Background: Aromatase inhibitors are more effective neoadjuvant endocrine therapy than tamoxifen and preoperative aromatase inhibitor treatment is gaining acceptance as a non-toxic approach to improving surgical outcomes in older postmenopausal women with estrogen receptor positive (ER+) tumors who are not eligible for breast conserving surgery. This clinical setting opens a significant opportunity to investigate the molecular basis for responsiveness to aromatase inhibitor therapy in a situation where the primary tumor can be repeatedly accessed for gene expression profiling and predictive biomarker analysis. Hypothesis: Gene expression profiling can distinguish between ER+ positive, aromatase inhibitor sensitive breast cancer from ER+, aromatase inhibitor resistant disease. Plan of investigation: Ninety postmenopausal patients with ER+ breast cancer requiring neoadjuvant treatment will receive four months preoperative letrozole in a multi-center Phase 2 study. Tumor biopsies will be obtained before treatment and subjected to Affymetrix GeneChip analysis. Supervised analyses, based on structured factor regression modeling and class membership predictor algorithms, will be used to search for gene expression profiles that predict clinical response, radiological response and a decline in proliferation with treatment. The expression patterns of the most predictive genes will be confirmed by in situ mRNA hybridization. Post-treatment samples taken at one month and at surgery will be used to further investigate the nature of ER+ tumors that do not respond to estrogen deprivation treatment. Differences in the changes in gene expression profiles between responding and non-responding tumors will provide insight into the molecular basis for this important clinical problem. Long-term objectives: To improve long-term outcomes and reduce the toxicity of breast cancer treatment in older patients with ER+ breast cancer by developing more effective endocrine therapy regimens. Accurate predictive biomarkers for aromatase inhibitor therapy would allow: a) increased use of neoadjuvant endocrine therapy as a non-toxic means to improve surgical outcomes, b) the identification of patients with aromatase inhibitor-sensitive disease in whom adjuvant chemotherapy can be safely avoided and c) lead to insights into aromatase inhibitor resistance that can be addressed by future clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA095614-01A1
Application #
6574085
Study Section
Subcommittee G - Education (NCI)
Program Officer
Xie, Heng
Project Start
2003-08-01
Project End
2008-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
1
Fiscal Year
2003
Total Cost
$621,180
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Lei, Jonathan T; Shao, Jieya; Zhang, Jin et al. (2018) Functional Annotation of ESR1 Gene Fusions in Estrogen Receptor-Positive Breast Cancer. Cell Rep 24:1434-1444.e7
Goncalves, Rodrigo; DeSchryver, Katherine; Ma, Cynthia et al. (2017) Development of a Ki-67-based clinical trial assay for neoadjuvant endocrine therapy response monitoring in breast cancer. Breast Cancer Res Treat 165:355-364
Ma, Cynthia X; Gao, Feng; Luo, Jingqin et al. (2017) NeoPalAna: Neoadjuvant Palbociclib, a Cyclin-Dependent Kinase 4/6 Inhibitor, and Anastrozole for Clinical Stage 2 or 3 Estrogen Receptor-Positive Breast Cancer. Clin Cancer Res 23:4055-4065
Haricharan, Svasti; Punturi, Nindo; Singh, Purba et al. (2017) Loss of MutL Disrupts CHK2-Dependent Cell-Cycle Control through CDK4/6 to Promote Intrinsic Endocrine Therapy Resistance in Primary Breast Cancer. Cancer Discov 7:1168-1183
Ellis, Matthew J (2017) Lessons in precision oncology from neoadjuvant endocrine therapy trials in ER+ breast cancer. Breast 34 Suppl 1:S104-S107
Ellis, Matthew J; Suman, Vera J; Hoog, Jeremy et al. (2017) Ki67 Proliferation Index as a Tool for Chemotherapy Decisions During and After Neoadjuvant Aromatase Inhibitor Treatment of Breast Cancer: Results From the American College of Surgeons Oncology Group Z1031 Trial (Alliance). J Clin Oncol 35:1061-1069
Miller, Christopher A; Gindin, Yevgeniy; Lu, Charles et al. (2016) Aromatase inhibition remodels the clonal architecture of estrogen-receptor-positive breast cancers. Nat Commun 7:12498
Ma, Cynthia X; Reinert, Tomás; Chmielewska, Izabela et al. (2015) Mechanisms of aromatase inhibitor resistance. Nat Rev Cancer 15:261-75
Ben-Baruch, Noa Efrat; Bose, Ron; Kavuri, Shyam M et al. (2015) HER2-Mutated Breast Cancer Responds to Treatment With Single-Agent Neratinib, a Second-Generation HER2/EGFR Tyrosine Kinase Inhibitor. J Natl Compr Canc Netw 13:1061-4
Goncalves, Rodrigo; Warner, Wayne A; Luo, Jingqin et al. (2014) New concepts in breast cancer genomics and genetics. Breast Cancer Res 16:460

Showing the most recent 10 out of 34 publications