Abstract P1-09-04: Down-regulation of trefoil protein 1(TFF1) in normal breast tissue of postmenopausal women at increased risk for breast cancer on exemestane
Authors: Gatti-Mays M , Kallakury BVS , Makariou E , Venzon D , Permaul E , Isaacs C , Cohen P , Warren R , Gallagher A , Eng-Wong J 
Published: August 2014

Abstract
Background: Aromatase inhibitors (AI) are effective for breast cancer risk reduction in postmenopausal women. TFF1, also known as pS2, is an estrogen response gene present in normal mammary tissue with increased expression in estrogen receptor positive breast cancer. Previous studies have demonstrated down-regulation of TFF1 and Ki-67, a marker of proliferation, in postmenopausal women with locally advanced breast cancer who receive neoadjuvant AIs. TFF1 and proliferating cell nuclear antigen (PCNA) may serve as biomarkers of effect of AIs in women at increased risk for breast cancer.
Methods: We conducted a single-arm phase II trial of exemestane in women at increased risk for breast cancer and examined the impact on TFF1 and PCNA. Postmenopausal women at increased risk for invasive breast cancer by clinical or histological criteria received 25mg of exemestane daily for 2 years. Subjects were required to have stopped any hormonal medication ≥ 3 months prior to enrollment. Image guided breast biopsies targeting dense breast tissue were performed at baseline and at 12 months. Core specimens were obtained under local anesthesia at each time point from the same area of the breast. One core biopsy sample was formalin-fixed, paraffin-embedded and examined for pathologic abnormalities, as well as TFF1 and PCNA. TFF1 was assessed by intensity of stain (0 to 3+) and percent of cells with any staining; PCNA was assessed by percent of cells staining within the tissue section. The pathologist (B.K.) was blinded to the time of biopsy. Change in intensity and % positive cells were evaluated by paired t-test.
Results: Thirty four subjects underwent both baseline & 12 month breast biopsies. Eight biopsies at baseline and 5 biopsies at 12 months did not contain any ductal or lobular tissue and were not analyzed. Twenty-two subjects had evaluable breast tissue at both time points for TFF1 analysis and 23 subjects for PCNA analysis. No high risk lesions or invasive cancers were identified. Of the baseline specimens, 95.5% were positive for TFF1: 59.1% (13 of 22) were scored as 3+(intense), 31.8% (7 of 22) were 2+(moderate) and 4.5% (1 of 22) were 1+(low). Percent of cells staining for TFF1 ranged from 0 to 20% (median = 1%). After 1 year on exemestane TFF1 intensity decreased in 17 subjects (77.3%), 4 had no change and 1 increased. Mean TFF1 change was −1.32 (95% CI −1.87 to −0.76; p &lt; 0.001). The change in % positive cells for PCNA ranged from −15 to +30% (median = 0%).
Discussion: Assessing tissue biomarkers with repeat core needle biopsies in a phase II prevention trial in high risk women is feasible. Since prevention agents are not universally protective, determining biomarkers of effect may allow tailored therapy. TFF1 is a biologically plausible biomarker of AI activity that was down-regulated in 77% of breast tissue following exemestane therapy. This is the first study to evaluate this tissue marker in the prevention setting. Further study is needed to correlate with other biomarkers of interest, e.g. change in mammographic density, serum hormone levels and clinical outcomes.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-09-04.