Exemestane Use in Postmenopausal Women at High Risk for Invasive Breast Cancer: Evaluating Biomarkers of Efficacy and Safety

Abstract

This phase II trial evaluated clinical markers of efficacy and safety of exemestane in postmenopausal women at increased risk for breast cancer. Postmenopausal women (n=42) at risk for invasive breast cancer received 25mg exemestane daily for two years along with calcium and vitamin D. The primary outcome was change in mammographic density (MD) after one year. Secondary outcomes included change in serum steroid hormones as well as change in trefoil protein 1 (TFF1) and proliferating cell nuclear antigen (PCNA) in breast tissue. Safety and tolerability were also assessed. MD decreased at 1 year and was significant at 2 years (mean change = −4.1%; 95% CI −7.2, −1.1; p = .009). Serum estradiol and testosterone levels significantly decreased at three months and remained suppressed at 12 months. After 1 year of treatment, TFF1intensity decreased (mean change −1.32; 95% CI −1.87 to −0.76; p < 0.001). Exemestane was safe and well tolerated. Exemestane decreased MD and expression of breast tissue TFF1. It was well tolerated with few clinically relevant side effects. MD and breast tissue TFF1 are potential biomarkers of breast cancer preventive effects of exemestane in high-risk postmenopausal women.

Mammographic density: a potential monitoring biomarker for adjuvant and preventative breast cancer endocrine therapies

“…Of six relevant studies, three uncontrolled studies showed MD reductions with two reaching significance [32, 43, 44]. Three further trials with control arms demonstrated no MD reduction relative to untreated patients, although numbers in all trials were low [45–47].…”

“…Despite the proven therapeutic efficacy of aromatase inhibitors (AIs) in the adjuvant setting [ 42 ], MD has not been observed to change consistently or significantly in response to these agents (Table 2 ). Of six relevant studies, three uncontrolled studies showed MD reductions with two reaching significance [ 32 , 43 , 44 ]. Three further trials with control arms demonstrated no MD reduction relative to untreated patients, although numbers in all trials were low [ 45 – 47 ].…”

Transcriptome analysis of endometrial tissues following GnRH agonist treatment in a mouse adenomyosis model

“…To our knowledge, Tff1, Sprr2a1, and Aldh3b2 have not previously been implicated in adenomyosis. Tff1 is an estrogen response gene that has been reported to be a potential tumor marker in the diagnosis of breast cancer 43–4546 that encodes small proline-rich protein (SPRR)2a, which is a member of the SPRR family.…”

“…Tff1 is an estrogen response gene that has been reported to be a potential tumor marker in the diagnosis of breast cancer. 43 – 45 Sprr2a is an estrogen-responsive gene 46 that encodes small proline-rich protein (SPRR)2a, which is a member of the SPRR family. This binds to and activates SH3 domain-containing proteins, resulting in physiological effects in a broad range of tissues.…”

Variation in the UGT2B17 genotype, exemestane metabolism and menopause-related toxicities in the CCTG MAP.3 trial

“…Exemestane is an aromatase inhibitor (AI) with demonstrated efficacy in reducing the incidence or recurrence of breast cancer in postmenopausal women [1][2][3]. However, menopause-related side-effects due to estrogen suppression from exemestane can limit uptake and adherence.…”