A randomized presurgical trial of alternative dosing of exemestane in postmenopausal women with early-stage ER-positive breast cancer.

Abstract

519 Background: Successful therapeutic cancer prevention requires definition of the minimal effective dose of the proposed agent. Aromatase inhibitors substantially decreased breast cancer incidence in high risk postmenopausal women in phase III trials but their clinical use in prevention and adherence in adjuvant setting is limited by adverse events. We conducted a randomized presurgical phase IIb trial to evaluate two alternative doses of exemestane. Methods: We conducted a multi-center, pre-surgical, double-blind, 3-arm, non-inferiority phase IIb study in postmenopausal women with histologically confirmed estrogen receptor (ER)-positive breast cancer. Patients were randomized to receive either exemestane 25 mg/day (QD), or 25 mg/three times/week (TIW), or 25 mg once a week (QW) for 4-6 weeks before surgery. Blood and tissue biomarkers were collected at baseline and final visit. The primary aim was a non-inferiority percent change of circulating estradiol relative to the standard dose. Secondary endpoints were the change in Ki-67 and PgR expression in cancer tissue, blood sex hormones, lipid profile, toxicity and menopausal symptoms. For the power calculation we assumed a non-inferiority difference of 6% in the percentage change of estradiol among arms, using a one-sided, two-sample t-test. Assuming a 10% drop-out rate, a total sample size of 180 participants (60 per arm) had 80% power to detect a 6% margin of equivalence. The significance level for the main endpoint was 0.025 to account for multiple comparisons and 0.05 for secondary endpoints. Results: A total of 230 women were screened, 180 agreed to participate and 173 were evaluable for response. The median percent change of estradiol was -98%, -98%, and -70% for exemestane QD (n = 56), TIW (n = 57), and QW (n = 60), respectively, showing no significant difference between QD and TIW arms (p = 0.9). Similarly, no differences were observed for estrone, total estrone and estrone sulfate between QD and TIW arms. The QW arm showed some modulation in all hormones, even though less significantly so. Among the secondary endpoints, Ki-67 and PgR were reduced in all arms, with a median change of -5% vs -7.5% for Ki-67(p = 0.124), and -9 vs -17 for PgR (p = 0.246) in the TIW vs QD arms, respectively. SHBG and HDL-cholesterol had a more favorable profile with the TIW dose compared to the daily dose. Adverse events, measured according to the CTCAE (v4), and menopausal symptoms according to MENQOL were similar in all arms, but the short treatment time may not be representative. Conclusions: Exemestane 25 mg TIW retains a comparable activity than 25 mg QD. This activity was similar in both arms throughout the primary and the main secondary endpoints. This new schedule should be further assessed in prevention studies and in women on adjuvant treatment who do not tolerate the daily dose. Clinical trial information: NCT02598557.

Validation Study on Risk-Reduction Activities after Exposure to a Personalized Breast Cancer Risk-Assessment Education Tool in High-Risk Women in the WISDOM Study

“…48 In addition, new evidence suggests a lower dose of an AI is likely to be just as effective in lowering serum estradiol. 49 Limitations Our study has several limitations. First, the COVID-19 pandemic began during our data collection process, so results may be confounded by the public health crisis.…”

Targeting nuclear hormone receptors for the prevention of breast cancer

“…To alleviate the unwanted side effects, low-dose exemestane trials are currently in progress. A recent phase IIb trial in postmenopausal women with early stage breast cancer demonstrated that exemestane given three days a week is not inferior to daily dosing [NCT02598557 ( 88 )]. Future comparison studies of low-dose exemestane and low-dose tamoxifen in the prevention setting are needed.…”