The Endocrine Society Centennial: 40 Years of Aromatase Inhibitors as Targeted Therapy for Breast Cancer
Year: 2016
Type: editorial
Abstract: The October issue of The Endocrine Society Centennial is devoted to women’s health. For many years, basic and translational endocrinologists in The Endocrine Society have studied how hormones play a role in many aspects of a women’s life, including reproductive (eg, puberty, pregnancy, menopause) and lifestyle (eg, energy, mood) factors. Fluctuation of hormone levels is associated with many clinical issues, thus engaging many clinical endocrinologists. Not surprisingly, The Endocrine Society, its members, and its journals have played a major role in promoting awareness and research into women’s health issues. One of the major areas of study has been the role of hormones in women’s cancer. This editorial will briefly cover the fascinating story of how researchers and clinicians identified and validated aromatase inhibitors (AIs) as a targeted therapy for breast cancer. This subject is fitting given that October is breast cancer awareness month. It is 120 years since Sir George Beatson showed that bilateral oophorectomy was effective for the treatment of breast cancer (1). This surgical approach was ahead of its time, being more than 30 years before the identification and characterization of estrogens (2). However, the concept of surgical treatment of breast cancer continued with the use of surgical adrenalectomy and hypophysectomy (3). With the discovery and biochemical characterization of estrogens and other hormones, the concept of using hormone action (either hormone addition or chemical ablation) as a treatment for breast cancer gained traction. The initial concept was to give hormones such as androgens, glucocorticoids, estrogens, and progesterone, and some of these therapies remain in use and/or are still under active clinical investigation, such as treatment with high-dose estrogen (4). But the biochemical studies of estrogen synthesis from the 1950s–1970s, and the finding of aromatization of androgens to estrogens, led to the concept that one might be able to inhibit estrogen synthesis. The dedicated studies of a large number of endocrinologists studying the basic endocrinology of hormone action bore fruit, with aminoglutethimide, an AI, causing an objective response in a patient with breast cancer (5). This editorial focuses on a publication in Endocrinology in 1977 from Angela and Harry Brodie on the identification and functional characterization of 4-hydroxy-4-androstene-3,17-dione (4-OH-A) as an AI (Figure 1) (6). The 1970s saw great interest in the pharmacologic inhibitor of estrogen and estrogen receptor (ER) using antiestrogens, such as tamoxifen, or AI, such as aminoglutethimide. In a search for more potent inhibitors of aromatase, Harry Brodie reported in Endocrinology an in-depth characterization of over 100 different compounds that could inhibit estrogen biosynthesis in human placental microsomes (7). Angela and Harry settled on 4-OH-A as the most suitable candidate for further testing. They performed detailed in vitro kinetic studies showing that 4-OH-4A was effective as an AI (6). They further showed that in vivo administration of 4-OH-A to the rat caused an 80% reduction in estradiol levels and resulted in inhibition of ovulation and implantation (6). More importantly, 4-OH-A was effective at inhibiting growth of mammary tumors in rats, laying the preclinical groundwork for movement of these inhibitors into clinical use. The Centennial Paper was chosen for its critical role in validating 4-OH-A as an AI in vitro and in vivo and the ability of 4-OH-A to block mammary cancer growth. This work laid the foundation for movement of 4-OH-A to clinical trials and the eventual use of AIs as first-line therapy for early and advanced hormone receptor-positive breast cancer. Although the Brodie’s provided evidence that 4-OH-A was an effective AI, further preclinical work was needed. The rodent model of mammary cancer generally represented growth with premenopausal levels of estrogen, yet AIs were predicted to work best when given to postmenopausal women. To mimic this preclinically using human breast cancer models, Shiuan Chen’s laboratory transfected MCF-7 breast cancer cells with the human aromatase gene and created a model (MCF7/Aro), in which breast cancer cells generated their own estrogen by aromatization of androgens (8). The Brodie lab grew these MCF7/Aro cells in nude mice to create a preclinical model of postmenopausal breast cancer that could be inhibited with AI (9). MCF7 and MCF7/Aro cells have been critical as preclinical models for the study of estrogen, antiestrogen, and AIs and identification of mechanisms of resistance to antihormone therapy (anti-HT), where preclinical results have guided numerous clinical studies (10). The use of anti-HT has changed the outcomes of millions of women with ER-positive breast cancer, with current data showing a 5-year survival from early breast cancer of approximately 99%. Anti-HT is clearly the gold standard for successful targeted therapy in cancer. However, the story is not over. The last 3–4 years have revealed that the gene encoding for ERα (ESR1) is mutated at a relatively high frequency (∼15%–35%) in hormone-resistant advanced breast cancer (11). ESR1 mutations seem to be particularly prevalent in women who have received AI therapy. The concept is that the low levels of estrogen, which can be achieved with third generation AIs, cause clonal selection of rare mutations in ESR1, which cause constitutive activity, and allow breast cancer cells to evade therapy. Basic and translational studies support this concept (11). It is clear that there will be a new wave of studies examining how breast cancers evade AI therapy, and the hope is that this next round of targeted therapies or combinations of therapies, such as AI combined with mTOR or CDK4/6 inhibitors, will show as much success as the development of anti-HT. The Endocrinology manuscript from Angela and Harry Brodie (6) is an exemplary example of the importance of basic, translational, and clinical endocrinology in breast cancer research and how this can have a major impact upon millions of women. Disclosure Summary: The author has nothing to disclose. aromatase inhibitor estrogen receptor hormone therapy 4-hydroxy-4-androstene-3,17-dione.
Source: Endocrinology
DOI: 10.1210/en.2016-1623
Author: Adrian V. Lee
Institutions: University of Pittsburgh, UPMC Hillman Cancer Center
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2509621407