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MB BMedSci MRCPI
Guy’s and St Thomas’ Hospital
Postoperatively many women receive adjuvant systemic chemotherapy and radiotherapy to the chest wall or remaining breast. Patients whose tumours stain positively for hormone receptors are then strongly advised to take hormone-manipulating drugs for five years to reduce the risk of tumour recurrence. Hormone therapy, or endocrine therapy, is the most important systemic treatment of hormone receptor-positive breast cancer at all stages, in the adjuvant setting as well as metastatic disease.
The concept of oestrogen-driven breast cancer was initially considered in the late 19th century, when it was noted that some advanced breast cancers regressed after oophorectomy. More recently it became possible to predict which patients might respond to hormone manipulation when quantitative analysis of tumour oestrogen receptors became possible.
Many breast cancers express oestrogen receptors (ER) and progesterone receptors (PR). Hindering the access of oestrogen to the ER reduces the proliferation of the ER-positive breast cancer cell. Antioestrogens bind to the ER and block the oestrogen signal transduction pathway, thereby hampering tumour cell proliferation.(1)
Selective oestrogen receptor modulators (SERMS)
Tamoxifen is a nonsteroidal oestrogen receptor antagonist. It binds to the ER to block oestrogen signalling. It is the firstline adjuvant endocrine treatment for ER-positive breast cancer.(2) Tamoxifen has also been shown to reduce the incidence of breast cancer in preventive studies.(3)
Tamoxifen has oestrogen-antagonist effects in breast tissue; however, it works as an oestrogen agonist within bone, increasing bone density, thus reducing the risk of osteoporosis and fractures. It also has cardioprotective effects. Negatively, tamoxifen has oestrogen-agonist effects on the uterus. This stimulation of endometrium causes an increased risk of uterine carcinoma. Increased thromboembolic risks have also been reported, leading to an increased incidence of deep vein thrombosis (DVT). Menopausal side-effects of tamoxifen can be difficult to control – hot flushes, vaginal dryness and weight gain. Partial agonist activity may also be a mechanism for tamoxifen resistance.
Raloxifene was designed as an antibreast cancer drug but performed poorly against tamoxifen in metastatic breast cancer. However, raloxifene does prevent osteoporosis, lowers circulating cholesterol, has an antioestrogenic effect on breast cells, and has no oestrogen-like effects on the uterus.(4) It is currently under scrutiny for the prevention of breast cancer.
Medroxyprogesterone and megestrol are progesterone derivatives. They are commonly used as hormonal agents in advanced breast cancer. The exact mechanism of the antitumour effect of progestins is unclear. Theories include suppression of adrenal steroid synthesis, alteration of tumour hormone metabolism, and suppression of oestrogen receptor receptor levels and other growth factors.
Progesterone is well tolerated, with the most prominent side-effect being appetite stimulation and weight gain. Certainly this is beneficial in cachectic patients, and megestrol is extensively used for the treatment of anorexia and cachexia related to other cancers. However, weight gain can be a distressing problem for many patients with breast cancer. There may also be a slightly increased incidence of thromboembolic phenomena in patients receiving megestrol, a risk which appears to be higher with concomitant use of chemotherapy. Megestrol also causes menstrual irregularities, particularly withdrawal menstrual bleeding within a few weeks of discontinuing the drug.
These drugs act by blocking the conversion of androstenedione and testosterone, secreted by the adrenal glands, into oestrogens in peripheral tissues.
Aminoglutethimide has been replaced by newer aromatase inhibitors that are better tolerated. Currently there are three aromatase inhibitors in use: anastrozole, letrozole and exemastane. Each is capable of effectively suppressing circulating levels of oestrogen and oestrogen metabolites. They are used in advanced breast cancer and are also under trial as adjuvant treatments. Two agents, anastrozole and letrozole, are nonsteroidal reversible inhibitors of aromatase. Exemastane is a steroidal molecule that can irreversibly inhibit aromatase.
Aromatase inhibitors are restricted to use in the postmenopausal state. The use of aromatase inhibitors in patients with functioning ovaries increases the number of cycling follicles, with increased fertility and potentially subsequent pregnancy.
Aromatase inhibitors appear to cause fewer thromboembolic episodes and fewer vasomotor symptoms than tamoxifen. There are also fewer uterine problems. Menopausal symptoms and rashes are the main side-effects of aromatase inhibitors. Low-dose vaginal oestrogen has been used in patients taking tamoxifen to address vaginal dryness, but this practice is counterintuitive in patients taking aromatase inhibitors.
In premenopausal women with functioning ovaries, luteinising hormone-releasing hormone (LHRH) super- agonists desensitise the pituitary gland and cause a decrease in gonadotropin release. This results in a chemical oophorectomy. Goserelin is one of the more commonly used LHRH agonists and is administered by subcutaneous injection on a monthly basis.
Pure antioestrogen drugs
Fulvestrant is the first in a new class of novel, steroidal, “pure” antioestrogens. It competitively inhibits oestrogen by binding to the ER. It is a candidate for the treatment of advanced breast cancer in both pre- and postmenopausal women.
Fulvestrant may have advantages over tamoxifen in the treatment of oestrogen-dependent disease because it has no oestrogen agonist action on the uterus and vagina. However, it also lacks the beneficial effects of tamoxifen on the bone and serum lipid profile.
Fulvestrant appears to be at least as good as anastrozole in the treatment of postmenopausal women with advanced breast cancer who had relapsed or progressed on prior endocrine therapy. A phase III trial of fulvestrant versus tamoxifen, as firstline treatment for metastatic breast cancer, is ongoing.
The identification of molecular targets is an exciting section of oncology. Targeted biologic therapies, such as the humanised anti-HER2 antibody trastuzumab, selectively attack the tumour cell, preventing toxicity.
HER2 (C-erbB2) overexpression was identified in the 1980s on the cell surface of breast cancer cells in approximately 30% of tumours. Such amplification of HER2 was associated with a poor prognosis. A monoclonal antibody against HER2 was developed – trastuzumab. Trastuzumab causes growth arrest by decreasing the expression of activated HER2 receptors on the cancer cell membrane. Trastuzumab induces antitumour response in patients with HER2-overexpressing tumours.(5)
Trastuzumab is no panacea. Its use is limited to fewer than 30% of patients. The tumour eventually escapes control. The main acute toxicity is mild “flu-like” symptoms. Concern exists regarding trastuzumab and cardiotoxicity, which is increased in combination with cardiotoxic drugs such as anthra-cyclines. There is reservation regarding the use of trastuzumab as adjuvant treatment. The survival advantages of combination chemobiological therapy could be offset by significant debilitating cardiac toxicity in a proportion of women.
In the treatment of breast cancer it is important to define the objectives for each patient at all stages of the disease. Individuals will benefit differently from many approaches, and no single sequence of treatment is optimal.
In a health service of limited resources, the cost-benefits of expensive cytotoxic drugs such as taxanes, new hormonal therapies and biological treatments are complex. The pharmacoeconomics of breast cancer treatment is a difficult and emotive topic. Financial issues shall continue to enforce constraints as newer drugs become ever more expensive to develop.