Association of ADME gene polymorphisms on toxicity to CDK4/6 inhibitors in patients with HR+ HER2- metastatic breast cancer

Elena Peruzzi; Lorenzo Gerratana; Marcella Montico; Bianca Posocco; Serena Corsetti; Michele Bartoletti; Sara Gagno; Marco Orleni; Elena De Mattia; Massimo Baraldo; Erika Cecchin; Fabio Puglisi; Giuseppe Toffoli; Rossana Roncato

doi:10.1016/j.biopha.2023.115479

Association of ADME gene polymorphisms on toxicity to CDK4/6 inhibitors in patients with HR+ HER2- metastatic breast cancer

Biomed Pharmacother. 2023 Nov:167:115479. doi: 10.1016/j.biopha.2023.115479. Epub 2023 Sep 19.

Affiliations

¹ Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy.
² Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy.
³ Clinical Trial Office, Scientific Direction, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy.
⁴ Clinical Pharmacology and Toxicology Institute, University Hospital Friuli Centrale ASUFC, 33100 Udine, Italy; Department of Medicine (DAME), University of Udine, Udine, Italy.
⁵ Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy; Department of Medicine (DAME), University of Udine, Udine, Italy.
⁶ Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy. Electronic address: gtoffoli@cro.it.
⁷ Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy; Department of Medicine (DAME), University of Udine, Udine, Italy. Electronic address: rroncato@cro.it.

PMID: 37734262
DOI: 10.1016/j.biopha.2023.115479

Abstract

A wide interindividual variability in therapeutic response to cyclin-dependent kinases 4 and 6 inhibitors (CDKis) palbociclib, ribociclib and abemaciclib, among patients with HR+/HER2- metastatic breast cancer has been reported. This study explored the impact of genetic polymorphisms in ADME genes (responsible for drug absorption, distribution, metabolism, and elimination) on CDKis safety profiles in 230 patients. Selected endpoints include grade 3/4 neutropenia at day 14 of the first treatment cycle, early dose-limiting toxicities (DLTs), and dose reductions within the initial three cycles. Our analysis revealed associations between these endpoints and polymorphisms in CYP3A4, CYP3A5, ABCB1, and ABCG2 genes. Their impact on CDKis plasma concentrations (C_trough) was also examined. Specifically, ABCB1 c.1236C>T and c.2677C>T polymorphisms correlated significantly with grade 3/4 neutropenia at day 14 (OR 3.94, 95% CI 1.32-11.75; p = 0.014 and OR 3.32, 95% CI 1.12-9.85; p = 0.030). Additionally, ABCB1 c.3435C>T was associated with an elevated risk of early DLTs and dose reductions (OR 3.28, 95% CI 1.22-8.84, p = 0.019; OR 2.60, 95% CI 1.20-5.60, p = 0.015). Carriers of the CYP3A4*22 allele also demonstrated in univariate a higher risk of early DLTs (OR 3.10, 95% CI 1.01-9.56, p = 0.049). Furthermore, individuals with the ABCB1 1236T-3435T-2677T(A) variant haplotype exhibited significant associations with grade 3/4 neutropenia at day 14 (OR 3.36, 95% CI 1.20-9.41; p = 0.021) and early DLTs in univariate (OR 3.08, 95% CI 1.19-7.95; p = 0.020). Homozygous carriers of the ABCB1 T-T-T(A) haplotype tended to have a higher mean ribociclib C_t_rough (934.0 ng/mL vs. 752.0 ng/mL and 668.0 ng/mL). Regardless preliminary, these findings offer promising insights into the role of pharmacogenetic markers in CDKis safety profiles, potentially contributing to address the interindividual variability in CDKis responses.

Keywords: ADME genes polymorphisms; CDK4/6 inhibitors; Dose-limiting toxicity; HR+/HER2- metastatic breast cancer; Pharmacogenetics.