The estrogen receptor coactivator AIB1 is a new putative prognostic biomarker in ER-positive/HER2-negative invasive lobular carcinoma of the breast

Abstract

Purpose: According to the 2017 St Gallen surrogate definitions of the intrinsic subtypes, Ki67, progesterone receptor (PR) and Nottingham histological grade (NHG) are used for prognostic classification of estrogen receptor (ER) positive/HER2-negative breast cancer into luminal A- or luminal B-like. The aim of the present study was to investigate if additional biomarkers, related to endocrine signaling pathways, e.g., amplified in breast cancer 1 (AIB1), androgen receptor (AR), and G protein-coupled estrogen receptor (GPER), can provide complementary prognostic information in a subset of ER-positive/HER-negative invasive lobular carcinoma (ILC).

Methods: Biomarkers from 224 patients were analyzed immunohistochemically on tissue microarray. The primary endpoint was breast cancer mortality (BCM), analyzed with 10- and 25-year follow-up (FU). In addition, the prognostic value of gene expression data for these biomarkers was analyzed in three publicly available ILC datasets.

Results: AIB1 (high vs. low) was associated to BCM in multivariable analysis (adjusted for age, tumor size, nodal status, NHG, Ki67, luminal-like classification, and adjuvant systemic therapy) with 10-year FU (HR 6.8, 95% CI 2.3-20, P = 0.001) and 25-year FU (HR 3.0, 95% CI 1.1-7.8, P = 0.03). The evidence of a prognostic effect of AIB1 could be confirmed by linking gene expression data to outcome in independent publicly available ILC datasets. AR and GPER were neither associated to BCM with 10-year nor with 25-year FU (P > 0.33). Furthermore, Ki67 and NHG were prognostic for BCM at both 10-year and 25-year FU, whereas PR was not.

Conclusions: AIB1 is a new putative prognostic biomarker in ER-positive/HER2-negative ILC.

Keywords: Amplified in breast cancer 1 (AIB1); Androgen receptor (AR); G protein-coupled estrogen receptor (GPER); Gene expression; Invasive lobular carcinoma (ILC); Prognostic biomarkers.

Fig. 1

Consort diagram: Breast cancer patients with tumors primarily classified as invasive lobular carcinomas (ILC) at the Department of Pathology, Skåne University Hospital Lund and Helsingborg Hospital, (1980–1991), N = 319. ER positivity (≥ 1%) was confirmed with IHC staining on tissue microarray in N = 200 and whole tissue sections in N = 21, and with cytosol-based methods in N = 3 tumor samples

Fig. 2

Representative images of immunohistochemical staining of AIB1, AR, and GPER: a AIB1 low (score 0) b AIB1: high (score 6) c AR negative (≤ 10%) d AR positive (> 10%). e Total GPER negative (level 0) f Total GPER very weak (level 1) g Total GPER weak (level 2) h Total GPER moderate (level 3). None of the TMAs were classified as total GPER strong (level 4)

Fig. 3

AIB1: Breast cancer mortality (10- and 25-year FU)

Fig. 4

AIB1: Risk of breast cancer death assessed by gene expression data in three independent publicly available datasets of invasive lobular carcinoma (P value: log-rank test)