Neoadjuvant exemestane or exemestane plus docetaxel and cyclophosphamide tailored by clinicopathological response to 12 weeks' exemestane exposure in patients with estrogen receptor-positive breast cancer: A multicenter, open-label, phase II study

Abstract

Our aim was to investigate the efficacy and safety of initial neoadjuvant endocrine therapy with exemestane alone followed by tailored treatment, either continued exemestane monotherapy or exemestane plus docetaxel-cyclophosphamide (TC) combination therapy, in postmenopausal patients with primary invasive estrogen receptor-positive, human epidermal growth factor receptor 2-negative, stage I-IIIA breast cancer and Ki67 labeling index ≤30%. In this open-label phase II study, patients initially received exemestane 25 mg/d for 12 weeks. Responders were defined as patients who achieved complete response (CR), partial response (PR) with Ki67 labeling index ≤5% after treatment, or stable disease with Ki67 labeling index ≤5% both before and after treatment. For the subsequent 12 weeks, exemestane monotherapy was continued for responders (group A), whereas nonresponders received exemestane plus four cycles of TC (docetaxel 75 mg/m² and cyclophosphamide 600 mg/m² every 3 weeks) (group B). Clinical response rate (ie the proportion of patients with CR or PR) at 24 weeks was the primary endpoint. Of 64 patients provisionally enrolled between December 2010 and May 2016, 58 (median age 60 years) started the study treatment. Five patients discontinued treatment in the initial exemestane monotherapy period, and 39 completed the study treatment. Clinical response rates at 8-12 and 24 weeks were 71% (10/14, 95% confidence interval [CI] 41.9%-91.6%) and 57% (8/14, 95% CI 28.9%-82.3%), respectively, in group A, and 16% (4/25, 95% CI 4.5%-36.1%) and 56% (14/25, 95% CI 34.9%-75.6%), respectively, in group B. Grade ≥3 adverse events were reported in 8% (1/15) and 53% (20/38) in group A and group B, respectively. The tailored treatment maintained the favorable clinical response to exemestane alone in responders and improved clinical response in nonresponders. TRIAL NUMBER: UMIN000004752 (UMIN Clinical Trials Registry).

Keywords: Ki67 labeling index; aromatase inhibitors; breast neoplasms; docetaxel and cyclophosphamide; tailored therapy.

Figure 1

Study design. ^†Responders were defined as patients with complete response, partial response with Ki67 labeling index <5% after treatment, or stable disease with Ki67 labeling index <5% before and after treatment. PD, progressive disease

Figure 2

Patient disposition during the study. AE, adverse event

Figure 3

Waterfall plots showing clinical response to exemestane‐based neoadjuvant therapy at 8‐12 wk and 24 wk in patients who responded to initial treatment with exemestane alone and who continued to receive monotherapy (group A), and nonresponders, who were switched to exemestane plus docetaxel–cyclophosphamide (group B). Results obtained by (A) ultrasound and (B) computed tomography or magnetic resonance imaging. The horizontal axes indicate paired data from individual patients for whom data were available. The vertical axes show percentage change in tumor size from baseline; positive values indicate tumor progression, and negative values indicate tumor regression

Figure 4

Change in median Ki67 labeling index in patients who responded to initial treatment with exemestane alone and who continued to receive exemestane monotherapy (group A), and nonresponders, who were switched to combination therapy with exemestane plus docetaxel–cyclophosphamide (group B). Data from the full analysis set. *indicates extreme outliers

Figure 5

Change in Ki67 labeling index over the course of the study in individual patients in (A) group A (continued exemestane monotherapy) and (B) group B (exemestane plus docetaxel–cyclophosphamide). Baseline data from the full analysis set