Molecular response to aromatase inhibitor treatment in primary breast cancer.
BACKGROUND
Aromatase inhibitors such as anastrozole and letrozole are highly effective suppressants of estrogen synthesis in postmenopausal women and are the most effective endocrine treatments for hormone receptor positive breast cancer in such women. Little is known of the molecular effects of these agents on human breast carcinomas in vivo.


METHODS
We randomly assigned primary estrogen receptor positive breast cancer patients to treatment with anastrozole or letrozole for 2 weeks before surgery. Expression profiling using cDNA arrays was conducted on pretreatment and post-treatment biopsies. Sample pairs from 34 patients provided sufficient RNA for analysis.


RESULTS
Profound changes in gene expression were seen with both aromatase inhibitors, including many classical estrogen-dependent genes such as TFF1, CCND1, PDZK1 and AGR2, but also many other genes that are likely to represent secondary responses; decrease in the expression of proliferation-related genes were particularly prominent. Many upregulated genes are involved in extracellular matrix remodelling, including collagens and members of the small leucine-rich proteoglycan family (LUM, DCN, and ASPN). No significant differences were seen between letrozole and anastrozole in terms of molecular effects. The gene changes were integrated into a Global Index of Dependence on Estrogen (GIDE), which enumerates the genes changing by at least twofold with therapy. The GIDE varied markedly between tumours and related significantly to pretreatment levels of HER2 and changes in immunohistochemically detected Ki67.


CONCLUSIONS
Our findings identify the transcriptional signatures associated with aromatase inhibitor treatment of primary breast tumours. Larger datasets using this approach should enable identification of estrogen-dependent molecular changes, which are the determinants of benefit or resistance to endocrine therapy.
Mackay
Alan
A
The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, Fulham Road, London, SW3 6JB, UK. alan.mackay@icr.ac.uk
Urruticoechea
Ander
A
Dixon
J Michael
JM
Dexter
Tim
T
Fenwick
Kerry
K
Ashworth
Alan
A
Drury
Suzanne
S
Larionov
Alexey
A
Young
Oliver
O
White
Sharon
S
Miller
William R
WR
Evans
Dean B
DB
Dowsett
Mitch
M
D000077384:Anastrozole; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D047072:Aromatase Inhibitors / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000601:surgery; D003131:Combined Modality Therapy; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D000077289:Letrozole; D009570:Nitriles / Q000627:therapeutic use; D016133:Polymerase Chain Reaction; D017698:Postmenopause; D011960:Receptors, Estrogen / Q000032:analysis / Q000187:drug effects; D014230:Triazoles / Q000627:therapeutic use; D015854:Up-Regulation
D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D009570:Nitriles; D011960:Receptors, Estrogen; D014230:Triazoles; D000077384:Anastrozole; D000077289:Letrozole