Elevated mRNA expression of herstatin predicts poor outcome in patients with high-risk early breast cancer. A possible molecular predictor of treatment benefit in the context of a Hellenic cooperative oncology group trial.

Abstract

Abstract Abstract #6066 Background: Herstatin is a naturally occurring product of the HER2 gene generated by alternative mRNA splicing. It functions as a secreted inhibitor that binds to the extracellular domains of EGFR and HER2, disrupting multiple receptor combinations in response to a variety of ligands. This mode of action supports the potential utility of herstatin in the development of novel therapeutics against breast cancer. The aim of the present study was to evaluate the association of herstatin with HER family expression at the m-RNA level, as well as with other clinicopathological characteristics of patients with high-risk operable breast cancer enrolled in a randomized phase III trial. The effect of herstatin on disease-free survival (DFS) and overall survival (OS) was also investigated.
 Patients and Methods: 595 high-risk breast cancer patients were treated with anthracycline-based chemotherapy in the adjuvant setting (HE10/97 trial). This was a two-arm trial (E-CMF vs. E-T-CMF) investigating postoperative dose-dense sequential chemotherapy with epirubicin (E) followed by CMF with or without paclitaxel (T). RNA was extracted from 279 formalin-fixed paraffin-embedded tumor tissue samples followed by kinetic one-step RT-PCR for assessment of mRNA expression of herstatin, EGFR, HER2, HER3, and HER4. Values of RNA above the median were considered as positive expression, except for EGFR, where the 75th percentile was used as a cut-off. DFS and OS were estimated by the Kaplan-Meier method and compared using the log-rank test. Cox analysis for DFS and OS was also performed.
 Results: Positive herstatin expression was found to be significantly associated with ductal histology (χ2 test, p=0.004), and marginally associated with infiltrated lymph nodes (p=0.062). Furthermore, herstatin was found to be strongly correlated with HER2 expression (r=0.783, p<0.001) and weakly correlated with HER3 expression (r=0.144, p=0.02). Positive herstatin expression was associated with poor DFS and OS (log-rank, p=0.004 and 0.008, respectively). This remained unchanged when adjusted for treatment group, whereas no interaction between herstatin and treatment was identified. Interaction of HER2 overexpression (>75th percentile) with herstatin was found to be significant for OS (Wald, p=0.03), thus implying a possible prophylactic effect of herstatin in the subgroup of patients with HER2 overexpression.
 Conclusions: Herstatin was shown to be associated with a poor prognosis. Given the high correlation between herstatin and HER2, this finding may reflect the effect of HER2 on patient's prognosis. Our results suggest that the effect of herstatin may be altered in case of HER2 overexpression. This hypothesis should be investigated in future studies, focusing in patients with HER2 overexpression. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6066.