Effects of SERMs on important indicators of cardiovascular health: lipoproteins, hemostatic factors, and endothelial function

Management of metabolic complications of long-term adjuvant endocrine therapy in early breast cancer remained an unmet need. We aimed to compare the effects of tamoxifen (TMX) and aromatase inhibitors (AIs) on the risk of fatty liver in conjunction with longitudinal changes in the serum lipid parameters.

Among 1203 subjects who were taking adjuvant TMX or AI (anastrozole or letrozole) without fatty liver at baseline, those taking TMX or AI were 1:1 matched on the propensity score. The primary outcome was newly developed fatty liver detected on annual liver ultrasonography.

Among 328 matched subjects (mean age 53.5 years, body mass index 22.9 kg/m²), 62 cases of fatty liver in the TMX group and 41 cases in the AI group were detected in a total of 987.4 person-years. The incidence rate of fatty liver was higher in the TMX group than in the AI group (128.7 versus 81.1 per 1000 person-years, P = 0.021), particularly within the first 2 years of therapy. TMX was associated with an increased 5-year risk of newly developed fatty liver (adjusted hazard ratio 1.61, P = 0.030) compared with AI independent of obesity and cholesterol level. Subjects who developed fatty liver had higher triglycerides (TGs) and lower high-density lipoprotein cholesterol (HDL-C) level at baseline than those without, which was sustained during follow-up despite the serum cholesterol–lowering effect of TMX.

TMX independently increased the 5-year risk of newly developed fatty liver compared with AI in postmenopausal women with early breast cancer. Our findings suggest the need for considering the risk of fatty liver as a different adverse event profile between AI and TMX, particularly in patients with obesity, high TGs and low HDL-C.

Adjuvant therapy with the third-generation aromatase inhibitors (AIs) anastrozole, letrozole, and exemestane has largely replaced the use of tamoxifen (TAM) as standard adjuvant endocrine treatment for postmenopausal women with hormone-sensitive early breast cancer. Treatment strategies investigated in large, randomized, well-controlled clinical studies include the use of an AI as an upfront replacement for TAM, as an alternative to continued treatment with TAM, and in the extended adjuvant setting after at least 5 years of TAM. The efficacy of AIs over TAM has been demonstrated, particularly in terms of improving disease-free survival (DFS), and reductions in early distant metastasis with AIs may ultimately translate into improved overall survival. As AI therapy offers prolonged DFS, safety is an important concern over the long term. The AIs are better tolerated than TAM in terms of troublesome gynecologic adverse events such as vaginal bleeding and discharge, as well as life-threatening complications such as venous thromboembolic events and endometrial cancer. On the other hand, AI therapy has been associated with losses in bone density and a potential effect on lipids and cardiovascular risk. In trials comparing AIs with TAM, only limited conclusions can be made because of the putative cardioprotective, lipid-lowering, and bone-sparing effects of TAM. Studies comparing AIs with placebo, and/or in healthy women, may be more useful in understanding the long-term safety of adjuvant AI therapy. Results of ongoing safety analyses within some of the large AI trials should provide further insight into the long-term tolerability of AI therapy in the adjuvant setting.

Inhibiting estrogen production is a common means of preventing breast cancer recurrence. The aromatase inhibitors (AIs) are becoming the preferred treatment over tamoxifen as adjuvant therapy for postmenopausal women with hormone-sensitive early breast cancer. Like all adjuvant therapies, AIs have adverse events (AEs) associated with their use, many of which resemble symptoms common to menopause. Because of the greater efficacy of AIs in preventing breast cancer recurrence over tamoxifen, these AEs may be considered tolerable by many patients and often can be effectively managed and/or prevented. Educating patients about anticipated AEs may help them understand, accept, and cope with these AEs. This article reviews the AEs associated with different adjuvant AI treatments and highlights some strategies to manage them effectively. It also highlights the importance of patient education regarding AI therapy and involvement in treatment decisions, which may lead to better long-term adherence and ultimately to better outcomes.

Adjuvant endocrine therapy plays an important role in the management of hormone-receptor-positive early breast cancer, and has increased life expectancy for millions of women. Many patients receive adjuvant treatment for at least 5 years following tumor resection, hence good long-term safety is important for endocrine agents to gain widespread acceptance. Tamoxifen has been used as adjuvant therapy for early breast cancer for many years, and safety data have been well documented, but a poor risk:benefit profile limits treatment duration to 5 years. Increased efficacy over tamoxifen and good tolerability have recently made the third-generation aromatase inhibitors (AIs) the first-choice agents for adjuvant endocrine therapy; however, it is currently not known whether AI therapy, like tamoxifen, will be limited to 5 years. Many side effects of endocrine therapy, such as hot flushes and mood disturbances, are related to estrogen deprivation and are common to tamoxifen and AIs, reflecting the mechanism of action of these drugs. In addition, tamoxifen has estrogenic effects that are beneficial in some tissues: tamoxifen lowers serum cholesterol levels and protects against bone loss and cardiovascular disease, but is also associated with potentially life-threatening side effects, such as endometrial cancer and thromboembolic disease. As AIs lack estrogenic activity, they are not associated with these serious adverse events. Clinical trials comparing AIs with tamoxifen in the adjuvant setting have shown that AIs are well tolerated and are associated with a lower incidence of gynecological symptoms and hot flushes than tamoxifen. However, AIs are associated with musculoskeletal side effects, such as arthralgia, myalgia and bone loss, but these events are preventable or manageable. The effects of AIs on lipid metabolism and the cardiovascular system are still debatable, but placebo-controlled trials provide no evidence to suggest that AIs adversely affect these systems. Furthermore, the AIs allow women to maintain a good quality of life, comparable with women receiving tamoxifen or placebo, and are a cost-effective therapeutic option. Ongoing trials will provide more information regarding the long-term effects of AI therapy and will provide comparative data on the efficacy and safety of the different AIs, thereby helping to determine the optimal treatment strategy for these highly effective and well-tolerated drugs.

Following primary treatment for early breast cancer, systemic adjuvant therapy is given to reduce the risk of recurrence by targeting any undetectable micrometastatic deposits. Adjuvant systemic treatment may include endocrine therapy, chemotherapy and antibody therapy, depending on the presence or absence of hormone receptors, HER2 status and the estimated risk of relapse. In recent years, an increasing number of tumor characteristics have been identified that influence the risk of relapse and the likelihood of achieving the desired outcome with a given therapy. Hence, choosing the optimum therapy for early breast cancer is becoming an increasingly complicated task. Decision tools have been developed that can be used by physicians to select the most appropriate therapy on an individual basis. Treatment recommendations are, therefore, based on available data from a large number of sources. Hormone-receptor positivity (HR+) is the primary factor when considering whether or not patients should receive adjuvant endocrine therapy. For several decades, tamoxifen has been the gold standard of endocrine therapy, and has significantly reduced recurrences and deaths among the millions of women with HR+ breast cancer worldwide. However, prolonged use of tamoxifen is associated with potentially life-threatening side effects, and resistance is a common problem. In fact, many women will experience disease relapse while on tamoxifen. In particular, the peak of early relapses that occurs in the first 2–3 years after surgery is not prevented by tamoxifen. The third-generation aromatase inhibitors (AIs), letrozole, anastrozole and exemestane, have recently been shown to significantly improve outcomes compared with tamoxifen in large, randomized, controlled trials; however, how the AIs should be incorporated into adjuvant therapy to optimize outcomes requires further investigation. Clinical differences between the AIs, and whether tumor estrogen/progesterone receptor status and HER2 overexpression affect the response to AI therapy, are among the questions that remain to be answered. Ongoing and future studies will help to address these questions and, together with improved patient and disease profiling, will help physicians to optimize adjuvant treatment for individual patients.

Systemic adjuvant therapy has proven highly effective at reducing recurrences and deaths in patients who have received primary therapy for early breast cancer. However, as with all treatments, adjuvant therapy can cause unwanted side effects, and effective management of these events is essential to ensure that patients comply with, and continue, treatment. Adjuvant endocrine therapy is not associated with the more severe, acute toxicities of chemotherapy, and can therefore be taken for many years. At present, the standard duration of postoperative adjuvant endocrine therapy is 5 years. Prevention and treatment of adverse events associated with long-term endocrine therapy is particularly important in the adjuvant setting, where patients are clinically cancer free. In this situation, the efficacy benefits are not, therefore, obvious to the patient, but side effects may have a negative impact on daily life. Tamoxifen has been the gold standard endocrine therapy for hormone-receptor-positive early breast cancer for many years, and the long-term side effects of this agent are well documented. In recent years, the aromatase inhibitors (AIs) have begun to displace tamoxifen as the adjuvant therapy of choice, owing to greater efficacy and good tolerability. Predictably, the AIs and tamoxifen have partially overlapping side-effect profiles. Both therapies are associated with typical symptoms of estrogen deprivation; however, tamoxifen also has estrogenic activity in some tissues, which can cause either detrimental (genital tract) or beneficial (bone, cardiovascular system, lipids) effects that are not associated with AI use. To reduce treatment discontinuations, it is important that patients are made aware of the possible side effects of adjuvant therapy and the management strategies available to them, prior to starting therapy. The role of physical, alternative and pharmaceutical therapies in the management of adverse events associated with endocrine therapy has been investigated, and strategies are now available to alleviate symptoms and enable patients to benefit from adjuvant endocrine therapy without a significant adverse impact on quality of life.