Aromatase inhibitors

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Third-generation AIs (anastrozole, letrozole, and exemestane) act via the inhibition of the cytochrome P450 enzyme aro­matase, which converts androgens into estrogens.24 In meta­static disease, many trials have shown that AIs have great benefits when compared to megestrol acetate. Most of the use of AIs in the preventive setting derives from adjuvant studies in postmenopausal women with early breast cancer.

Adjuvant trials

The use of AIs has been widely investigated in postmenopausal women with early breast cancer (Table 1).25–30 Several differ­ent study designs have been investigated, and most trials used the AI as an initial treatment,27 some used it after 2–3 years of tamoxifen,26,28,30 or as an extended treatment after 5 years of tamoxifen use.29,31 All these trials, irrespective of the study design, have shown a consistent reduction in contralateral breast cancer. Specifically, the Anastrozole, Tamoxifen, Alone or in Combination trial showed that 5 years of anastrozole use significantly improved disease-free survival when compared to tamoxifen,25,32–34 and the updated results confirmed the better efficacy of anastrozole over tamoxifen as initial adjuvant treat­ment in postmenopausal women with early breast cancer.33

Based on these findings, AIs are being routinely used in the treatment of breast cancer. Furthermore, a recently conducted meta-analysis of adjuvant trials with AIs indicated that these agents consistently showed lower recurrence rates when com­pared to tamoxifen, either as initial therapy or after 2–3 years of tamoxifen use.35 This overview provides clear evidence that AIs achieve significant reductions in breast cancer recurrence.

Prevention trials

The use of AIs in the preventive setting has not yet been extensively investigated. Two main prevention trials have reported their results to date. The Mammary Prevention 3 (MAP3) trial compared the steroidal AI exemestane with placebo in postmenopausal women at increased risk of breast cancer, whereas the International Breast cancer Intervention Study-II (IBIS-II) trial investigated the use of anastrozole in a similar population.

The MAP3 trial enrolled over 4,500 postmenopausal women who were at risk of developing breast cancer and ran­domized them to either exemestane or placebo for 5 years. After a median of 35 months of follow-up, 11 invasive breast cancers were found with exemestane versus 32 with placebo, resulting in a 65% reduction of invasive breast cancers with exemestane.36 No effect was seen for ER-negative disease. No statistically significant differences were found between treatment arms for adverse events, suggesting a good risk–benefit profile. How­ever, this trial had some limitations, most importantly the short follow-up period of only 35 months. Due to this immaturity, the MAP3 trial does not allow for any conclusion of the safety and long-term efficacy of this drug. Furthermore, after publications of the results, women on placebo were offered the opportunity to cross-over to exemestane, which does not permit the assess­ment of long-term efficacy of this drug, including overall, and specifically, breast cancer mortality.

The IBIS-II trial compares anastrozole with placebo in postmenopausal women at increased risk of breast cancer. The main results were recently reported after a median of 5 years of follow-up,37 and a highly significant reduction of invasive ER-positive breast cancers was seen with anastrozole compared with placebo in this high-risk population (58%, HR = 0.42 [0.25–0.71]), which was similar to the results reported in the MAP3 trial. As in the MAP3 trial, no effect of anas­trozole was found for ER-negative breast cancer. Vasomotor and musculoskeletal side effects were increased with the use of anastrozole, and these side effects were also reported by many women on placebo. Strengths of the IBIS-II trial were the large number of breast cancers reported and the median follow-up of 5 years. All women remain blinded for long-term follow-up, which is important since overall long-term efficacy of anastrozole, or any other AI, for healthy postmenopausal women at increased risk of breast cancer has not yet been established.

Overall, the reported reductions for both exemestane and anastrozole were larger than those seen for tamoxifen or any other SERMs, and these results indicate that both drugs are attractive options for breast cancer prevention in postmenopausal women at increased risk of the disease. For premenopausal women, the only option remains tamoxifen. Tamoxifen, exemestane, and anastrozole are all out of patent, and registering these drugs for use in the preventive setting will most probably not be marketed. Although approved by several regulatory authorities for the use in the preventive setting, these drugs, despite their effectiveness, are unfortu­nately not widely accepted as breast cancer preventive drugs by high-risk women and their physicians. Reasons for the low uptake of chemopreventive agents, SERMs or AIs, are fear of side effects, general practitioners not being aware of chemopreventive options for high-risk women, and the drug industry not promoting the drugs for primary prevention.