ER and HER2 Expression Are POSITIVELY Correlated in HER2 Non-Over Expressing Breast Cancer.
Authors: Pinhel I. , Pinhel I. , Hills M. , Drury S. , Drury S. , Salter J. , Salter J. , Johnson L. , Barrett-Lee P. , Harris A. , Dowsett M. ,   on Behalf of the NCRI Adjuvant Breast Cancer Trialists
Published: December 2010

Abstract
Aim: To determine the relationship between ER and HER2 expression according to HER2 amplification status.Background: ER and HER2 are the most commonly measured biomarkers in breast cancer and are important targets for therapy. It is known that ER and HER2 positivity are inversely correlated and that among ER+ tumours ER expression is higher in HER2 non-overexpressing (−ve) than HER2 overexpressing (+ve) disease (Konecny et al, JNCI 2003, 95: 142-53). There are however, very few data on the quantitative relationship between ER and HER2 expression in HER2−ve tumours. We therefore measured the expression of ER and HER2 at both the mRNA and protein level in HER2 +ve and −ve breast carcinomas.Methods: ER and HER2 levels were assessed by IHC (6F11 antibody and HercepTest, respectively) on tissue microarrays and q-RT-PCR in formalin-fixed primary breast cancers from 429 patients in the tamoxifen arm of the ABC Trial (ABC Trialists, JNCI 2007, 99: 506-15). HER2 amplification status was assessed with the PathVysion 2-probe FISH test. ER IHC was H-scored. Transcript levels for ER and HER2 from 1139 HER2−ve TransATAC tumours were available from the Oncotype DX test (Dowsett et al, Cancer Res 2009, 69suppl: 75s).Results: Matched results were available from all analyses for 257 ABC patients except for 25 cases where HER2 was by IHC or FISH. HER2 was amplified in 14.4% and equivocal in 1.3% of cases. ER was +ve in 67% of cases. The expected negative correlation between levels of ER and HER2 expression was found in HER2 +ve tumours (r=-0.45, p=0.0028). In contrast in HER2-ve tumours (ER+ve and ER-ve combined) there was a significant POSITIVE correlation between ER and HER2 mRNA levels (r=0.43, p&lt;0.0001). As a result in HER2−ve tumours the quantitative level of HER2 was higher in ER+ve than ER−ve tumours (mean fold difference 1.74, p&lt;0.0001). There was a mean 5.8-fold higher HER2 transcript levels in HER2+ve vs HER2−ve tumours in ER+ve disease and 12.9-fold higher in ER−ve disease. The positive correlation though weaker was maintained in the ER+ve HER2−ve group (r=0.24, p=0.0023) and was present to a similar extent in that subgroup in TransATAC (r=0.25, p&lt;0.00001). The positive association was also significant in ER IHC analyses in ABC: mean±95%CI H-scores were 90±19 and 134±19 in the 0 and 1+ HER2 IHC categories, respectively (p=0.0013).Conclusions: ER and HER2 expression are positively correlated at both protein and transcript levels in HER2−ve breast cancer in contrast to their negative correlation in HER2+ve disease. The distinction between HER2+ve and HER2−ve is greater in ER−ve than ER+ve disease and this may lead to greater diagnostic uncertainties in ER+ve patients. These findings may also have importance for signaling pathways and application of targeted therapy in HER2−ve disease.*Acknowledgement: We are grateful to the ABC Trial Working and Biological Studies Groups, the ATAC Trialists and Cancer Research UK for funding.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 703.