, Volume 1, Issue 2, pp 102-114
Date: 11 Jun 2005

Endocrine management of breast cancer—biology and current practice

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Abstract

Breast cancer frequency is related to age. There are impressive advances in the diagnostic armament and surgical techniques of breast cancer, and yet, it has continued its deadly impact. In women with operable breast cancer, the histologic status of the axillary lymphnodes remains the most useful prognostic information. Today, breast cancer is viewed as a systemic disease with spreads to local and distant sites at the same time. There is a high rate of occult disease. Factors of major influence on breast cancer include reproductive experience, ovarian activity, benign breast disease, familial tendency, genetic differences, dietary considerations and specific endocrine factors. Tamoxifen still is the standard endocrine treatment for hormone-receptor-positive breast cancer both in the adjuvant and metastatic settings. Because of its weak oestrogenicity, tamoxifen may not be optimally effective and can increase the risk of endometrial cancer and stroke. Patients may also be refractory or become resistant to tamoxifen treatment. Aromatase inhibitors block the synthesis of oestrogen, have low intrinsic oestrogenic activity and, thereby, offer the potential of being more effective than tamoxifen. The challenge of the coming years is to identify women who are best treated with an aromatase inhibitor upfront rather than a tamoxifen-to-aromatase inhibitor sequence. Third-generation aromatase inhibitors offer greater benefits in oestrogen receptor (ER)-positive, progesterone-negative and HER-2 overexpressing tumours. Overall, no more than 2–3% of breast cancer occurrences can be attributed to the inherited mutation of either maternal or paternal origin. Autocrine and paracrine regulation of local oestrogen biosynthesis in normal and tumour breast tissue is via growth factors acting upon aromatase activity, which is preferably expressed in the tumour-bearing quadrant. Aromatase regulation operates against a concentration gradient of oestrogens, comparing peripheral plasma to local tissue levels in both premenopausal and postmenopausal women. Clinical observations suggest to routinely determine both ER subtypes and its variants, by which, the prediction of the response of the breast tumours to endocrine therapy may improve. Polymorphisms of cytochrome CYP-17, CYP-1A1 and COMT are found to be associated with an increased risk of breast cancer. To identify high-risk genotypes in women may delineate the individual at increased risk of breast cancer. Arguments in favour of an impact of postmenopausal oestrogen–progestin therapy on pre-existing tumours derive from observations in epidemiologic studies showing no increase in non-invasive breast cancer with hormone therapy; on the other hand, several studies point to a lower grade and earlier stage of disease in hormone users, with subsequently better survival rates. The older a postmenopausal woman, the greater her risk of developing an increase in breast density with hormone therapy. This is considered a good reason to recommend discontinuation of hormone therapy for at least 2 weeks prior to mammography in women older than age 65 who have dense breasts. As yet, there is no endocrine or biological evidence as to a sequential use of non-cross-resistant endocrine therapies. After progression on adjuvant and first-line tamoxifen, ovarian ablation is an appropriate second-line therapy. For premenopausal women with ovarian ablation, the use of a third-line therapy with an aromatase inhibitor appears feasible. In postmenopausal women, a wide choice of endocrine treatment options is available and an optimal sequence has yet to be determined. The widening range of adjuvant endocrine options represents an opportunity to prolong patient benefits in the treatment of hormone-receptor-positive breast cancer. Further refinement is currently investigated. For example, tamoxifen therapy followed by an aromatase inhibitor may lead to a reduction in endometrial pathologies associated with tamoxifen. New adjuvant treatments with chemotherapy or endocrine agents is being used increasingly to down-stage locally advanced and large operable breast cancers, which often become fully resectable; in addition, initially operable tumours requiring mastectomy may be successfully removed by breast-conserving surgery. Patient selection is important to optimise new adjuvant endocrine therapy; only patients with oestrogen-receptor-rich breast cancer are candidates, and postmenopausal women are likely to benefit the most.

An erratum to this article can be found at http://dx.doi.org/10.1007/s11296-005-0020-7