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What are efficient approaches for triage of human papillomavirus–positive women in cervical cancer screening?
This cohort study of 3225 women found that p16/Ki-67 dual stain, alone or in combination with human papillomavirus 16/18 genotyping, provides better risk stratification than comparable cytologic-based strategies.
Triage of human papillomavirus–positive women with dual stain may lead to lower referral to undergo colposcopy with similar detection of precancerous lesions compared with cytologic screening, making cervical cancer screening more efficient.
As cervical cancer screening transitions from Papanicolaou cytologic screening to primary human papillomavirus (HPV) testing worldwide, effective triage tests are needed to decide who among the HPV-positive women should receive further diagnostic evaluation to avoid unnecessary colposcopies and biopsies.
To evaluate the performance of the p16/Ki-67 dual stain (DS) and HPV16/18 genotyping for the triage of HPV-positive women.
Design, Setting, and Participants
A prospective observational study was conducted within the cervical cancer screening program at Kaiser Permanente Northern California of 3225 HPV-positive women undergoing HPV and Papanicolaou cytologic testing with a valid DS result from September 16 to October 31, 2015, with follow-up through December 31, 2018.
Human papillomavirus screening with partial genotyping and cytologic triage compared with DS triage.
Main Outcomes and Measures
Cervical intraepithelial neoplasia grade 3 or more severe (CIN3+) and grade 2 or more severe (CIN2+), diagnosed within 3 years after sample collection.
A total of 3225 women (mean [SD] age, 37.9 [11.3] years) participated in the study. For triage of HPV-positive women with partial genotyping, DS showed better risk stratification for CIN3+ than did Papanicolaou cytologic testing, with women with positive DS results having a higher risk than women with positive Papanicolaou test results for CIN3+ (218 of 1818 [12.0%; 95% CI, 10.5%-13.5%] vs 219 of 2128 [10.3%; 95% CI, 9.0%-11.6%]; P = .005). Similarly, DS showed better risk stratification for CIN3+ compared with Papanicolaou cytologic testing in HPV-positive women, irrespective of genotyping. The greatest reassurance against CIN3+ was observed in HPV16/18-negative women with negative DS results, with a risk low enough to extend retesting intervals. Dual stain triage strategies required substantially fewer colposcopies per detection of CIN3+ compared with Papanicolaou cytologic testing, with a 32.1% (859 of 2677) reduction of colposcopies compared with the currently recommended triage strategy of HPV screening with Papanicolaou cytologic testing. Results for CIN2+ were very similar.
Conclusions and Relevance
Triage of HPV-positive women with DS was superior to Papanicolaou cytologic testing in this study, demonstrating equal immediate detection of precancerous lesions and substantially reduced referral to colposcopy. These findings suggest that DS can safely replace Papanicolaou cytologic testing as a triage strategy for primary HPV screening, and that retesting intervals in HPV16/18-negative women with negative DS results can be safely extended to 3 years.
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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.
Accepted for Publication: January 23, 2019.
Published Online: May 13, 2019. doi:10.1001/jamainternmed.2019.0306
Correction: This article was corrected on June 10, 2019, to add the Open Access paragraph to the acknowledgments section and again on July 1, 2019, to fix errors in the caption to Figure 2.
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2019 Wentzensen N et al. JAMA Internal Medicine.
Corresponding Author: Nicolas Wentzensen, MD, PhD, MS, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Dr, Room 6-E448, Bethesda, MD 20892 (firstname.lastname@example.org).
Author Contributions: Drs Wentzensen and Clarke had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Wentzensen, Castle, Schiffman, Lorey.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Wentzensen, Bremer, Poitras, Tokugawa, Castle, Schiffman.
Critical revision of the manuscript for important intellectual content: Wentzensen, Clarke, Goldhoff, Castle, Schiffman, Kingery, Grewal, Locke, Kinney, Lorey.
Statistical analysis: Wentzensen, Clarke, Bremer, Poitras, Castle, Schiffman.
Obtained funding: Wentzensen, Schiffman.
Administrative, technical, or material support: Wentzensen, Poitras, Tokugawa, Goldhoff, Schiffman, Kingery, Grewal, Kinney, Lorey.
Conflict of Interest Disclosures: Dr Wentzensen reported being employed by the National Cancer Institute (NCI), which has received cervical cancer screening assays in-kind or at reduced cost from BD and Roche for studies that Dr Wentzensen is conducting. Dr Goldhoff reported receiving grants from the National Institutes of Health (NIH)/NCI during the conduct of the study. Dr Castle reported receiving cervical screening tests and diagnostics from Roche, Becton Dickinson, Cepheid, and Arbor Vita Corp at a reduced cost or no cost for research. Dr Schiffman reported being employed by the NCI, which has received cervical cancer screening assays in-kind or at reduced cost from companies involved in cervical screening, including Roche, BD, Qiagen, and MobileODT. Dr Kingery reported receiving grants from the NIH and the NCI during the conduct of the study and receiving grants from the NIH and the NCI outside the submitted work. Dr Grewal reported receiving grants from the NIH and the NCI during the conduct of the study and grants from the NIH and the NCI outside the submitted work. Dr Lorey reported receiving grants from the NIH and the NCI during the conduct of the study and grants from the NIH and the NCI outside the submitted work. No other disclosures were reported.
Additional Information: This article is dedicated to Barbara Fetterman, SCT.
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