Luminal A breast cancer resistance mechanisms and emerging treatments

Abstract Breast cancer is the most common cancer in women and the second leading cause of death in women due to cancer. The majority (~ 70%) of breast cancers are of the luminal A subtype, defined by the expression of the estrogen receptor (ER +), but lacking amplification of the human epidermal growth factor receptor (HER2 −). Since they are typically estrogen-dependent cancers, luminal A breast cancer can be successfully treated with approaches that block estrogen receptor function. These treatments are often quite effective; however, over time the tumor evolves and becomes resistant through a variety of different mechanisms. Recurrent breast cancer has lost its estrogen dependence, necessitating distinct therapies tailored to the newly emerging molecular characteristics of the evolving disease. This chapter will describe emerging treatments for luminal A breast cancer that include targeting cell growth and survival pathways using phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR pathway inhibitors, cell cycle progression via the cyclin-dependent kinase 4/6 (CDK4/6)/RB pathway, and DNA repair pathways via poly (ADP-ribose) polymerase (PARP) inhibition. Investigations into combination therapies, optimal timing of their delivery, and the ideal sequence for multiline treatments hold the promise of circumventing some mechanisms of resistance. Research efforts focused on the identification of biomarkers that accurately predict which patients will benefit from specific targeted treatments will also be discussed. The development of tumor panels to analyze these validated biomarkers will facilitate clinical decision-making and help us to realize the promise of precision medicine—the right treatment, for the right patient, at the right time.