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The QIAsure Methylation Test

The QIAsure Methylation Test is intended to be used as a triage test for women with a positive HPV DNA test or for women with ASC-US cytology to identify those women who need to be referred for colposcopy.

The QIAsure Methylation Test is a multiplex real-time methylation specific PCR-based (qMSP) assay that detects hyper methylation of 2 disease related marker genes, FAM19A4 and mir124-2, to distinguish women with cervical (pre)cancer. The test specifically detects women with a cancer-like methylation profile, which are indicative for the women who have a short-term high risk for progression to cervical cancer.

The QIAsure Methylation test is a rebrand of the  Precursor-M+.

Why QIAsure Methylation Test?

  • Because HPV primary screening ‘only’ identifies women at risk. Effective triage is mandatory to identify in this risk population those women with underlying disease.

After having identified women at risk by a positive HPV test, the majority of these women (~80-90%) will clear the HPV infection by their immune system and thus not develop cervical (pre)cancer. However, the smaller group of HPV positive women, who develop (pre)cancerous lesions need to be filtered out – this is called triage – by a test that identifies the women with a progressive lesion profile developing into (pre) cancer.

  • Because current triage strategies are not ideal to do the above. Current triage strategies
    • Are lacking a good clinical sensitivity and specificity for disease
    • Do not guide clinicians to clear decision making
    • Are subjective while labor intensive
    • Induce over diagnosis, over referral and overtreatment

Therefore methylation marker based assays are an promising resolution while they comply with all of the above

  • Because manageable lab workflows are essential in high volume screening programs

Therefore a fully molecular test workflow is highly advantageous

  • Because the burden on health care systems is unnecessary growing without a change towards better triage model

A QIAsure triage solution improves clinical output while decreasing costs

What makes the QIAsure Methylation test unique?

  • The  QIAsure Methylation Test is clinically validated among several European patient cohorts and laboratories. It demonstrates good clinical sensitivity, clinical specificity and highly reproducible intra- and inter laboratory performance.

Clinical Performance QIAsure on Rotor-Gene Q

Clinical sensitivity cancer98.3%
Clinical sensitivity CIN3+78.6%
Clinical specificity CIN3+76.8%
NPV96.9%
PPV28.2%
Reproducibility• Overall agreement: 90%
• Kappa value: 0.76
  • Very high sensitivity for cervical cancer (independent of histotype, FIGO, and geography) and CIN3+.
  • Long term risk cancer significantly lower than cytology (long term CIN3+ risk equal)
  • Highest number of clinical publications (Validscreen)
  • An internal sample control checks for sample quality assuring reliable results.
  • The QIAsure Methylation Test is validated for different sampling types, i.e. physician-taken cervical scrapes and self-collected vaginal specimens, and for different collection media, i.e. PreservCyt® and SurePath®.
  • The QIAsure Methylation Test is compatible with the RotorGene Q, ABI7500 and VIIA7 platforms.

Clinical use cases for QIAsure methylation Assay

  • Triage test for
    • hrHPV-positive women
    • ASC-US/LSIL population
  • Reassurance test: a negative QIAsure result indicates a very low risk of developing (pre)cancer (1.7% ref) .
  • Guidance to clinicians: a positive QIAsure result indicates follow up by colposcopic examination of the cervix by a health care professional to guide patient management. A negative QIAsure result allows safe monitoring preventing unnecessary follow up and overtreatment

Literature

Methylation markers FAM19A4 and miR124-2 as triage strategy for primary HPV screen positive women; A large European multi-center study. Bonde J, Floore A, Ejegod D, et al. Int J Cancer. 2020;10.1002/ijc.33320. doi:10.1002/ijc.33320

 

The use of host cell DNA Methylation analysis in the detection and management of women with advanced cervical intraepithelial neoplasia: a review. Kremer et al. BJOG, 2020 Jul 3, DOI: 10.1111/1471-0528.16395

 

Long-term CIN3+ risk of HPV positive women after triage with FAM19A4/miR124-2 methylation analysis. Dick et al. Gynecol Oncol. 2019 Aug;154(2):368-373. doi: 10.1016/j.ygyno.2019.06.002. Epub 2019 Jun 8. PubMed PMID: 31182225.

 

FAM19A4/miR124-2 methylation in invasive cervical cancer: A retrospective cross-sectional worldwide study. Int J. Vink et al, Cancer. 2019 Aug 7. doi: 10.1002/ijc.32614. [Epub ahead of print] PubMed PMID: 31390052.

 

Reliable identification of women with CIN3+ using hrHPV genotyping and methylation markers in a cytology-screened referral population.
Leeman et al, Int J Cancer. 2019 Jan 1;144(1):160-168.

 

Intra- and inter-laboratory agreement of the FAM19A4/mir124-2 methylation test: Results from an international study. Floore et al., J Clin Lab Anal. 2019 Feb 13:e22854.

 

Role of FAM19A4/miR124-2 methylation analysis in predicting regression or non-regression of CIN2/3 lesions: a protocol of an observational longitudinal cohort study. Kremer et al. BMJ Open. 2019 Jul 9;9(7):e029017. doi: 10.1136/bmjopen-2019-029017. PubMed PMID: 31289088; PubMed Central PMCID: PMC6629415.

 

The use of molecular markers for cervical screening of women living with HIV in South Africa. Kremer et al. AIDS. 2019 Nov 1;33(13):2035-2042. doi: 10.1097/QAD.0000000000002325. PubMed PMID: 31385866; PubMed Central PMCID: PMC6791588.

 

Defining hrHPV genotypes in cervical intraepithelial neoplasia by laser capture microdissection supports reflex triage of self-samples using HPV16/18 and FAM19A4/miR124-2 methylation. Leeman et al. Gynecol Oncol. 2018 Nov;151(2):311-318. doi: 10.1016/j.ygyno.2018.09.006. Epub 2018 Sep 13. PubMed PMID: 30219239.

 

Cervical cancer risk in HPV-positive women after a negative FAM19A4/mir124-2 methylation test: A post hoc analysis in the POBASCAM trial with 14 year follow-up. De Strooper et al. Int J Cancer. 2018 Sep 15;143(6):1541-1548. doi: 10.1002/ijc.31539. Epub 2018 Apr 27. PubMed PMID: 29663363; PubMed Central PMCID: PMC6099282.

 

Human Papillomavirus Triage of Women With Atypical Squamous Cells of Undetermined Significance-Reduction of Overtreatment Needed. Meijer et al. JAMA Oncol. 2017 Oct 1;3(10):1310-1311. doi: 10.1001/jamaoncol.2017.1522. PubMed PMID: 28654967.

 

Management of high-risk HPV-positive women for detection of cervical (pre)cancer. Luttmer et al. Expert Rev Mol Diagn. 2016 Sep;16(9):961-74. doi: 10.1080/14737159.2016.1217157. Epub 2016 Aug 5. Review. PubMed PMID: 27459506.

 

FAM19A4 methylation analysis in self-samples compared with cervical scrapes for detecting cervical (pre)cancer in HPV-positive women. Luttmer et al. Br J Cancer. 2016 Aug 23;115(5):579-87. doi: 10.1038/bjc.2016.200. Epub 2016 Jul 14. PubMed PMID: 27415009; PubMed Central PMCID: PMC4997542.

 

Validation of the FAM19A4/mir124-2 DNA methylation test for both lavage- and brush-based self-samples to detect cervical (pre)cancer in HPV-positive women. De Strooper et al. Gynecol Oncol. 2016 May;141(2):341-347. doi: 10.1016/j.ygyno.2016.02.012. Epub 2016 Mar 3. PubMed PMID: 26921784; PubMed Central PMCID: PMC4851217.

 

Comparing the performance of FAM19A4 methylation analysis, cytology and HPV16/18genotyping for the detection of cervical (pre)cancer in high-risk HPV-positive women of a gynecologic outpatient population (COMETH study). Luttmer et al.  Int J Cancer. 2016 Feb 15;138(4):992-1002. doi: 10.1002/ijc.29824. Epub 2015 Sep 14. PubMed PMID: 26317579.

 

Clinical implications of (epi)genetic changes in HPV-induced cervical precancerous lesions.
Steenbergen et al. Nat Rev Cancer. 2014, 14:395-405.

 

Methylation marker analysis of self-sampled cervico-vaginal lavage specimens to triage high-risk HPV-positive women for colposcopy.
Hesselink et al. Int J Cancer. 2014;135:880-6.

 

Triage by methylation-marker testing versus cytology in women who test HPV-positive on self-collected cervicovaginal specimens (PROHTECT-3): a randomised controlled non-inferiority trial.
Verhoef et al. Lancet Oncol. 2014;15:315-22.

 

Methylation analysis of the FAM19A4 gene in cervical scrapes is highly efficient in detecting cervical carcinomas and advanced CIN2/3 lesions. De Strooper et al.  Cancer Prev Res (Phila). 2014 Dec;7(12):1251-7. doi: 10.1158/1940-6207.CAPR-14-0237. Epub 2014 Oct 3. PubMed PMID: 25281488.

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