HPV Genotyping: A New Dimension in Cervical Cancer Screening Tests

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1 HPV Genotyping: A New Dimension in Cervical Cancer Screening Tests Lee P. Shulman MD The Anna Ross Lapham Professor in Obstetrics and Gynecology and Chief, Division of Clinical Genetics Feinberg School of Medicine of Northwestern University The$natural$history$of$cervical$cancer$ Normal cell Abnormal cell HPV infection Months CIN1 CIN2 Years or decades CIN3 carcinoma Surface Basal layer Doorbar J. Clin Sci (London) 2006; 110: CIN, cervical intraepithelial neoplasia (terminology used to describe histology of squamous cell lesions). 1&

2 Screening$to$prevent$cervical$cancer$ Screening$with$cervical$cytology:& A&triumph and a tragedy * * Koss L. The Papanicolaou test for cervical cancer detection. A triumph and a tragedy. JAMA. 1989;261(5): New Cases, Deaths and 5-Year Relative Survival SEER 9 Incidence & U.S. Mortality Year Year Survival In recent years cervical cancer incidence has leveled off, as cytology is not reducing incidence further 68.1% 67.9% 66.4% 71.0% 70.9% 71.6% 70.4% 68.0% SEER 9 Incidence & U.S. Mortality , All Races, Females. Rates are Age-Adjusted. (accessed 12/29/13) 2&

3 Screening$history$of$women$diagnosed$with$invasive$ cervical$carcinoma$(icc)$ Cause, n (%) Kaiser study 1 Swedish study 2 No recent screen 464 (56%) 789 (64%) Cytology detection failure 263 (32%) 300 (24%) Failure of follow-up of abnormal cytology 106 (13%) 91 (7%) 1. Leyden WA, et al. J Natl Cancer Inst 2005; 97: ; 2. Andrae B, et al. J Natl Cancer Inst 2008; 100: ICC, invasive cervical carcinoma. Reasons$for$moving$from$cytology$to$HPV$co@tesAng:$ Cytology$is$subjecAve,$HPV$tesAng$is$objecAve$ The&subjec4vity&of&cytology&decreases&&&&&&&&&&&&&&&&&&&& clinical&confidence,&increasing&costs& Highly&variable&results&between&laboratories& && Wright TC et al. Inter-laboratory Variation in the Performance of Liquid-based Cytology; Insights from the ATHENA trial. Stoler M.H, Schiffman M. JAMA 2001;285(11): &

4 ATHENA$Trial$ Test LAB A (n=12,294) Sensitivity for CIN 2+(%) LAB B (n=4,218) LAB C (n=16,979) LAB D (n=12,442) Cytology HPV testing Conclusion:$The$accuracy$of$cytology$varies$significantly$even$across$good$labs,$ whereas$hpv$tesang$does$not$ Wright TC et al. Int J Cancer Oct 7. doi: /ijc [Epub ahead of print] Cytology$has$low$sensiAvity$for$detecAng$CIN2$or$worse $ SensiAvity$of$cytology$vs.$HPV$DNA$for$ CIN2$ 100 Sensitivity* for CIN2 (%) Cytology HPV DNA Test Average increase 35.7% 0 Bigras (N=13,842) Cardenas (N=1,850) Coste (N=3,080) Kulasingam (N=774) Mayrand (N=9,977) Petry (N=7,908) Whitlock EP, et al. Ann Intern Med. 2011; 155: , W Studies performed in developed countries in women 30 years and older. 4&

5 Results$from$two$rounds$of$HPV$DNA$tesAng$versus$ cytology$screening:$$$$$$$$$$$$$$$$$$$$$$$$$$ 94,000 women screened twice 3 years apart HPV arm Cytology arm When found CIN3 Cancer CIN3 Cancer Round one Round two In total HPV testing identified approximately double the number of CIN3 cases compared to cytology at round one and ~40% more overall Ronco G, et al. Lancet Oncol 2010; 11: Italian women aged at recruitment. The$incidence$of$adenocarcinoma$conAnues$to$rise$ despite$cytology$screening:&& SCC&and&adenocarcinoma&incidence&rates& Age-adjusted rates per 100,000 women in the US Squamous cell carcinoma Adenocarcinoma SCC incidence is decreasing while ADC incidence is increasing Smith HO, et al. Gynecol Oncol 2000; 78:97 105;. US data shown. SCC, squamous cell carcinoma; ADC, adenocarcinoma. 5&

6 DetecAon$of$CIN3,$AIS,$adenocarcinoma$and$SCC$in$the$ ATHENA$Trial$ Sensitivity Histology (number) Cytology HPV testing CIN3 (254) 52% (132) 92% (254) AIS (16) 63% (10) 88% (14)* Adenocarcinoma and AdenoSq Ca (1) 100% (1) 100% (1) Squamous cell carcinoma (3) 100% (3) 100% (3) *a 25% difference Castle PE et al. Lancet Oncol Sep;12(9): Trial$design:$The$cobas$HPV$test$was$evaluated$in$the$largest$ US$screening$trial:$$ATHENA$ Baseline phase Follow-up phase (subset of ~8,000 women) Enrolled >47,000 women Follow-up Year 1 Follow-up Year 2 Follow-up Year 3 Evaluating screening with cytology vs. cytology plus HPV (cotesting) All women age were screened with an HPV test with 16/18 genotyping (the Cobas 3 in 1 HPV test) and a Pap Any abnormal Pap (>ASC-US) or positive HPV test was referred to colposcopy >1000 women with a negative Pap and negative HPV test were also referred to colposcopy Everyone was biopsied: When no lesion was seen a random biopsy was required Wright TC Jr, et al. Am J Obstet Gynecol 2012; 206:46.e1 46.e11 ASC-US, atypical squamous cells of undetermined significance. 6&

7 Absolute$risk$of$ CIN2$straAfied$by$hrHPV$status$in$the$ ATHENA$normal$Pap$populaAon$ 20 Estimated absolute risk (%) Normal Pap hrhpv hrhpv+ Wright TC Jr, et al. Am J Clin Pathol 2011; 136: Absolute$risk$of$ CIN2$straAfied$by$hrHPV$status$in$the$ ATHENA$normal$Pap$populaAon$ 20 Estimated absolute risk (%) Normal Pap hrhpv hrhpv hrhpv HPV HPV18+ cobas HPV16 genotyping results identify a sub-population of women with negative cytology who are at the highest risk of CIN2 Wright TC Jr, et al. Am J Clin Pathol 2011; 136: &

8 pooled$hrhpv+$and$normal$pap$populaaon$hpv16+$ Absolute risk of CIN2* (%) hrhpv+ HPV years 30 years ASC-US Pap 1 NILM (normal Pap) 2 0 Women with ASC-US who test pooled hrhpv positive have a risk for CIN2 equivalent to that of HPV16 and/or HPV18 positive women with negative cytology 1. Stoler MH, et al. Am J Clin Pathol 2011; 135: ; 2. Wright TC Jr, et al. Am J Clin Pathol 2011; 136: ASC-US, atypical squamous cells of undetermined significance; NILM, negative for intraepithelial lesion or malignancies; * Estimated absolute risk shown for NILM;. Note absolute risk measurements are estimates based on raw study data. ASCCP$and$ACOG$2012$Management$Guidelines$ Management(of(co,tes.ng(results:((women&30)65&years& Pap & HPV Normal Pap & HPV+ Option 2 Immediate HPV 16/18 genotyping HPV 16/18 neg HPV 16/18 + Cotest 3 years Repeat cotest 12 mo Colposcopy Both neg Either positive Massad LS, et al. Am J Obstet Gynecol &

9 US Guidance on Primary HPV Screening ASCCP & SGO (2015) Primary HPV testing can be considered as an alternative to current US cytology-based cervical cancer screening methods for women starting at age 25. Women with a negative primary HPV test result should not be retested again for at least three years. An HPV test positive for HPV 16 or 18 should be followed with colposcopy. A test that is positive for the 12 other high risk types should be followed with cytology testing. Clinicians should not use an FDA-approved test without a specific primary hrhpv screening indication. Huh, W. et al. Gynecol Oncol. 2015; 136: Huh, W. et al. Obstet Gynecol 2015; 125: Primary Screening Algorithm Routine screening HPV NILM Follow-up in 12 months other hrhpv+ Cytology hrhpv HPV16/18+ ASC-US COLPOSCOPY COLPOSCOPY hrhpv=high risk HPV 9&

10 Comparison to ASC-US Triage CIN3 Strategy Relative Sensitivity 1 Relative Specificity 1 % % ASC-US Triage Co-testing with 16/18 Genotyping 1.28* 0.99* HPV with Genotyping and Reflex Cytology 1.40* 0.99* Data from Medical Devices Advisory Committee Microbiology Panel Meeting: Sponsor Executive Summary Adjusted results 1 Relative to Cytology with Reflex HPV Strategy *Statistically significant differences compared to Cytology with Reflex HPV Strategy Co-testing: Cytology with ASC-US triage in women 25-29, Co-testing with cytology and HPV in women 30+ Summary HPV16 and HPV18 genotyping identifies a subset of hrhpv-positive women with NILM cytology who would benefit from colposcopy 1 * >1 in 10 women who tested positive for HPV16 had CIN3 at baseline despite having negative cytology HPV16-positive women are at high and immediate risk of cervical precancer HPV18-positive women appear to have lower baseline risk of having high-grade disease, but are at risk of developing precancer in the future 2 A negative HPV is far better predictor of reduced progression to advanced cervical dysplasia and malignancy than cytology HPV DNA testing with integrated HPV16 and HPV18 genotyping adds medical value to adjunct screening programmes Wright TC Jr, et al. Am J Obstet Gynecol 2011; 136: ; 2. Khan MJ, et al. J Natl Cancer Inst 2005; NILM, negative for intraepithelial 97: ; 3. ASCCP, HPV Genotyping Clinical Update 2009, (accessed December 2011), available lesion or malignancies. from from * Supported by current ASCCP guidelines. 10&