Aromatase Inhibitors in Breast Cancer: An Update

Diana E. Lake, MD, Clifford Hudis, MD

Disclosures

Cancer Control. 2002;9(6) 

In This Article

Aromatase Inhibitors vs Tamoxifen

The currently available aromatase inhibitors have been compared with tamoxifen[9,10,11,12,13,14] in randomized trials for the treatment of metastatic disease, as well as with megestrol[8] and the nonselective aromatase inhibitor, aminoglutethimide.

The Target trial[9] was a randomized study comparing anastrozole 1 mg vs tamoxifen 20 mg. Eligibility for this trial included patients with metastatic breast cancers that were ER+ or unknown. Of the 668 patients stud-ied, 340 were randomized to anastrozole and 328 to tamoxifen. More than half had tumors of unknown receptor status. The objective response rate was 33% in both arms; time to progression was 8.2 months in the anastrozole arm and 8.3 months in the tamoxifen arm. No statistically significant difference was demonstrated.

A similar North American study[10] evaluated patients with tumors that were ER+ or ER-/PR+. Of the 353 evaluable patients, 182 were treated with 20 mg of tamoxifen alone and 171 with 1 mg of anastrozole. The response rate was 17% in the tamoxifen arm and 21% in the anastrozole arm, a statistically nonsignificant result. Time to progression was 5.6 months in the tamoxifen arm and 11.1 months in the anastrozole arm (P=.005).

The Barcelona trial[11] evaluated 238 patients who were ER+. The two arms consisted of 40 mg of tamoxifen daily given to 117 patients and 1 mg of anastrozole given to 121 patients. Response rates were not statistically different: 23% in the tamoxifen arm and 34% in the anastrozole arm. However, time to progression was 5 months in the tamoxifen arm vs 9 months in the anastrozole arm (P =.005).

Hence, several randomized trials have confirmed similar or perhaps greater benefit for anastrozole compared with tamoxifen, the "gold standard." In these studies, anastrozole did not appear to be more toxic than tamoxifen, and in many cases it appeared safer.

The European Organization for Research and Treatment of Cancer (EORTC) reported a randomized phase II trial of exemestane vs tamoxifen.[13] Fifty-six patients received 20 mg of tamoxifen, and 56 received 25 mg of exemestane. The response rate for exemestane was 44%, and the response rate for tamoxifen was 14% (P ≥.005).

A trial comparing the aromatase inhibitor letrozole with tamoxifen as first-line treatment for advanced breast cancer (Protocol 025) was reported by Mouridsen et al[12] and subsequently was updated at the San Antonio Breast Conference with a median follow-up of 33 months.[14] The study population consisted of 907 postmenopausal, locally advanced, locoregionally recurrent, or metastatic breast cancer patients with tumors that were ER+ and/or PR+ or unknown. In this double-blind, randomized trial, patients were treated with either tamoxifen 20 mg daily or letrozole 2.5 mg daily and, at the time of progression, had an option to cross over to treatment with the "opposite" drug. If after progression of disease or stopping treatment the patient remained suitable for further endocrine therapy, changing to the alternative treatment in a double-blind fashion was optional (crossover). Crossover upon disease progression occurred in 52% of patients in the letrozole arm and in 50% in the tamoxifen arm. The median time to crossover in the letrozole group was 17 months compared with 13 months in the tamoxifen group. Hence, time to progression, which was the primary endpoint of the study, favored the first-line use of letrozole instead of tamoxifen. Secondary endpoints were overall response rate (ie, a confirmed complete or partial response), duration of objective response, rate of clinical benefit (defined as a confirmed CR or PR or no change for ≥24 weeks), duration of the clinical benefit, time to treatment failure, overall survival, and safety/tolerability. The study arms were evenly populated, with 453 patients using letrozole and 454 using tamoxifen. The groups were well balanced in terms of age, performance status, disease-free survival, dominant sites of disease, and hormone receptor status (65% of patients were hormone receptor-positive for letrozole vs 67% for tamoxifen). Prior chemotherapy and prior adjuvant antiestrogen therapy was 19% on letrozole and 18% on tamoxifen. The median time to progression, which was the primary endpoint, was 9.4 months in the letrozole arm and 6 months in the tamoxifen arm (P =.0001). The percentage of patients progressing was 79% letrozole and 85% tamoxifen, with a hazard ratio of 0.72 (P >=.0001). The time to treatment failure was 9 months in the letrozole arm and 5.7 months in the tamoxifen arm, with a hazard ratio of .73 (P >=.0001). As of September 2001, 11% of patients were still receiving initial treatment of letrozole in the letrozole arm vs 6% in the tamoxifen arm. Response to letrozole was independent of prior adjuvant therapy. Patients in the tamoxifen arm with prior exposure to tamoxifen had low response rates. Letrozole was superior to tamoxifen in the overall response and clinical benefit rate: 32% CR and PR vs 21% (odds ratio, 1.78). Clinical benefit was documented in 50% of patients treated with letrozole and 38% in those treated with tamoxifen, with an odds ratio of 1.62. However, the median duration of response was short. The median time to chemotherapy was 16 months for letrozole and 9 months for tamoxifen (P=.005). The medi-an overall survival was 34 months in the letrozole arm and 30 months in the tamoxifen arm, although the impact of crossover appeared to be significant early on. By 36 months, 99% of the patients had crossed over, and this likely affected the overall survival out-come. With censoring the survival curve at the time of crossover, letrozole was reported to have a median survival of 42 months and tamoxifen 30 months. Of those who did not cross over, median survival for letrozole was 33 months and 19 months for tamoxifen.

Drug toxicity is an important variable in the choice of therapy for stage IV disease, and letrozole and tamoxifen appear similar in terms of nausea, vomiting, and hot flushes. The incidence of hot flushes was 14% with tamoxifen vs 17% with letrozole; nausea was reported in 7% with tamoxifen vs 6% with letrozole. Alopecia and hair thinning were slightly greater with the aromatase inhibitors, which may be due to the increase in circulating androgens with the use of letrozole.[12,14]

Thrombotic events are another area of concern. These events include phlebitis and venous thrombosis of a limb (deep venous thrombosis and superficial venous thrombosis). Considering all of the thrombotic adverse events, the results are similar with tamoxifen and the aromatase inhibitors. Significant adverse thrombotic events occurred at a rate of 1% for letrozole and 2% for tamoxifen.

Combining these data, we can conclude that in postmenopausal patients with ER+ metastatic breast cancer, the overall response rate with aromatase inhibitors is at least as high as -- and sometimes higher than -- tamoxifen, and the time to progression is often longer with aromatase inhibitors than with tamoxifen. Survival is similar, but the toxicity profiles of these endocrine agents tend to favor the aromatase inhibitors.

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