		Professor Emeritus, Pathology and Cell Biology

Cervical cancer screening based on identification of human papillomavirus (HPV) strains outperformed primary liquid cytology for detection of high-grade cervical intraepithelial neoplasia (CIN), data from a large cohort study showed.

As compared with four other screening strategies, primary HPV testing with HPV 16/18 genotyping and reflex cytology offered the best combination of sensitivity and efficiency. The approach detected the most cases of CIN+3 (grade 3 or higher), missed the fewest cases, and required 12.8 colposcopies to detect 1 case of CIN3+.

Co-testing with cytology and HPV analysis resulted in a slightly lower rate of colposcopies per CIN3+ case detected but required 73% more screening tests. Other strategies proved to be less sensitive for detecting CIN3+, as reported at the Society of Gynecologic Oncology 45th Annual Meeting on Women’s Cancer in Tampa, Florida, in March.

“All of the primary HPV strategies are more sensitive for CIN3+ than cytology with ASC-US triage,” said lead author Thomas Wright, MD, professor emeritus of Pathology and Cell Biology at the New York-Presbyterian Hospital, Columbia University Medical Center. “Primary HPV screening with 16/18 genotyping and reflex cytology for 12 other high-risk HPV strains is the most sensitive approach and results in only slightly more colposcopy than hybrid co-testing; it also requires far fewer screening tests.” (

The results came from analysis of the pivotal ATHENA trial, which provided support for the 2011 FDA approval of the cobas HPV Test as a cervical cancer diagnostic. The test detects HPV 16/18 plus a pool of 12 other high-risk HPV strains.

On April 24, the FDA approved the cobas HPV Test as a primary, stand-alone screening tool for women 25 years and older, after a review of 3-year follow-up data from ATHENA. The decision marked the first approved alternative to Pap cytology testing in a frontline setting and has prompted discussion of screening strategies.

In its internal review, the FDA found that the cobas HPV Test “detects more women with disease and requires fewer women without disease to go to colposcopy than cytology alone.”

ATHENA involved 40,901 women 25 years or older who had valid baseline co-testing with liquid- based cytology plus three HPV tests: Amplicor, Linear Array, and the cobas test. All three tests are manufactured by Roche Molecular Systems, which funded the ATHENA study.

Patients who had positive HPV tests or atypical squamous cells of undetermined significance (ASC-US) on baseline screening were referred for colposcopy (8067), as were a random sample of patients who were HPV negative and had normal cytology (895). Patients who had negative HPV tests and cytology exited the study. During a 3-year follow-up period, patients continuing with the study had annual gynecologic exams that included liquid-based cytology and high-resolution HPV testing.

During follow-up, women who developed ASCUS were referred for colposcopy but remained in the study unless CIN2+ was detected. After 3 years, all women (4063) had repeat colposcopy with cervical biopsy.

Wright reported results for detection of CIN3+ by five screening strategies: cytology alone, co-testing, HPV with genotyping, HPV and reflex cytology for patients with positive tests, and HPV with genotyping and reflex cytology.

Cytology alone detected 143 cases of CIN3+ at baseline and an additional 36 cases during follow-up, but missed 168 cases detected by HPV testing. The strategy was associated with 43,521 screening tests, leading to 1927 colposcopy procedures, and a colposcopy rate of 10.8 per each case of CIN3+ detected.

Co-testing detected 143 cases of CIN3+ at baseline and 140 during follow-up but missed 64 cases. The strategy involved 91,156 screening tests, 3527 colposcopy procedures, and a colposcopy rate of 12.5 per CIN3+ detected.

HPV with genotyping identified 150 cases of CIN3+ at baseline and 126 during follow-up but missed 71 cases. Performance parameters consisted of 49,830 screening tests, 3218 colposcopies, and a colposcopy rate of 11.7 per each case of CIN3+ detected.

HPV detection with reflex cytology identified 133 cases of CIN3+ at baseline and 138 cases during follow-up but missed 76 cases. The strategy involved 54,098 screening tests and 3191 colposcopy procedures, resulting in a colposcopy/CIN3+ rate of 11.8. The combination of HPV with genotyping followed by reflex cytology detected 294 cases of CIN3+ (197 at baseline and 97 during follow-up) and missed 53 cases. The strategy resulted in 52,651 screening tests, 3767 colposcopies, and a colposcopy/CIN3+ rate of 12.8.

		Figure. Comparison of Screening Strategies

		CIN3+ indicates cervical intraepithelial neoplasia grade 3 or higher; HPV, human papillomavirus. Wright et al. SGO 45th Annual Meeting on Women’s Cancer; March 22-25, 2014; Tampa, FL. Abstract 3.

			Wright TC, Stoler MH, Behrens CM, et al. Comparison of the performance of human papillomavirus (HPV) primary screening strategies with cytology-based strategies: results from the ATHENA trial 3-year follow-up phase. Presented at: SGO 45th Annual Meeting on Women’s Cancer; March 22-25, 2014; Tampa, FL. Abstract 3.

			US Food and Drug Administration. Meeting materials of the microbiology devices panel: FDA executive summary. http://goo.gl/tJ4Jb9. Published March 12, 2014. Accessed May 2, 2014.

Thomas Wright, MD

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HPV Test With Genotyping Tops Cervical Cancer Screening Strategies