Endocrine manipulation has been recognized as a treatment modality for breast cancer for over 100 years. Oestrogen is an important promoter in the pathogenesis of breast cancer and endocrine response, for the most part, is dependent on the presence of oestrogen receptor, a protein which can be detected in about 70% of primary breast cancers.
Historically, treatments 30–40 years ago involved surgical removal of endocrine glands such as the ovaries, adrenal glands, or hypophysis. However, a better understanding of the mechanisms that result in oestrogenic deprivation of breast cancer cells has enabled medical therapeutics to be developed which have largely replaced surgical ablative procedures (Box 11.2.1.1). Firstly, hormonal manipulation can be achieved at a cellular level by competing for oestrogen receptor in the breast tumour, using so-called antioestrogens, such as tamoxifen which, although antioestrogenic on breast cancer cells, can have oestrogenic effects in other tissues. More antioestrogenic agents known as selective oestrogen receptor modulators (SERMs), and ‘pure’ antioestrogens such as fulvestrant have now been developed that have little or no oestrogenic effects, and these are being clinically evaluated.
An alternative approach is to lower systemic oestrogen levels in premenopausal women by the use of luteinizing hormone releasing hormone (LHRH) agonists and in postmenopausal women by the use of aromatase inhibitors, which block oestrogen synthesis in nonovarian tissues. Additional, endocrine agents with more ill-defined mechanisms, such as progestogens, androgens, and corticosteroids, can also cause endocrine responses.
In patients with oestrogen receptor-positive advanced breast cancer, endocrine treatments in general achieve a response rate of between 20 and 40%, according to the type of therapy and prior exposure to endocrine treatment. Predictors of response to hormone therapy include a previous response to endocrine treatment, the site of metastases, coexpression of progesterone receptor, and the age of the patient. The median response duration to endocrine therapy in advanced disease is about 8–14 months and for some patients response duration can last several years.
In patients with early stage oestrogen receptor-positive breast cancer, adjuvant endocrine therapy given for 5 years after primary surgery delays local and distal relapse and prolongs survival. It also substantially reduces the incidence of contralateral breast cancer in patients with primary breast cancers, and similarly will reduce the incidence of breast cancer in healthy women by about 50%. As such, endocrine therapy can be used as chemoprevention of breast cancer.
Overall, the development of relatively low toxicity endocrine treatments for advanced and for operable breast cancer has had a substantial impact on the management of this disease, and the types of treatment will be reviewed in this chapter.
Conjugation of palbociclib with MHI-148 has an increased cytotoxic effect for breast cancer cells and an altered mechanism of action
