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26.07.2019 | Preclinical study

Overexpression of TK1 and CDK9 in plasma-derived exosomes is associated with clinical resistance to CDK4/6 inhibitors in metastatic breast cancer patients

verfasst von: Marzia Del Re, Ilaria Bertolini, Stefania Crucitta, Lorenzo Fontanelli, Eleonora Rofi, Claudia De Angelis, Lucrezia Diodati, Diletta Cavallero, Giulia Gianfilippo, Barbara Salvadori, Stefano Fogli, Alfredo Falcone, Cristian Scatena, Antonio Giuseppe Naccarato, Manuela Roncella, Matteo Ghilli, Riccardo Morganti, Andrea Fontana, Romano Danesi

Erschienen in: Breast Cancer Research and Treatment | Ausgabe 1/2019

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Abstract

Purpose

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) improve progression-free survival (PFS) in patients with hormone receptor-positive (HR+) advanced breast cancer. However, a better knowledge of predictive biomarkers of response and resistance to CDK4/6i is needed. Therefore, the present article addresses the role of the mRNA expression of thymidine kinase 1 (TK1), CDK4, 6 and 9 in plasma-derived exosomes and their relevance in the pharmacologic activity of CDK4/6i.

Methods

Blood samples of 40 HR+/HER2- advanced breast cancer patients were collected before (T0) the administration of palbociclib plus hormonal therapy and after 3 months (T1). RNA was isolated from exosomes and analysed for the expression of TK1, CDK 4, 6 and 9 by digital droplet PCR (ddPCR).

Results

A higher value of TK1 copies/ml at baseline (T0) was significantly associated with the number of previous lines of chemotherapy (p = 0.009). In patients with PD, a significant increase was observed in the number of copies/ml of TK1 (p = 0.01) and CDK9 (p = 0.03) comparing T1 vs. T0 values. No significant correlations between response to treatment and clinical parameters were found at univariate analysis. High baseline CDK4 expression was significantly correlated with longer PFS in patients treated with fulvestrant + palbociclib (low versus high: 6.45 months vs. not reached, p = 0.01).

Conclusions

The present study demonstrates that, in plasma-derived exosomes, high baseline CDK4 mRNA levels are associated with response to palbociclib plus hormonal therapy, while the increase in TK1 and CDK9 mRNA copies/ml is associated with clinical resistance.

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Titel: Overexpression of TK1 and CDK9 in plasma-derived exosomes is associated with clinical resistance to CDK4/6 inhibitors in metastatic breast cancer patients
verfasst von: Marzia Del Re
Ilaria Bertolini
Stefania Crucitta
Lorenzo Fontanelli
Eleonora Rofi
Claudia De Angelis
Lucrezia Diodati
Diletta Cavallero
Giulia Gianfilippo
Barbara Salvadori
Stefano Fogli
Alfredo Falcone
Cristian Scatena
Antonio Giuseppe Naccarato
Manuela Roncella
Matteo Ghilli
Riccardo Morganti
Andrea Fontana
Romano Danesi
Publikationsdatum: 26.07.2019
Verlag: Springer US
Erschienen in: Breast Cancer Research and Treatment / Ausgabe 1/2019
Print ISSN: 0167-6806
Elektronische ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-019-05365-y

Springer Medizin

Overexpression of TK1 and CDK9 in plasma-derived exosomes is associated with clinical resistance to CDK4/6 inhibitors in metastatic breast cancer patients