Abstract P3-07-12: Identification of luminal A-like subgroup among ER+/PR+/HER2+ breast cancers and its clinical implications
Authors: Zhao S , Jin X , Jiang Y-Z , Shao Z-M 
Published: May 2019

Abstract
Background Triple positive breast cancers (TPBCs), i.e. estrogen receptor-positive (ER+)/ progesterone receptor-positive (PR+)/ human epidermal growth factor receptor 2-positive (HER2+) breast cancers, constitute a therapeutic challenge due to the functional crosstalk between the hormone receptors and HER2 pathways. The intrinsic molecular subtyping of TPBCs has rarely been studied and may have implications for the prognostic evaluation and therapeutic decision-making.
Methods Our study included four cohorts of patients with TPBC. The first one consisted of 82 patients from The Cancer Genome Atlas (TCGA). The second and third ones were from two publicly available microarray datasets (GSE2603 and GSE2109) and included 37 and 30 patients respectively. The forth one comprised 165 patients from Fudan University Shanghai Cancer Center. First, we examined the PAM50 intrinsic subtypes of TPBCs in the first three cohorts. Then, we tried to find several differentially expressed genes (DEGs) between luminal A and the other subtypes. In cohort 1, we identified DEGs using LIMMA. In cohort 2 and 3, we further filtered and validated them using Wilcoxon's rank sum test. We also performed Receiver operating characteristic analyses to evaluate the accuracy of candidate DEGs in identifying TPBCs of luminal A subtype and determined the top 3 DEGs according to the area under the curve. Finally, in cohort 4, we detected the expression of these 3 genes by immunohistochemical (IHC) staining of tissue sections, defined a group of luminal A-like TPBCs and examined the prognosis and effect of adjuvant trastuzumab for them.
Results The distribution of PAM50 intrinsic subtypes of TPBCs was shown as follows. The three genes that exhibited the highest accuracy in identifying TPBCs of luminal A subtype were STC2, BCL2 (highly expressed in luminal A subtype) and MKI67 (lowly expressed in luminal A subtype). In cohort 4, we defined a group of luminal A-like TPBCs as TPBCs with low expression of MKI67 as well as high expression of STC2 and/or BCL2. Compared with patients with non-luminal A-like TPBC (n = 110), those with luminal A-like TPBC (n = 55) had better disease-free survival (DFS) in both univariate (Log-rank P = 0.029) and multivariate analyses (hazard ratio = 0.25, P = 0.025). In the group with non-luminal A-like TPBCs, patients treated with trastuzumab (n = 67) showed better DFS than those not treated with it (n = 43) (Log-rank P = 0.019), while in the group with luminal A-like TPBCs, there is no difference in DFS between patients treated with trastuzumab (n = 22) and those not treated with it (n = 33) (Log-rank P = 0.993).
PAM50 intrinsic subtypes of TPBCsPAM50 intrinsic subtypeCohort 1Cohort 2Cohort 3 N (%)N (%)N (%)Luminal A43 (52.4)15 (40.5)13 (43.3)Luminal B28 (34.1)17 (45.9)12 (40.0)HER2-enriched9 (11.0)2 (5.4)3 (10.0)Normal-like1 (1.2)2 (5.4)1 (3.3)Basal-like1 (1.2)1 (2.7)1 (3.3)
Conclusions TPBCs are heterogeneous in terms of intrinsic molecular subtype. Evaluating the expression of STC2, BCL2 and MKI67 by IHC staining can help us to conveniently identify a group of luminal A-like TPBCs. Patients with this group of TPBCs have relatively good prognosis and may only gain limited benefit from adjuvant trastuzumab.
Citation Format: Zhao S, Jin X, Jiang Y-Z, Shao Z-M. Identification of luminal A-like subgroup among ER+/PR+/HER2+ breast cancers and its clinical implications [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-07-12.