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.