Modulation of Rb phosphorylation and antiproliferative response to palbociclib. The Preoperative-Palbociclib (POP) randomized Clinical Trial

Abstract

Background

The CDK4/6 inhibitor Palbociclib is a new standard treatment in hormone-receptor positive breast cancer patients. No predictive biomarkers have been identified and no pharmacodynamics has properly been described so far.

Patients and methods

Patients with early breast cancer were randomized 3:1 to oral palbociclib 125mg daily for 14 days until the day before the surgery vs. no treatment. Primary objective was antiproliferative response defined as a natural logarithm of Ki67 expression at day 15 below 1. Secondary end-points were subgroups analyses and safety. Exploratory analyses included search for predictive biomarkers. Immunostainings (Ki67, RB, pRB, p16, pAKT, pER, pCDK2, CyclinD1), FISH (CCND1) and gene expression arrays were performed at baseline and at surgery. In addition, activating PIK3CA and AKT1 mutations were assessed at baseline.

Results

74 patients were allocated to palbociclib and 26 to control. Most patients (93%) were hormone-receptor (HR)-positive, whereas 8% were HER2-positive. Palbociclib led to significantly more antiproliferative responses as compared to control (58% vs. 12%, p<0.001), and to a significantly higher Ki67 decrease (p < 0.001). In the HR-positive/HER2-negative subgroup, this antiproliferative effect was even more marked in the palbociclib arm as compared to control (70% vs. 9%, p<0.001). Palbociclib treatment led also to a significantly higher decrease from baseline in phospho-Rb as compared to control (p<0.001). Among treated patients, changes in Ki67 correlated with changes in phospho-Rb (Spearman rank r = 0.41, p<0.0001). Gene expression analyses confirmed a major effect on proliferation and cell cycle genes. Among treated patients, CCNE2 expression was significantly more decreased in anti-proliferative responders vs. non-responders (p=0.006).

Conclusion

Short-term pre-operative palbociclib decreases Ki67 in early breast cancer patients. Early decrease of Rb phosphorylation correlates with drug's effect on cell proliferation and could potentially identify patients with primary resistance.