Systematic Review of Molecular Biomarkers Predictive of Resistance to CDK4/6 Inhibition in Metastatic Breast Cancer

Abstract

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have revolutionized the treatment of hormone-positive metastatic breast cancers (mBCs). They are currently established as standard therapies in combination with endocrine therapy as first- and second-line systemic treatment options for both endocrine-sensitive and endocrine-resistant mBC populations. In the first-line metastatic setting, the median progression-free survival for the three currently approved CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, with aromatase inhibitors is greater than 2 years (palbociclib 27.6 months; ribociclib 25.3 months; and abemaciclib 28.18 months). Although CDK4/6 inhibitors have significant clinical benefits and enable physicians to delay starting chemotherapy, they are expensive and can be associated with drug toxicities. Here, we have performed a systemic review of the reported molecular markers predictive of drug response including intrinsic and acquired resistance for CDK4/6 inhibition in mBC. The rapidly emerging molecular landscape is captured through next-generation sequencing of breast cancers (DNA with or without RNA), liquid biopsies (circulating tumor DNA), and protein analyses. Individual molecular candidates with robust and reliable evidence are discussed in more depth.

HER2-Low Status Does Not Affect Survival Outcomes of Patients with Metastatic Breast Cancer (MBC) Undergoing First-Line Treatment with Endocrine Therapy plus Palbociclib: Results of a Multicenter, Retrospective Cohort Study

“…Despite this indisputable success, the knowledge of resistance mechanisms and the identification of potential biomarkers still represent an unmet clinical need. To this aim, several retrospective and prospective biomarker studies have been conducted [ 20 ]. Exploratory analyses of PALOMA-2 and 3 and MONALEESA trials have suggested a possible correlation between intrinsic subtypes and survival outcomes of MBC patients treated with CDK4/6i in addition to ET [ 21 , 22 , 23 , 24 ].…”

The spindle assembly checkpoint is a therapeutic vulnerability of CDK4/6 inhibitor–resistant ER + breast cancer with mitotic aberrations

“…To date, numerous genomic alterations affecting cell cycle-related genes have been demonstrated to induce acquired resistance to CDK4/6i in patients and preclinical models. These alterations include loss of RB1 and FAT1; down-regulation of the intrinsic CDK4/6 repressors p27 and p21; activating mutations in the phosphatidylinositol 3-kinase (PI3K) signaling pathway; amplification of CDK6, CCNE1, FGFR1, and AURKA; and up-regulation of cyclin D1, cyclin D2, CDK2, MYC, PDK1, and SKP2, among others (4,(13)(14)(15)(16)(17)(18)(19). The diversity of mechanisms that have been associated with CDK4/6i resistance has complicated the understanding of this disease entity, as well as the development of second-line therapeutic strategies to effectively address it.…”

Modeling Breast Cancer Proliferation, Drug Synergies, and Alternating Therapies

“…Since our ultimate goal is to delay or prevent the onset of drug resistance, adding resistance mechanisms to the model is a critical requirement for future work (Wander et al, 2020; Asghar et al, 2022; Pandey et al, 2022, Papadimitriou et al, 2022). The cyclinD1 change mentioned above is a minor step in that direction, but the development of resistance is a complex, multi-faceted process and there are many different pathways that lead to a drug resistant state (Lloyd et al, 2022; Watt et al, 2022).…”