HER-2 Amplification, HER-1 Expression, and Tamoxifen Response in Estrogen Receptor-Positive Metastatic Breast Cancer

Abstract

Purpose: Preclinical data indicate that expression of the ErbB family of receptors, such as HER-2 and HER-1 (EGFR) may be involved in endocrine resistance. Evidence of resistance from clinical studies has been inconsistent. The present study examined whether HER-2 gene amplification or HER-1 expression predicted response to tamoxifen.Patients and Methods: Three hundred and forty nine patients had estrogen receptor (ER)-positive breast cancer and received daily tamoxifen as initial therapy for advanced disease. HER-2 gene amplification, detected by fluorescence in situ hybridization, and HER-1 expression, evaluated by immunohistochemistry, was determined on 136 and 204 patients, respectively.Results: HER-2 amplification was correlated with lower ER (P ‫؍‬ 0.02), HER-1 positivity (P ‫؍‬ 0.004), and HER-2 protein overexpression (P < 0.00001). The response rate was 56% for HER-2 non-amplified versus 47% for HER-2 amplified tumors (P ‫؍‬ 0.38), and 58% for HER-1-negative versus 36% for HER-1-positive (P ‫؍‬ 0.05). Time to treatment failure (TTF) was 7 months for non-amplified HER-2 tumors and 5 months (P ‫؍‬ 0.007) for amplified HER-2 tumors, and there was a trend toward a better overall survival (OS) in patients with non-amplified HER-2 tumors (median 31 versus 25 months, respectively, P ‫؍‬ 0.07). For positive versus negative HER-1 tumors, TTF was 4 versus 8 months (P ‫؍‬ 0.08) and median survival was 24 versus 31 months (P ‫؍‬ 0.41). Combining HER-1 expression and HER-2 gene status, patients with both negative HER-1 expression and non-amplified HER-2 had longer TTF (P ‫؍‬ 0.001) and OS (P ‫؍‬ 0.03) than if either were positive. In multivariate analysis, HER-2 was not an independent factor for TTF and OS, although HER-1 was significant for TTF only (P < 0.001).Conclusion: Patients with HER-2 amplification and HER-1 expression had lower ER levels and were modestly less responsive to tamoxifen, suggesting that molecular events in addition to those involving the ErbB receptors are important in determining the endocrine-resistant phenotype.

The relation between survival and expression of HER1 and HER2 depends on the expression of HER3 and HER4: a study in bladder cancer patients

“…Abnormal function of the members of the EGF family has been linked to bladder cancer prognosis. Several reports, based mainly on the expression of HER1 and HER2, demonstrate that the EGF family of receptors are involved in poor prognosis in various cancers including bladder cancer (Lonn et al, 1995;Arpino et al, 2004;Blackwell et al, 2004;Popov et al, 2004). In contrast to HER1 and HER2, our study on bladder tumours (Memon et al, 2004) and other studies on breast tumours (Abd El-Rehim et al, 2004) have suggested that increased expression of HER3 and HER4 is associated with improved survival.…”

Mechanisms of endocrine resistance and novel therapeutic strategies in breast cancer

“…Several retrospective analysis of studies with tamoxifen in advanced breast cancer have shown a worse outcome for patients expressing high levels of ErbB-2 as compared with ErbB-2-negative patients, although this evidence was not confirmed in all studies (Wright et al 1992, Elledge et al 1998, Houston et al 1999, Arpino et al 2004. However, this phenomenon confirms a worse prognosis for ErbB-2-expressing patients treated with tamoxifen, rather than a predictive role of ErbB-2 in the response to this drug.…”

Breast Cancer Version 3.2014

“…180 Selected studies suggest that HER2 + breast cancers may be less sensitive to some endocrine therapies, although other studies have failed to confirm this finding. 145,[181][182][183][184][185][186][187][188] A retrospective analysis of tumor blocks collected in the ATAC trial indicated that HER2 amplification is a marker of relative endocrine resistance independent of type of endocrine therapy. 189 However, given the favorable toxicity profile of the available endocrine therapies, the panel recommends the use of adjuvant endocrine therapy in most women with hormone receptor-positive breast cancer regardless of menopausal status, age, or HER2 status of the tumor.…”