Molecular signatures of neoadjuvant endocrine therapy for breast cancer: characteristics of response or intrinsic resistance.
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.
Harvell
Djuana M E
DM
Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Colorado Health Sciences Center, Aurora, CO 80045, USA. djuana.harvell@uchsc.edu
Spoelstra
Nicole S
NS
Singh
Meenakshi
M
McManaman
James L
JL
Finlayson
Christina
C
Phang
Tzu
T
Trapp
Susan
S
Hunter
Lawrence
L
Dye
Wendy W
WW
Borges
Virginia F
VF
Elias
Anthony
A
Horwitz
Kathryn B
KB
Richer
Jennifer K
JK
D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000378:metabolism* / Q000628:therapy*; D002352:Carrier Proteins; D016000:Cluster Analysis; D019008:Drug Resistance, Neoplasm; D020847:Estrogen Receptor Modulators / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D020360:Neoadjuvant Therapy / Q000379:methods*; D020411:Oligonucleotide Array Sequence Analysis; D000070778:Perilipin-1; D010750:Phosphoproteins / Q000737:chemistry; D011960:Receptors, Estrogen / Q000378:metabolism; D009418:S100 Proteins / Q000737:chemistry; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology
D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D020847:Estrogen Receptor Modulators; D000070778:Perilipin-1; D010750:Phosphoproteins; D011960:Receptors, Estrogen; D009418:S100 Proteins; D013629:Tamoxifen