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

• Published in: Breast cancer research and treatment 2019-11, Vol.178 (1), p.57-62
• Main Authors: Del Re, Marzia, Bertolini, Ilaria, Crucitta, Stefania, Fontanelli, Lorenzo, Rofi, Eleonora, De Angelis, Claudia, Diodati, Lucrezia, Cavallero, Diletta, Gianfilippo, Giulia, Salvadori, Barbara, Fogli, Stefano, Falcone, Alfredo, Scatena, Cristian, Naccarato, Antonio Giuseppe, Roncella, Manuela, Ghilli, Matteo, Morganti, Riccardo, Fontana, Andrea, Danesi, Romano
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic Agents, Hormonal - therapeutic use; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Cancer; Cancer patients; Cancer research; Cancer therapies; Care and treatment; Chemotherapy; Cyclin-dependent kinase 4; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-Dependent Kinase 4 - genetics; Cyclin-Dependent Kinase 6 - antagonists & inhibitors; Cyclin-Dependent Kinase 6 - genetics; Cyclin-Dependent Kinase 9 - genetics; Cyclin-dependent kinases; Drug Resistance, Neoplasm; ErbB-2 protein; Ethylenediaminetetraacetic acid; Exosomes; Exosomes - genetics; Female; Fulvestrant; Gene expression; Gene Expression Regulation, Neoplastic; Humans; Medicine; Medicine & Public Health; Metastases; Metastasis; Middle Aged; Neoplasm Metastasis; Oncology; Patients; Piperazines - therapeutic use; Preclinical Study; Pyridines - therapeutic use; RNA; Thymidine; Thymidine kinase; Thymidine Kinase - genetics; Treatment Outcome; Up-Regulation
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-019-05365-y

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.