Abstract 147: DNA methylation patterns are associated with cisplatin and docetaxel response and survival among NSCLC cases

Abstract

Abstract Cisplatin and docetaxel have historically been considered important chemotherapeutic agents with activity against NSCLC, both in the palliative treatment of metastatic (stage IV) disease and combined-modality therapy of stage III disease. However, de novo and acquired drug resistance is common and patients may have only a partial response to therapy. DNA methylation has recently been recognized as a useful marker for diagnosing and monitoring the progression of many types of cancer. CpG island sites frequently become hypermethylated during tumorigenesis, and often exhibit distinctive tumor type and stage related patterns. Here, we examined the DNA methylation profile of 1505 autosomal CpG loci in 807 genes, in relation to response to therapy, time to progression and overall survival in 154 stage III and IV NSCLC cases. The Illumina GoldenGate Methylation Cancer Panel I with DNA isolated from peripheral blood mononuclear cells from patients who were treated with cisplatin and docetaxel. Response to therapy was assessed using RECIST guidelines. Stable disease was noted in 49 cases, 29 cases showed partial response and 54 had progressive disease (22 cases not evaluated). The mean time to progression was 5.2 + 4.5 months (range 3.4-27 months) and mean overall survival was 11.4 + 8.2 months (range 0.1-35 months). Due to assay sensitivity limits, CpG loci with β scores < 0.25 or > 0.75 in at least 75% of the samples were excluded from the analysis. Similarly, in order to screen for differential methylation patterns, we excluded the loci with small β score ranges which were defined as the mean score ± 12.5% for at least 75% of the cases. Following this screening process, 259 loci were included in the association analyses. Using these loci in an unsupervised correlation-based machine learning feature selection algorithm, we further reduced the relevant data pool to 6 significant loci. β scores of these 6 loci were then used in a neural network analysis and predictions significantly correlated with observed time to progression (r=0.74, p<0.0001). Although previous studies have reported an association between the methylation index of specific candidate DNA damage response genes in relation to platinum based chemotherapy response in ovarian cancer, a significant association with the promoter methylation status for BRCA1, MGMT, MLH1, RASSF1 and p16 was not observed among these NSCLC cases in a secondary analysis. These data suggest that methylation status may not only represent a useful biomarker for early detection of NSCLC, but may also aid in the identification of genes differentially regulated that closely correlate with patient survival, which in turn could lead to novel strategies for molecular targeted therapies and patient quality of life. A larger study population with extended follow-up data is required to further validate the observed correlation between DNA methylation and survival. [NIH 5U01CA114771] Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 147.