Advances in Therapy for Hormone Receptor (HR)-Positive, Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Advanced Breast Cancer Patients Who Have Experienced Progression After Treatment with CDK4/6 Inhibitors

Abstract

Approximately 70% of breast cancer (BC) cases are hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) BC. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have acted as star drugs for reversing endocrine therapy (ET) resistance and improving the prognosis of patients with HR+ advanced breast cancer (ABC) since they were initially approved. However, progression eventually occurs. In this review, we summarize the recent treatment strategies post CDK4/6 inhibitors: 1) CDK4/6 inhibitors plus exemestane and everolimus; 2) phosphoinositide-3-kinase (PI3K) inhibitor alpelisib plus fulvestrant for patients with PIK3CA mutation; 3) poly (ADP-ribose) polymerase (PARP) inhibitor for patients with germline PALB2 mutations, somatic BRCA1/2 mutations, or germline BRCA1/2 mutations; 4) exemestane and everolimus; and (5) chemotherapy. These strategies are all supported by evidence from clinical trials and retrospective studies. We also describe potential future treatment strategies post CDK4/6 inhibitors, such as the trophoblast cell surface antigen 2 (Trop-2) directed antibody–drug conjugate, cyclin-dependent kinase 7 (CDK7) inhibitors, and B-cell lymphoma-2 (BCL-2) inhibitors.

Elevation of effective p53 expression sensitizes wild-type p53 breast cancer cells to CDK7 inhibitor THZ1

“…CDK7 is not directly connected to the PIK inhibitor, but its downstream factor CDK4/6 has been used in clinical trials with PIK inhibitor alpelisib. According to SOLAR-1 (NCT02437318) and BYLieve (NCT03056755, cohort A) trials, breast cancer patients carrying PIK3CA mutations who received any CDK4/6 inhibitor and fulvestrant treatment followed by alpelisib had a better prognosis [ 33 ]. Rat sarcoma virus (Ras), a member of the small GTPase superfamily, regulates cell growth, differentiation, and survival by recruiting and activating downstream effectors, including factors involved in AKT and ERK pathways.…”

CDK4/6 inhibitor resistance: A bibliometric analysis

“…Secondly, due to the overexpression of CDK2 after drug resistance, co-inhibition of CDK2 has also become a director of research (47)(48)(49)(50). The rest of the mentioned therapies include MEK inhibition, FGFR inhibition, MDM2 inhibition, CDK7 inhibition, immunotherapy, etc (41,(51)(52)(53)(54)(55)(56). CDK4/6 inhibitor resistance involves multiple pathways and multiple aspects.…”

CDK4/6 Inhibitors after Chemotherapy for Patient with HR+ve, HER2-ve Metastatic Breast Cancer Presented with Visceral Crisis: A Case Report

“…Breast cancer is the most common cancer among women and one of the common causes of cancer related mortality especially those with metastatic disease, where the tumor metastasizes to other organs, such as the bone, liver, lung and brain [1,2]. As known, Palbociclib is an oral drug that inhibit cyclin-dependent kinases 4 and 6(CDK4/6) which play a critical role in cell cycle proliferation and regulation [3].…”