Identification of ADME genes polymorphic variants linked to trastuzumab-induced cardiotoxicity in breast cancer patients: Case series of mono-institutional experience

Abstract

Background: Long-term survival induced by anticancer treatments discloses emerging frailty among breast cancer (BC) survivors. Trastuzumab-induced cardiotoxicity (TIC) is reported in at least 5% of HER2+BC patients. However, TIC mechanism remains unclear and predictive genetic biomarkers are still lacking. Interaction between systemic inflammation, cytokine release and ADME genes in cancer patients might contribute to explain mechanisms underlying individual susceptibility to TIC and drug response variability. We present a single institution case series to investigate the potential role of genetic variants in ADME genes in HER2+BC patients TIC experienced.

Methods: We selected data related to 40 HER2+ BC patients undergone to DMET genotyping of ADME constitutive variant profiling, with the aim to prospectively explore their potential role in developing TIC. Only 3 patients ("case series"), who experienced TIC, were compared to 37 "control group" matched patients cardiotoxicity-sparing. All patients underwent to left ventricular ejection fraction (LVEF) evaluation at diagnosis and during anti-HER2 therapy. Each single probe was clustered to detect SNPs related to cardiotoxicity.

Results: In this retrospective analysis, our 3 cases were homogeneous in terms of clinical-pathological characteristics, trastuzumab-based treatment and LVEF decline. We identified 9 polymorphic variants in 8 ADME genes (UGT1A1, UGT1A6, UGT1A7, UGT2B15, SLC22A1, CYP3A5, ABCC4, CYP2D6) potentially associated with TIC.

Conclusion: Real-world TIC incidence is higher compared to randomized clinical trials and biomarkers with potential predictive value aren't available. Our preliminary data, as proof of concept, could suggest a predictive role of pharmacogenomic approach in the identification of cardiotoxicity risk biomarkers for anti-HER2 treatment.

Keywords: ADME; ADME genes polymorphic variants; SNPs; absorption; anti-HER2; breast cancer; cardiotoxicity; distribution; metabolism and excretion genes; single nucleotide polymorphisms; trastuzumab.