Improving Hormonal Therapy for Breast Cancer

Abstract: Since Beatson's observation of breast cancer regression after oophorectomy one hundred years ago (1), therapies directed toward the estrogen-estrogen receptor (ER) endocrine axis have become a cornerstone of breast cancer treatment. Surgical ablative techniques, such as oophorectomy, adrenalectomy, and hypophysectomy have been largely replaced by pharmacological approaches that inhibit estrogen-dependent breast cancer growth, either by reducing estrogen synthesis (LHRH agonists, aromatase inhibitors, and progestins), by blocking ER function (tamoxifen) or by interfering with the cellular response to ER activation (androgens). Indeed, one could argue that hormone therapy for breast cancer represents one of the most successful areas of logical drug design in cancer treatment. Recent drug developments have led to improved side-effect profiles for hormonal agents. In addition, the remarkable organ-selective agonist/antagonist properties of tamoxifen-related compounds are the basis for an effort to develop hormone replacement therapies that combine breast cancer treatment/prevention with reduced osteoporosis and heart disease risk. While the ER axis will remain a primary focus for the further development of hormonal therapies (Table 1), the value of ER as a therapeutic target will always be limited by the primary or acquired estrogen insensitivity that nearly all breast cancers ultimately display. Current hopes for circumventing this problem lie in the vast therapeutic potential afforded by recent molecular insights into growth regulatory pathways. Logical choices for novel therapeutic targets for “estrogen insensitive” breast cancer includes alternative nuclear hormone receptors, growth factor receptors, and signal transduction molecules in “ER-independent” growth-regulatory pathways. Inhibitors of pathophysiological processes intrinsic to tumor progression, such as angiogenesis, invasion, and metastasis are also promising noncytotoxic alternatives in breast cancer therapy (Table 2). Studies of growth regulators in breast cancer are also likely to lead to new tumor markers to accurately guide choices from the increasing array of therapeutic options available.