Real-world clinical multi-omics analyses reveal bifurcation of ER-independent and ER-dependent drug resistance to CDK4/6 inhibitors.

Moreover, the MYC/E2F Activation factor significantly increased post-treatment in all samples ( p = 6.9e-06, WRST) with a marginally significant increase among paired samples ( p = 0.052, paired WRST) (Supplementary Fig. 5c ).

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We also observed an increasing trend of PT from Luminal A to Luminal B and then to Her2 and Basal ( p = 0.089, Mann–Kendall Trend Test - MKT), consistent with the prior knowledge that non-Luminal subtypes are more aggressive with worse clinical outcome than Luminal subtypes (Supplementary Fig. 10d ).

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Furthermore, we observed strong increasing trends from branches A to C for stem cell division and HIPPO/YAP pathway signatures in contrast to a decreasing trend from branches A to B, implicating cellular reprogramming and dedifferentiation in the transition into ER independence (Supplementary Fig. 14e, f ).

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