- Ovarian cancer - A silent killer
- Urine as a promising sample type
- Proteomics - HE4 is a promising urinary biomarker for OC
- Metabolomics - A promising field of study for OC
- Transcriptomics – miRNAs are promising biomarkers for OC
Ovarian cancer (OC) is the seventh most common malignancy among women worldwide. More than 70% of women present the disease at an advanced stage, making the cancer type the most lethal of all gynecological malignancies. Patients with advanced stage OC have a 20 to 40% five-year survival rate, compared to 90% in women with stage I (1), highlighting the importance of early detection and treatment.
However, due to lack of clear symptoms and efficient diagnostic tools, OC is difficult to detect at an early stage (2). Current diagnostic methods are invasive, consisting of a pelvic examination, transvaginal ultrasonography (TVUS), and blood tests to detect cancer antigen 125 (CA125), often preventing women from testing early and easily. In many cases, surgery is also required to make a positive diagnosis (3).
To improve detection and reduce the high death rate among OC patients, better and more noninvasive diagnostic tests are needed (4).
As urine is less invasive than blood and available in larger quantities, it is an excellent liquid biopsy that could provide a more convenient and accurate way for diagnosing malignant tumors (1). Moreover, urine can be more stable compared to serum in relation to pre-analytical handling procedures (5).
The potential of urine as a source of biomarkers has been investigated in different cancers, including OC (6). Biomarker testing in urine can provide a non-invasive method for the early detection of ovarian carcinoma. It can also allow frequent testing of women who belong to high-risk groups (7) as well as provide longitudinal follow-up of patients (8).
The study of proteins, especially urinary proteins has shown to be promising for non-invasive OC detection. The urinary proteome is a direct product of renal filtration, resulting in a less complex matrix, consisting of soluble, low molecular weight peptides compared to the serum. Consequently, it contains fewer factors known to interfere with biomarker assays, which can be advantageous in a proteomic analysis (1).
Among a wide spectrum of biomarkers, human epidermis protein 4 (HE4), approved by the FDA in 2008 for monitoring patients with OC for disease recurrence has shown to be the most promising. Unlike CA125, HE4 is not overexpressed in normal ovarian tissue, benign ovarian disease, or tumors with low malignant potential. The results of a meta-analysis indicated that 76% of OC patients had high HE4 levels, while 92% of the non OC patients had low HE4 levels (9).
Further, the urinary concentration of 17 biomarkers obtained from 295 patients with pelvic masses scheduled for surgery, showed significant differences between OC and benign tumors. HE4, vascular cell adhesion molecule (VCAM), and transthyretin (TTR) were present in higher concentrations in OC patients, with HE4 demonstrating the highest performance in all samples (1). Additionally, patients with tumors of low malignant potential were more often positive for HE4 in urine compared to serum (10).
However, there is yet some debate in the field – a review concluded that currently the urinary biomarkers may be insufficient for the effective detection of OC at stage I and II, but may be superior when used alongside other non-urinary biomarkers and TVUS (3).
Consequently, additional studies must be performed to verify the potential and accuracy of proteins as a diagnostic biomarker for OC (9).
Metabolomics, the study of chemical processes involving metabolites, has shown to provide insights into various disease pathologies (11). A variety of metabolomics signatures specific to OC have been identified. Lipids and amino acid pathways have shown to be the most promising circulating signatures of OC (2). The clinical applications of metabolomics, however, is still limited. To effectively use these metabolomics signatures for OC screening and monitoring, further studies on large homogeneous populations including validation are needed (2).
Transcriptomics, the study of RNA transcripts, including post- transcriptional regulation of gene expression microRNAs (miRNAs), are an emerging source of biomarkers for many cancer types (3). A study identified significant upregulation of miR-30a-5p in urine samples of OC patients when compared to healthy controls (12).
While further evaluation and validation may be necessary, initial evidence is promising for urinebased OC detection. Urine testing in conjunction with other diagnostic tools could help screen for the cancer type more quickly and precisely, allowing treatment to begin sooner.
However, to use urine for clinical applications, the pre-analytical variation, including collection, transport and storage must be kept to a minimum. Collection through a standard urine cup can be awkward, messy and inconvenient for the user.
To overcome many of these challenges, Novosanis developed Colli-Pee®, a urine collection device that allows for standardized and volumetric collection of urine. The device architecture also enables immediate mixing with preservative, improving sample stability. Further, to allow multiomic testing and address low biomarker concentrations, we are also developing a Colli-Pee® Large Volumes variant, which collects 45 mL instead of 20 mL of urine.