<p>Supplemental Table 1A: Clinical and pathologic characteristics of postmenopausal patients with estrogen receptor-positive breast cancer treated with neoadjuvant aromatase inhibitors at MD Anderson under Z1031 protocol (n = 58) Supplemental Table 1B Biomarkers in the residual tumor Supplemental Table 2: Comparison of Clinical and pathologic characteristics of the MD Anderson cohort and the none-MD Anderson cohort on the Z1031 study. Supplemental Table 3: Ki67, preoperative endocrine prognostic index (PEPI) score, cytoplasmic low molecular weight cyclin E (LMW-E), and cytoplasmic phospho-CDK2 (pCDK2) in postmenopausal patients with estrogen receptor-positive breast cancer treated with neoadjuvant aromatase inhibitors at MD Anderson under Z1031 protocol (n = 58)</p>
ARTICLE ABSTRACT
Purpose: Preoperative aromatase inhibitor (AI) therapy has demonstrated efficacy in hormone receptor (HR)-positive postmenopausal breast cancer. However, many patients have disease that is either intrinsically resistant to AIs or that responds initially but develops resistance after prolonged exposure. We have shown that patients with breast tumors expressing the deregulated forms of cyclin E [low molecular weight forms (LMW-E)] have poor overall survival. Herein, we hypothesize that LMW-E expression can identify HR-positive tumors that are unresponsive to neoadjuvant AI therapy due to the inability of AIs to induce a cytostatic effect.Experimental Design: LMW-E was examined in breast cancer specimens from 58 patients enrolled in the American College of Surgeons Oncology Group Z1031, a neoadjuvant AI clinical trial. The mechanisms of LMW-E–mediated resistance to AI were evaluated in vitro and in vivo using an inducible model system of cyclin E (full-length and LMW-E) in aromatase-overexpressing MCF7 cells.Results: Breast cancer recurrence-free interval was significantly worse in patients with LMW-E–positive tumors who received AI neoadjuvant therapy, compared with those with LMW-E negative tumors. Upon LMW-E induction, MCF7 xenografts were unresponsive to letrozole in vivo, resulting in increased tumor volume after treatment with AIs. LMW-E expression overcame cell-cycle inhibition by AIs in a CDK2/Rb-dependent manner, and inhibition of CDK2 by dinaciclib reversed LMW-E–mediated resistance, whereas treatment with palbociclib, a CDK4/6 inhibitor, did not.Conclusions: Collectively, these findings suggest that cell-cycle deregulation by LMW-E mediates resistance to AIs and a combination of CDK2 inhibitors and AIs may be an effective treatment in patients with HR-positive tumors that express LMW-E. Clin Cancer Res; 23(23); 7288–300. ©2017 AACR.
