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

Marzia Del Re; Stefania Crucitta; Giulia Lorenzini; Claudia De Angelis; Lucrezia Diodati; Diletta Cavallero; Irene Bargagna; Paola Cinacchi; Beatrice Fratini; Barbara Salvadori; Matteo Ghilli; Manuela Roncella; Andrea Fontana; Romano Danesi; Federico Cucchiara

doi:10.1016/j.phrs.2020.105241

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

Pharmacol Res. 2021 Jan:163:105241. doi: 10.1016/j.phrs.2020.105241. Epub 2020 Oct 10.

Authors

Affiliations

¹ Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Italy.
² Unit of Medical Oncology, Department of Translational Research and New Technologies in Medicine, University of Pisa, Italy.
³ Unit of Breast Surgery, Breast Cancer Center, University Hospital of Pisa, Italy.
⁴ Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Italy. Electronic address: romano.danesi@unipi.it.

PMID: 33049397
DOI: 10.1016/j.phrs.2020.105241

Abstract

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 R² = 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.

Keywords: Advanced breast cancer; CDK4/6 inhibitors; Liquid biopsy; PI3K; Personalized medicine.

MeSH terms

Adult
Antineoplastic Agents / therapeutic use*
Breast Neoplasms / drug therapy
Breast Neoplasms / genetics*
Breast Neoplasms / mortality
Breast Neoplasms / pathology
Class I Phosphatidylinositol 3-Kinases / genetics*
Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
Cyclin-Dependent Kinase 6 / antagonists & inhibitors*
Drug Resistance, Neoplasm / genetics*
Female
Humans
Liquid Biopsy
Middle Aged
Mutation
Pilot Projects
Progression-Free Survival
Retrospective Studies

Substances

Antineoplastic Agents
Class I Phosphatidylinositol 3-Kinases
PIK3CA protein, human
CDK4 protein, human
CDK6 protein, human
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase 6