Fig. 4: The addition of palbociclib may recondition endocrine responsiveness through concerted actions on CDK4 and ER signaling networks.

a Hierarchical clustering analysis of gene expression/PFS association across the four treatment arms from PALOMA-2 (II) and PALOMA-3 (III). Distance metric was defined using 1 minus correlation coefficient; average linkage was used for clustering. b PCA of global gene expression/PFS association by molecular subtype. LumA or LumB subtype classification is represented by shape, treatment arm represented by color, and cohort represented by number in label (“2” for PALOMA-2 and “3” for PALOMA-3). The percentage values on the axes refer to the proportion of total variance accounted for by the first two principal components respectively. c The expression (top panel) and activity (bottom panel) of ER after palbociclib treatment in ER + cells. Transcript-level change in ESR1 on vehicle control or palbociclib at Day 1 or Day 7. GSEA enrichment plots for ER regulon (estrogen response genes) from MCF7 at Day 1 or Day 7. Genes were rank ordered from most downregulated by palbociclib (vs vehicle control) on the left to most upregulated on the right; each vertical line corresponds to a signature gene. ER estrogen receptor; ET endocrine therapy; FDR false discovery rate; FUL fulvestrant; GSEA gene set enrichment analysis; LET letrozole; LumA luminal A; LumB luminal B; NES normalized enrichment score; PAL palbociclib; PC principal component; PCA principal component analysis; PFS progression-free survival.