Cervical Cancer Resources
The IMPACT Trial
The IMPACT (IMproving Primary screening And Colposcopy Triage) trial is a landmark cervical cancer screening study that was designed to support the FDA approval of multiple products, including CINtec® PLUS Cytology and the cobas® HPV test for use on the cobas® 6800/8800 Systems. The multi-center, prospective trial enrolled close to 35,000 women in the U.S. and is representative of the routine cervical cancer screening population.
In April 2020, the FDA approved the cobas® HPV test for use on the cobas® 6800/8800 Systems. Previously, in 2011 it was FDA approved for use on only the cobas® 4800 System. The cobas® HPV test is approved for primary HPV screening in women 25 and older, as a reflex (follow-up) test for ASC-US (Atypical Squamous Cells of Undetermined Significance) Pap cytology results in women 21 and older, and as a co-test with Pap cytology for women 30 and older using ThinPrep PreservCyt Solution.
While most HPV infections resolve on their own, some women who test positive for the virus or whose co-testing results are inconclusive – HPV-positive and Pap cytology-negative – may develop pre-cancerous cervical lesions that, if left untreated, may progress to cervical cancer. Early identification of women who are most at risk is vital. The IMPACT trial also clinically validated CINtec® PLUS Cytology, which received its first FDA approval in March 2020. CINtec® PLUS Cytology is a dual-stain test that uses biomarker-based technology to detect the simultaneous presence of p16 and Ki-67 within a single cell. This abnormality is associated with HPV infections that are transforming and can, if left untreated, progress to pre-cancer or cancer. A positive result of these two biomarkers in a single cell signals that a woman is more significantly at risk for disease.
Study data will be broadly shared, pending publication of the key findings.
ATHENA Landmark Study
Shaping our Understanding of the Role of High-Risk HPV Testing in Cervical Cancer Screening
The ATHENA HPV trial was a large, prospective clinical study evaluating the performance of the cobas® HPV test in three relevant populations*: women with ASC-US (Atypical Squamous Cells of Undetermined Significance) cervical cytology (≥21 years), women with normal cervical cytology (≥30 years), and an overall screening population (25+ years) to explore HPV as a first-line test (longitudinal 3 year study).1, 2, 3, 4 ATHENA, with over 47,000 women enrolled, also set out to evaluate the medical value of testing for pooled hrHPV DNA as well as genotypes HPV 16 and HPV 18 individually.
*Women <25 years (n=4,183) with normal cytology exited the study.
ATHENA Key Findings:
The cobas® HPV test was clinically validated in ATHENA, the first screening trial for registration that evaluated simultaneous real-time genotyping of 12 pooled hrHPV genotypes plus HPV 16 and HPV 18 individually. The ATHENA trial evaluated the performance of the cobas® HPV test in multiple clinical situations, including ASC-US triage and co-testing (HPV and Pap cytology).
ATHENA not only validated the cobas® HPV test as comparable to the current standard of pooled hrHPV testing within the ASC-US population, but the trial also quantified risk of precancer and cervical cancer in HPV 16+ and/or HPV 18+ women who had ASC-US or who had normal cytology.
The ATHENA study demonstrated that one in four women who are HPV 16 positive will have cervical disease within three years and that nearly 1 in 7 women with normal Pap cytology who were HPV 16 positive actually had high-grade cervical disease that was missed by cytology.
In addition, results from the ATHENA trial included a comparison of a cobas® HPV test screening strategy to alternative strategies using Pap cytology and HPV testing. The comparison showed that a strategy leveraging the ability of the cobas® HPV test to identify women testing positive for HPV 16 or 18, and using cervical cytology (Pap) as a triage, follow-up test, would allow clinicians to detect more disease without referring a significantly greater number of women to unnecessary follow-up. In 2014, based on ATHENA study data, the U.S. FDA approved for the first time the use of the Roche cobas® HPV test instead of Pap cytology for first-line primary screening in women 25 and older.
ATHENA Principal Publications
- High-risk human papillomavirus testing in women with ASC-US cytology: results from the ATHENA HPV study (Stoler MH, et al. Am J Clin Pathol. 2011;135(3):468-75.)
- Evaluation of HPV-16 and HPV-18 genotyping for the triage of women with high-risk HPV+ cytology-negative results (Wright TC, Jr., et al. Am J Clin Pathol. 2011;136(4):578-86.)
- Primary cervical cancer screening with human papillomavirus: end of study results from the ATHENA study using HPV as the first-line screening test (Wright TC, et al. Gynecol Oncol. 2015;136(2):189-97.)
- Comparison of cervical cancer screening strategies incorporating different combinations of cytology, HPV testing, and genotyping for HPV 16/18: results from the ATHENA HPV study (Cox JT, Castle PE, Behrens CM, et al. Am J Obstet Gynecol 2012; 184:e1-e11.)
- Performance of carcinogenic human papillomavirus (HPV) testing and HPV16 or HPV18 genotyping for cervical cancer screening of women aged 25 years and older: a subanalysis of the ATHENA study (Castle PE, Stoler MH, Wright TC Jr., et al. Lancet Oncol 2011; 12:880-890.)
- The ATHENA human papillomavirus study: design, methods, and baseline results (Wright TC Jr, Stoler MH, Behrens CM, Apple R, Derion T, Wright TL. Am J Obstet Gynecol 2011; 1:e1-e11.)
The CERTAIN Study
The CERTAIN (CERvical Tissue Adjunctive aNalysis) Study is one of the largest, most rigorous immunochemistry clinical studies done to date, evaluating use of the p16 biomarker for clinical/IVD use in the evaluation of cervical biopsy specimens.
The CERTAIN Study included:
- 38,500 interpretations
- 1,100 biopsies
- 70 individual surgical pathologists
- 3 globally recognized expert gynecopathologists
As a result of the CERTAIN Study, CINtec® Histology achieved ≥ 99% acceptability for staining, morphology, and background. CAP (College of American Pathologists), the ASCCP (American Society for Colposcopy and Cervical Pathology) and WHO (World Health Organization) recommend the adjunctive use of p16 IHC in evaluation of cervical biopsies. Use of CINtec® Histology is supported by >100 peer-reviewed publications. The CINtec®Histology test is the only p16 biomarker test CE marked and U.S. 510(k) cleared for clinical use in the evaluation of cervical biopsy specimens. Learn more by accessing our training module on CINtec® Histology-CERTAIN Study.
Journals & Articles
Many published articles and papers support the advancement of science around HPV and cervical cancer prevention. The science behind HPV and its role in disease progression has opened up new pathways for patient management and care. Please see below for a summary of clinical study publications that have been significant in shaping and supporting today's understanding to guide clinical practice.
HPV and Cervical Cancer Screening Prevention:
- Simms et al., Impact of scaled up human papillomavirus vaccination and cervical screening and the potential for global elimination of cervical cancer in 181 countries, Lancet Oncology 2020–99: a modelling study, Volume 20, Issue 3, March 2019, Pages 394-407 https://www.sciencedirect.com/science/article/pii/S1470204518308362 (accessed 1June 2020).
- Saslow D, Solomon D. Lawson HW, et al. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. Am J Clin Pathol. 2012; 137:516-542.
- Castle PE, Stoler MH, Wright TC Jr, Sharma A, Wright TL, Behrens CM. Performance of carcinogenic human papillomavirus (HPV) testing and HPV16 or HPV18 genotyping for cervical cancer screening of women aged 25 years and older: a subanalysis of the ATHENA study [published online August 23, 2011]. Lancet Oncol. doi:10.1016/S1470-2045(11)70188- 7.
- Herzog TJ, Monk BH. Reducing the burden of glandular carcinomas of the uterine cervix. Am J Obstet Gynecol. 2007;197:566-571.
- Rijkaart DC, Berkhof J, Rozendaal L, et al. Human papillomavirus testing for the detection for high-grade cervical intraepithelial neoplasia and cancer: final results of the POBASCAM randomized controlled trial. Lancet Oncol. 2012; 13:78-88.
- Bosch FX, de Sanjosé S. Chapter 1: Human papillomavirus and cervical cancer—burden and assessment of causality. J Natl Cancer Inst Monogr. 2003;31:3-13.
- Whitlock EP, Vesco KK, Eder M, Lin JS, Senger CA, Burda BU. Liquid-based cytology and human papillomavirus testing to screen for cervical cancer: a systematic review for the U.S. Preventative Services Task Force. Ann Intern Med. 2011; 155:687-697.
- Cox JT, Castle PE, Behrens CM, et al. Comparison of cervical cancer screening strategies incorporating different combinations of cytology, HPV testing and genotyping for HPV 16/18: results from the ATHENA HPV study. Am J Ob Gyn. 2012:In Press.
- Leyden WA, Manos MM, Geiger AM, et al. Cervical cancer in women with comprehensive health care access: attributable factors in the screening process. J Natl Cancer Inst. 2005;97(9):675-683.
- Andrae B, Kemetli L, Sparén P, et al. Screening-preventable cervical cancer risks: evidence from a nationwide audit in Sweden.J Natl Cancer Inst. 2008;100(9):622-629.
- Darragh TM, Colgan TJ, Cox JT, et al. The lower anogenital squamous terminology standardization project for HPV associated lesions: Background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. J Low Genit Tract Dis. 2012;16:205-242. Erratum in J Low Genit Tract Dis. 2013;17:368.
- Bergeron, C., et al, Conjunctive p16INK4a Testing Significantly Increases Accuracy in Diagnosing High-Grade Cervical Intraepithelial Neoplasia. Am J Clin Pathol 2010;133:395-406. DOI: 10.1309/AJCPXSVCDZ3D5MZM
- Galgano, M, et al, Using Biomarkers as Objective Standards in the Diagnosis of Cervical Biopsies. Am J Surg Pathol. 2010;34:1077–1087.
- Ordi, J., et al. p16INK4a Immunostaining Identifies Occult CIN Lesions in HPV-positive Women. International Journal of Gynecological Pathology 2008; 28:90–97. DOI: 10.1097/PGP.0b013e31817e9ac5
The following publications provide further evidence of the clinical utility of p16/Ki-67 dual staining in cervical cancer screening:
- T.C. Wright Jr. et al., Triaging HPV-Positive Women with p16/Ki-67 Dual-stained Cytology: Results from a Sub-study Nested into the ATHENA Trial. Gynecologic Oncology 144 (2017) 51-56. doi: 10.1016/j.ygyno.2016.10.031.
- Schmidt D, Bergeron C, Denton KJ, Ridder R for the European CINtec Cytology Study Group. p16/Ki-67 dual-stain cytology in the triage of ASCUS and LSIL papanicolaou cytology: results from the European equivocal or mildly abnormal Papanicolaou cytology study. Cancer Cytopathol. 2011;119(3):158-166. doi: 10.1002/cncy.20140. Epub 2011 Mar 25.
- Petry KU, Schmidt D, Scherbring S, et al. Triaging Pap cytology negative, HPV positive cervical cancer screening results with p16/Ki-67 dual-stained cytology. Gynecol Oncol. 2011;121(3);505-509. doi: 10.1016/j.ygyno.2011.02.033. Epub 2011 Mar 21.
- Killeen JL, Dye T, Grace C, Hiraoka M. Improved abnormal Pap smear triage using cervical cancer biomarkers. J Low Genit Tract Dis. 2014;18(1):1-7. DOI:10.1097/LGT.0b013e31828aeb39.
- Ikenberg, H. et al., Screening for Cervical Cancer Precursors With p16/Ki-67 Dual-Stained Cytology: Results of the PALMS Study. J Natl Cancer Inst. 2013 Oct 16; 105(20): 1550–1557.
- Petry KU et al., A model to evaluate the costs and clinical effectiveness of human papilloma virus screening compared with annual papanicolaou cytology in Germany. European Journal of Obstetrics & Gynecology and Reproductive Biology 212 (2017) 132–139.
- Bergeron, C. et al., Prospective evaluation of p16/Ki-67 dual-stained cytology for managing women with abnormal Papanicolaou cytology: PALMS study results. Cancer Cytopathol. 2015 Jun;123(6):373-81. doi: 10.1002/cncy.21542. Epub 2015 Apr 17.
- Wentzensen N., et al., Performance of p16/Ki-67 Immunostaining to Detect Cervical Cancer Precursors in a Colposcopy Referral Population. Clin Cancer Res. 2012 Aug 1;18(15):4154-62. doi: 10.1158/1078-0432.CCR-12-0270. Epub 2012 Jun 6.
- Wentzensen N., et al., p16/Ki-67 Dual Stain Cytology for Detection of Cervical Precancer in HPV-Positive Women. J Natl Cancer Inst. 2015 Sep 15;107(12):djv257. doi: 10.1093/jnci/djv257. Print 2015 Dec.
- Wentzensen N., et al.,Clinical Evaluation of Human Papillomavirus Screening With p16/Ki-67 Dual Stain Triage in a Large Organized Cervical Cancer Screening Program JAMA Intern Med. 2019;179(7):881-888. doi:10.1001/jamainternmed.2019.0306. Published online May 13, 2019 (accessed 1June 2020).
- Waldstrøm, M., et al., Evaluation of p16INK4a/Ki-67 Dual Stain in Comparison With an mRNA Human Papillomavirus Test on Liquid-Based Cytology Samples With Low-Grade Squamous Intraepithelial Lesion. Cancer Cytopathol. 2013 Mar;121(3):136-45. doi: 10.1002/cncy.21233. Epub 2012 Sep 17.
- Wright TC, Jr., et al. The ATHENA human papillomavirus study: design, methods, and baseline results. Am J Obstet Gynecol. 2012;206(1):46 e1- e11
- Stoler MH, et al. High-risk human papillomavirus testing in women with ASC-US cytology: results from the ATHENA HPV study. Am J Clin Pathol. 2011;135(3):468-75. (for ASC-US CYTOLOGY)
- Wright TC, Jr., et al. Evaluation of HPV-16 and HPV-18 genotyping for the triage of women with high-risk HPV+ cytology-negative results. Am J Clin Pathol. 2011;136(4):578-86. (FOR CO-TESTING)
- Wright TC, et al. Primary cervical cancer screening with human papillomavirus: end of study results from the ATHENA study using HPV as the first-line screening test. Gynecol Oncol. 2015;136(2):189-97. (FOR PRIMARY SCREENING)