Patients with persistent HPV ctDNA in serum relapsed with a median time of 10 months (range, 2-15) from HPV ctDNA detection.

Conclusions: HPV ctDNA detection is a useful marker to predict relapse in cervical cancer.See related commentary by Wentzensen and Clarke, p. 5733.

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Figures

Figure 1. Workflow diagram for patient selection and ctDNA analysis.
Figure 1.
Workflow diagram for patient selection and ctDNA analysis.
Figure 2. ctDNA detection by droplet digital PCR before treatment. A, HPV E7 ctDNA levels according to FIGO stages (P = Kruskal–Wallis test) and para-aortic (PA) lymph node status (P = Mann–Whitney test). B, Positive correlation between HPV E7 ctDNA level and tumor HPV E7 copy number. Spearman correlation r = 0.39 (P < 0.001). For undetectable HPV ctDNA cases, the points “a,” “b,” “c,” and “d” refer to 5, 6, 3, and 5 tumors, respectively. C, HPV ctDNA levels according to HPV E7 gene and HPV integration site (n = 23). D, ctDNA detection according to HPV E7 gene and PIK3CA mutation (n = 27).
Figure 2.
ctDNA detection by droplet digital PCR before treatment. A, HPV E7 ctDNA levels according to FIGO stages (P = Kruskal–Wallis test) and para-aortic (PA) lymph node status (P = Mann–Whitney test). B, Positive correlation between HPV E7 ctDNA level and tumor HPV E7 copy number. Spearman correlation r = 0.39 (P < 0.001). For undetectable HPV ctDNA cases, the points “a,” “b,” “c,” and “d” refer to 5, 6, 3, and 5 tumors, respectively. C, HPV ctDNA levels according to HPV E7 gene and HPV integration site (n = 23). D, ctDNA detection according to HPV E7 gene and PIK3CA mutation (n = 27).
Figure 3. Progression-free survival of patients according to the positivity of HPV ctDNA detection. A, Before treatment (n = 94). B, At the end of treatment (n = 40).
Figure 3.
Progression-free survival of patients according to the positivity of HPV ctDNA detection. A, Before treatment (n = 94). B, At the end of treatment (n = 40).
Figure 4. HPV ctDNA dynamics from the EOT to the end of follow-up. Each line corresponds to a patient (n = 44); patients without relapse and with relapse are identified in blue (top of the figure) and red (bottom), respectively. The length of the lines (top) corresponds to the duration of follow-up. Red () and blue () correspond to HPV-positive and HPV-negative serum samples, respectively. Serum samples in dashed area correspond to EOT samples. Patients with HPV ctDNA in their EOT samples are indicated by a black arrow. Diagnosis of relapse corresponds to the end of the line. S1, serum sample before treatment; R, relapse.
Figure 4.
HPV ctDNA dynamics from the EOT to the end of follow-up. Each line corresponds to a patient (n = 44); patients without relapse and with relapse are identified in blue (top of the figure) and red (bottom), respectively. The length of the lines (top) corresponds to the duration of follow-up. Red (formula image) and blue (formula image) correspond to HPV-positive and HPV-negative serum samples, respectively. Serum samples in dashed area correspond to EOT samples. Patients with HPV ctDNA in their EOT samples are indicated by a black arrow. Diagnosis of relapse corresponds to the end of the line. S1, serum sample before treatment; R, relapse.
Figure 5. ctDNA dynamics according to HPV E7 (black line) and PIK3CA mutation (gray line).
Figure 5.
ctDNA dynamics according to HPV E7 (black line) and PIK3CA mutation (gray line).
See this image and copyright information in PMC

Comment in

References

    1. de Martel C, Plummer M, Vignat J, Franceschi S. Worldwide burden of cancer attributable to HPV by site, country and HPV type. Int J Cancer 2017;141:664–70. - PMC - PubMed
    1. Forman D, de Martel C, Lacey CJ, Soerjomataram I, Lortet-Tieulent J, Bruni L, et al. Global burden of human papillomavirus and related diseases. Vaccine 2012;30:F12–23. - PubMed
    1. Keys HM, Bundy BN, Stehman FB, Okagaki T, Gallup DG, Burnett AF, et al. Radiation therapy with and without extrafascial hysterectomy for bulky stage IB cervical carcinoma: a randomized trial of the Gynecologic Oncology Group. Gynecol Oncol 2003;89:343–53. - PubMed
    1. Marth C, Landoni F, Mahner S, McCormack M, Gonzalez-Martin A, Colombo N, et al. Cervical cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017;28:iv72–83. - PubMed
    1. Kim JY, Byun SJ, Kim YS, Nam JH. Disease courses in patients with residual tumor following concurrent chemoradiotherapy for locally advanced cervical cancer. Gynecol Oncol 2017;144:34–9. - PubMed

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