An ER Activity Profile Including ER, PR, Bcl-2 and IGF-IR May Have Potential As Selection Criterion for Letrozole or Tamoxifen Treatment of Patients with Advanced Breast Cancer

Introduction: The purpose of this study was to evaluate the association between response at recurrence to letrozole versus tamoxifen and the expression of estrogen regulated proteins individually and combined in an "ER activity profile" in primary tumor tissue. Our hypothesis is that letrozole may be more effective than tamoxifen for treatment of tumors with high intratumoral estrogen content, whereas tamoxifen may be more efficient for treatment of tumors with high levels of the estrogen receptor (ER) and low intratumoral estrogen content.

Materials And Methods: For this study, we produced tissue microarrays from formalin fixed paraffin embedded primary tumor material from a subgroup of patients (9.4%), who have participated in the international, randomized, phase III clinical trial PO25 comparing letrozole with tamoxifen in 907 patients with advanced breast cancer. The expression levels of ER, the progesterone receptor (PR), the anti-apoptotic protein Bcl-2 and the Insulin like Growth Factor Receptor I (IGF-IR) were determined by semi-quantitative immunohistochemistry.

Results: Response to letrozole and tamoxifen treatment, measured as time to progression (TTP), was independent of primary tumor expression level of ER, Bcl-2 and IGF-IR. However, high expression of PR as well as high expression of three different ER activity profiles; ER/PR/Bcl-2, ER/PR/IGF-IR and ER/PR/Bcl-2/IGF-IR identified letrozole treated patients with significantly longer TTP. The ER activity profile including ER, PR, Bcl-2 and IGF-IR showed a trend towards being a selection criterion for letrozole versus tamoxifen therapy.

Discussion: This small sub-study supports our hypothesis that letrozole is superior to tamoxifen primarily in patients expressing high levels of estrogen regulated proteins in the primary tumor tissue. Furthermore, it seems that the "ER activity profile" with high PR, IGF-IR and Bcl-2 is a promising selection criterion, regarding prediction of response to letrozole versus tamoxifen.