Relationship between Quantitative HER2 Protein Expression and Clinical Outcomes in ER-Positive and ER-Negative Sub-Groups of Patients with Trastuzumab-Treated Metastatic Breast Cancer.
Authors: Bates M. , Sperinde J. , Leitzel K. , Ali S. , Ali S. , Fuchs E. , Koestler W. , Singer C. , Huang W. , Paquet A. , Weidler J. , Lipton A. 
Published: December 2010

Abstract
Background: HER-2/neu over-expression is associated with poor prognosis and with improved outcomes on trastuzumab in patients with metastatic breast cancer (MBC). Estrogen receptor (ER)-mediated signaling in breast cancer cells has been linked to HER2 gene expression, and some ER+/HER2- patients fail tamoxifen with HER2+ disease. These data suggest an interaction between the ER and HER2 signaling mechanisms that may complicate trastuzumab responsiveness in MBC. We have previously reported that quantitative measurements of HER2 protein expression (H2T) using the HERmark assay identifies sub-populations of previously characterized “HER2-positive” patients (by IHC and/or FISH) that have different clinical outcomes on trastuzumab (Leitzel, ASCO 2008; Lipton, SABCS 2008). Here we investigate whether the relationship between quantitative HER2 protein expression and clinical outcomes on trastuzumab are the same in ER+ and ER- sub-populations.Methods: 100 patients who had received trastuzumab in the metastatic setting and for whom ER status was known were tested by the HERmark assay and H2T levels were determined. Only 6 of 36 ER+ patients that had received hormonal therapy in the adjuvant setting subsequently received hormonal therapy (exemestane) concomitantly with trastuzumab in the metastatic setting. The HERmark measurements were correlated with TTP and OS using Kaplan-Meier and Cox proportional hazards regression analyses stratified by ER status.Results: 64 patients in the cohort were ER-negative and 36 were ER-positive. Considering all patients and using an optimized cutoff defined by positional scanning to discriminate high from low H2T, patients with high H2T levels experienced longer TTP than those with lower H2T levels (median TTP 11.3 vs. 4.5 mos., HR=0.5, p=0.002). Those patients that were ER-negative showed similar results (median TTP = 11.3 vs. 4.5 mos, HR=0.42, p=0.002) whereas there was no significant relationship between H2T and TTP in ER+ tumors (median TTP 9.6 vs. 6.7 mos, HR=0.58, p=0.15). For OS, there was no statistically significant relationship with H2T in the whole population (median OS 35.5 vs. 28.7 mos, HR=0.74, p=0.26) or the ER+ sub-group (HR=0.9, p=0.84), but there was in the ER-negative sub-group favoring high H2T (median OS 31.7 vs. 26.6 mos, HR=0.52, p=0.047).Conclusions: These data suggest that HER2 levels in ER+ breast tumors may change in response to hormonal treatment and such changes may alter the predictive value of HER2 assessments made prior to treatment. Studies comparing quantitative HER2 levels in ER+ tumors before and after exposure to hormonal therapy are needed. These data are not conclusive given the small number of ER+ tumors studied, and require confirmation in larger datasets.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5136.