Originally published as JCO Early Release 10.1200/JCO.2008.16.8849 on February 17 2009

This Article Full Text Full Text (PDF) Data Supplements Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Miller, W. R. Articles by Dixon, J. M. Search for Related Content PubMed PubMed Citation Articles by Miller, W. R. Articles by Dixon, J. M. Social Bookmarking                            What's this?

Gene Expression Profiles Differentiating Between Breast Cancers Clinically Responsive or Resistant to Letrozole

From the Breast Research Group, University of Edinburgh, Edinburgh, United Kingdom; Genomics Institute of the Novartis Research Foundation, San Diego, CA; and Novartis Pharma AG, Basel, Switzerland.

Corresponding author: William R. Miller, DSc, University of Edinburgh, Paderewski Building, Western General Hospital, Edinburgh EH4 2XU, United Kingdom; e-mail: w.r.miller{at}ed.ac.uk.

Purpose Endocrine agents, such as letrozole, are established in the treatment of hormone-dependent breast cancer. However, response rates are only 50% to 70% in the neoadjuvant setting and lower in advanced disease. Thus there is a need to identify novel markers predicting for response and to understand molecular mechanisms of resistance.

Patients and Methods Sequential tumor biopsies were taken before and after 10 to 14 days of neoadjuvant treatment with letrozole in patients with estrogen receptor–rich breast cancer. Expression profiles on high-density microarray chips were then related to clinical responses as assessed from tumor volume measurements after 3 months of treatment.

Results Of 52 patients, 37 (71%) were classified as having a clinical response to letrozole and 15 being clinically resistant. Bioinformatic analysis identified 205 covariables (69 baseline expression, 45 day 14 expression, and 91 change in expression with treatment) which differentiated between clinical responders and nonresponders. Hierarchical clustering using the variables separated responders and nonresponders into two distinct groups. Ontological assessment indicated that discriminating genes were enriched toward cellular biosynthetic processes. In particular, functional gene assessment showed ribosomal protein probes to have higher baseline expression in tumors responsive to letrozole and increased expression with treatment in nonresponding cases.

Conclusion To our knowledge, this is the first study to describe genetic covariables and molecular processes discriminating between tumors clinically responsive and resistant to an aromatase inhibitor. The understanding of such molecular phenotypes will be important in optimizing the clinical use of aromatase inhibitors, both in terms of identifying responsive breast cancers and developing new agents to target resistance pathways.

Molecular analyses were supported by an unrestricted educational grant from Novartis.

Presented in part at the 29th Annual San Antonio Breast Cancer Symposium. December 14-17, 2006, San Antonio, TX; and the 6th Cambridge Conference on Endocrine and Targeted Manipulation of Breast Cancer, April 30-May 1, 2007, Cambridge, MA.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?