Anti-Proliferative Effect and Predictive Biomarkers to Palbociclib in Early Breast Cancer

The results from the POP randomised trial

Short-term preoperative palbociclib treatment in patients with early breast cancer significantly decreased Ki67; this effect depended on molecular subtypes and correlated with changes in pRB, suggesting that activity of palbociclib could be the main determinant of its short-term effect on proliferation. The results of Preoperative Palbociclib (POP) randomised phase II study were presented by Monica Arnedos at the AACR Annual Meeting 2016 (April 16-20, New Orleans, US) during the Clinical Trials Plenary Session on Transformative Clinical Trials in Breast Cancer.

In this study, the investigators from the Institut Gustave Roussy, Villejuif, France aimed to identify if short-term preoperative palbociclib is associated with decreased proliferation and early biomarker changes in patients with early breast cancer. Untreated patients were randomised 3:1 to oral palbociclib 125 mg daily for 2 weeks until the day before the surgery vs no treatment.

FFPE and frozen samples were extracted at baseline and at surgery.

Primary objective was anti-proliferative response defined as Ki67 expression. Immunostaining for Ki67, RB, pRB, p16, pAKT, and pER, FISH for CCND1 and gene expression arrays were performed pre- and post-treatment. PIK3CA and AKT1 mutations were assessed before the treatment.

In total, 74 patients were randomised in the palbociclib arm and 26 in the control arm. Furthermore, 93% of tumours were hormone receptor(HR)-positive and 8% HER2-positive.

Palbociclib treatment led to significantly more patients with anti-proliferative response as compared to control (58% vs 10%, p=0.0003). In addition, mean decrease from baseline Ki67 was significantly higher at day 15 in the palbociclib arm (p<0.0001). In patients with HR-positive/HER2-negative tumours, palbociclib decreased Ki67 in 72% of the patients vs 5% in the control group. No Ki67 response was observed in triple-negative breast cancer or HER2-positive tumours (interaction test, p=0.0038).

Palbociclib significantly decreased pRB as compared to control (p=0.0027, ANCOVA model). Baseline RB (interaction test, p=0.36), pRB (p=0.89) and p16 (p=0.13) did not predict palbocicilb effect on Ki67. Palbociclib effect in Ki67 correlated with changes in pRB from baseline (Spearman rank correlation r=0.42, p<0.0001). Additional analyses were ongoing at time of the abstract submission in term of CCND1 amplification, gene expression, pAKT, pER, PIK3CA, and AKT1 analysis.

Although further research will be needed to confirm the findings of this study, the results are promising.

This study was funded by Pfizer Inc., and the Breast Cancer Research Foundation.

Palbociclib, an inhibitor of cyclin-dependent kinases (CDK) 4 and 6, was approved by the US Food and Drug Administration (FDA) in February 2015 for use in combination with letrozole for treatment of postmenopausal women with oestrogen receptor-positive, HER2-negative, metastatic breast cancer.

This year's theme of the American Association for Cancer Research (AACR) Annual Meeting was "Delivering Cures Through Cancer Science"; it reinforced the inextricable link between research and advances in patient care.