Sequential Treatment with Exemestane and Non-Steroidal Aromatase Inhibitors in Advanced Breast Cancer

Abstract

Background: The steroidal aromatase inactivator exemestane has demonstrated activity after prior failure of non-steroidal aromatase inhibitors (including third-generation inhibitors letrozole and anastrozole) in postmenopausal women with advanced breast cancer. If exemestane is used as first anti-aromatase agent, however, it is unclear whether patients can still benefit from letrozole or anastrozole after progression. Patients and Methods: Postmenopausal patients with advanced, hormone receptor-positive or -unknown breast cancer were eligible for this study. Patients with no prior exposure to anti-aromatase drugs received exemestane, 25 mg daily, as first anti-aromatase agent. At the time of progression, patients were crossed-over to anastrozole or letrozole if further endocrine therapy was considered appropriate. Patients with prior exposure to anti-aromatase agents were also included in the study, and were given anastrozole or letrozole if they had previously received exemestane, or exemestane if they had previously received anastrozole or letrozole. The primary endpoint of the study was the clinical benefit rate (complete response + partial response + stabilization of disease for ≧24 weeks). Results: Forty patients received exemestane 25 mg daily as first anti-aromatase agent, with a CB rate of 67.5% (95% CI 52.9–82.0%) and a median time to progression (TTP) of 9.6 months. In 18 patients, letrozole (n = 17) or anastrozole (n = 1) were used after failure of exemestane: the CB rate was 55.6% (95% CI 32.6–78.5%) with a median TTP of 9.3 months. In 23 patients, exemestane was used after failure of letrozole or anastrozole: the CB rate was 43.5% (95% CI 23.2–63.7%) with a median TTP of 5.1 months. Conclusions: Our study confirms that exemestane is active after prior failure of letrozole or anastrozole. We have also shown that patients can receive exemestane as their first anti-aromatase agent and still benefit from letrozole or anastrozole after progression. This suggests that the partial non-cross resistance between steroidal and non-steroidal anti-aromatase agents is independent of the sequence employed.

Aromatase Inhibitors: Are There Differences Between Steroidal and Nonsteroidal Aromatase Inhibitors and Do They Matter?

“…In general, objective response rates with a second-line AI are not high (0%-26%), but clinical benefit (which includes stable disease of Ն6 months' duration) is observed in 20%- 62% of patients. This effect is observed regardless of the treatment sequence: nonsteroidal AI followed by steroidal AI [48 -56] or steroidal AI followed by nonsteroidal AI [55,57]. It must be noted that these were open-label trials, many of which were single-center studies with a small number of enrolled patients, receiving a range of prior and/or concomitant therapies (e.g., chemotherapy), and at least one study used a higher dose of the second AI than is recommended [51].…”

The breast cancer continuum in hormone-receptor–positive breast cancer in postmenopausal women: evolving management options focusing on aromatase inhibitors

“…Another option for second-line endocrine treatment is fulvestrant, which has been shown to be as effective as anastrozole in patients whose disease progressed during tamoxifen treatment [67] (see above). Several studies have evaluated sequential hormone therapy and found small but consistent response regardless of the order in which therapy was administered [68][69][70]. The recently presented phase III EFECT trial evaluated sequential therapy with an AI compared to fulvestrant [66].…”

“…Interestingly, patients will respond to further endocrine therapy even after their disease has progressed while on tamoxifen [73]. Little cross-resistance has been reported either between the antiestrogens and the AIs or within the group of AIs [68,70,74,75]. Use of drugs such as fulvestrant with a novel mechanism of action may also help to reduce the development of cross-resistance [76].…”

Aromatase inhibitors for breast cancer: different structures, same effects?

“…Therefore, the authors were able to conclude that objective response or durable stable disease achieved by exemestane after ns-AIs could not be explained by enhanced aromatase inhibition. Several publications have addressed this issue, showing that significant benefit can be achieved with exemestane after second-generation and third-generation non-steroidal AIs (Table 5; Geisler et al 1996, Thürlimann et al 1997, HarperWynne & Coombes 1999, Carlini et al 2001, Bertelli et al 2005, Iaffaioli et al 2005, Steele et al 2006. Furthermore, partial non-cross-resistance between steroidal and nonsteroidal AIs may be independent of the sequence employed, according to the results of a small study of sequential treatment with exemestane and non-steroidal AIs in advanced breast cancer (Bertelli et al 2005).…”