Biologic Basis of Sequential and Combination Therapies for Hormone-Responsive Breast Cancer

Abstract

Abstract Learning Objectives After completing this course, the reader will be able to: Explain the possible role of alternate growth factor signaling pathways in the development of resistance to endocrine therapies in estrogen receptor (ER)-positive breast cancer.Describe how the proposed mechanisms of action of tamoxifen, fulvestrant, aromatase inhibitors, and estrogens differ from one another.Summarize the rationale for use of sequential endocrine therapy in postmenopausal women with ER-positive breast cancer. Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.com Although pharmacologic therapies that reduce or block estrogen signaling are effective treatments of estrogen receptor (ER)-positive breast cancer, acquired resistance to individual drugs can develop. Furthermore, this approach is ineffective as initial therapy for a subgroup of receptor-positive patients. The mechanisms of drug resistance are not completely understood, but the presence of alternative signaling pathways for activating ER response appears to play a significant role. Cross-talk between signaling pathways can activate ERs when conventional ER pathways are blocked or inactivated. For example, signaling via epidermal growth factor or HER-2 receptors, mitogen-activated protein kinases, phosphatidylinositol 3′ kinase/protein kinase B, and vascular endothelial growth factor receptor can lead to estrogen-independent stimulation of ERs and tumor growth. The discovery that alternative pathways are involved in estrogen signaling has prompted development of newer endocrine therapies, such as aromatase inhibitors and pure estrogen antagonists, with distinct mechanisms for interrupting signal transduction. The existence of multiple pathways may explain the effectiveness of follow-up therapy with a different class of endocrine agents after failure of prior endocrine treatment. Because they do not have the partial agonist activity of tamoxifen that is enhanced by the adaptive hypersensitivity process, these alternative endocrine agents may play an increasingly important role in the treatment of ER-positive breast cancer. Although optimal sequencing of these agents has not been determined and is continuing to evolve, current evidence allows rational recommendations to be made. The multiple pathways involved in activating ERs also provide a rationale for combining endocrine and non-endocrine therapies that block different signaling pathways, which may have synergistic and overlapping interactions.