Side Effects with Aromatase Inhibitors
Abstract & Commentary
By Leon Speroff, MD, Editor, Professor of Obstetrics and Gynecology, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.
Synopsis: The risk of cardiovascular events is increased in women receiving aromatase inhibitors compared with tamoxifen for early breast cancer.
Source: Cuppone F, et al. Cancer. 2008;112:260-267.
Cuppone and colleagues primarily from the Regina Elena National Cancer Institute in Rome, Italy, performed a meta-analysis of randomized trials comparing aromatase inhibitors with tamoxifen in early breast cancer, focusing on cardiovascular risk.1 The meta-analysis included 7 randomized trials with a total of 19,818 patients. The relative risk for cardiovascular adverse events with aromatase inhibitors was 1.31 (CI=1.07-1.60). The number of patients needed to harm 1 patient was 189. There was a 47% reduced risk of thromboembolic events with aromatase inhibitors, RR=0.53, CI=0.42-0.65. The authors concluded that the risk for cardiovascular events was relatively low
Commentary
Randomized trials have demonstrated the superiority of aromatase inhibitors compared with tamoxifen for the treatment of hormone-sensitive early breast cancer. The superiority includes better disease-free survival, a reduction in new contralateral primary tumors, and an increased time to recurrence. Because of this superiority, the standard has shifted from tamoxifen to aromatase inhibitors. Current recommendations state that postmenopausal women with hormone-sensitive breast cancers should be treated with an aromatase inhibitor, women on tamoxifen should be switched to an aromatase inhibitor, and women who have finished a course of tamoxifen should consider a course of treatment with an aromatase inhibitor.
Because tamoxifen is both an estrogen agonist and antagonist, it is associated with increases in estrogen-related side effects such as endometrial abnormalities, including cancer, and venous thromboembolism. Aromatase inhibitors have an advantage of being free of these estrogenic side effects; however, the inhibitors have the potential to increase the risks of problems related to estrogen deficiency.
The aromatase enzyme is present in the stromal tissue of normal and abnormal breast tissue, and in breast epithelial cells. Growth stimulation of hormonally sensitive breast cancer is believed to be influenced by local estrogen synthesis in adjacent stromal cells, an activity that is increased in a paracrine fashion when malignant cells activate aromatase gene promoters. This stromal activity is the specific target for aromatase inhibition, but the inhibitors affect estrogen production throughout the body, reducing total body aromatization of precursors by 97% to 99%.
The side effect problems, therefore, arise from the fact that aromatase inhibitors nearly completely inhibit total body production of estrogen in postmenopausal women, with a somewhat lesser effect in premenopausal women. It is not surprising that this severe estrogen deficiency over a 5-year period should cause some major problems. Besides hot flushing, the major side effects are reduced sexual function, arthralgia, myalgia, an increase in fractures, and an increase in cardiovascular events.
The increase in cardiovascular disease reflects the absence of a beneficial influence of estrogen on the lipid profile and on important vascular epithelial functions such as nitric oxide synthesis. The current study suggested that this was a relatively low risk, but the actual risk will not be known until the ongoing trials comparing aromatase inhibitors to placebo treatment are completed. Furthermore, it is inadvisable to consider only one of the estrogen deficiency side effects. The overall impact on a patient will be determined by the additive effects on all estrogen target tissues. The effect on cognition and the risk of Alzheimer's disease is a major issue yet to be addressed.
Adequate calcium and vitamin D supplementation is essential in women being treated with aromatase inhibitors, and if bone loss occurs, treatment with a bisphosphonate is indicated. Hot flushing is best treated with fluoxetine (Prozac), paroxetine (Paxil), venlafaxine (Effexor), or the new extended-release form of the major metabolite of venlafaxine, desvenlafaxine succinate (Pristiq). Gabapentin (Neurontin) is also an acceptable treatment. However, all of these agents are less effective than estrogen treatment. Similar symptomatic treatment is indicated for the problems of joint and muscle complaints. Lifestyle changes that maximize an emphasis on diet and exercise should not be neglected. Nevertheless, it is likely that a price will have to be paid to gain the benefit of effective adjuvant treatment for breast cancer. The magnitude of that price can be expected to vary from individual to individual, and a precise estimate will require longer follow-up of the women who participated in the clinical trials.
Reference
- Cuppone F, et al. Cancer. 2008;112:260-267.
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