Co-expression of estrogen receptor α and Apolipoprotein D in node positive operable breast cancer – possible relevance for survival and effects of adjuvant tamoxifen in postmenopausal patients

Abstract

Background. Estrogen receptor-α (ERα) is an important prognostic and predictive marker in breast cancer. ERα signaling normally down-regulates expression of Apolipoprotein D (ApoD), a lipocalin that binds, transports or chelates lipophilic ligands, including tamoxifen (TAM). Hence, the co-expression of ApoD may therefore identify clinical relevant subgroups of ERα positive breast cancer patients. Material and methods. ApoD, ERα, and progesterone receptor (PR) protein expressions were determined by immunohistochemistry (IHC) in primary tumors of 290 patients with operable breast cancer. The median follow-up was 12 years. Patients were stratified according to age, nodal stage and the expression of ERα and the combined cytoplasm and nuclear staining of ApoD (ApoD_CN). Results. In elderly women (≥70 years) (n = 76), ApoD_CN expression identified different prognostic subgroups in ERα positive patients (Trend: p < 0.0001). Multivariate analysis in this age group (n = 72), showed that the ERα-positive /ApoD_CN-negative subgroup had a better breast cancer specific survival (BCSS) compared with the ERα-positive/ApoD_CN-positive group (hazard ratio (HR) = 4.3; 95% CI = 1.6–11.9; p = 0.005). This difference was predominantly seen in the node positive patients (n = 30) (HR = 10.5; 95% CI = 2.3–47.6; p = 0.002). In a subset of postmenopausal ERα-positive/node positive patients (n = 60) previously enrolled in a trial on 2 year adjuvant TAM 20 mg vs. placebo, a better BCSS was observed in ApoD_CN negative patients compared to placebo (p = 0.02). In ApoD_CN positive patients, adjuvant TAM did not provide any survival benefit. Discussion. ERα and ApoD_CN co-expression seems to be of prognostic importance in node positive elderly patients with operable breast cancer. In addition, we hypothesize that ApoD_CN expression may be a novel marker and/or mechanism of TAM resistance in postmenopausal node positive patients. Thus, when targeting the ERα pathway in these patients, the ApoD status of the tumor may be of clinical relevance.