1. PI3K mutations detected in liquid biopsy are associated to reduced sensitivity to CDK4/6 inhibitors in metastatic breast cancer patients
- Author
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Lucrezia Diodati, Stefania Crucitta, Barbara Salvadori, Beatrice Fratini, Giulia Lorenzini, Paola Cinacchi, Andrea Fontana, Marzia Del Re, Irene Bargagna, Federico Cucchiara, Diletta Cavallero, Matteo Ghilli, Claudia De Angelis, Manuela Roncella, and Romano Danesi
- Subjects
0301 basic medicine ,Oncology ,Adult ,medicine.medical_specialty ,Class I Phosphatidylinositol 3-Kinases ,medicine.medical_treatment ,Antineoplastic Agents ,Breast Neoplasms ,Pilot Projects ,medicine.disease_cause ,PI3K ,03 medical and health sciences ,CDK4/6 inhibitors ,0302 clinical medicine ,Breast cancer ,Internal medicine ,medicine ,Advanced breast cancer ,Liquid biopsy ,Personalized medicine ,Humans ,neoplasms ,PI3K/AKT/mTOR pathway ,Retrospective Studies ,Pharmacology ,Mutation ,Kinase ,business.industry ,Liquid Biopsy ,Cyclin-Dependent Kinase 4 ,Cyclin-Dependent Kinase 6 ,Middle Aged ,medicine.disease ,Metastatic breast cancer ,Progression-Free Survival ,030104 developmental biology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Female ,Hormone therapy ,business - 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.
- Published
- 2020