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Gene expression patterns for doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan) (AC) response and resistance

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Summary

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.

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Acknowledgements

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.

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Authors and Affiliations

  1. Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom

    Susan Cleator, Alan Ashworth, Mitch Dowsett, Timothy Dexter & Trevor Powles

  2. Breast Center and the Departments of Medicine, and Molecular and Cellular Biology, Baylor College of Medicine, and The Methodist Hospital, Houston, TX, USA

    Anna Tsimelzon, Susan Hilsenbeck, Helen Wong, C. Kent Osborne & Jenny C. Chang

  3. The Royal Marsden Hospital, London, United Kingdom

    Mitch Dowsett & Trevor Powles

  4. Virginia Commonwealth University Medical Center, Richmond, Virginia, USA

    Peter O’Connell

Authors
  1. Susan Cleator
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  2. Anna Tsimelzon
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  3. Alan Ashworth
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  4. Mitch Dowsett
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  5. Timothy Dexter
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  6. Trevor Powles
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  7. Susan Hilsenbeck
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  8. Helen Wong
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  9. C. Kent Osborne
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  10. Peter O’Connell
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  11. Jenny C. Chang
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Corresponding author

Correspondence to Jenny C. Chang.

Additional information

Address for offprints and correspondence: Jenny Chang, Breast Center, Baylor College of Medicine, 1 Baylor Plaza, MS 600, Houston, TX 77030, USA; Tel.: +1-713-798-1905; Fax: +1-713-798-1642; E-mail: jcchang@breastcenter.tmc.edu

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Cleator, S., Tsimelzon, A., Ashworth, A. et al. Gene expression patterns for doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan) (AC) response and resistance. Breast Cancer Res Treat 95, 229–233 (2006). https://doi.org/10.1007/s10549-005-9009-7

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  • DOI: https://doi.org/10.1007/s10549-005-9009-7

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