Multi-Gene Expression Predictors of Single Drug Responses to Adjuvant Chemotherapy in Ovarian Carcinoma: Predicting Platinum Resistance

Abstract

Despite advances in radical surgery and chemotherapy delivery, ovarian cancer is the most lethal gynecologic malignancy. Standard therapy includes treatment with platinum-based combination chemotherapies yet there is no biomarker model to predict their responses to these agents. We here have developed and independently tested our multi-gene molecular predictors for forecasting patients' responses to individual drugs on a cohort of 55 ovarian cancer patients. To independently validate these molecular predictors, we performed microarray profiling on FFPE tumor samples of 55 ovarian cancer patients (UVA-55) treated with platinum-based adjuvant chemotherapy. Genome-wide chemosensitivity biomarkers were initially discovered from the in vitro drug activities and genomic expression data for carboplatin and paclitaxel, respectively. Multivariate predictors were trained with the cell line data and then evaluated with a historical patient cohort. For the UVA-55 cohort, the carboplatin, taxol, and combination predictors significantly stratified responder patients and non-responder patients (p = 0.019, 0.04, 0.014) with sensitivity = 91%, 96%, 93 and NPV = 57%, 67%, 67% in pathologic clinical response. The combination predictor also demonstrated a significant survival difference between predicted responders and non-responders with a median survival of 55.4 months vs. 32.1 months. Thus, COXEN single- and combination-drug predictors successfully stratified platinum resistance and taxane response in an independent cohort of ovarian cancer patients based on their FFPE tumor samples.

Pathobiology of pulmonary arterial hypertension and right ventricular failure

“…As new treatment strategies appear on the horizon, clinical trials should consider investigating the mechanisms of treatment success or treatment failure by comparing treatment responders and non-responders, as is currently the novel approach developed for cancer treatment trials [111, 112]. PAH should be viewed as a cardiopulmonary system disease, which is based on the paradox of apoptosis, apoptosis-resistant growth of phenotypically abnormal cells and angiogenesis in the lungs, and apoptosis and capillary loss in the heart.…”

Identification of Prognostic Groups in High-Grade Serous Ovarian Cancer Treated with Platinum–Taxane Chemotherapy

“…As an independent validation set, we used a prospective ovarian cancer cohort consisting of 29 Patients were treated with either primary surgery followed by six cycles of platinum-and taxane-based chemotherapy or three cycles of neoadjuvant chemotherapy (NACT) followed by interval debulking surgery and three to six chemotherapy cycles. The treatment modality for each patient was determined on the basis of preoperative imaging studies and diagnostic laparoscopy.…”

A 10-gene expression signature of Notch pathway predicts recurrence in ovarian carcinoma

“…Three ovarian carcinoma gene expression datasets [The Cancer Genome Atlas (TCGA), GSE9891 and GSE30161] with documented recurrence information were selected for analysis in the present study (8)(9)(10). The expression data together with the curated and documented clinical metadata were extracted by the R curated Ovarian Data Bioconductor package, as previously described (11).…”