Phase II Single-Arm Study of Preoperative Letrozole for Estrogen Receptor-Positive Postmenopausal Ductal Carcinoma In Situ: CALGB 40903 (Alliance)

Abstract

Purpose: Primary endocrine therapy for ductal carcinoma in situ (DCIS) as a potential alternative to surgery has been understudied. This trial explored the feasibility of a short-term course of letrozole and sought to determine whether treatment results in measurable radiographic and biologic changes in estrogen receptor (ER)-positive DCIS.

Patients and methods: A phase II single-arm multicenter cooperative-group trial was conducted in postmenopausal patients diagnosed with ER-positive DCIS without invasion. Patients were treated with letrozole 2.5 mg per day for 6 months before surgery. Breast magnetic resonance imaging (MRI) was obtained at baseline, 3 months, and 6 months. The primary end point was change in 6-month MRI enhancement volume compared with baseline.

Results: Overall, 79 patients were enrolled and 70 completed 6 months of letrozole. Of these, 67 patients had MRI data available for each timepoint. Baseline MRI volumes ranged from 0.004 to 26.3 cm³. Median reductions from baseline MRI volume (1.4 cm³) were 0.6 cm³ (61.0%) at 3 months (P < .001) and 0.8 cm³ (71.7%) at 6 months (P < .001). Consistent reductions were seen in median baseline ER H-score (228; median reduction, 15.0; P = .005), progesterone receptor H-score (15; median reduction, 85.0; P < .001), and Ki67 score (12%; median reduction, 6.3%; P = .007). Of the 59 patients who underwent surgery per study protocol, persistent DCIS remained in 50 patients (85%), invasive cancer was detected in six patients (10%), and no residual DCIS or invasive cancer was seen in nine patients (15%).

Conclusions: In a cohort of postmenopausal women with ER-positive DCIS, preoperative letrozole resulted in significant imaging and biomarker changes. These findings support future trials of extended endocrine therapy as primary nonoperative treatment of some DCIS.

Trial registration: ClinicalTrials.gov NCT01439711.

FIG 1.

Study schema for CALGB 40903. The overall cohort included 108 patients. Of those enrolled in the study, 28 patients were deemed ineligible to proceed with the study. The most common reasons for exclusion were as follows: baseline magnetic resonance imaging (MRI) not assessable, missing, or volume = 0 (n = 11), no ductal carcinoma in situ (DCIS) found on baseline mammogram (n = 6), baseline mammogram extent < 10 mm or missing (n = 5), invasive or suspected invasive cancer found on central review of MRI (n = 4), and other reasons (n = 2). Three patients had surgery after 3 months of letrozole treatment because of concerns about possible disease progression on the basis of MRI; two patients withdrew because of adverse effects associated with letrozole treatment; and four withdrew for other reasons.

FIG 2.

Spectrum of magnetic resonance (MR)–based response patterns of hormone receptor–positive ductal carcinoma in situ to preoperative letrozole therapy. Patients exhibited variable patterns at baseline and at 3- and 6-month MR imaging timepoints. The predominant radiographic patterns were (A) no response (17.9% at 6 months), (B) partial response (49.2% at 6 months), or (C) complete response to therapy (32.8% at 6 months).

FIG 3.

Waterfall plot: change in MRI enhancement at 6 months by (A) baseline estrogen receptor (ER) H-score and (B) baseline progesterone receptor (PR) H-score.

FIG A1.

Correlation between (A) pathology size and baseline magnetic resonance imaging (MRI) maximum diameter, (B) pathology size and 6-month MRI maximum diameter, (C) 6-month mammogram maximum diameter, and (D) baseline MRI diameter and presurgical mammographic extent of disease. DCIS, ductal carcinoma in situ.