Serial expression analysis of breast tumors during neoadjuvant chemotherapy reveals changes in cell cycle and immune pathways associated with recurrence and response

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  • Magbanua, Mark J M
    • Other Affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, USA; Division of Hematology/Oncology, University of California San Francisco, San Francisco, USA
  • Wolf, Denise M
    • Other Affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, USA
  • Yau, Christina
    • Other Affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, USA; Department of Surgery, University of California San Francisco, San Francisco, USA; Buck Institute for Research on Aging, Novato, USA
  • Davis, Sarah E
    • Other Affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, USA; Department of Surgery, University of California San Francisco, San Francisco, USA
  • Crothers, Julia
    • Other Affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, USA; Division of Hematology/Oncology, University of California San Francisco, San Francisco, USA
  • Au, Alfred
    • Other Affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, USA; Department of Surgery, University of California San Francisco, San Francisco, USA
  • Haqq, Christopher M
    • Other Affiliation: Department of Urology, University of California San Francisco, San Francisco, USA
  • Livasy, Chad
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Rugo, Hope S
    • Other Affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, USA; Division of Hematology/Oncology, University of California San Francisco, San Francisco, USA
  • Esserman, Laura
    • Other Affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, USA; Department of Surgery, University of California San Francisco, San Francisco, USA
  • Park, John W
    • Other Affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, USA; Division of Hematology/Oncology, University of California San Francisco, San Francisco, USA
  • van ’t Veer, Laura J
    • Other Affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, USA; Department of Laboratory Medicine, University of California San Francisco, San Francisco, USAN
Abstract
  • Abstract Introduction The molecular biology involving neoadjuvant chemotherapy (NAC) response is poorly understood. To elucidate the impact of NAC on the breast cancer transcriptome and its association with clinical outcome, we analyzed gene expression data derived from serial tumor samples of patients with breast cancer who received NAC in the I-SPY 1 TRIAL. Methods Expression data were collected before treatment (T1), 24–96 hours after initiation of chemotherapy (T2) and at surgery (TS). Expression levels between T1 and T2 (T1 vs. T2; n = 36) and between T1 and TS (T1 vs. TS; n = 39) were compared. Subtype was assigned using the PAM50 gene signature. Differences in early gene expression changes (T2 − T1) between responders and nonresponders, as defined by residual cancer burden, were evaluated. Cox proportional hazards modeling was used to identify genes in residual tumors associated with recurrence-free survival (RFS). Pathway analysis was performed with Ingenuity software. Results When we compared expression profiles at T1 vs. T2 and at T1 vs. TS, we detected significantly altered expression of 150 and 59 transcripts, respectively. We observed notable downregulation of proliferation and immune-related genes at T2. Lower concordance in subtype assignment was observed between T1 and TS (62 %) than between T1 and T2 (75 %). Analysis of early gene expression changes (T2 − T1) revealed that decreased expression of cell cycle inhibitors was associated with poor response. Increased interferon signaling (TS − T1) and high expression of cell proliferation genes in residual tumors (TS) were associated with reduced RFS. Conclusions Serial gene expression analysis revealed candidate immune and proliferation pathways associated with response and recurrence. Larger studies incorporating the approach described here are warranted to identify predictive and prognostic biomarkers in the NAC setting for specific targeted therapies. Clinical trial registration ClinicalTrials.gov identifier: NCT00033397 . Registered 9 Apr 2002.
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  • Article
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  • In Copyright
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  • Magbanua et al.
Language
  • English
Bibliographic citation
  • Breast Cancer Research. 2015 May 29;17(1):73
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  • BioMed Central

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