Can Molecular Markers Predict When to Implement Treatment with Aromatase Inhibitors in Invasive Breast Cancer?

Abstract

Purpose: Resistance to tamoxifen is linked to overexpression of HER2, and aromatase inhibitors show particular benefit in progesterone receptor (PR)^negative patients.We previously reported reduced survival in patients overexpressing HER1, HER2, and HER3. We now show that both HER1-3 and PR status predicts for early relapse in estrogen receptor (ER)^positive tamoxifentreated breast cancer patients. Experimental Design: Tissue microarray technology was used to analyze 402 ER-positive tamoxifen-treated patients. Immunohistochemistry using epidermal growth factor receptor, HER2, HER3, HER4, and PR antibodies was done. Kaplan-Meier life table and Cox Regression analysis (log-rank testing of differences in breast cancer^related relapse on tamoxifen) was done. Results: HER1-3 (but not HER4) overexpression predicted for early relapse on tamoxifen (P = 0.0060). PR-negative cases were also significantly more likely to relapse while on tamoxifen (P = 0.017). HER1-3-positive and/or PR-negative patients combined as a ''high-risk'' group were significantly more likely to relapse on tamoxifen in univariate (P < 0.0001) and Cox's multivariate analysis (P = 0.0069). However, this applied to early relapse on tamoxifen only, as any disease relapse after 3 years of tamoxifen was unrelated to PR/HER status. Conclusions: We show that HER1-3 and PR status can identify time-dependent de novo tamoxifen resistance with risk declining markedly after 3 years of tamoxifen treatment. These results parallel data from the ATAC and Intergroup Exemastane Study trials which suggest that whereas PR-negative patients derive greater benefit from initial aromatase inhibitor treatment, PR status has no effect on response when given as delayed treatment to those disease free on tamoxifen after 3 years.

PTK (protein tyrosine kinase)-6 and HER2 and 4, but not HER1 and 3 predict long-term survival in breast carcinomas

“…Our multivariate results further show independent prognostic values for HER2 and HER4 expression 60 (60 months), and HER2 expression 120 (120 months); however, these results are dependent on the time interval investigated. A similar time dependence in a prognostic marker has been reported by Tovey et al (2005). Investigating ER-positive tamoxifen-treated patients, the authors demonstrated a time-dependent predictive value of PR and HER1-3 expression and identified patients at high risk of tamoxifen resistance only in the first 3 years of treatment.…”

“…Studies on HER receptors in breast carcinoma so far focused mainly on HER1 and HER2, only some groups have evaluated the expression of the entire HER family (Bieche et al, 2003;Hudelist et al, 2003;Lodge et al, 2003;Witton et al, 2003;Abd El-Rehim et al, 2004;Wiseman et al, 2005;Bianchi et al, 2006). Those studies have demonstrated the importance of investigating these related proteins in the context of their ability to cooperatively modify intracellular signalling pathways (Bieche et al, 2003;Hudelist et al, 2003;Lodge et al, 2003;Witton et al, 2003;Abd El-Rehim et al, 2004;Tovey et al, 2005;Wiseman et al, 2005, Bianchi et al, 2006. We observed in our study strong overexpression 2 þ /3 þ (2 þ /3 þ ) of the HER receptors rarely for HER1 (5% of tumours), most frequently for HER2 (26%), HER3 (74%), and for HER4 (51% of the tumours), in general in agreement with other studies (Bieche et al, 2003;Witton et al, 2003;Abd El-Rehim et al, 2004).…”

“…There is a growing body of evidence that members of the HER family are involved in breast cancer development and progression, but the protein expression pattern of all four HER receptors remains poorly understood (Bieche et al, 2003;Witton et al, 2003;Abd El-Rehim et al, 2004;Tovey et al, 2005;Bianchi et al, 2006). HER1 and HER2 have been consistently associated with a poor prognosis (Witton et al, 2003;Abd El-Rehim et al, 2004;Wiseman et al, 2005), whereas conflicting evidence is available on the prognostic significance of HER3 (Kew et al, 2000;Bieche et al, 2003;Tovey et al, 2004), and HER4 has been more consistently linked to good prognostic factors (PFs) (Witton et al, 2003;Abd El-Rehim et al, 2004;Tovey et al, 2004).…”

The ERBB3 receptor in cancer and cancer gene therapy

“…The relationship between ERBB3 and ER may be important to understand, since overexpression of ERBB3 predicted relapse during tamoxifen treatment for breast cancer. 203 At present it seems that simple determination of levels of ERBB3 mRNA or protein in mammary cancers does not lead to sure biological or clinical predictions, probably due to the many other factors that influence its expression, activity, localization and pathway interactions.…”

Emerging anti-cancer antibodies and combination therapies targeting HER3/ERBB3

“…77 The roles of HER3 in evolving resistance extends to chemotherapy, such as resistance of HER2-overexpressing breast cancer cells to paclitaxel 65,78 and acquisition of resistance to tamoxifen by luminal B breast cancer. 79 Signature of HER3 activation and use as a biomarker As aforementioned, HER3 is trans-activated by its dimerization partners. This activation leads to phosphorylation of some of the 14 tyrosine residues located at the C-terminal tail of HER3 ( Fig.…”