Endocrine therapy

The link between ovarian hormones and breast cancer began to be formed as early as 1882 when TW Nunn observed the spontaneous regression of breast cancer in a woman 6 months after her menstruation ceased [1]. Oophorectomy was first proposed by the German clinician, Schinzinger, on the basis of his observation that younger women had more aggressive breast cancer [2]. However, it was not until 1896 that Beatson reported the first results of therapeutic oophorectomy in women with recurrent and locally advanced breast cancer, demonstrating regressions in three cases [3]. This paved the way for several other surgeons to replicate his work and demonstrate response rates in the order of 20-30% in terms of pain control and objective regression [4-6]. Oestrogen itself wasn't isolated and identified until 1923, and the first man-made oestrogen was synthesised in 1933 [7, 8]. In the mid 1940s, such synthetic oestrogens became some of the first addivive systemic therapies for breast cancer and it wasn't until the early 1970s that the first systemic anti-oestrogen, tamoxifen, came into clinical practice (Table 18.1). Tamoxifen, largely overtook additive oestrogen therapy, not due to increased efficacy, but rather its better tolerability. The majority of subsequent developments in breast cancer endocrine pharmacotherapy have centred around the generation of alternative strategies to abrogate the effects of oestrogen on breast cancer cells, including inhibition of the aromatase enzyme, oestrogen receptor (ER) downregulation and pharmacological suppression of ovarian oestrogen production (Table 18.1). In the following chapter, we review the available data on such endocrine agents. As with the drug development paradigm in all fields of oncology, we start with advanced breast cancer and then describe how such therapies have been translated to the adjuvant and neoadjuvant settings. Table 18.1 Timeline of the introduction of endocrine therapies in use today ^a Therapy Author^b (reference) Date Ovarian ablation (OA) Beatson [3] 1896 Ovarian irradiation DeCourmelles [9] 1922 Androgens Ulrich [97] 1938 Oestrogens Haddow [84] 1944 Progestins Escher [106] 1951 Hypophysectomy Perrault [61] 1952 Adrenalectomy Huggins [69] 1953 Tamoxifen Cole [32] 1971 Aminoglutethamide Griffiths [71] 1973 LHRHHanalogues Klijn [19] 1982 Raloxifine Buzdar [42] 1988 Letrozole Iveson [162] 1993 Exemestane Zilembo [163] 1995 Pureanti-oestrogens Howell [55] 1995 Anastrazole Jonat [164] 1996 ^aIncludes the important conceptual advances of hypophysectomy and adrenalectomy ^bfirst author of first paper