Clinical and Economic Benefits of Aromatase Inhibitor Therapy in Early-stage Breast Cancer

Stefan Glück; Fariborz Gorouhi


Am J Health Syst Pharm. 2011;68(18):1699-1706. 

In This Article

Efficacy Measures

Overall survival is generally accepted as the most reliable efficacy endpoint in patients with breast cancer. However, in the majority of clinical trials, disease-free survival has been the accepted measure of clinical efficacy, particularly when survival may be prolonged, such as in patients receiving adjuvant therapy for early-stage breast cancer, for whom overall survival becomes an impractical endpoint.[14] The disadvantage of disease-free survival is that its definition varies among clinical trials.[15] It has been argued that distant metastasis, a component of disease-free survival, should be a preferred endpoint, particularly because of its strong association with mortality.[16]

Distant metastasis is the most frequent type of first recurrence. In a study of node-positive patients treated with a variety of adjuvant chemotherapy regimens without adjuvant hormonal therapy, 315 of 1973 women experienced a recurrent event.[17] Of these women, 241 (77%) developed distant metastasis alone or concurrently with local disease. In a retrospective analysis of 3614 surgically resected patients treated with tamoxifen, 335 (70%) of the 476 first recurrent events were at distant sites (alone or in combination with locoregional recurrence).[18] The annual distant recurrence rate was 3.4% at 2 years and 3.5% at 3.5–4 years. By contrast, the annual locoregional and contralateral recurrence rates never exceeded 1%.

Distant metastasis is the most deadly type of first recurrence event. Doughty and colleagues[19] found that 476 of 3614 postsurgery tamoxifen-treated postmenopausal patients experienced a recurrence. Of the 344 women who experienced distant metastasis as the first event, 50% died within 7.8 months of recurrence. In total, 260 (76%) died due to distant metastasis. Similarly, in patients treated with surgery and radiotherapy with or without adjuvant systemic therapy (tamoxifen, chemotherapy, or both with ovarian suppression in premenopausal women), the 5- and 10-year survival rates in the 335 patients who experienced distant metastasis as the first event were 22% (95% confidence interval [CI], 18–27%) and 9% (95% CI, 7–13%), respectively.[20] In comparison, the 5- and 10-year survival rates for the 105 patients who developed an isolated local recurrence were 76% (95% CI, 67–83%) and 56% (95% CI, 45–65%), respectively. In a retrospective analysis of data from 1616 women enrolled in a large integrated health care system, 192 patients had recurrent disease.[21] Those whose first event was at distant sites had the highest risk of death compared with those with no recurrence (hazard ratio [HR] = 13.6, p < 0.001) and a median time to all-cause mortality of 41.2 months. This is shorter than the 76.9 and 89.5 months associated with locoregional and contralateral recurrences, respectively. The risk of breast-cancer-related mortality was also higher in women with distant recurrence compared with those with locoregional recurrence (HR = 3.6, p < 0.001). Wiederkehr and colleagues[22] reported that 232 (14%) of 1649 surgically resected breast cancers in postmenopausal women enrolled in a large health care system had a recurrence. Of these, 101 (44%) events occurred at distant sites; 56% of these women died within 1 year, considerably higher than the 14% and 4% mortality rates associated with locoregional and contralateral recurrences, respectively. Thus, it may be beneficial to consider distant metastasis as the first recurrent event an appropriate measure of clinical efficacy.


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