Diagnostic markers for the detection of ovarian cancer in BRCA1 mutation carriers

Abstract

BackgroundScreening for ovarian cancer (OC) in women at high risk consists of a combination of carbohydrate antigen 125 (CA125) and transvaginal ultrasound, despite their low sensitivity and specificity. This could be improved by the combination of several biomarkers, which has been shown in average risk patients but has not been investigated until now in female BRCA mutation carriers.MethodsUsing a multiplex, bead-based, immunoassay system, we analyzed the concentrations of leptin, prolactin, osteopontin, insulin-like growth factor II, macrophage inhibitory factor, CA125 and human epididymis antigen 4 in 26 healthy wild type women, 26 healthy BRCA1 mutation carriers, 28 wildtype OC patients and 26 OC patients with BRCA1 mutation.ResultsUsing the ROC analysis, we found a high overall sensitivity of 94.3% in differentiating healthy controls from OC patients with comparable results in the wildtype subgroup (sensitivity 92.8%, AUC = 0.988; p = 5.2e-14) as well as in BRCA1 mutation carriers (sensitivity 95.2%, AUC = 0.978; p = 1.7e-15) at an overall specificity of 92.3%.The used algorithm also allowed to identify healthy BRCA1 mutation carriers when compared to healthy wildtype women (sensitivity 88.4%, specificity 80.7%, AUC = 0.895; p = 6e-08), while this was less pronounced in patients with OC (sensitivity 66.7%, specificity 67.8%, AUC = 0.724; p = 0.00065).ConclusionWe have developed an algorithm, which can differentiate between healthy women and OC patients and have for the first time shown, that such an algorithm can also be used in BRCA mutation carriers. To clarify a suggested benefit to the existing early detection program, large prospective trials with mainly early stage OC cases are warranted.

Prolactin signaling drives tumorigenesis in human high grade serous ovarian cancer cells and in a spontaneous fallopian tube derived model

“…Prolactin was part of a six protein panel of proteins used for early detection of ovarian cancer called Ovasure [20], demonstrating that it is specifically increased in tumorigenesis. Recently, PRL was retested along with seven other proteins and found to be an efficient diagnostic marker for screening OVCA with BRCA1 mutation [37]. However, the presence of PRL in the serum does not address if this is a biomarker of cancer or a driver of tumorigenesis.…”

Biomarker-Based Models for Preoperative Assessment of Adnexal Mass: A Multicenter Validation Study

“…The Luminex ® /xMAP ® technology is a bead-based immunoassay that allows for multiplex detection of up to 100 analytes simultaneously [ 41 ]. The commercially available bead panel—applied in [ 29 , 42 , 43 , 44 , 45 ] and our research [ 34 , 35 , 36 ]—offers a wide spectrum of pre-defined biomarkers. Selection and validation of the best performing marker panels is essential for their reasonable and cost-effective use.…”

“…In a study including patients with BRCA1 mutation, we observed an excellent performance of the six-protein panel (modified by replacing IGF-2 with HE4) both in OC patients with BRCA1 mutation (AUC 0.98) and wildtype (AUC 0.99). Of particular interest was that the test enabled differentiation between healthy BRCA1 mutation carriers and healthy wildtype women (with 0.88 sensitivity, 0.81 specificity and AUC 0.9) [ 35 ]. Lastly, we re-estimated the six-protein panel and calculated the Proteomic Model 2017, which consisted of CA125, HE4, PRL, OPN and leptin, and reached an AUC of 0.96 in the training cohort [ 36 ].…”

Osteopontin, Macrophage Migration Inhibitory Factor and Anti-Interleukin-8 Autoantibodies Complement CA125 for Detection of Early Stage Ovarian Cancer

“…MIF has been implicated in the angiogenic switch during progression of early cancers and plays a role in macrophage-induced ovarian cancer cell invasiveness [41,42]. Furthermore, Serum levels of MIF have been used as part of algorithms to detect disease in women with BRCA1/2 mutations and for distinguishing malignant from benign disease [43].…”