In
breast cancer, the promising efficacy of
farnesyltransferase inhibitors (FTIs) in preclinical studies is in contrast to only limited effects in clinical Phase II-III trials. The objective of this study was to explore the clinical relevance of
farnesyltransferase β-subunit (FNTB) single
nucleotide promoter polymorphisms (FNTB-173 6G > 5G (rs3215788), -609 G > C (rs11623866) and -179 T > A (rs192403314)) in early
breast cancer. FNTB genotyping was performed by pyrosequencing in 797 patients from a prospective multicentre observational PiA trial (NCT01592825). In the total cohort, the FNTB-173 6G > 5G polymorphism was an independent predictor of RFI (HR = 0.568; 95% CI = 0.339-0.949, p = 0.031), OS (HR = 0.629; 95% CI = 0.403-0.980, p = 0.040) and BCSS (HR = 0.433; 95% CI = 0.213-0.882; p = 0.021), whereas the FNTB-609 G > C polymorphism was an independent predictor of RFI (HR = 0.453; 95% CI = 0.226-0.910, p = 0.026) and BCSS (HR = 0.227; 95% CI = 0.075-0.687, p = 0.009). Subtype analysis revealed the independent prognostic relevance of FNTB promoter polymorphisms, particularly in TNBC but not in
luminal or HER2-positive intrinsic subtypes. Finally, we used electrophoretic mobility shift assays (EMSAs) to confirm in vitro that the polymorphism FNTB-173 6G > 5G resulted in the differential binding of
nuclear proteins from five different
breast cancer cell lines. This is the first study on
breast cancer suggesting that FNTB promoter polymorphisms (i) are independent prognostic
biomarkers, particularly in patients with early TNBC, and (ii) could modulate FNTB's transcriptional activity.