Breast cancer models of acquired tamoxifen resistance, oestrogen receptor (ER) + /ER -de novo resistance and gene transfer studies cumulatively demonstrate the increased importance of growth factor receptor signalling, notably the epidermal growth factor receptor (EGFR)/HER2, in tamoxifen resistance. Our recent in vitro studies also suggest that EGFR signalling productively cross-talks with insulin-like growth factor receptor (IGF-1R) and, where present, activates ER on key AF-1 serine residues to facilitate acquired tamoxifen-resistant growth. This paper presents our immunohistochemical evidence that EGFR/HER2 signalling (i.e. transforming growth factor (TGF)a, EGFR and HER2 expression; phosphorylation of EGFR, HER2 and ERK1/2 MAP kinase) is also prominent in clinical de novo resistant and modestly increased in acquired tamoxifen-resistant states, suggesting that anti-EGFR/HER2 strategies may prove valuable treatments. Primary breast cancer samples employed were obtained for (1) patients subsequently treated with tamoxifen for advanced disease where endocrine response and survival data were available and (2) ER + elderly patients during tamoxifen response and relapse. We also present our clinical immunohistochemical findings that IGF-1R expression, its phosphorylation on tyrosine 1316, and also phosphorylation on serine 118 of ER are not only prominent in ER + tamoxifen-responsive disease, but are also detectable in ER + de novo and acquired tamoxifen-resistant breast cancer, where there is evidence of EGFR/ER cross-talk. Our data suggest that agents to deplete effectively ER or IGF-1R signalling may be of value in treating ER + de novo/acquired tamoxifen resistance in addition to tamoxifenresponsive disease in vivo. IGF-1R inhibitors may also prove valuable in ER -patients, since considerable IGF-1R signalling activity was apparent within 50% of such tumours.Endocrine-Related Cancer (2005) 12 S99-S111

Median survival from liver metastases secondary to breast cancer is only a few months, with very rare 5-year survival. This study reviewed 145 patients with liver metastases from breast cancer to determine factors that may influence survival. Data were analysed using Kaplan -Meier survival curves, univariate and multivariate analysis. Median survival was 4.23 months (range 0.16 -51), with a 27.6% 1-year survival. Factors that significantly predicted a poor prognosis on univariate analysis included symptomatic liver disease, deranged liver function tests, the presence of ascites, histological grade 3 disease at primary presentation, advanced age, oestrogen receptor (ER) negative tumours, carcinoembryonic antigen of over 1000 ng ml À1 and multiple vs single liver metastases. Response to treatment was also a significant predictor of survival with patients responding to chemo-or endocrine therapy surviving for a median of 13 and 13.9 months, respectively. Multivariate analysis of pretreatment variables identified a low albumin, advanced age and ER negativity as independent predictors of poor survival. The time interval between primary and metastatic disease, metastases at extrahepatic sites, histological subtype and nodal stage at primary presentation did not predict prognosis. Awareness of the prognostic implications of the above factors may assist in selecting the most appropriate treatment for these patients.

The aim of this study was to identify factors that may be associated with the development of bone metastases in patients with metastatic breast carcinoma and to see if any of these factors had a bearing on subsequent survival. In total, 492 patients presented to the Nottingham City Hospital with metastatic breast carcinoma between July 1997 and December 2001. Of these, 267 patients had bone metastases at presentation with metastatic disease, 91 patients in this group had bone as their only site of metastatic disease. Sites of first presentation of metastatic disease were prospectively recorded, as were histological features of the primary tumour (tumour type, histological grade, lymph node stage, tumour size and oestrogen receptor (ER) status). The radiological features of the bone metastases, the metastasis-free interval and serological tumour marker levels at presentation with metastases were all recorded. There was a significant association between the development of bone metastases and lower grade tumours (P ¼ 0.019), ER-positive tumours (Po0.0001) and the lymph node stage of the primary tumour (P ¼ 0.047). A multivariate analysis found that metastasis-free interval, additional sites of metastatic disease other than bone, ER status and serological tumour marker levels all independently contributed to survival from time of presentation with bone metastases. British Journal of Cancer (2003) The survival of patients with metastases is variable ranging from a matter of months to many years. The ability to predict prognosis and response to treatment has a considerable impact on patient management. It is well established that oestrogen receptor (ER) status and site of presentation of metastatic disease have the greatest impact on patient survival, with additional contributions made by patient age, disease-free interval and histological grade.Bone is the most common site of metastases in patients with breast carcinoma and so patients with bone metastases make up the largest single group of patients presenting with metastatic disease. It has previously been reported that 20% of patients with bone metastases survive for more than 5 years, which emphasises the wide variation in survival seen in this group of patients (Coleman et al, 1987). The aim of this study was to identify factors that may be associated with the development of bone metastases and to see if any of these factors had any bearing on subsequent survival.We have assessed traditional factors such as ER status, histological grade, lymph node stage and size of the primary tumour, patient age, metastasis-free interval and the presence of metastases at sites other than bone. We have examined the radiological appearance of the bone metastases and looked for associations with the histological features of the tumour and patient survival. In common with other centres, we increasingly use serological tumour markers in the diagnosis and monitoring of patients with metastatic breast carcinoma. The prognostic significance of elevated tumour markers at presentation ...

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Studies of cell models and profiling of clinical breast cancer material to reveal the mechanisms of resistance to anti-oestrogen therapy, and to tamoxifen in particular, have reported that this phenomenon can be associated with increased expression and signalling through erbB Type 1 growth factor receptors, notably the epidermal growth factor receptor (EGFR) and HER2. Further molecular studies have revealed an intricate interlinking between such growth factor receptor pathways and oestrogen receptor (ER) signalling. Inhibition of receptor tyrosine kinase activity involved in the EGFR signalling cascade forms the basis for the use of EGFR specific tyrosine kinase inhibitors exemplified by gefitinib (ZD1839, Iressa) and erlotinib (OSI-774, Tarceva). Such agents have proved promising in pre-clinical studies and are currently in clinical trials in breast cancer, where gefitinib has been studied more extensively to date. Here, we present an overview of the current development of gefitinib in clinical breast cancer. This includes results from our clinical breast cancer trial 1839IL/0057 that demonstrate the efficacy of gefitinib within ER-positive, tamoxifen-resistant patients with locally advanced/metastatic disease, where parallel decreases in EGFR signal transduction and the Ki67 (MIB1) proliferation marker can be detected as predicted from model system studies. We also consider trials examining combination treatment with gefitinib and anti-hormonal strategies that will begin to address the clinically important question of whether gefitinib can delay/prevent onset of anti-hormone resistance.Endocrine-Related Cancer (2005) 12 S135-S144