Modulation of rb phosphorylation and antiproliferative response to palbociclib: The preoperative-palbociclib (POP) randomized clinical trial

M. Arnedos, M. A. Bayar, B. Cheaib, V. Scott, I. Bouakka, A. Valent, J. Adam, V. Leroux-Kozal, V. Marty, A. Rapinat, C. Mazouni, B. Sarfati, I. Bieche, C. Balleyguier, D. Gentien, S. Delaloge, M. Lacroix-Triki, S. Michiels, F. Andre

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    Résumé

    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 ¼ 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 ¼ 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.

    langue originaleAnglais
    Pages (de - à)1755-1762
    Nombre de pages8
    journalAnnals of Oncology
    Volume29
    Numéro de publication8
    Les DOIs
    étatPublié - 1 août 2018

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