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.

Figure 1. Schematic Summary of COXEN Predictor Development and Test.

Figure 2. COXEN Biomarkers and Gene Networks for Carboplatin.

Clustering heatmap analysis with major gene networks with x-axis responder (red) and non-responder (green) patients and y-axis Immunological disease/cell death entwork (red), Cell cycle/Connective tissue disorders/Inflammator disease network (green), Cellular movement/Hematological system/Immune cell trafficking network (yellow), and Free radical scavenging/cellular movement/cancer/cellular growth and proliferation network (blue).

Figure 3. Evaluation and Validation result on ovarian patients.

Figures 3A, 3B, and 3C are evaluation resulton the Dressman-119 cohort; (A) the distribution of COXEN scores for Carboplatin; (B) COXEN scores for paclitaxel; (C) COXEN scores for the drug combination of Carboplatin and Paclitaxel. Figures 3D, 3E, and 3F are validation result on the UVA-55 cohort for Carboplatin, Paclitaxel, and for the drug combination of Carboplatin and Paclitaxel, respectively. Coxen scores of responder (black) and non-responder(gray). P-values calculated by Wilcoxon rank sum test.

Figure 4. Overall Survival Difference between COXEN Predicted Responders vs. Non-Responders.

(A) Kaplan Meier survival plot of Dressman-119 cohort. (B) Kaplan Meier survival plot of UVA-55 cohort. The survival curves of patients predicted to be responders (Red) and non-responders (Green) showed significant differences between COXEN predicted responders and non-responders with median survival times 77.8 and 22.3 months for the Dressman-119 cohort and 55.4 and 32.2 months for the UVA-55 cohort between the two groups. P-values were calculated by Log-rank test.