Long-Term Toxicities of Selective Estrogen-Receptor Modulators and Antiaromatase Agents

Hormonal therapies have long played an important role in the treatment of metastatic and early-stage breast cancer. After demonstrating equivalent efficacy and less toxicity than high-dose estrogen, tamoxifen(Drug information on tamoxifen)-a selective estrogen-receptor modulator (SERM)-has been widely used for the treatment of metastatic breast cancer.[1] Multiple randomized adjuvant trials subsequently demonstrated that patients treated with tamoxifen experienced fewer breast cancer recurrences, leading to its widespread use in the adjuvant setting.[2] In women with ductal carcinoma in situ, tamoxifen reduced the incidence of subsequent invasive and noninvasive cancers.[3] Finally, the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial demonstrated that tamoxifen could reduce a woman's likelihood of being diagnosed with breast cancer.[4] The benefits derived from a course of treatment with tamoxifen are quite clear, but they must be considered in light of potential side effects. Because of its size and its doubleblinded nature, the NSABP P-1 trial represents the most definitive source of toxicity data for tamoxifen. The trial demonstrated an increased risk of uterine cancer, cataracts, and venous thromboembolic events in tamoxifen-treated women as compared to placebo. There was also a nonsignificant increase in stroke risk in the tamoxifen group, mostly in women over age 50. Additionally, the drug was found to cause an increase in uncomfortable hot flashes, genitourinary symptoms, and difficulty with sexual functioning.[5] Agents Developed After Tamoxifen
Raloxifene(Drug information on raloxifene) (Evista), another SERM, is currently approved by the US Food and Drug Administration (FDA) for the prevention and treatment of osteoporosis. In the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, a lower than expected number of breast cancers developed in the raloxifene arm, suggesting that the drug may have efficacy in terms of breast cancer risk reduction.[6] These results led to the ongoing Study of Tamoxifen and Raloxifene (STAR), which is randomizing highrisk postmenopausal women to tamoxifen vs raloxifene for breast cancer prevention. However, raloxifene has not been effective in the treatment of metastatic breast cancer, and the drug is not currently indicated for use in treatment or risk reduction of breast cancer. Anastrozole(Drug information on anastrozole) (Arimidex), letrozole (Femara), and exemestane(Drug information on exemestane) (Aromasin), the three third-generation aromatase inhibitors available in the United States, have gained FDA approval for the treatment of metastatic breast cancer. Anastrozole has also been approved for use in the adjuvant setting. These drugs prevent the peripheral conversion of adrenal androgens into estrogen, leading to a marked reduction in estrogen levels in postmenopausal women. In recent years, the third-generation aromatase inhibitors have been used increasingly in the treatment of women with metastatic breast cancer. Short-term toxicity data indicate that all three agents are well tolerated.[ 7-9] Given the relatively short duration of therapy in the advanceddisease setting, long-term toxicity data are not available from trials in women with metastatic breast cancer. Ultimately, the adjuvant trials will provide long-term toxicity data for women who have taken an aromatase inhibitor for 5 years, but at this time, no study is sufficiently mature to provide this much-needed information. Difficult Comparison
In their review article in this issue of ONCOLOGY, Mortimer and Urban compare the long-term toxicities of the aromatase inhibitors and the selective estrogen-receptor modulators. This comparison is made difficult by the relative paucity of long-term toxicity data for the aromatase inhibitors, especially for the drugs letrozole(Drug information on letrozole) and exemestane. As the authors point out, most of the available data comes from trials in the metastatic setting, in which women were treated with these agents for relatively short periods of time. To make up for this, the authors have provided important preclinical and/ or preliminary data. Although such data are extraordinarily useful for hypothesis generation, they cannot substitute for rigorous clinical data. The Anastrozole, Tamoxifen Alone or in Combination (ATAC) trial supplies the only data we have regarding the long-term use of the aromatase inhibitors.[10] This trial randomized postmenopausal women with early-stage breast cancer to anastrozole, tamoxifen, or the combination of the two. Anastrozole gained FDA approval for use in the adjuvant setting based on the efficacy results from this trial, which showed that at 33 months' follow-up, patients in the anastrozole arm displayed significantly superior disease-free survival and a significantly lower incidence of contralateral breast cancers than did the tamoxifen arm. ATAC toxicity data revealed that uterine cancer, hot flashes, venous thromboembolic events, and ischemic cerebrovascular events were significantly more common in the tamoxifen group, whereas osteopenia and fractures were significantly more common in the anastrozole group. In a substudy looking at quality of life, there were no overall differences between the groups in quality-of-life measures, but there was a suggestion of more sexual side effects in women treated with anastrozole.[11] Effects on Bone
Prior studies have also suggested that the aromatase inhibitors and tamoxifen have different effects on bone mineral density and fracture risk. Data suggest that the effect of tamoxifen on bone mineral density depends on menopausal status, with postmenopausal women experiencing a positive impact on bone density and premenopausal women tending to experience bone loss when treated with this agent.[12] Love et al demonstrated a significant increase in bone mineral density in postmenopausal women with node-negative breast cancer treated with tamoxifen compared to those treated with placebo.[ 13] The NSABP prevention study demonstrated a nonsignificant reduction in hip, radius, and spine fractures in women treated with tamoxifen compared to those treated with placebo.[4] However, these groups were not separated by menopausal status. Of note, tamoxifen does not have an indication for the prevention or treatment of osteoporosis. The aromatase inhibitors effectively lower estrogen levels in postmenopausal women to below the lower limits of detection in most assays. The ATAC trial represents the only data to date concerning the longterm effects of aromatase inhibitors on bone density. At 33 months' median follow-up, there were significantly more fractures in the anasedtrozole group than in the tamoxifen group.[10] This increase in fracture risk was also seen in the updated toxicity analysis. Further work will be necessary to fully quantify the fracture risk in patients treated with anastrozole, as well as to develop strategies to prevent this complication. Studies looking at the use of bisphosphonates to reduce the risk of osteopenia and fractures in women treated with aromatase inhibitors are currently in progress. There is currently almost no clinical information regarding the effect of letrozole or exemestane on bone density, especially after prolonged administration of the drugs. Further conclusions regarding the effect of these agents on bone density cannot be drawn until data from adjuvant studies using these drugs becomes available. Cardiovascular Effects
The authors also discuss differences in cardiovascular mortality among patients treated with tamoxifen and the aromatase inhibitors. Postmenopausal hormone-replacement therapy and tamoxifen have both been shown to have a beneficial effect on lipid profiles, which was believed to lead to a reduction in cardiovascular mortality. With the results of the Women's Health Initiative[14] and the Heart and Estrogen/ Progestin Relacement Study (HERS),[15] estrogen-replacement therapy is no longer believed to be beneficial in the primary or secondary prevention of heart disease. Likewise, the NSAPB P-1 prevention trial has not suggested a reduced risk of cardiovascular disease in patients treated with tamoxifen.[4] Furthermore, the Early Breast Cancer Trialists' overview analysis examined the rates of non-breast/endometrial cancer-related deaths and found no difference between tamoxifen and placebo groups.[2] A subanalysis of only cardiovascular deaths again revealed no differences between the groups. Conclusions
As the authors point out in their conclusion, the majority of postmenopausal women with hormone receptor- positive, early-stage breast cancer will die of other causes. After many thousands of patient-years of experience with tamoxifen, the side-effect profile of this drug is well understood. Early evidence suggests that the aromatase inhibitors probably avoid some of the more serious toxicities associated with tamoxifen use, such as uterine cancer and venous thromboembolism. However, there is virtually no information available concerning the side effects of these agents when they are used for 5 years. Clinicians and patients alike await the availability of long-term toxicity data. This information will be indispensable as postmenopausal women and their physicians consider adjuvant treatment decisions in the years ahead.