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Zhu, Zhou; Turner, Nicholas C.; Loi, Sherene; Andre, Fabrice; Martin, Miguel; Dieras, Veronique; Gelmon, Karen A.; Harbeck, Nadia; Zhang, Cathy; Cao, Joan Q.; Yan, Zhengming; Lu, Dongrui R.; Wei, Ping; VanArsdale, Todd L.; Rejto, Paul A.; Huang, Xin; Rugo, Hope S.; Loibl, Sibylle; Cristofanilli, Massimo; Finn, Richard S. and Liu, Yuan (2022): Comparative biomarker analysis of PALOMA-2/3 trials for palbociclib. In: Npj Precision Oncology, Vol. 6, No. 1, 56

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While cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, including palbociclib, combined with endocrine therapy (ET), are becoming the standard-of-care for hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer, further mechanistic insights are needed to maximize benefit from the treatment regimen. Herein, we conducted a systematic comparative analysis of gene expression/progression-free survival relationship from two phase 3 trials (PALOMA-2 [first-line] and PALOMA-3 [>= second-line]). In the ET-only arm, there was no inter-therapy line correlation. However, adding palbociclib resulted in concordant biomarkers independent of initial ET responsiveness, with shared sensitivity genes enriched in estrogen response and resistance genes over-represented by mTORC1 signaling and G2/M checkpoint. Biomarker patterns from the combination arm resembled patterns observed in ET in advanced treatment-naive patients, especially patients likely to be endocrine-responsive. Our findings suggest palbociclib may recondition endocrine-resistant tumors to ET, and may guide optimal therapeutic sequencing by partnering CDK4/6 inhibitors with different ETs.

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