Use Of Peripheral Blood Genomic Markers Whose Expression Levels Reflect That Of Breast Tumor Genomic Markers To Predict Drug Treatment And Sensitivity

3588 Background: Tumor gene expression signatures have been used to predict drug response, and we have previously reported drug-induced signatures to be more informative than the untreated baseline signatures. However, repeated tumor sampling during treatment is not feasible for most patients. We studied peripheral mononuclear cell (PBMC) gene expression levels in association with tumor gene expression levels in an attempt to identify peripheral blood markers that may serve as more accessible surrogates to predict drug treatment and response. Methods: Chemonaive breast cancer patients were treated with an alternating sequential regimen of doxorubicin and docetaxel and randomized to start with either drug. RNA from primary tumor before and 3 weeks, and from PBMC before and 24 hours after the first cycle of each drug was hybridized on the Affymetrix HG-U133+2 array containing 54,675 probe sets. Results: Pre- and post-treatment tumors from 47 patients were studied, including 35 with paired PBMC samples. 230 pre- and 85 posttreatment PBMC probe sets showed strong correlation in expression level (Pearson correlation coefficient >0.9) with the corresponding pre- and posttreatment tumor probe set, and included genes involved in transcription regulation and binding. Of the 975 tumor probe sets whose changes distinguished doxorubicin from docetaxel treatment, 12 corresponding PBMC probe sets were identified (p < 0.001) whose changes at 24 hours distinguished the two treatments with 77% accuracy. Of the 1,081 and 1,526 tumor probe sets whose changes predicted treatment response to doxorubicin and docetaxel, 19 and 15 informative PBMC probe sets predicted response to each drug with 100% and 80% accuracy, and included TNF receptor associated protein 1 and trefoil factor 1 for doxorubicin-, and folliculin and dynein for docetaxel-response. When the PBMC probe sets were validated in an independent test set treated with docetaxel (n = 23), 87% was correctly classified as docetaxel-treated, while 89% of non-responders clustered together. Conclusions: Peripheral blood contains genomic markers whose expression levels closely reflect that of breast tumor markers, and may be promising as surrogates to predict drug treatment and sensitivity. No significant financial relationships to disclose.