Biomarkers for Systemic Therapy in Ovarian Cancer

Abstract

Epithelial ovarian cancer (EOC) is the most deadly tumor of the female reproductive system. Despite improvements in understanding the biology of EOC, therapeutic strategies still depend on surgery and combination of taxane and platinum agents. Here, we provide a summary of clinically tested biomarkers potentially useful to predict drug response. Resistance against platinum derivatives can result from lower drug concentrations, alterations in the target molecule and changes in the cellular signal transduction pathways. Taxane resistance can develop due to decreased intracellular drug concentration, alterations in microtubuli structure and changes in the cellular response including ERBB2 (epidermal growth factor receptor 2). A few key genes have been suggested as biomarkers for hormonal therapy. Currently, the only targeted therapy agent approved for ovarian cancer is the VEGF (vascular endothelial growth factor) inhibitor bevacizumab. Response to bevacizumab is correlated with VEGF-A levels and hypertension. The primary problems in identifying reliable biomarkers for EOC are the usage of different clinical endpoints, multivariate analysis for a panel of clinical parameters and the lack of published comprehensive clinical information of patients enrolled in these studies. The future lies in adding targeted agents to the taxane/platinum gold standard and in a more detailed stratification of patients into sub-cohorts enabling a more effective therapy. In conclusion, a large-scale coordinated effort is needed for the robust validation of the numerous biomarker candidates available in EOC therapy.

Tumor characterization by ultrasound-release of multiple protein and microRNA biomarkers, preclinical and clinical evidence

“…The variability of biomarkers pre-treatment and percent change levels, both in mice and humans, indicate the usefulness of a panel of biomarkers for characterization. Biomarker panels would allow for an easier and more robust characterization of metastatic as well as primary lesions as is the consensus for the detection and management of disease [ 15 – 17 , 19 , 47 ].…”

“…In the clinical environment of blood-based biomarker studies it has been shown that a single biomarker is generally not effective in detecting or guiding management and detection of disease, and that panels of multiple biomarkers are required [ 15 – 19 ]. Protein blood biomarkers such as carcinoembryonic antigen (CEA), cancer antigen 19–9 (CA19-9) and prostate specific antigen (PSA) used in this study, have been widely studied for many decades and are used in mainstream clinical disease management [ 20 – 24 ].…”

Predictive biomarkers of platinum and taxane resistance using the transcriptomic data of 1816 ovarian cancer patients

“…To deliver personalized treatment decisions, a clear understanding of the exact mechanisms of drug resistance is required; resistance can be caused by multiple independent mechanisms, some of which have been extensively studied in patient samples and cell culture model systems. We and others have shown previously that resistance mechanisms against platinum-based agents include decreased drug accumulation [6], drug inactivation by glutathione and glutathione Stransferases [7], increased autophagy [8], and increased levels of DNA repair [9]. Taxane resistance can result from overexpressed efflux pump genes [10], modulated microtubule dynamics [11], altered expression of β tubulin isotypes [11] and enhanced epithelial-tomesenchymal transition [12].…”

Transducin-Like Enhancer of Split 3 (TLE3) Expression Is Associated with Taxane Sensitivity in Nonserous Ovarian Carcinoma in a Three-Cohort Study

“…Chemoresistance in ovarian cancer develops in response to alterations in intracellular drug concentration (increased sequestration, increased efflux), DNA repair/cell cycle regulation and/or intracellular signaling (5). In taxane-treated tumors, resistance may also result from alterations in microtubule structure (6). Whole-genome sequencing studies of primary high-grade serous carcinomas (93% of whom were treated with taxane-containing therapy) and matched tumor cells from recurrent ascites samples demonstrate a higher mutational burden in the recurrent samples compared to the primary tumors (7).…”