Endocrine Therapy — What Else?

摘要

Endocrine therapy was the first targeted therapy in breast cancer. In 1896, George Thomas Beatson reported the successful treatment of three young women who had locally advanced breast cancer by removing the ovaries [1]. Beatson understood that ‘there is some ovarian influence which works the change'. This seminal work founded oophorectomy the treatment of choice for premenopausal women with breast cancer. Elwood Jensen discovered the estrogen receptor as the target for this type of treatment [2]. Approximately three quarters of all invasive breast tumors and at least half of all cancers in premenopausal women are estrogen or progesterone receptor-positive. The natural history of hormone receptor-positive disease differs from that of receptor-negative disease regarding time to recurrence, site of recurrence and overall survival. Most important, however, is the enhanced sensitivity of hormone receptor-positive tumors to endocrine therapy. Hormone receptor expression is only a weak prognosticator. Despite the powerful action of endocrine manipulation on tumor biology endocrine therapy has been more and more displaced by chemotherapy [3]. The evolution of adjuvant therapy especially in younger women is complex and several reasons explain the present attitude towards endocrine therapy. Especially in early trials both, hormone receptor-positive and -negative patients, have been included. Several of the early trials were small and underpowered and led to misleading results. One very important confounding factor is the effect of adjuvant chemotherapy on ovarian function. Therapy induced amenorrhea explains at least in part the beneficial effects of cytotoxic therapy [4]. Indeed, several randomized trials testing chemotherapy versus endocrine therapy did not find a significant difference and if, endocrine therapy was superior. Further analyses indicate that preferentially those women experienced a beneficial effect by chemotherapy who developed therapy induced amenorrhea. However, there remain some incomprehensible aspects of endocrine therapy: In postmenopausal women aromatase inhibitors have been shown to be superior to anti-estrogen treatment [5]. In premenopausal women the ABCSG-12 trial failed to demonstrate superiority of anastrozole over tamoxifen combined with gosereline [6]. The major difference between the treatment arms was caused by the addition of zoledronic acid. Bis-phosphonate treatment not only reduces therapy induced bone loss, but in addition displayed marked anti-tumor efficacy. It was very interesting to note that not only occurrence of bone metastases but also other distant as well as local recurrence of the disease was affected. This was surprising and opens new discussion. Since aromatase inhibitors are known to cause bone loss and osteoporosis a high proportion of patients should be given bisphosphonates as additional treatment. This might affect outcome and an unequal distribution of this therapy in a randomized trial might cause an important bias.