Epigenetic markers on the horizon: how to triage hrhpv positive women

Transcription

1 Epigenetic markers on the horizon: how to triage hrhpv positive women Baseline results from ongoing cohort study Adrienn Kocsis 1, Márta Benczik 1,4, Róbert Koiss 2, ZsuzsaSchaff 3, Miklós Nyiri 1, Tibor Takács 1,4 1 Cellcall Kft., Budapest, Hungary 2 Department of Obstetrics and Gynaecology, St. Stephan's Hospital, Budapest, Hungary 3 Second Department of Pathology, Semmelweis University, Budapest, Hungary 4 GenoID Molecular Diagnostic Laboratory, Synlab Hungary Kft., Budapest, Hungary 30 th International Papillomavirus Conference, Sept , Lisbon, Portugal

2 Disclosing conflict of interest 2/18 I am the Deputy Clinical Director of Cellcall. The presented Study was partially funded by the Hungarian Government (KMR_ ). The tests were purchased atcommercial price bycellcall. Ethics approval number: V-R-021/ /2013. I understand that the information presented must be unbiased, scientifically balanced, and based on best available evidence and best practices in medicine. I attest that relationships with commercial interests does not influence or bias my involvement and/or planning of the CME activity. All scientific research referred to, reported, or used in support or justification of patient care recommendations conform to the generally accepted standards of experimental design, data collection, and analysis. Adrienn Kocsis MD, MSc

3 3/18 of current cervical screening technologies, molecular HPV testing offers by far best negative predictive value for detection of high grade CIN (Dillner et al, 2008) in most clinical settings, women ages should not be screened with HPV testing alone (ASCCP, 2012) The use of HPV 16/18 genotyping and reflex cytology for women positive for the 12 other hrhpv genotypes achieves a reasonable balance of disease detection with the number of screening tests and colposcopies required to achieve that detection. (Huh et al 2015)

4 Promising results 4/18 Cellcall CONFIDENCE Marker TM performance among hrhpv+ patients CIN % CIN % SENSITIVITY hrhpv+ women aged Follow-up group (46/48) CI95%: (34/35) CI95%: SPECIFICITY hrhpv+ women aged Screening population 82.2 % (490/596) CI95%: % (490/597) CI95%:

5 Biomarker triage 5/18 Cellcall CONFIDENCE TM Test PRIMARY HPV TEST hrhpv + hrhpv - Specific marker Repeat in 5 yr + Colposcopy - Repeat in 1 yr Ongoing, multicentric clinical study since 2013 (n 6000, 18-65)

6 6/18 Study sites and testing laboratories Cellcall Kft., Budapest, Hungary GenoID Molecular Diagnostic Laboratory, Synlab Hungary Kft, Budapest, Hungary Second Department of Pathology, Semmelweis University, Budapest, Hungary Amóra Kft, Budapest, Hungary Department of Obstetrics and Gynaecology, St. Stephan's Hospital, Budapest, Hungary Jósa András County Hospitals and University Teaching Hospital, Nyíregyháza, Hungary Profilakt Kft, Budapest, Hungary Healthcare Center of Ferencváros, Budapest, Hungary Medserv Kft, Budapest, Hungary Second Department of Obstetrics and Gynaecology, Semmelweis University, Budapest, Hungary

7 The Cellcall CONFIDENCE TM Test 7/18 CONFIDENCE HPV TM CONFIDENCE Marker TM Viral DNA test Multiplex RT-PCR hrhpv genotyping 16, 18, 31, 45 Other hrhpv in group 33, 35, 39, 51, 52, 56, 58, 59, 66, 68 Epigenetic biomarker Quantitative RT-PCR on bisulphite converted DNA Measuring methylationof a single target gene

8 Study design Baseline visit women aged 25-65, n=2451 8/18 LBC sampling LBC cytology hrhpv Biomarker Diagnostic result and treatment Comparator HPV Roche cobas HPV Cellcall CONFIDENCE HPV TM Cellcall CONFIDENCE Marker TM Histologically confirmed cases n=81 (3.3% of total) gold standard Clinical performance measured in each group

9 Good agreement 9/18 CONFIDENCE HPV TM HPV detection HPV genotyping hrhpv + 14 HR 16, 18 cobas HPV HR 16, 18, 31, 45 CONFIDENCE HPV TM 406 Women ages 30-65, n=1849 Positive agreement 68,4% ĸ value 0.76 n=303 CI95%: HC2, cobas, CLART and APTIMA 42 to 58% positive agreement on any compared pair of assays kappa value (HORIZON Study, Rebolj et al, 2014)

10 Independent & specific 10/18 CONFIDENCE Marker TM Methylation level of the target gene is independent from hrhpv positivity and elevated in high risk lesions. <CIN2 HPV-/+ n=2530 <CIN2 HPV+ n=604 CIN2+ n=12 Screening population, women 18-65

11 Patient population 11/18 n=2451, women aged years BASELINE SAMPLE based on medical history in the previous 2 years Negative history (No hrhpv and no positive Pap test result ) Positive history (hrhpv and/or ASCUS) n=2188 SCREENING POPULATION baseline visit is regular screening 9% ASCUS 22% hrhpv+ n=263 RISK GROUP baseline visit is a follow-up or scheduled treatment visit 50% ASCUS 62% hrhpv+

12 12/18 Screening population (n=2188) hrhpvhrhpv+ MET+ (87) (482) hrhpv+ MET+ specific marker: less than 20% (87 of 482) of the hrhpv+ cases were also marker positive, including 6 of the total 7 CIN2+ cases total n=7 CIN2+

13 13/18 Risk group (n=263) hrhpvhrhpv+ MET+ hrhpv+ MET sensitive marker: 44 of 49 (90%) of the CIN2+ cases were bothhrhpv+ & markerpositive 1 total n=49 CIN2+

14 Can we improve referral rates? 14/18 CONFIDENCE TM protocol Primary HPV test with biomarker triage Recent primary HPV protocol Primary HPV test with genotyping and cytology triage (reflex) Referral to colposcopy CONFIDENCE TM hrhpv+ & MET+ Referral to colposcopy HPV16/18+ OR other hrhpv+ & ASCUS

15 Sensitive & specific marker 15/18 RISK GROUP age: 25-65, endpoint: CIN2+, 26% (n=68) histologically confirmed n=263 total, n=49 CIN2+, CI95%

16 16/18 ASCCP colposcopy referral population (n=435) Referral to colposcopy according to ASCCP guidelines (2013) 30 NILM & HPV16/ NILM & other hrhpv+, if 12m repeat hrhpv+ or ASC 25 ASCUS & hrhpv+ 25 ASCUS, if 12m repeat ASCUS ASCUS/LSIL between ages 21-24, if 12m repeat ASCH LSIL & hrhpv+ LSIL at ages ASCH or AGC or HSIL Clinical performance of Cellcall CONFIDENCE TM in ASCCP colposcopy referral population

17 Results in an ASCCP colposcopy referral population 17/18 ASCCP COLPOSCOPY REFERRAL age: 25-65, endpoint: CIN2+, 15% (n=66) histologically confirmed n=435 total, n=64 CIN2+, CI95%

18 18/18 Cellcall CONFIDENCE TM We recommend primary hrhpv screening with biomarker triage: CONFIDENCE HPV TM hrhpv DNA test with genotyping HPV16, 18, 31, 45 CONFIDENCE Marker TM host gene methylation test of single target Good agreement Roche cobas HPV compared to High accuracy in the management of hrhpv positive women CONFIDENCE HPV TM & Marker TM test provides high accuracy: 95.8% sensitivity (hrhpv+, aged 18-65, follow-up group) 82.2% specificity (hrhpv+, aged 18-65, screening population)