Biomarker Analyses of Response to Cyclin Dependent Kinase 4/6 Inhibition and Endocrine Therapy in Women With Treatment-Naïve Metastatic Breast Cancer

Background: Preclinical data identified the CDK4/6 inhibitor palbociclib as synergistic with anti-estrogens in inhibiting growth of hormone receptor‒positive/human epidermal growth factor receptor 2‒negative (HR+/HER2‒) human breast cancer models. This observation was validated clinically in the randomized, placebo-controlled, phase 3 PALOMA-2 study. Methods: To determine markers of sensitivity and resistance to palbociclib plus letrozole, we performed comprehensive biomarker analyses, investigating the correlation with progression-free survival (PFS), on baseline tumor tissues from PALOMA-2. Results: Despite a broad biomarker search, palbociclib plus letrozole demonstrated consistent PFS gains versus placebo plus letrozole, with no single biomarker or cassette of markers associated with lack of benefit from combination treatment. Palbociclib plus letrozole confers efficacy on both luminal A and B patients. Higher CDK4 levels were associated with endocrine resistance which was mitigated by the addition of palbociclib, while lower PD1 levels were associated with greater palbociclib plus letrozole benefit. Tumors with more active growth factor signaling, as determined by increased expression of FGFR2 and ERBB3 mRNA, appeared to be associated with greater PFS gain from the addition of palbociclib. Conclusions: These data underscore the importance of CDK4/6 signaling in HR+/HER2‒ breast cancer and suggest that the interplay between steroid hormone and peptide growth factor signaling could drive dependence on CDK4/6 signaling. (Pfizer; NCT01740427)