Cervical cancer is preventable when detected and treated in an early stage. Despite extensive screening programs, mortality rates are increasing (443,000 yearly deaths expected by 2030 globally, up from 266,000 in 2012). Screening in most EU countries is based on cytology, which requires a physician-taken cervical scrape and is challenged by low sensitivity (30% false-negatives) and high non-compliance (63% EU coverage). The main reasons for women to not attend are the accessibility to and acceptability of the pelvic examination, in addition to practical issues (e.g. no time to visit the clinic). As the majority of cervical cancer occurs in women who do not regularly participate in screening, cytology is gradually being replaced by testing for HPV (the causative agent of cervical cancer) which allows self-sampling to increase participation. However, ~95-98% of HPV infections are transient and do not cause cancer. Triage is necessary to identify only those HPV+ women with clinically relevant disease in order to control overreferral, overtreatment and costs. Currently, triage relies mainly on cytology, which requires repeat testing to ensure sufficient protection and is not compatible with self-samples. This two-step process is associated with 25-40% loss to follow-up. There is thus a great need for the development of new, molecular screening assays for cervical cancer that can be used on self-samples.
In the ERC-AdG MASS-CARE, we investigate the value of two classes of molecular markers, DNA methylation and miRNA for the detection of cervical disease in self-samples. In our analyses, we frequently observed variations at the 3’ end of the miRNA markers. Such variations (isomiRs) have great impact on their detectability by standard assays and thus constitute a great improvement compared to using the canonical miRNA sequence. In MIMICS, we aimed to investigate the technical and commercial feasibility of developing an isomiR panel as a molecular, non-morphology-based, objective screening assay for cervical cancer fully compatible with self-sampling.
Within the project, we have built predictive models and have selected potential biomarkers from both miRNAs and isomiRs to distinguish self-collected cervico-vaginal specimens of HPV-positive women with and without precancerous disease. In addition, we tested several methods for the reliable detection of these markers. Unfortunately, cross-reactivity between canonical miRNAs and isomiRs prevented us from developing a robust assay within the short timeframe of the project. This means that, although validation in an independent cohort of women with and without cervical disease showed promising results, novel approaches to detection first need to be tested prior to developing a commercial assay. In parallel, we performed extensive market research to investigate the different uses (i.e. position in the screening algorithm) of this hypothetical assay, which also allowed us to examine new markets. Within MIMICS, we have confirmed the potential of using molecular biomarkers in screening for cervical disease.
