Three inhibitors of CDK4/6 kinases were recently FDA approved for use in combination with endocrine therapy, and they significantly increase the progression-free survival of patients with advanced estrogen receptor-positive (ER+) breast cancer in the first-line treatment setting. As the new standard of care in some countries, there is the clinical emergence of patients with breast cancer that is both CDK4/6 inhibitor and endocrine therapy resistant. The strategies to combat these cancers with resistance to multiple treatments are not yet defined and represent the next major clinical challenge in ER+ breast cancer. In this review, we discuss how the molecular landscape of endocrine therapy resistance may affect the response to CDK4/6 inhibitors, and how this intersects with biomarkers of intrinsic insensitivity. We identify the handful of pre-clinical models of acquired resistance to CDK4/6 inhibitors and discuss whether the molecular changes in these models are likely to be relevant or modified in the context of endocrine therapy resistance. Finally, we consider the crucial question of how some of these changes are potentially amenable to therapy.

Endocrine therapy forms the backbone of systemic therapy for the majority of persons with early and late-stage breast cancer. However, the side effects can negatively affect quality of life, and impact treatment adherence and overall oncological outcomes. Adverse effects on cognition are common, underreported and challenging to manage. We aim to describe the nature, incidence, risk factors and underlying mechanisms of endocrine therapy-induced cognitive dysfunction. We conducted a comprehensive literature review of the studies reporting on cognitive dysfunction associated with endocrine therapies for breast cancer. We also summarise prevention and treatment strategies, and ongoing research. Given that patients are taking endocrine therapies for longer durations than ever before, it is essential that these side effects are managed pro-actively within a multi-disciplinary team in order to promote adherence to endocrine therapy and improve patients’ quality of life.