Gene expression profiling of ATP-binding cassette (ABC) transporters as a predictor of the pathologic response to neoadjuvant chemotherapy in breast cancer patients

Abstract

Drug resistance is a major obstacle to the successful chemotherapy. Several ATP-binding cassette (ABC) transporters including ABCB1, ABCC1 and ABCG2 have been known to be important mediators of chemoresistance. Using oligonucleotide microarrays (HG-U133 Plus 2.0; Affymetrix), we analyzed the ABC transporter gene expression profiles in breast cancer patients who underwent sequential weekly paclitaxel/FEC (5-fluorouracil, epirubicin and cyclophosphamide) neoadjuvant chemotherapy. We compared the ABC transporter expression profile between two classes of pretreatment tumor samples divided by the patients' pathological response to neoadjuvant chemotherapy (residual disease [RD] versus pathologic complete response [pCR]) ABCB3, ABCC7 and ABCF2 showed significantly high expression in the pCR. Several ABC transporters including ABCC5, ABCA12, ABCA1 ABCC13, ABCB6 and ABCC11 showed significantly increased expression in the RD (p<0.05). We evaluated the feasibility of developing a multigene predictor model of pathologic response to neoadjuvant chemotherapy using gene expression profiles of ABC transporters. The prediction error was evaluated by leave-one-out cross-validation (LOOCV). A multigene predictor model with the ABC transporters differentially expressed between the two classes (p<or=0.003) showed an average 92.8% of predictive accuracy (95% CI, 88.0-97.4%) with a 93.2% (95% CI, 85.2-100%) positive predictive value for pCR, a 93.6% (95% CI, 87.8-99.4%) negative predictive value, a sensitivity of 88.1%(95% CI, 76.8-99.4%), and a specificity of 95.9% (91.1% CI, 87.8-100%). Our results suggest that several ABC transporters in human breast cancer cells may affect the clinical response to neoadjuvant chemotherapy, and transcriptional profiling of these genes may be useful to predict the pathologic response to sequential weekly paclitaxel/FEC in breast cancer patients.

The predictive value of the 70-gene signature for adjuvant chemotherapy in early breast cancer

“…These signatures comprise known signatures such as the genomic grade index as well as several new classifiers [25][26][27][28][29][30][31][32][33][34][35][36][37]. Additional data to support the predictive potential for the 70-gene assay comes from the neoadjuvant study of Straver et al [38].…”

Use of arrays to investigate the contribution of ATP-binding cassette transporters to drug resistance in cancer chemotherapy and prediction of chemosensitivity

“…One of these studies was performed using Affymetrix HG-U133 Plus 2.0 GeneChip which contains all 49 human ABC transporter genes (Table 2). ABC transporter expression profiles were generated using this array from breast cancer patients who received neoadjuvant chemotherapy including 5-FU and paclitaxel [25]. Comparison between patients who had complete response and those who had residual disease revealed that the expression of ABCA1, ABCA12, ABCB6, ABCC5, ABCC11, ABCC13 was elevated in the residual disease group, suggesting that their expression may contribute to the incomplete response of these patients to neoadjuvant therapy.…”

“…Gillet et al also performed an analysis of 16 breast cancer samples using their low density DualChip human ABC microarray (see below) and found 23 ABC transporters including ABCC1 and ABCC5 were expressed in the majority (≥10 of 16) of the breast cancer samples tested [28]. Unlike the study by Park et al [25], however, the Gillet study [28] did not have the correlation analysis between patient response to chemotherapy and their ABC transporter expression level. Thus, the implication of ABC transporter expression in this study is limited.…”

EGF Induces Cell Motility and Multi-Drug Resistance Gene Expression in Breast Cancer Cells

“…1,2 However the development of drug resistance is a formidable barrier to successful treatment and correlated with a poor clinical prognosis for the patient. [3][4][5] Furthermore once the breast cancer has metastasized, it is more difficult to effectively treat. Cell motility and multidrug resistance can be governed by extracellular signals from growth factors, 6,7 however the mechanisms responsible for these processes are still not fully known.…”