Pathologic and biologic response to preoperative endocrine therapy in patients with ER-positive ductal carcinoma in situ

Abstract

Background: Endocrine therapy is commonly recommended in the adjuvant setting for patients as treatment for ductal carcinoma in situ (DCIS). However, it is unknown whether a neoadjuvant (preoperative) anti-estrogen approach to DCIS results in any biological change. This study was undertaken to investigate the pathologic and biomarker changes in DCIS following neoadjuvant endocrine therapy compared to a group of patients who did not undergo preoperative anti-estrogenic treatment to determine whether such treatment results in detectable histologic alterations.

Methods: Patients (n = 23) diagnosed with ER-positive pure DCIS by stereotactic core biopsy were enrolled in a trial of neoadjuvant anti-estrogen therapy followed by definitive excision. Patients on hormone replacement therapy, with palpable masses, or with histologic or clinical suspicion of invasion were excluded. Premenopausal women were treated with tamoxifen and postmenopausal women were treated with letrozole. Pathologic markers of proliferation, inflammation, and apoptosis were evaluated at baseline and at three months.Biomarker changes were compared to a cohort of patients who had not received preoperative treatment.

Results: Median age of the cohort was 53 years (range 38-78); 14 were premenopausal. Following treatment, predominant morphologic changes included increased multinucleated histiocytes and degenerated cells, decreased duct extension, and prominent periductal fibrosis. Two postmenopausal patients had ADH only with no residual DCIS at excision. Postmenopausal women on letrozole had significant reduction of PR, and Ki67 as well as increase in CD68-positive cells. For premenopausal women on tamoxifen treatment, the only significant change was increase in CD68. No change in cleaved caspase 3 was found. Two patients had invasive cancer at surgery.

Conclusion: Preoperative therapy for DCIS is associated with significant pathologic alterations. These changes may be clinically significant. Further work is needed to identify which women may be the best candidates for such treatment for DCIS, and whether best responders may safely avoid surgical intervention.

Trial registration: ClinicalTrials.gov NCT00290745.

Figures

Figure 1

Histology of baseline (A, C, E) and endocrine-treated (B, D, F) DCIS from patient H-20 (magnification: 100×). A, B: H&E stain of baseline (A) and treated (B) samples. The treated DCIS is less distended and demonstrates increased periductal sclerosis and inflammation compared to baseline. C, D: Ki67; reduction in Ki-67 after treatment compared to baseline; E, F: CD68 (inset: 400×); increased CD68-positive macrophages after treatment compared to baseline.

Figure 2

Changes in Ki67 labeling index (A, B) and CD68-positive macrophage count (C, D) between baseline and treated DCIS. There was significant reduction in Ki67 in premenopausal cases (p = 0.04) and in postmenopausal cases (p = 0.01). Similarly, CD68-positive macrophage density increased in both premenopausal (p = 0.002) and in postmenopausal cases (p < 0.0001). Significance was determined by the rank-sum test comparing treated to baseline values.