Variation in baseline estrogen levels, menopause-related adverse events and early study discontinuation among women on the placebo-controlled MAP.3 exemestane prevention trial.

Abstract

BACKGROUND: Breast cancer prevention has been demonstrated using aromatase inhibitors (AIs) including exemestane, but menopause-related adverse events can limit adherence. We hypothesized that estrogens are potential biomarkers that could be measured at baseline to predict the probability of AI-related adverse events. PATIENTS AND METHODS: Estrone (E1) and estradiol (E2) levels were measured from Mammary Prevention 3 trial baseline serum samples (n = 4111) using liquid chromatography with tandem mass spectrometry. Hot flashes, fatigue, and joint pain were assessed using the Common Terminology Criteria for Adverse Events v4.0. Severe toxicity (grade ≥3) and moderate toxicity (grade ≥2) were contrasted with less severe toxicity. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for each symptom (years 1 and 5) and baseline E1 and E2 levels. RESULTS: Women on exemestane with the highest levels of E1 or E2 at baseline were significantly more likely to develop severe hot flashes (E1: ORyr-1 = 3.8, 95% CI 1.6-10.5) and (E2: ORyr-1 = 4.2, 95% CI 1.6-13.1) compared with women in the lowest quartile, with a clear dose-response observed at year 1. Severe joint pain was associated with higher baseline E1 and E2 levels in women on exemestane at year 1 but was only statistically significant for E1 (quartiles 2 and 3). There were no significant associations in the placebo group. Women in the highest quartile of E1 or E2 were significantly more likely to discontinue protocol therapy within the first 12 months, independent of assigned treatment, compared with women in the lowest quartile. CONCLUSIONS: Postmenopausal women with elevated estrogen levels who initiate exemestane are at greater risk for the development of severe hot flashes and joint pain and may benefit from measures to limit early discontinuation.

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