Aromatase Inhibitors in Breast Cancer: An Update

Diana E. Lake, MD, Clifford Hudis, MD


Cancer Control. 2002;9(6) 

In This Article

Aromatase Inhibitors and HER2 Overexpression

Several provocative observations have addressed the potential interaction between HER2 expression level and response or benefit from hormonal treatment for breast cancers.[31,32,33,34,35,36] Ellis et al[34] reported a randomized neoadjuvant trial comparing preoperative tamoxifen with preoperative letrozole. Thirty-nine patients had HER1 or HER2 overexpressing tumors, and the response to treatment was 69% in the letrozole-treated group vs 17% in the tamoxifen-treated group. Further subanalysis of the hormone receptor-positive plus HER1- or HER2-positive patients was associated with an 88% response to letrozole and a 21% response to tamoxifen.

Lipton[35] reported a retrospective serum analysis from a trial of letrozole vs tamoxifen for metastatic breast cancer. Twenty-nine percent of the patients had elevated serum levels of HER2, defined as an extracellular domain concentration of greater than 15 ng/mL. Overall response rate, clinical benefit, and time to treatment failure were reduced in patients with increased HER2 levels in contrast to those with normal levels. In patients with elevated levels, there appeared to be no difference in any outcome measured for patients treated with letrozole or tamoxifen. Lipton and colleagues[37] recently published a larger analysis of serum from 719 patients who had been randomized in three comparable second-line endocrine therapy trials. Results have lent further support to the conclusion that HER2 is a molecular marker that predicts decreased response to hormonal therapy in breast cancer. In this study, all patients had metastatic disease. Hormonal therapy received included megestrol acetate vs fadrozole (in two studies) and megestrol acetate vs letrozole (in one study). The overall chance of achieving a clinical benefit from hormonal therapy was noted to be lower by 50% if serum levels of extracellular domain were elevated (ie, >15 ng/mL). The response rate (CR, PR, and stable disease) was 23% for those with elevated serum HER2 vs 45% for those with normal levels. The median response duration was 11.7 months in patients with elevated serum HER2 levels and 17.4 months in those with normal levels. The time to progression and the time to treatment failure were also significantly shorter (3 vs 6 months, P<.0001) in the patients with elevated levels. The mechanism of action for this effect is being studied. Lipton et al[37] offer as a possible mechanism of action the enhanced phosphorylation of both serine and tyrosine residues in the ER, as well as the activation of the RAS/MAPK signaling pathway in breast cancer with HER2 overexpression. Both of these may interfere with the inhibitory effect of tamoxifen on ER transcription.

Colomer et al[36] reported a prospective trial addressing this issue. Eligible patients were postmenopausal, with tumors that were ER+ or PR+. All of the patients had prior tamoxifen exposure. The endpoint of this study was time to treatment failure on letrozole in HER2 overexpressors in contrast to HER2 nonoverexpressors. The serum level of the extracellular domain was considered positive if it was 30 ng/mL or greater. Of the 211 evaluable patients, 16 (8%) had HER2 overexpression. Time to treatment failure was 5.6 months in HER2-overexpressing patients and 11.6 months in HER2-normal patients (P=.005), which is consistent with the possibility that HER2 expression influences the amount of benefit from hormonal treatment.

In situations where an aromatase inhibitor is selected for use, a difficult question concerns which agent is preferred among the three available -- anastrozole, letrozole, or exemestane. One trial designed to answer this question is ongoing and needs further analysis. The trial FEMINT-01[38] enrolled 713 postmenopausal, hormone receptor-positive women with metastatic or locally advanced breast cancer after failure on tamoxifen. These patients were randomly assigned to treatment with letrozole 2.5 mg per day (356 patients) or anastrozole 1 mg daily (357 patients). For the primary endpoint (time to treatment failure), no difference was seen. For one secondary endpoint (response rate), there was an advantage for letrozole, although this was only seen in the slight majority of patients whose tumors had unknown receptor status. In receptor-positive patients, anastrozole and letrozole had comparable antitumor activity. The significance of this result in communities where knowledge of receptor status is nearly 100% is uncertain. Currently, there is no clearly demonstrated difference in efficacy between these two nonsteroidal aromatase inhibitors.

Provocative preclinical data suggest that exemestane, the steroidal aromatase inhibitor, may protect against bone mineral loss.[23] If confirmed in ongoing clinical trials, this may be an important criterion in selecting among these agents in the adjuvant setting. On the other hand, infrequent dosing with an intra-venous bisphosphonate, or continued use of an oral one, may mitigate the negative impact of any of the aromatase inhibitors on bone metabolism.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.