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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

PreCursor-M+/ QIAsure literature and studies

Clinical indications – Triage testing by methylation

Primary triage of HPV positive women

Vink et al, Int J Cancer 2020 – FAM19A4/miR1242 methylation in invasive cervical cancer: A retrospective crosssectional worldwide study. https://pubmed.ncbi.nlm.nih.gov/31390052/

Bonde et al, Int J Cancer 2020 – Methylation markers FAM19A4 and miR124-2 as triage strategy for primary human papillomavirus screen positive women: A large European multicenter study. https://pubmed.ncbi.nlm.nih.gov/32997803/

Secondary triage in cases of ASC-US/ LSIL 

Dick et al, BMJ 2021 – Risk-stratification of HPV-positive women with low-grade cytology by FAM19A4/miR124-2 methylation and HPV genotyping. https://www.nature.com/articles/s41416-021-01614-4

Clinical indications – Reassurance test against cancer – safety in HPV positive women

De Strooper et al, Int J Cancer 2018 – Cervical cancer risk in HPVpositive women after a negative FAM19A4/mir1242 methylation test: A post hoc analysis in the POBASCAM trial with 14-year followup. https://pubmed.ncbi.nlm.nih.gov/29663363/

Dick et al, Gyn Onc 2019 – Long-term CIN3+ risk of HPV positive women after triage with FAM19A4/miR124-2 methylation analysis. https://pubmed.ncbi.nlm.nih.gov/31182225/

Kremer et al, BMJ 2019 – 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. https://pubmed.ncbi.nlm.nih.gov/31289088/

Kremer et al, J Clinical Oncology 2022 – Clinical regression of high-grade cervical intraepitehelial neoplasia is associated with absence of FAM19A4/miR124-2 DNA methylation (CONCERVE Study) https://ascopubs.org/doi/full/10.1200/JCO.21.02433

Clinical indications – Treatment guidance for clinicians

Kremer et al, AIDS 2019 – The use of molecular markers for cervical screening of women living with HIV in South Africa. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791588/

Vink et al, Tumor Markers and Signatures, 2021 – Classification of high-grade cervical intraepithelial neoplasia by p16ink4a, Ki-67, HPV E4 and FAM19A4/miR124-2 methylation status demonstrates considerable heterogeneity with potential consequences for management. https://pubmed.ncbi.nlm.nih.gov/33729551/

Hampl et al, IJC 2022 – Evaluation of managing CIN3+ diagnosed pregnant women by methylation using QIAsure Methylation Test. https://onlinelibrary.wiley.com/doi/10.1002/ijc.34153

•Vink et al, Clin. Inf Diseases 2022, FAM19A4/miR124-2 methylation testing and HPV16/18 genotyping in HPV-positive women under the age of 30 years

Self-sampling

•De Strooper et al, Gyn Oncol 2016 – 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4851217/

Reproducibility

•Floore et al, J Clin. Lab Anal 20219 – Intra- and inter-laboratory agreement of the FAM19A4/mir124-2 methylation test: Results from an international study. https://pubmed.ncbi.nlm.nih.gov/30758084/

Review papers on the clinical application of Methylation tests in cervical cancer diagnostics

•Steenbergen et al, Nature Rev 2014 – Clinical implications of (epi)genetic changes in HPV-induced cervical precancerous lesions https://pubmed.ncbi.nlm.nih.gov/24854082/

•Kelly et al, Brit J Cancer 2019 – Performance of DNA methylation assays for detection of high-grade cervical intraepithelial neoplasia (CIN2+): a systematic review and meta-analysis https://pubmed.ncbi.nlm.nih.gov/31616037/

•Kremer et al, J Obs Gyn 2021 – The use of host cell DNA methylation analysis in the detection and management of women with advanced cervical intraepithelial neoplasia; a review https://obgyn.onlinelibrary.wiley.com/doi/full/10.1111/1471-0528.16395

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