Biological Processes Associated with Breast Cancer Clinical Outcome Depend on the Molecular Subtypes

Abstract

Purpose: Recently, several prognostic gene expression signatures have been identified; however, their performance has never been evaluated according to the previously described molecular subtypes based on the estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2), and their biological meaning has remained unclear. Here we aimed to perform a comprehensive meta-analysis integrating both clinicopathologic and gene expression data, focusing on the main molecular subtypes. Experimental Design: We developed gene expression modules related to key biological processes in breast cancer such as tumor invasion, immune response, angiogenesis, apoptosis, proliferation, and ER and HER2 signaling, and then analyzed these modules together with clinical variables and several prognostic signatures on publicly available microarray studies (>2,100 patients).Results: Multivariate analysis showed that in the ER+/HER2-subgroup, only the proliferation module and the histologic grade were significantly associated with clinical outcome. In the ER-/HER2-subgroup, only the immune response module was associated with prognosis, whereas in the HER2+ tumors, the tumor invasion and immune response modules displayed significant association with survival. Proliferation was identified as the most important component of several prognostic signatures, and their performance was limited to the ER+/HER2-subgroup. Conclusions: Although proliferation is the strongest parameter predicting clinical outcome in the ER+/HER2-subtype and the common denominator of most prognostic gene signatures, immune response and tumor invasion seem to be the main molecular processes associated with prognosis in the ER-/HER2-and HER2+ subgroups, respectively. These findings may help to define new clinicogenomic models and to identify new therapeutic strategies in the specific molecular subgroups.

Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists

“…Recently, several groups have identified a subgroup of good prognosis ERÀ cancers, encompassing a subgroup of triple-negative and basal-like tumors, which is characterized by the expression of an immune response module. [125][126][127][128] This transcriptomic profile may prove helpful for the identification of patients with triple-negative and basal-like cancers that have a better outcome. In this context, the finding of higher expression of CT-X antigens (in particular MAGE and NY-ESO) in this subgroup opens up another potential avenue for therapy as vaccines against these antigens are already in clinical trial for lung cancer.…”

Dynamic evaluation of the immune infiltrate and immune function genes as predictive markers for neoadjuvant chemotherapy in hormone receptor positive, HER2 negative breast cancer

“…Following previously published results in the same cohort that established immune function as a predictor for pCR in HR positive, HER2 negative patients 18 using a gene module previously published by Desmedt et al 19 we herein explore the predictive power for chemosensitivity of baseline and longitudinal changes after 2 cycles of NACT in the composition of the immune infiltrate and of immune gene expression. The present study is a direct continuation of a previous correlative analysis published from our group regarding HR positive metastatic BC 20 where we used another immune gene signature published by Denkert et al 21 …”

Concordance of clinical and molecular breast cancer subtyping in the context of preoperative chemotherapy response

“…IHC tumors, which may be ER? or ER-; and triple negative tumors (TN IHC ) when ER, PR and HER2 are all negative [13,14].…”