TY - JOUR
T1 - Gene expression patterns for doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan) (AC) response and resistance
AU - Cleator, Susan
AU - Tsimelzon, Anna
AU - Ashworth, Alan
AU - Dowsett, Mitch
AU - Dexter, Timothy
AU - Powles, Trevor
AU - Hilsenbeck, Susan
AU - Wong, Helen
AU - Osborne, C. Kent
AU - O'Connell, Peter
AU - Chang, Jenny C.
N1 - Funding Information:
This study is supported in part by Breast Cancer Research Foundation, the Emma Jacobs Clinical Breast Cancer Fund, and the Breast Cancer SPORE, P50 CA50183 from the National Cancer Institute. Role of Funding Sources: The study sponsors did not contribute to the study design, collection, analysis, and interpretation of data.
PY - 2006/2
Y1 - 2006/2
N2 - Introduction. Doxorubicin and cyclophosphamide (Adriamycin/cytoxan, AC) is a standard chemotherapy regimen for breast cancer, but de novo resistance is frequent. We hypothesized that gene expression profiles predictive of AC response may be different from our previously published patterns with docetaxel. Methods. Core biopsies from 40 patients were obtained before treatment with AC (6 cycles, 60/600 mg/m2q3 weeks), and clinical responses recorded after treatment. Gene expression patterns were analyzed using Affymetrix U133A chips which comprise ∼22,200 genes. Results. Clinical complete responses (cCR) were observed in 22, partial responses in 7, stable disease in 11 patients. Differential expression between sensitive cCR and resistant tumors with a low false discovery rate (< 5%) was obtained. Of these 253 differentially expressed genes, pathways up-regulated in sensitive tumors included cell cycle (BUB3, CDKN1B), survival (BCL2, BAG1, BIRC1, STK39), stress response (CYP2B6, MAPK14), and estrogen-related pathways (ER, IRS1). Resistant tumors expressed gene promoting transcription (GTF3C1, ILF3), differentiation (ST14, CTNNBIP1), signal transduction (EIF1AX, EIF4EBP1), and amino acid metabolism (SRM, PLOD1, PLOD3). With leave-one-out cross validation, 67% of the samples were correctly classified, with a permutation p-value of 0.4. The previously published 92-gene molecular portrait for docetaxel sensitivity could not discriminate AC sensitivity and resistance. Conclusions. This preliminary study supports that molecular profiles for AC response are likely to exist, with unique expression patterns for individual chemotherapy regimens. Larger validation studies are necessary to define and refine patterns for different agents.
AB - Introduction. Doxorubicin and cyclophosphamide (Adriamycin/cytoxan, AC) is a standard chemotherapy regimen for breast cancer, but de novo resistance is frequent. We hypothesized that gene expression profiles predictive of AC response may be different from our previously published patterns with docetaxel. Methods. Core biopsies from 40 patients were obtained before treatment with AC (6 cycles, 60/600 mg/m2q3 weeks), and clinical responses recorded after treatment. Gene expression patterns were analyzed using Affymetrix U133A chips which comprise ∼22,200 genes. Results. Clinical complete responses (cCR) were observed in 22, partial responses in 7, stable disease in 11 patients. Differential expression between sensitive cCR and resistant tumors with a low false discovery rate (< 5%) was obtained. Of these 253 differentially expressed genes, pathways up-regulated in sensitive tumors included cell cycle (BUB3, CDKN1B), survival (BCL2, BAG1, BIRC1, STK39), stress response (CYP2B6, MAPK14), and estrogen-related pathways (ER, IRS1). Resistant tumors expressed gene promoting transcription (GTF3C1, ILF3), differentiation (ST14, CTNNBIP1), signal transduction (EIF1AX, EIF4EBP1), and amino acid metabolism (SRM, PLOD1, PLOD3). With leave-one-out cross validation, 67% of the samples were correctly classified, with a permutation p-value of 0.4. The previously published 92-gene molecular portrait for docetaxel sensitivity could not discriminate AC sensitivity and resistance. Conclusions. This preliminary study supports that molecular profiles for AC response are likely to exist, with unique expression patterns for individual chemotherapy regimens. Larger validation studies are necessary to define and refine patterns for different agents.
KW - AC chemotheraphy
KW - Breast cancer
KW - Gene expression patterns
KW - Non cross-resistant chemotherapy
KW - Predictive markers
KW - Taxotere
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U2 - 10.1007/s10549-005-9009-7
DO - 10.1007/s10549-005-9009-7
M3 - Article
C2 - 16322899
AN - SCOPUS:33645221975
SN - 0167-6806
VL - 95
SP - 229
EP - 233
JO - Breast Cancer Research and Treatment
JF - Breast Cancer Research and Treatment
IS - 3
ER -