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Gene expression pathway analysis to predict response to neoadjuvant docetaxel and capecitabine for breast cancer

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Abstract

Neoadjuvant chemotherapy has been shown to be equivalent to post-operative treatment for breast cancer, and allows for assessment of chemotherapy response. In a pilot trial of docetaxel (T) and capecitabine (X) neoadjuvant chemotherapy for Stage II/III BC, we assessed correlation between baseline gene expression and tumor response to treatment, and examined changes in gene expression associated with treatment. Patients received four cycles of TX. Tumor tissue obtained from Mammotome™ core biopsies pretreatment (BL) and post-cycle 1 (C1) of TX was flash frozen and stored at −70°C until processing. Gene expression analysis utilized Affymetrix HG-U133 Plus 2.0 GeneChip arrays. Statistical analysis was performed using BRB Array Tools after RMA normalization. Gene ontology (GO) pathway analysis used random variance t tests with a significance level of P < 0.005. For gene categories identified by GO pathway analysis as significant, expression levels of individual genes within those pathways were compared between classes using univariate t tests; those genes with significance level of P < 0.05 were reported. PAM50 analyses were performed on tumor samples to investigate biologic subtype and risk of relapse (ROR). Using GO pathway analysis, 39 gene categories discriminated between responders and non-responders, most notably genes involved in microtubule assembly and regulation. When comparing pre- and post-chemotherapy specimens, we identified 71 differentially expressed gene categories, including DNA repair and cell proliferation regulation. There were 45 GO pathways in which the change in expression after one cycle of chemotherapy was significantly different among responders and non-responders. The majority of tumor samples fell into the basal-like and luminal B categories. ROR scores decreased in response to chemotherapy; this change was more evident in samples from patients classified as responders by clinical criteria. GO pathway analysis identified a number of gene categories pertinent to therapeutic response, and may be an informative method for identifying genes important in response to chemotherapy. Larger studies using the methods described here are necessary to fully evaluate gene expression changes in response to chemotherapy.

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Acknowledgments

This research was supported by the Intramural Research Program of the NIH and National Cancer Institute. We would like to thank Drs. Matthew Ellis and Charles E. Perou for their assistance with analysis and interpretation of PAM50. We would also like to thank the patients involved in this study for their participation.

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Authors and Affiliations

  1. Division of Medical Oncology, Department of Medicine University of Washington/Seattle Cancer Care Alliance, G3639, 825 Eastlake Ave, E, Seattle, WA, 98109, USA

    Larissa A. Korde

  2. Institute for Biostatistics and Medical Informatics, University of Ljubljana, Ljubljana, Slovenia

    Lara Lusa

  3. Glaxo Smith Kline, Collegeville, USA

    Peter F. Lebowitz

  4. Biometric Research Branch, Division of Cancer Treatment and Diagnosis (DCTD), NCI, Bethesda, USA

    Lisa McShane

  5. Laboratory of Population Genetics, NCI, Bethesda, USA

    LuAnne Lukes & Kent Hunter

  6. Radiation Oncology Branch, Center for Cancer Research, NCI, Bethesda, USA

    Kevin Camphausen

  7. Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, USA

    Joel S. Parker

  8. Washington Hospital Center, Washington, USA

    Sandra M. Swain

  9. Clinical Investigations Branch, Cancer Therapy Evaluation Program, DCTD, NCI, Bethesda, USA

    Jo Anne Zujewski

Authors
  1. Larissa A. Korde
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  2. Lara Lusa
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  3. Lisa McShane
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  4. Peter F. Lebowitz
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  5. LuAnne Lukes
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  7. Joel S. Parker
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  8. Sandra M. Swain
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  9. Kent Hunter
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Correspondence to Larissa A. Korde.

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Korde, L.A., Lusa, L., McShane, L. et al. Gene expression pathway analysis to predict response to neoadjuvant docetaxel and capecitabine for breast cancer. Breast Cancer Res Treat 119, 685–699 (2010). https://doi.org/10.1007/s10549-009-0651-3

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  • DOI: https://doi.org/10.1007/s10549-009-0651-3

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