Loss of the FAT1 tumor suppressor promotes resistance to CDK4/6 inhibitors via the Hippo pathway

To determine whether genomic alterations in pre-treatment tumor samples might be associated with resistance to CDK4/6 inhibitors (CDK4/6i) in patients with metastatic breast cancer, we subjected 348 ER+/HER2- breast cancer tumor samples to targeted sequencing using MSK-IMPACT assay. A total of 15 tumors did not harbor somatic non-synonymous mutations and were not included in this submission. All the tumors were procured prior to initiation of any of the three clinically efficacious CDK4/6i (palbociclib, ribociclib or abemaciclib; although the majority of patients received palbociclib in this cohort). We then performed an analysis to determine the association between somatic mutations and copy number alterations inferred to be biologically and therapeutically relevant with progression-free survival on CDK4/6i.