Related Experiment Video
Updated: Feb 9, 2026
In Silico Clinical Trials for Cardiovascular Disease
Published on: May 27, 2022
Modulation of Rb phosphorylation and antiproliferative response to palbociclib: the preoperative-palbociclib (POP)
Background:
The cyclin-dependent kinase 4 (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 125 mg daily for 14 days until the day before the surgery versus 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 (GE) arrays were carried out 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 when compared with control (58% versus 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 when compared with control (70% versus 9%, P < 0.001). Palbociclib treatment led also to a significantly higher decrease from baseline in phospho-Rb when compared with control (P < 0.001). Among treated patients, changes in Ki67 correlated with changes in phospho-Rb (Spearman rank r = 0.41, P < 0.0001). GE analyses confirmed a major effect on proliferation and cell cycle genes. Among treated patients, CCNE2 expression was significantly more decreased in antiproliferative responders versus nonresponders (P = 0.006).
Conclusion:
Short-term preoperative 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.
Clinical Trial Registration:
NCT02008734.
Insights
Short-term use of Palbociclib, a CDK4/6 inhibitor, significantly reduced proliferation markers like Ki67 in early breast cancer patients. Early changes in Rb phosphorylation may predict treatment response and identify resistance.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Palbociclib (a CDK4/6 inhibitor) is a standard treatment for hormone-receptor-positive breast cancer.
- Predictive biomarkers and pharmacodynamics for Palbociclib are not well-established.
Purpose of the Study:
- To evaluate the antiproliferative effect of short-term preoperative Palbociclib in early breast cancer.
- To identify potential predictive biomarkers for Palbociclib response.
Main Methods:
- Randomized trial comparing oral Palbociclib (14 days) versus no treatment before surgery.
- Primary endpoint: antiproliferative response (log Ki67 < 1).
- Assessed Ki67, Rb phosphorylation, and gene expression changes.
Main Results:
- Palbociclib significantly increased antiproliferative responses (58% vs 12%) and Ki67 decrease.
- A marked effect was observed in HR-positive/HER2-negative subgroup (70% vs 9%).
- Decreased Rb phosphorylation correlated with Ki67 reduction; CCNE2 expression was lower in responders.
Conclusions:
- Preoperative Palbociclib effectively reduces Ki67 in early breast cancer.
- Early Rb phosphorylation decrease correlates with antiproliferative effects and may indicate primary resistance.
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