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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.
Malorni, Luca; Piazza, Silvano; Ciani, Yari; Guarducci, Cristina; Bonechi, Martina; Biagioni, Chiara; Hart, Christopher D; Verardo, Roberto; Di Leo, Angelo; Migliaccio, Ilenia.
Afiliação
  • Malorni L; "Sandro Pitigliani" Translational Research Unit, Hospital of Prato-AUSL Toscana Centro, Istituto Toscano Tumori, Prato, Italy.
  • Piazza S; "Sandro Pitigliani" Medical Oncology Department, Hospital of Prato-AUSL Toscana Centro, Istituto Toscano Tumori, Prato, Italy.
  • Ciani Y; Laboratorio Nazionale CIB (LNCIB), Area Science Park, and Functional Genomics & Bioinformatics Units, Trieste, Italy.
  • Guarducci C; Bioinformatics Core Facility, Centre for Integrative Biology (CIBIO), University of Trento, Trento, Italy.
  • Bonechi M; Laboratorio Nazionale CIB (LNCIB), Area Science Park, and Functional Genomics & Bioinformatics Units, Trieste, Italy.
  • Biagioni C; "Sandro Pitigliani" Translational Research Unit, Hospital of Prato-AUSL Toscana Centro, Istituto Toscano Tumori, Prato, Italy.
  • Hart CD; "Sandro Pitigliani" Translational Research Unit, Hospital of Prato-AUSL Toscana Centro, Istituto Toscano Tumori, Prato, Italy.
  • Verardo R; "Sandro Pitigliani" Translational Research Unit, Hospital of Prato-AUSL Toscana Centro, Istituto Toscano Tumori, Prato, Italy.
  • Di Leo A; "Sandro Pitigliani" Medical Oncology Department, Hospital of Prato-AUSL Toscana Centro, Istituto Toscano Tumori, Prato, Italy.
  • Migliaccio I; "Sandro Pitigliani" Medical Oncology Department, Hospital of Prato-AUSL Toscana Centro, Istituto Toscano Tumori, Prato, Italy.
Oncotarget ; 7(42): 68012-68022, 2016 09 13.
Article em En | MEDLINE | ID: mdl-27634906
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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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Piperazinas / Piridinas / Neoplasias da Mama / Biomarcadores / Proteína do Retinoblastoma / Antineoplásicos Tipo de estudo: Diagnostic_studies / Prognostic_studies / Risk_factors_studies Limite: Female / Humans Idioma: En Revista: Oncotarget Ano de publicação: 2016 Tipo de documento: Article País de afiliação: Itália País de publicação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Piperazinas / Piridinas / Neoplasias da Mama / Biomarcadores / Proteína do Retinoblastoma / Antineoplásicos Tipo de estudo: Diagnostic_studies / Prognostic_studies / Risk_factors_studies Limite: Female / Humans Idioma: En Revista: Oncotarget Ano de publicação: 2016 Tipo de documento: Article País de afiliação: Itália País de publicação: Estados Unidos