Endocrine Therapy With or Without CDK4/6 Inhibitors in Women With Hormone-receptor Positive Breast Cancer: What do we Know About the Effects on Cognition?

Adjuvant endocrine therapy (ET) is the cornerstone of treatment for hormone-receptor positive breast cancer. Recently, ET is increasingly combined with "cyclin-dependent kinases 4 and 6'' (CDK4/6) inhibitors. Given the importance of estrogens in neural processes and the role of cyclin D in hippocampal cell proliferation, it is plausible that these therapies affect cognition, but studies on these potential cognitive effects are sparse. In this review, we summarize existing knowledge on the cognitive effects of ET and CDK4/6 inhibitors in pre-, peri- and postmenopausal patients with breast cancer. We show that several clinical studies support adverse cognitive effects, especially on verbal memory, after ET-induced decrease of estrogen-levels or inactivation of estrogen-receptors. Clinical studies on the cognitive effects of CDK4/6 inhibitors are virtually non-existent and no conclusions can yet be drawn. Longitudinal studies on the cognitive effects of the combined ET-CDK4/6 inhibitors are highly needed to properly inform patients about potential short-term and long-term cognitive side effects. These studies should preferably include cognitive assessments (including a measurement prior to ET), and be designed in such a way that they can account for variables such as type and duration of ET, CDK4/6 inhibition, menopausal status, and other disease- and treatment-related symptoms that can impact cognition, such as fatigue and distress.