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Introduction

Over the past 25 years, great strides have been made in the treatment of patients with breast cancer. The rate of new cases has remained constant, while survival continues to improve.¹ In 2015, the year for which the most recent data is available, the 5-year survival rate was 98.7% for women with localized disease and 85.3% for women with regional disease (T3 N1-3 M0). Unfortunately, the 5-year survival rate is only 27% for women with distant metastatic disease.

About 80% of breast cancers express hormone receptors (HR+), being either estrogen-receptor (ER) and/or progesterone-receptor (PR) positive.^2-3 Luminal A (typically HR+/HER2-negative [HER2-]) account for approximately 71% of breast cancers and luminal B (typically HR+/HER2-positive [HER2+]) account for approximately 12% of breast cancers. Luminal A subtypes tend to be slower-growing, less aggressive, and more responsive to antihormone therapy and have the most favorable prognosis. Luminal B breast cancers tend to be higher grade and are associated with poorer survival, as one might expect from HER coexpression. Pathological tests using immunohistochemistry are typically reported as a fraction or a percentage of the cells that are positive for that marker or on a scale of 0 to 3, with 3 being the darkest-staining intensity. Different labs will have different cutoff values for positivity, both for the intensity of staining and the fraction of cells needed.⁴

Endocrine therapy resistance takes many forms and involves changes in expression or function of cellular proteins^5-7:

• Loss of ER expression (15%–20%) or function due to mutation in the ER (approximately 1%) or downstream effectors (12%–39%)^8-9
• Gain of growth factor receptor expression (eg, epidermal growth factor receptor [EGFR], HER-2, insulin-like growth factor receptor 1 [IGF-1R])
• Alteration of signaling pathway function (eg, phosphatidylinositol 3 kinase [PI3K], extracellular signal-regulated kinase [ERK], AKT, Pak1)
• Changes to cell cycle regulators (eg, cyclin D, cyclin E, p21^WAF1/CIP1, p27^Kip1)

This activity focuses on the role of cell cycle dysregulation, particularly involving D-type cyclins, in managing HR+ metastatic breast cancer.