The web supplement to
Monica Arnedos et al. 2017
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| Modulation of Rb phosphorylation and antiproliferative response to palbociclib. The Preoperative Palbociclib (POP) randomized trial |
| Monica Arnedos, MD1,2, Mohamed Amine Bayar3,4†, Bianca Cheaib, MD1†, Stefan Michiels3,4, Veronique Scott2, Alexander Valent, Julien Adam2,4, Valerie Leroux-Kozal4, Virginie Marty4, Audrey Rapinat5, Chafika Mazouni MD6, Benjamin Sarfati6, Ivan Bieche7, Corinne Balleyguier MD8, David Gentien5, Suzette Delaloge MD1, Magali Lacroix-Triki4, Fabrice Andre MD, PhD1,2 |
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1Breast Cancer Committee and Department of Cancer Medicine. Gustave Roussy, Villejuif, France 2INSERM Unit 981, Gustave Roussy, Villejuif, France 3Service de Biostatistique et d’Epidémiologie, Gustave Roussy, 94800, Villejuif, France 4CESP, Faculté de médecine, Université Paris Sud, Faculté de médecine UVSQ, INSERM, Université Paris Saclay, 94805, Villejuif, France 5Institut Curie, PSL Research University, Translational Research Department, Genomic platform, Paris, F-75248, France 6Department of Surgery, Gustave Roussy, Villejuif, France 7Department of Genetics, Institut Curie, Paris, France 8Department of Radiology, Gustave Roussy, Villejuif, France †These authors contributed equally to the study |
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Abstract Importance: Palbociclib is a new standard treatment in hormone-receptor positive (HR+) breast cancer patients. No predictive biomarkers have been identified; no pharmacodynamics has properly been described. Objective: Primary objective was to determine whether 14 days of preoperative palbociclib had an impact in proliferation in early breast cancer (EBC) patients, and to identify biomarkers of sensitivity and resistance to this treatment. Design: The POP study was a randomized open-label versus no treatment phase II trial conducted between 2014 and 2015. First analyses were reported at the 2016 AACR Annual meeting. . Setting: Monocenter clinical trial conducted at Gustave Roussy Cancer Campus. Participants: One hundred patients with EBC candidate to surgery upfront were included. Initially tumors were HR+; later all type of breast cancer tumors were accepted. Intervention: Patients were either treated with palbociclib 125mg for 14 consecutive days until day prior to surgery or no treatment in a 3:1 randomization. Main outcomes and measures: Primary objective was antiproliferative response defined as a natural logarithm of Ki67 expression at day 15 being below 1; designed to detect an increase in ln(Ki67)<1 at surgery from 5% (control arm) to 35% (palbociclib arm); 92% power. Results: 74 patients were randomized in the palbociclib arm and 26 in the control arm. 93% HR+; 8% HER2-positive. Palbociclib led to significantly more antiproliferative response than control (58% vs 10%, p=0.0003) and higher mean decrease from baseline in ln(Ki67) at day 15 (p<0.0001). In patients with HR+/Her2-, Ki67 was significantly decreased in 70% of the palbociclib-treated patients (vs 5% in controls). No Ki67 response was observed in triple-negative and Her2-positive tumors (interaction test, p=0.0038). Palbociclib significantly decreased Rb phosphorylation as compared to control (p=0.0027), and the impact on pRb correlated with drug’s effect on Ki67 (Spearman rank correlation r=0.42, p<0.0001). GE array confirmed a major effect on proliferation and cell cycle genes. CCNE2 expression decreased in palbociclib responders; but not in refractory patients (p=0.006). Conclusions and relevance: Short-term pre-operative palbociclib decreases Ki67 in patients with EBC. Early decrease of Rb phosphorylation correlates with drug’s effect on cell proliferation and could be used to identify patients with primary resistance. |
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| Last modified August 22 2017 18:05:07 |