A gene expression signature of retinoblastoma loss-of-function is a predictive biomarker of resistance to palbociclib in breast cancer cell lines and is prognostic in patients with ER positive early breast cancer
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Luca Malorni1,2, Silvano Piazza3,4, Yari Ciani3, Cristina Guarducci1, Martina Bonechi1, Chiara Biagioni1,2, Christopher D. Hart2, Roberto Verardo3, Angelo Di Leo1,2 and Ilenia Migliaccio1
1 “Sandro Pitigliani” Translational Research Unit, Hospital of Prato-AUSL Toscana Centro, Istituto Toscano Tumori, Prato, Italy
2 “Sandro Pitigliani” Medical Oncology Department, Hospital of Prato-AUSL Toscana Centro, Istituto Toscano Tumori, Prato, Italy
3 Laboratorio Nazionale CIB (LNCIB), Area Science Park, and Functional Genomics & Bioinformatics Units, Trieste, Italy
4 Bioinformatics Core Facility, Centre for Integrative Biology (CIBIO), University of Trento, Trento, Italy
Ilenia Migliaccio, email:
Luca Malorni, email:
Keywords: breast cancer, CDK4/6 inhibitors, retinoblastoma loss of functions
Received: July 14, 2016 Accepted: August 03, 2016 Published: September 13, 2016
Palbociclib is a CDK4/6 inhibitor that received FDA approval for treatment of hormone receptor positive (HR+) HER2 negative (HER2neg) advanced breast cancer. To better personalize patients treatment it is critical to identify subgroups that would mostly benefit from it. We hypothesize that complex alterations of the Retinoblastoma (Rb) pathway might be implicated in resistance to CDK4/6 inhibitors and aim to investigate whether signatures of Rb loss-of-function would identify breast cancer cell lines resistant to palbociclib. We established a gene expression signature of Rb loss-of-function (RBsig) by identifying genes correlated with E2F1 and E2F2 expression in breast cancers within The Cancer Genome Atlas. We assessed the RBsig prognostic role in the METABRIC and in a comprehensive breast cancer meta-dataset. Finally, we analyzed whether RBsig would discriminate palbociclib-sensitive and -resistant breast cancer cells in a large RNA sequencing-based dataset. The RBsig was associated with RB1 genetic status in all tumors (p <7e-32) and in luminal or basal subtypes (p < 7e-11 and p < 0.002, respectively). The RBsig was prognostic in the METABRIC dataset (discovery: HR = 1.93 [1.5-2.4] p = 1.4e-08; validation: HR = 2.01 [1.6-2.5] p = 1.3e-09). Untreated and endocrine treated patients with estrogen receptor positive breast cancer expressing high RBsig had significantly worse recurrence free survival compared to those with low RBsig (HR = 2.37 [1.8 − 3.2] p = 1.87e−08 and HR = 2.62 [1.9− 3.5] p = 8.6e−11, respectively). The RBsig was able to identify palbociclib resistant and sensitive breast cancer cells (ROC AUC = 0,7778). Signatures of RB loss might be helpful in personalizing treatment of patients with HR+/HER2neg breast cancer. Further validation in patients receiving palbociclib is warranted.
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