Expression of chemokine (C-C motif) ligand-2 (CCL2) is predictive of response to chemotherapy and overall survival in primary ovarian cancer

Abstract

16013 Background: CCL2, a determinant of macrophage infiltration in tumors, is expressed in normal human ovarian surface epithelium but silenced or down-regulated in ovarian adenocarcinomas (Br J Cancer 92:2024, 2005). We determined the association between quantitative expression of CCL2 with platinum-taxane based chemotherapy response and clinical outcome in patients with primary ovarian cancer. Methods: Tumor samples from chemotherapy-naïve patients with advanced serous ovarian adenocarcinoma were obtained at the time of primary cytoreductive surgery. Gene expression profiles using RNA extracted from tissue enriched for >90% tumor from 2 chemotherapy sensitive (CS) and 8 chemotherapy resistant (CR) patients were performed using the Illumina Sentrix Human-6 Expression Bead-Chip microarray. Gene expression was quantified by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) in a larger patient cohort. Statistics were generated using Wilcoxon rank sum tests and Kaplan-Meier survival curves. Results: Clustering analysis of gene expression profiles identified several genes, including CCL2, that were differentially expressed between the CS and CR tumor specimens. Levels of CCL2 were significantly (p<.001) under-expressed in all 8 CR patient tumors as compared to the 2 CS tumors. Quantification of CCL2 gene expression in 9 CS and 16 CR tumors by RT-PCR demonstrated that CCL2 was significantly down-regulated in the CR tumors when compared to the CS tumors (p<.001). Using normalized PCR cycle threshold scores, 22 of the 25 tumors were correctly classified, i.e., 8/9 CS had low CCL2 expression (sensitivity = 89%) and 14/16 CR had high expression (specificity = 88%). For patients with low CCL2 expression, progression free survival was 12 months versus 18.6 months for those with high CCL2 expression (p=.05). Median overall survival (OS) was 20.8 months for patients with low CCL2 expression, while OS was not yet reached for those with high CCL2 levels (p=.01). Conclusions: Results demonstrate that expression of CCL2 correlates with response to chemotherapy and survival in patients with primary ovarian cancer. Expression of CCL2 may be a useful independent biomarker of response to treatment and clinical outcome. No significant financial relationships to disclose.