Preclinical Study

Breast Cancer Research and Treatment

, 112:475

First online:

Molecular signatures of neoadjuvant endocrine therapy for breast cancer: characteristics of response or intrinsic resistance

  • Djuana M. E. HarvellAffiliated withDepartment of Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Colorado Health Sciences Center
  • , Nicole S. SpoelstraAffiliated withDepartment of Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Colorado Health Sciences Center
  • , Meenakshi SinghAffiliated withDepartment of Pathology, University of Colorado Health Sciences Center
  • , James L. McManamanAffiliated withDepartment of Obstetrics and Gynecology, University of Colorado Health Sciences Center
  • , Christina FinlaysonAffiliated withDepartment of Surgery, University of Colorado Health Sciences Center
  • , Tzu PhangAffiliated withDepartment of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center
  • , Susan TrappAffiliated withComputational Bioscience Program, University of Colorado Health Sciences Center
  • , Lawrence HunterAffiliated withComputational Bioscience Program, University of Colorado Health Sciences Center
  • , Wendy W. DyeAffiliated withDepartment of Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Colorado Health Sciences Center
    • , Virginia F. BorgesAffiliated withDepartment of Medicine, Division of Medical Oncology, University of Colorado Health Sciences Center
    • , Anthony EliasAffiliated withDepartment of Medicine, Division of Medical Oncology, University of Colorado Health Sciences Center
    • , Kathryn B. HorwitzAffiliated withDepartment of Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Colorado Health Sciences CenterDepartment of Pathology, University of Colorado Health Sciences Center
    • , Jennifer K. RicherAffiliated withDepartment of Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Colorado Health Sciences CenterDepartment of Pathology, University of Colorado Health Sciences Center Email author 

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Abstract

Approximately 30% of patients with estrogen receptor (ER) positive breast cancers exhibit de novo or intrinsic resistance to endocrine therapies. The purpose of this study was to define genes that distinguish ER+ resistant from ER+ responsive tumors, prior to the start of hormone therapies. Previously untreated post-menopausal patients with ER+ breast cancers were treated for 4 months in a neoadjuvant setting with the aromatase inhibitor exemestane alone, or in combination with the antiestrogen tamoxifen. Matched pre- and post-treatment tumor samples from the same patient, were analyzed by gene expression profiling and were correlated with response to treatment. Genes associated with tumor shrinkage achieved by estrogen blockade therapy were identified, as were genes associated with resistance to treatment. Prediction Analysis of Microarrays (PAM) identified 50 genes that can predict response or intrinsic resistance to neoadjuvant endocrine therapy of ER+ tumors, 8 of which have been previously implicated as useful biomarkers in breast cancer. In summary, we identify genes associated with response to endocrine therapy that may distinguish ER+, hormone responsive breast cancers, from ER+ tumors that exhibit intrinsic or de novo resistance. We suggest that the estrogen signaling pathway is aberrant in ER+ tumors with intrinsic resistance. Lastly, the studies show upregulation of a “lipogenic pathway” in non-responsive ER+ tumors that may serve as a marker of intrinsic resistance. This pathway may represent an alternative target for therapeutic intervention.

Keywords

Breast cancer Neoadjuvant endocrine therapy Estrogen receptors Androgen receptors Expression profiling Aromatase inhibitors Tamoxifen Lipogenic phenotype