CDK4/6 Inhibitors—Overcoming Endocrine Resistance Is the Standard in Patients with Hormone Receptor-Positive Breast Cancer

Abstract

Purpose of review: Tamoxifen and aromatase inhibitors can be considered as some of the first targeted therapies. For the past 30 years, they were the endocrine treatment standard in the advanced and early breast cancer setting. CDK4/6 inhibitors, however, are the first substances in almost two decades to broadly improve the therapeutic landscape of hormone receptor-positive breast cancer patients for the upcoming years. This review is designed to discuss the recent history, current role, future directions and opportunities of this substance class. Recent findings: The CDK4/6 inhibitors abemaciclib, dalpiciclib, palbociclib and ribociclib have all demonstrated a statistically significant improvement in progression-free survival in advanced disease. However, to date, abemaciclib and ribociclib are the only CDK4/6 inhibitors to have shown an improvement in overall survival in patients with metastatic breast cancer. Moreover, abemaciclib is the first CDK4/6 inhibitor to also reduce the risk of recurrence in those with early-stage disease. Further CDK inhibitors, treatment combinations with other drugs and different therapy sequences are in development. Summary: Achieving significant improvements in survival rates in the advanced and early breast cancer treatment setting, CDK4/6 inhibitors have set a new standard of care for patients with advanced breast cancer. It remains important to better understand resistance mechanisms to be able to develop novel substances and treatment sequences.

Attrition in the First Three Therapy Lines in Patients with Advanced Breast Cancer in the German Real-World PRAEGNANT Registry

“…Several clinical trials with CDK4/6 inhibitors have recently reported median overall survival times around 5 years 6 – 10 . In this patient population, the time interval after the initial treatment becomes increasingly important, as median PFS times for CDK4/6 inhibitors are around 25 – 28 months 40 . As such, disease management will proceed beyond the first progression.…”

Update Breast Cancer 2024 Part 1 – Expert Opinion on Advanced Breast Cancer

“…The better understanding of the precise mechanisms of endocrine signaling pathways has translated into targeted therapies which modify these signaling pathways to achieve tumor control. Several drugs have been tested in clinical trials, including CDK4/6 inhibitors 13 , 14 , the Akt inhibitor capivasertib 15 and the PI3K inhibitor inavolisib 16 , and have been found to improve overall survival (ribociclib and abemaciclib) or have shown very promising trends with regards to overall survival (capivasertib and inavolisib).…”

“…Die Kenntnis der genauen Mechanismen der endokrinen Signalwege wurde gezielt in Therapien umgesetzt, die diese Signalwege im Sinne einer Tumorkontrolle modifizieren. Mit den CDK4/6-Inhibitoren 13 , 14 , dem Akt-Inhibitor Capivasertib 15 und dem PI3K-Inhibitor Inavolisib 16 sind in dem Bereich mehrere Medikamente in klinischen Studien getestet worden, die das Gesamtüberleben verbessern (Ribociclib und Abemaciclib) oder die bereits sehr vielversprechende Trends in Richtung Gesamtüberleben gezeigt haben (Capivasertib und Inavolisib).…”

Targeting LINC00152 activates cAMP/Ca2+/ferroptosis axis and overcomes tamoxifen resistance in ER+ breast cancer

“…The molecular mechanisms of tamoxifen resistance are partially understood and involves ER downregulation, ESR1 mutations, modulation of cell cycle regulators, activation of receptor tyrosine kinases and downstream effectors, and modulation of non-coding RNAs [6][7][8][9][10] . The clinical management of tamoxifen resistance involves the use of other endocrine therapies or CDK4/6 inhibitors 11 . However, resistance to the secondline therapies is also inevitable 12 .…”