full free access: Biomarkers in Medicine - The dire need to develop a clinically validated screening method for the detection of early-stage ovarian

Note:  I remember the LPA very well (breakthrough screening test for ovarian cancer and the resulting media hype extraordinaire)

Key Excerpts:
Multiple initiatives have been undertaken to discover strategies that detect and diagnose early-stage EOC, including the search for novel serum biomarkers and the development of new technologies, such as contrast-enhanced ultrasonography, with a number of them demonstrating hopeful results. The ideal screening test for ovarian cancer would be a simple measurement of biomolecules in bodily fluids, such as blood, serum or urine, whose absolute concentrations could differentiate cancer from noncancer and be organ specific. In the last decade, insights into the EOC microenvironment, as well as technological advances, such as microarrays and proteomics, have triggered the discovery of hundreds of potential clinically valuable biomarkers:


▪ Lysophosphatidic acid (LPA) is a phospholipid derivative consisting of a glycerol backbone, a single fatty acid chain and a free phosphate group. LPA has a variety of isoforms depending on fatty acid-chain variability at the sn-1 position. LPA was found to be elevated in the serum, plasma and malignant effusions of women with ovarian cancer and has known functions in cell proliferation, invasion and angiogenesis [3]. This molecule initially became of interest in 1998 for its reported high sensitivity and specificity to detect early-stage ovarian cancer [3]; however, its utility as a screening biomarker has been limited owing to the difficulty of isolating and detecting the different isoforms in patients’ serum and its specificity for ovarian cancer;


▪ Human epididymal protein (HE)4 is a relatively new biomarker used to monitor disease recurrence and disease progression in patients with ovarian cancer. It is the product of the WFDC2 (HE4) gene, which is overexpressed in ovarian cancer. HE4 has exhibited increased sensitivity to detect stage I disease [4] and has demonstrated promise as a sensitive and specific biomarker when combined with CA125 and other molecules [5]; although, more studies remain to be done to warrant its use as a biomarker for the detection of early-stage EOC;


▪ Osteopontin (OPN) is a glycoprotein involved in cell adhesion, inflammation and tumorigenesis, with elevated levels seen in ovarian cancer [6]. Similar to HE4, OPN has been used in combination assays to identify ovarian cancer [7]; however, OPN is also elevated in other cancers and benign conditions, limiting its specificity to be used as an ovarian cancer biomarker;


▪ Kallikreins (KLKs) are serine proteases that function in cell growth, angiogenesis and invasion. KLKs are elevated in patient serum with ovarian cancer. KLK8 was reported to be associated with early disease, while KLK5, -6, -10 and -13 have been combined with CA125 to improve the accuracy of ovarian cancer detection [8,9];


▪ Claudins are components of tight junctions that create selective barriers and maintain cell polarity. Multiple claudins have been found to be elevated in ovarian cancer; however, their specificity has yet to be determined and verified [10].

..................

Of particular note, traditional genetic pedigree analysis of ovarian cancer patients may provide information to help identify high-risk populations; for example, inherited BRCA1 and -2 mutations  increase the risk for women to develop ovarian and/or breast cancer [12]. In addition, molecular profiling at the epigenetic level, such as miRNA profiling, may allow for the identification of novel biomarkers for early detection of ovarian cancer, given that these epigenetic changes might be detectable before the development of the physical tumor.
................
Despite these advances, at present, no clinically validated screening protocol for the detection of early-stage EOC exists. The discovery of novel biomarkers relies on obtaining a better understanding of the initiation and progression of EOC. Clinical validation and implementation of biomarkers will also benefit from advancements in new molecular and imaging technologies as patient care is optimized. Fortunately, hundreds of biomarkers have been identified; however, their clinical utility remains to be determined. In addition, the enhanced imaging capabilities of the ovary by ultrasound are providing practitioners with the ability to more accurately and precisely identify changes specific to the newly transformed ovary. The combination of these two modalities, biomarker panels and biologically based imaging may be the future. Therefore, we must forge ahead to develop a validated early-detection protocol that will not only decrease the number of advanced-stage diagnoses and deaths attributed to ovarian cancer but, most importantly, positively impact the future of women’s healthcare.