Aromatase inhibitors and inactivators in breast cancer

Breast cancer is the commonest malignant disease among Western women, and, although overall survival has improved with earlier diagnosis by mammography and with adjuvant therapy, it still represents a leading cause of cancer related death. Endocrine treatment is recommended as first line therapy in patients with hormone sensitive tumours (oestrogen and progesterone receptor positive) as most forms of endocrine treatment cause fewer side effects than chemotherapy. No curative treatment is currently available for patients with distant metastases, and the goal of therapy is palliative. This stresses the need for treatments with low toxicity.

Aromatase inhibitors and inactivators are drugs that suppress oestrogen production in postmenopausal women through inhibition of the final step in their synthesis, conversion of androgens to oestrogens. While oestrogen synthesis in the ovary ceases at the menopause, oestrogens are still produced in different peripheral tissues, including benign and malignant breast tissue. Aromatase inhibitors are non-steroidal compounds that cause reversible enzyme inhibition, whereas aromatase inactivators bind irreversibly to and destroy the enzyme.¹

Aminoglutethimide, a first generation aromatase inhibitor, was used for the treatment of breast cancer three decades ago. Although its antitumour effect was similar to that of tamoxifen, its use was limited because of severe side effects. Second generation compounds like formestane and fadrozole were less toxic, but their efficacy was similar to that of conventional therapy. The introduction of the third generation aromatase inhibitors anastrozole and letrozole and the inactivator exemestane was a great leap forward. While aminoglutethimide and second generation compounds reduced oestrogen synthesis by 85-90%, the third generation compounds effectively inhibit oestrogen synthesis by 97-99%.²

These compounds have inconsistently shown superiority to conventional second line therapy (megestrol acetate or aminoglutethimide) with respect to relapse-free and overall survival and, more recently, to tamoxifen as a first line treatment for metastatic breast cancer.^3–7 Thus, one large study showed letrozole to be superior to tamoxifen, another suggested anastrozole was superior to tamoxifen, and a third showed that anastrozole and tamoxifen had similar efficacy.^8–10 Early results from an ongoing study of exemestane look promising, but more data are needed.¹¹ Importantly, as long as no study directly compares the clinical efficacy of the different third generation compounds, we will not know whether there is any significant difference between these compounds. Interestingly, there is a lack of complete cross resistance between aromatase inhibitors and inactivators.¹²

Aromatase inhibitors and inactivators should not be used in premenopausal women without concomitant ovarian blockade with gonadotrophin releasing hormone analogues. This is because ovarian aromatase escapes inhibition because of stimulation by gonadotrophin.

While tamoxifen controls tumour growth only temporarily in metastatic disease, it significantly improves long term, relapse-free survival and overall survival when used as an adjuvant treatment. This suggests that even a modest improvement in the therapy of metastatic disease may translate into real survival benefit in early disease. Thus, the encouraging results seen with third generation aromatase inhibitors and inactivators have prompted trials comparing each of these compounds with tamoxifen for adjuvant therapy. These different protocols are evaluating the test compounds as monotherapy as well as in combination or in sequence with tamoxifen to find the best regimen.¹³ In particular, the concept of using sequential therapy (as is done with exemestane) seems attractive. The lack of cross resistance between tamoxifen and aromatase inhibitors and inactivators in advanced disease suggests that sequential therapy could be beneficial in preventing the outgrowth of tamoxifen resistant micrometastases in some patients undergoing adjuvant therapy.

Primary medical treatment is being increasingly used not only for downstaging non-operable tumours but also for reducing the size of tumours to allow greater conservation of breast tissue. So far, most studies have used chemotherapy for this purpose, but results suggest that aromatase inhibitors could be a feasible option for postmenopausal women with oestrogen receptor positive breast cancer.¹

Several prospective studies have found that high plasma oestrogen concentration in postmenopausal women is a risk factor for subsequent breast cancer suggesting that aromatase inhibitors and inactivators may also have a future in preventing breast cancer.¹⁴ If ongoing adjuvant studies reveal clinical superiority and an acceptable toxicity profile for these compounds, a logical step would be to assess their role as agents to prevent breast cancer in postmenopausal women.