ER Status and Immune Module Are Central Determinants of HER2 Amplified Infiltrative Breast Carcinoma Prognosis and Pathologic Complete Response.
Authors: Reyal F. , Reyal F. , Reyal F. , Horlings H. , Horlings H. , Valet F. , Hamou L. , van Vliet M. , Halfwerk H. , Halfwerk H. , Kristel P. , Armstrong N. , Wessels L. , Van de Vijver M. , Van de Vijver M. 
Published: December 2010

Abstract
IntroductionGene expression profiling of invasive breast cancer has resulted in highlighting three main categories of breast cancer [luminal, basal, HER2] with very specific features. It has been shown that these subtypes differ in their response to neaoadjuvant systemic treatment, axillary lymph node involvement, metastasis pattern and time to metastasis. The aim of this study was to focus on gene-expression profile analysis of HER2 positive breast carcinoma to assess how the molecular subtype classification applies to the HER2+ve samples; whether subgroups of patients that have different prognosis can be identified and how subgroups can be identified that differ with respect to the likelihood to achieve pathologic complete response (pCR) after neoadjuvant systemic treatment?Materials and MethodWe selected breast carcinomas reported to have a HER2+ve status (IHC and CISH) from patients treated between January 1990 and December 2006 at the Netherlands Cancer Institute. 113 tumor samples were hybridized on the Human Genome Oligo Set Version 3.0 arrays. We identified 205 HER2+ve samples from 4 public microarrays datasets and 33 HER2+ve samples from one public neoadjuvant systemic treatment microarrays dataset.ResultsWe applied the molecular subtype classification to the whole datasets and found major classification instability. 43.3% of the HER2+ve samples were classified as “HER2 subtype”, 26% as “basal-like subtype”, and 21.9% as “luminal-like subtype”. The molecular subtype classification was not correlated to prognosis. Of the prognostic variables tested, only ER status was to the development of distant metastasis (IHC, HR=0.53 [0.36-0.77], p=0.0009). We identified a set of 109 ReporterID's highly enriched in gene ontology annotations link to the Immune Response and correlated to the prognosis of HER2+ve breast carcinoma (Inactivated Immune Module, HR=4.21 [1.94-9.17], logrank pvalue=8.1E-05). The Immune Module Signature was associated with prognosis of the HER2+ve samples in both ER positive and ER negative breast cancer. We validated this Immune Module signature combined with ER status on 205 independent samples.We applied the same classification tree to 33 samples from patients who were assessed for response to neo-adjuvant systemic chemotherapy (Anthracyclin-based) and showed an association between the Immune Module Signature combined with ER status and pCR rate (ER+ve Inactivated Immune Module 12.5% pCR, ER-ve Activated Immune Module 70% pCR, pvalue=0.1).ConclusionWe have shown that HER2+ve breast cancer samples often are not classified as HER2-like by gene expression profiling and that ER (IHC) status determines two major subgroups. We provide new evidence that an immune response relate gene expression classifier has prognostic impact in HER2+ve breast cancer; and that this classifier is potentially correlated to the pCR rate after neoadjuvant systemic treatment in HER2+ve breast cancer.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4037.