Journal of Steroid Biochemistry & Molecular Biology 79 (2001) 127–132 Stepwise estrogen suppression manipulating the estrostat  Per Eystein Lønning ∗ Section of Oncology, Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway Abstract Estrogen suppression is an effective endocrine treatment option in pre- as well as postmenopausal breast cancer patients. The fact that it produces clinical benefits not only in these two groups of patients that differ significantly with respect to plasma estrogen levels but also among patients with very low plasma estrogen levels due to previous hypophysectomy, adrenalectomy or treatment with first/second generation aromatase inhibitors, suggests estrogen deprivation to work independent of pretreatment plasma estrogen levels. Interestingly, in vitro studies have revealed MCF-7 cells to respond to estrogen deprivation by sensitization, causing maximum estradiol stimulation at a concentration 10 -5 to 10 -4 the concentration needed in wild-type cells. While results from recent phase III studies comparing novel aromatase inhibitors and inactivators to conventional therapy have suggested that a more effective hormone ablation may be translated into an improved clinical efficacy, the biochemical rationale for lack of complete cross-resistance between aromatase inhibitors and inactivators or aromatase inhibitors and megestrol acetate remains to be explained. Interestingly, patients becoming resistant to estrogen deprivation may still respond to estrogens administered in pharmacological doses. Future studies are warranted to explore alterations in gene expression and signaling mechanisms in response to different therapies in tumor tissue in vivo. © 2002 Elsevier Science Ltd. All rights reserved. Keywords: Breast cancer; Estrogen; Estradiol; Aromatase; Inhibition; Resistance 1. Introduction Estrogen deprivation, together with use of anti-estrogens, represents the major endocrine treatment options in breast cancer. Contemporary methods of estrogen suppression includes castration (surgical, radiological or medical) in premenopausals and treatment with aromatase inhibitors in postmenopausals. Previous strategies to suppress plasma es- trogens in postmenopausals, like adrenalectomy, hypophy- sectomy or use of glucocorticoids in pharmacological doses, have been abandoned from general clinical use due to mor- bidity (the surgical procedures) or poor efficacy (glucocor- ticoids; see [1,2]). Notably, while the mechanism(s) causing the anti-tumor effects of progestins are not fully understood [3], treatment with megestrol acetate 160 mg daily (the dose recommended for use in breast cancer) suppresses plasma estrogen levels in postmenopausals by about 80% [4]. The substantial amount of data generated over the years may allow us to make some general statements regarding the effects of estrogen deprivation. Most importantly, es- trogen deprivation may have anti-tumor effects in groups of breast cancer patients differing substantially with respect  Proceedings of the Symposium: ‘Aromatase 2000 and the Third Generation’ (Port Douglas, Australia, 3–7 November 2000). ∗ Tel.: +47-55-972-010; fax: +47-55-972-046. E-mail address: plon@haukeland.no (P.E. Lønning). to plasma estrogen levels. Thus, ovarian ablation may have significant anti-tumor effects in premenopausal women suf- fering from advanced breast cancer [5,6] and is effective as adjuvant therapy [7]. Treatment with aromatase inhibitors is effective in postmenopausals [8] as well as premenopausals on treatment with a LHRH-analogue [9]. Notably, patients failing on megestrol acetate (which suppresses plasma estro- gen levels by about 80% in postmenopausal women) have been found subsequently to respond to the first-generation aromatase inhibitor aminoglutethimide [10] as well as the third generation aromatase inactivator exemestane [11,12]. In a small study, patients previously exposed to adrenalec- tomy or hypophysectomy was found to respond to subse- quent treatment with aminoglutethimide [13]. 2. Relationship between degree of plasma estrogen deprivation and clinical outcome Indirect evidence support the hypothesis that there may be a dose-response relationship between the degree of es- trogen suppression achieved with different drugs and their clinical efficacy. The novel non-steroidal aromatase in- hibitors anastrozole (A) and letrozole (L) as well as the aro- matase inactivator exemestane were all found to cause more effective aromatase inhibition and plasma estrogen suppres- sion [4,14–17], and to improve clinical outcome [18–21] 0960-0760/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII:S0960-0760(01)00152-2