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Letrozole Inhibits Tumor Proliferation More Effectively than Tamoxifen Independent of HER1/2 Expression Status¹

Duke University Comprehensive Cancer Center, Durham, North Carolina 27710 [M. J. E., Y. T.]; Lombardi Cancer Center [A. C.] and Department of Pathology [B. S.], Washington, D. C. 20007; Instituto Valenciano de Oncologia, C/P Beltran Baguena 8 y 19, E-46009 Valencia, Spain [A. L-C.]; Universitaets Frauen-und Poliklinik UKE, Martinistrasse 25, D-20246, Hamburg, Germany [F. J.]; Institut Bergonie, 180 rue de Saint-Genès F-33076, Bordeaux Cedex, France [L. M.]; Novartis Pharma AG [E. Q-F.] and Novartis Institute for Biomedical Research, Oncology Research [H. A. C-R., D. B. E.], CH-4002 Basal, Switzerland; and Breast Research Unit, Puderewski Building, Western General Hospital, GB-Edinburgh EH4 2XU, Scotland [W. R. M.]

Background: The biological basis for the superior efficacy of neoadjuvant letrozole versus tamoxifen for postmenopausal women with estrogen receptor (ER)-positive locally advanced breast cancer was investigated by analyzing tumor proliferation and expression of estrogen-regulated genes before and after the initiation of therapy.

Methods: Tumor samples were obtained at baseline and at the end of treatment from 185 patients participating in a double blind randomized Phase III study of neoadjuvant endocrine therapy. These paired specimens were simultaneously analyzed for Ki67, ER, progesterone receptor (PgR), trefoil factor 1 (PS2), HER1 (epidermal growth factor receptor), and HER2 (ErbB2 or neu) by semiquantitative immunohistochemistry.

Results: The treatment-induced reduction in geometric mean Ki67 was significantly greater with letrozole (87%) than tamoxifen (75%; analysis of covariance P = 0.0009). Differences in the average Ki67 reduction were particularly marked for ER-positive tumors that overexpressed HER1 and/or HER2 (88 versus 45%, respectively; P = 0.0018). Twenty-three of 92 tumors (25%) on tamoxifen and 14 of 93 on letrozole (15%) showed a paradoxical increase in Ki67 with treatment, and the majority of these cases was HER1/2 negative. Letrozole, but not tamoxifen, significantly reduced expression of the estrogen-regulated proteins PgR and trefoil factor 1, regardless of HER1/2 status (P < 0.0001). ER down-regulation occurred with both agents, although levels decreased more with tamoxifen (P < 0.0001).

Conclusion: Letrozole inhibited tumor proliferation to a greater extent than tamoxifen. The molecular basis for this advantage appears complex but includes possible tamoxifen agonist effects on the cell cycle in both HER1/2+ and HER1/2- tumors. A pattern of continued proliferation despite appropriate down-regulation of PgR expression with estrogen deprivation or tamoxifen was also documented. This observation suggests the estrogenic regulation of proliferation and PgR expression may be dissociated in endocrine therapy resistant cells.

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