Overview
The inhibition of CDK4/6 has become essential in treating hormone receptor-positive, HER2-negative advanced breast cancer; however, resistance to these treatments remains a significant hurdle. A comprehensive understanding of different acquired resistance mechanisms to CDK4/6i-based treatment, and how they may vary based on patient demographics and clinical characteristics in a real-world population, is needed to more precisely optimize treatment. This study explores the mechanisms behind acquired resistance in the context of baseline characteristics using the novel US-based deidentified Flatiron Health-Caris Life Sciences Clinical-Molecular Database (CMDB), with clinical data from the Flatiron Health Research Database linked to whole exome sequencing, whole transcriptome sequencing, and immunohistochemistry data derived from Caris tumor profiling tests.
Researchers assessed data from patient cohorts with molecular testing on post-progression versus pre-treatment specimens from a total of 1,400 patients treated with the CDK4/6 inhibitors palbociclib, ribociclib, or abemaciclib to identify key genetic alterations and gene expression changes linked to treatment resistance. The study highlighted distinct acquired resistance mechanisms to CDK4/6i-based treatment are associated with baseline obesity status.
Why this matters
Understanding the mechanisms of resistance to CDK4/6 inhibitors is crucial for developing more effective treatment strategies. This research confirms known resistance pathways but also uncovers new ones, particularly emphasizing the role of baseline obesity in influencing resistance. By leveraging a comprehensive clinical-multiomics real-world database, these insights have the potential to lead to more personalized treatment approaches and pave the way for tailored interventions that address specific resistance mechanisms, ultimately enhancing patient care and survival.