A Francis

INTRODUCTION During the last 7 years the Breast Cancer Group within the Tenovus Cancer Research Centre has maintained an involvement in the use of pure antioestrogens in two important areas of breast cancer research. First, their development as clinical agents, where we hoped to induce total oestrogen deprivation and thereby improve the effectiveness of first-line endocrine therapy (Nicholson et al. 1992, Nicholson 1993, Nicholson et al. 1993a, DeFriend et al. 1994, Nicholson et al. 1994c). Second, as pharmacological probes to investigate the cellular and molecular actions of oestrogens and tamoxifen (Nicholson et al. 1988, Weatherill et al. 1988, Wilson et al. 1990). Implicit in each of these areas of research are questions associated with the impact which pure antioestrogens might have on the therapy of endocrine-resistant states and whether resistance develops as a consequence of incomplete oestrogen withdrawal, with tumour cells more efficiently utilising either a reduced oestrogenic pool

INTRODUCTION The last decade has seen the emergence of a new class of pharmacological agents termed pure antioestrogens (Wakeling 1991, 1993). These compounds, which were originally developed by ICI Pharmaceuticals Division in the UK, bind to the oestrogen receptor (ER) (Wilson et al. 1990, Wakeling et al. 1991). Figure 1 shows the structures of ICI 164384, the lead compound, and ICI 182780, which are 7α long chain analogues of oestradiol. Both the ER binding affinity and potency of ICI 182780 are greater than those observed for ICI 164384 due to the replacement of the amide function with a sulphoxide group and the fluorination of the terminal chain (Wakeling et al. 1991). Such differences, nevertheless, do not alter the intrinsic biological behaviour of the drugs, which are identical to other more recently developed steroidal and non-steroidal pure antioestrogens (Von Angerer et al. 1990, Day et al. 1991, Claussner et al. 1992,

Abstract This study examined the effects of the glucocorticoid receptor (GR) agonist RU28362 on stress‐induced gene expression in the pituitary of rats to investigate mechanisms of glucocorticoid negative feedback in vivo . In an initial experiment, acute restraint stress produced rapid (within 15 min) induction of c‐fos mRNA, zif268 mRNA and pro‐opiomelanocortin (POMC) hnRNA within the anterior and intermediate/posterior pituitary as determined by quantitative real‐time polymerase chain reaction. Treatment with RU28362 (150 µg/kg, i.p.) 60 min before restraint inhibited adrenocorticotrophic hormone (ACTH) and corticosterone secretion and selectively suppressed the stress‐induced increase in POMC hnRNA in the anterior pituitary gland. The failure of RU28362 to surpress the stress‐induced rise in c‐fos and expression of zif268 mRNA suggests that the central release of ACTH secretagogues was not affected at this time point by treatment with the GR agonist. Rather, the inhibition of ACTH release appeared to be due to a direct effect of RU28362 within the pituitary. A follow‐up time‐course study varied the interval (10, 60 or 180 min) between RU28362 pretreatment and the onset of restraint. The stress‐induced increase in POMC hnRNA was completely blunted by RU28362 treatment within 10 min of treatment, although the stress induced hormone secretion, c‐fos mRNA and zif268 mRNA were unaffected. The rapid inhibition of the stress‐induced rise in POMC hnRNA in the anterior pituitary appears to reflect direct, GR‐mediated suppression of POMC gene expression. RU28362 pretreatment 180 min before restraint onset was sufficient to suppress the stress‐induced expression in the anterior pituitary gland of all three genes examined. Thus, the delayed negative feedback effects on hypothalamic‐pituitary‐adrenal axis activity that emerged after 180 min after glucocorticoid treatment were not evident at 60 min. Taken together, the data suggest that the inhibition of the stress‐induced release of ACTH apparent within the first hour of glucocorticoid exposure is effected at the level of the pituitary gland. The delayed glucocorticoid effects evident 180 min after RU28362 treatment may include glucocorticoid actions in the brain and additional actions within the pituitary.

Human epidermal growth factor receptor 2 (HER2) testing is required for newly diagnosed breast cancer and advised for recurrent and metastatic breast cancer, to determine treatment planning using HER2-directed therapy in the neoadjuvant, adjuvant and advanced disease settings. Wide variation, nationally, in the turnaround time for HER2 testing may hinder equity of access for patients to both clinical trials and the timely implementation of HER2-directed therapy particularly in the neo-adjuvant setting. Process mapping from three recognised laboratories in the UK was applied to the logistics of HER2 testing in different geographic hub and spoke models. Consequently, recommendations for HER2 testing likely to facilitate access to clinical trials and timely patient care are presented.