PI3K mutations detected in liquid biopsy are associated to reduced sensitivity to CDK4/6 inhibitors in metastatic breast cancer patients.

Autor: Del Re M; Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Italy., Crucitta S; Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Italy., Lorenzini G; Unit of Medical Oncology, Department of Translational Research and New Technologies in Medicine, University of Pisa, Italy., De Angelis C; Unit of Medical Oncology, Department of Translational Research and New Technologies in Medicine, University of Pisa, Italy., Diodati L; Unit of Medical Oncology, Department of Translational Research and New Technologies in Medicine, University of Pisa, Italy., Cavallero D; Unit of Medical Oncology, Department of Translational Research and New Technologies in Medicine, University of Pisa, Italy., Bargagna I; Unit of Medical Oncology, Department of Translational Research and New Technologies in Medicine, University of Pisa, Italy., Cinacchi P; Unit of Medical Oncology, Department of Translational Research and New Technologies in Medicine, University of Pisa, Italy., Fratini B; Unit of Medical Oncology, Department of Translational Research and New Technologies in Medicine, University of Pisa, Italy., Salvadori B; Unit of Medical Oncology, Department of Translational Research and New Technologies in Medicine, University of Pisa, Italy., Ghilli M; Unit of Breast Surgery, Breast Cancer Center, University Hospital of Pisa, Italy., Roncella M; Unit of Breast Surgery, Breast Cancer Center, University Hospital of Pisa, Italy., Fontana A; Unit of Medical Oncology, Department of Translational Research and New Technologies in Medicine, University of Pisa, Italy., Danesi R; Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Italy. Electronic address: romano.danesi@unipi.it., Cucchiara F; Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Italy.
Jazyk: angličtina
Zdroj: Pharmacological research [Pharmacol Res] 2021 Jan; Vol. 163, pp. 105241. Date of Electronic Publication: 2020 Oct 10.
DOI: 10.1016/j.phrs.2020.105241
Abstrakt: Background: PI3K pathway hyperactivation due to PIK3CA mutations contributes to endocrine resistance, and PIK3CA is one of the most frequently mutated genes in breast cancer (BC), occurring approximately 40 % of HR+, HER2- advanced BC (ABC). Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have changed the treatment landscape of HR+, HER2- ABC. Putative mechanisms of resistance to CDK4/6i have been identified, but limited data are available on PI3K deregulation. The present study evaluates the impact of PIK3CA mutations on CDK4/6i plus hormone therapy and evaluates potential characteristics that may suggest for a PI3K screening in patients with ABC.
Methods: ABC patients were enrolled, and 12 mL of blood were collected in EDTA tubes at baseline prior to CDK4/6i plus hormone therapy. Plasma was separated and circulating free DNA (cfDNA) was extracted. PIK3CA mutation analysis was performed on a ddPCR. Selected and analyzed mutations included: p.C420R, p.E542 K, p.E545A, p.E545D, p.E545G, p.E545K, p.Q546E, p.Q546R, p.H1047L, p.H1047R, p.H1047Y. Statistical analysis were performed to investigate the predictive power of such mutations and any association with clinical factors.
Results: Thirty patients were enrolled. PIK3CA mutation status at baseline was independently associated with shorter median PFS (7.44 vs 12.9 months, p = 0.01) in subject receiving CDK4/6i plus hormone therapy. PIK3CA mutations were found to be associated to Ki67 expression in primary lesions (p = 0.006). Moreover, the probability to find a PI3K mutation improved considering also the therapeutic management in previous lines of treatment (McFadden's R 2 = 0.415, p = 0.004; AUC of the ROC curve = 0.914).
Conclusion: The findings of this pilot study suggest that the presence of a PI3K mutation in liquid biopsy correlates with a worse PFS in patients with ABC receiving CDK4/6i, and that liquid biopsy is a useful tool to suggests a better tailored pharmacological intervention.
(Copyright © 2020 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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