The Ongoing Search for Biomarkers of CDK4/6 Inhibitor Responsiveness in Breast Cancer

CDK4 inhibitors (CDK4/6i), such as palbociclib, ribociclib, and abemaciclib, are approved in combination with hormonal therapy as a front-line treatment for metastatic HR+, HER2-breast cancer. Their targets, CDK4 and CDK6, are cell-cycle regulatory proteins governing the G(1)-S phase transition across many tissue types. A key challenge remains to uncover biomarkers to identify those patients that may benefit from this class of drugs. Although CDK4/6i addition to estrogen modulation therapy essentially doubles the median progression-free survival, overall survival is not significantly increased. However, in reality only a subset of treated patients respond. Many patients exhibit primary resistance to CDK4/6 inhibition and do not derive any benefit from these agents, often switching to chemotherapy within 6 months. Some patients initially benefit from treatment, but later develop secondary resistance. This highlights the need for complementary or companion diagnostics to pinpoint patients who would respond. In addition, because CDK4 is a bona fide target in other tumor types where CDK4/6i therapy is currently in clinical trials, the lack of target identification may obscure benefit to a subset of patients there as well. This review summarizes the current status of CDK4/6i biomarker test development, both in clinical trials and at the bench, with particular attention paid to those which have a strong biological basis as well as supportive clinical data.