Aromatase inhibitors in breast cancer.
Doctor: Good morning. I’m Dr. Smith. I understand you’ve been experiencing some symptoms that have been concerning you?
Patient: Yes, Doctor. I am 56 y.o. I’ve had pain in my left breast, and I’ve been feeling really tired, nauseous, and I’ve lost some weight without trying.
Doctor: I see. We’ve done some tests, including a mammogram, which showed a 3-cm mass in your left breast. Unfortunately, the biopsy confirmed that it’s adenocarcinoma, a type of breast cancer.
Patient: (upset) Oh no… What does that mean?
Doctor: We’ve also done some additional tests, which showed that the tumor is estrogen receptor-positive and HER2-negative. This information helps us determine the best course of treatment.
Patient: Okay… What’s the treatment plan?
Doctor: We’re going to start you on a medication called Anastrozole. This medication works by blocking the production of estrogen in your body, which can help slow the growth of the tumor.
Patient: How does it do that?
Doctor: Anastrozole is an aromatase inhibitor, which means it blocks the enzyme that converts other hormones into estrogen. By reducing estrogen levels, we can help reduce the size of the tumor and slow its growth.
Patient: Okay, that makes sense. What can I expect from the treatment?
Doctor: We’ll monitor the size of the tumor regularly, and we expect to see a decrease in its size over time. We’ll also be monitoring you for any potential side effects from the medication.
Patient: Alright, thank you, Doctor. I feel a little better knowing what’s going on and what we can do to treat it.
The Role of Aromatase in Estrogen Synthesis
Aromatase, a cytochrome P450 enzyme, plays a crucial role in the biosynthesis of estrogens from androgens, primarily in ovarian granulosa cells, where its expression is regulated by gonadotropins such as follicle-stimulating hormone (FSH) through pathways like cAMP, PI3K, and ERK(Liu et al., 2021). In postmenopausal women, the decline in ovarian estrogen synthesis due to follicular atresia is compensated by extraovarian aromatase activity, particularly in adipose tissue, which becomes the predominant source of estrogen(Zhao et al., 2016). This peripheral aromatization is significant as it maintains low levels of circulating estrogens, which are crucial for various physiological processes, including bone health and metabolic regulation(Merlotti et al., 2011). The expression of aromatase in adipose tissue is influenced by factors such as obesity-related inflammation, with cytokines like IL-10 and CCL2 modulating its activity(Martínez-Chacón, 2020). Despite the reduction in ovarian estrogen production post-menopause, the ovaries and adrenal glands continue to produce androgens, which are then converted to estrogens by aromatase in peripheral tissues(Brodowska et al., 2014). This extraovarian estrogen production is vital for preventing conditions associated with estrogen deficiency, such as osteoporosis and metabolic disorders(“Aromatase in human physiology and pathology: implications of human aromatase deficiency”, 2022) (Merlotti et al., 2011). Furthermore, the regulation of aromatase involves multiple tissue-specific promoters, which are differentially activated in various tissues, including the breast, where shifts in promoter usage can lead to increased estrogen production and cancer risk(Zhao et al., 2016). Understanding the regulation and activity of aromatase across different tissues provides insights into its role in both normal physiology and pathologies related to estrogen imbalance(Nardo et al., 2021) (Wood & Cupp, 2013).
Mechanisms and Efficacy of Anastrozole, Letrozole, and Exemestane
Anastrozole, letrozole, and exemestane are aromatase inhibitors used in the treatment of estrogen receptor-positive breast cancer, each with distinct mechanisms and efficacy profiles. Letrozole has been shown to provide superior suppression of serum estrogens compared to exemestane, as evidenced by a study where letrozole reduced serum estrone (E1) and estradiol (E2) levels more significantly than exemestane in a neoadjuvant setting for breast cancer patients(Bertelsen et al., 2024). Anastrozole, on the other hand, is unique among these inhibitors as it can directly bind to estrogen receptor α (ERα), which is not observed with letrozole or exemestane. This binding capability allows anastrozole to activate estrogen response element-dependent transcription and stimulate growth in certain breast cancer cell lines, suggesting a potential for individualized therapy based on its distinct mechanism(“Data from Anastrozole has an Association between Degree of Estrogen Suppression and Outcomes in Early Breast Cancer and is a Ligand for Estrogen Receptor α”, 2023) (“Data from Anastrozole has an Association between Degree of Estrogen Suppression and Outcomes in Early Breast Cancer and is a Ligand for Estrogen Receptor α”, 2023) (“Data from Anastrozole Regulates Fatty Acid Synthase in Breast Cancer”, 2023). Furthermore, anastrozole has been associated with maintaining fatty acid synthase (FASN) protein levels, which can lead to increased breast cancer cell growth and may contribute to endocrine resistance. This mechanism is not shared by letrozole or exemestane, highlighting anastrozole’s unique pathway that could be targeted in resistant cases(“Data from Anastrozole Regulates Fatty Acid Synthase in Breast Cancer”, 2023) (“Data from Anastrozole Regulates Fatty Acid Synthase in Breast Cancer”, 2023)(“Anastrozole regulates fatty acid synthase in breast cancer”, 2021). In terms of clinical outcomes, a study indicated that higher levels of E1 and E2 after six months of anastrozole treatment were linked to an increased risk of early breast cancer events, emphasizing the importance of monitoring estrogen levels during therapy(Ingle et al., 2020). Additionally, the combination of letrozole or anastrozole with the CDK4/6 inhibitor dalpiciclib has shown promise in prolonging progression-free survival in advanced breast cancer, suggesting a potential enhancement of therapeutic efficacy when used in combination therapies(Zhang et al., 2023). Overall, while all three drugs effectively inhibit aromatase, their differing mechanisms and effects on estrogen suppression and receptor interaction offer varied therapeutic strategies and considerations for personalized treatment in breast cancer management.
