Farnesoid X receptor (FXR) status complements the evaluation of estrogen receptor alpha (ER) in breast cancer (BC) patients and predicts benefit from tamoxifen

Journe F, Durbecq V, Haibe-Kains B, Chaboteaux C, Rouas G, Laurent G, Larsimont D, Piccart MJ, Body JJ, Sotiriou C

Background: FXR is a nuclear receptor for bile acids. It is normally expressed in liver tissue and the GI tract. We recently detected FXR in BC and reported a significant correlation between FXR and ER expressions. Moreover, we observed that FXR is associated with proliferation markers in ER+ BC. We also showed that cheno deoxy cholic acid (CDCA) stimulates the proliferation of MCF-7 (ER+) cells through a physical interaction between FXR and ER, the latter resulting in ER activation. Finally, we demonstrated that CDCA increases the expressions of MMP-2/-9 in BC cells, indicating that bile acids/FXR might be involved in the invasiveness of tumor cells.

Material and Methods: We assessed the prognostic value of FXR expression in BC by retrospectively analyzing microarray data in a population of 2473 patients. We evaluated patient overall survival (OS) and distant metastasis-free survival (DMFS) in the total population and in subgroups characterized by ER, node and menopausal (age >50) status. We compared the prognostic value of FXR status with that of the proliferation marker Ki-67. In addition, we examined the predictive value of FXR with regard to response to tamoxifen.

Results: In the total population, a higher FXR expression was significantly associated with a shorter OS (p = 0.003; HR = 1.48; 95% CI [1.14–1.91]). The prognostic value of FXR was particularly good the in ER+/node+ subgroup (p = 0.02; HR = 2.16; 95% CI [1.32–3.54]), discriminating high versus low proliferative tumors as efficiently as Ki-67 level (p = 0.008; HR = 2.33; 95% CI [1.25–4.33]). In this subgroup of patients treated with tamoxifen, high FXR expression was significantly associated with a shorter DMFS (p = 0.039; HR = 2.20; 95% CI [1.04–4.64]). Additionally, the FXR prognostic value, with respect to OS evaluation, was also significant in the ER-/age ≤50 subpopulation (p = 0.038; HR = 1.75; 95% CI [1.03–2.97]), where Ki-67 determination is uninformative. In this subgroup, FXR tended to correlate with occurrence of distant relapses, but was significantly associated with late metastatic relapses (>1000 days) (p = 0.002; HR = 3.21; 95% CI [1.55–6.65]), which generally developed in skeleton.

Conclusions: FXR evaluation brings additional prognostic/predictive information mainly in ER- BC. In this subpopulation, FXR seems related to the occurrence of distant relapses, especially in young patients.