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Introduction: Preclinical data supports antitumor activity of tyrosine kinase inhibitor vandetanib with Ret as the therapeutic target in breast cancer. We investigated the effect of preoperative vandetanib on markers of proliferation and apoptosis in breast cancer., Methods: Patients with invasive breast cancer were randomly assigned vandetanib 300 mg or placebo PO daily for 2 weeks before operative resection from January 2014 to June 2017. Pretreatment and posttreatment specimens were analyzed by immunohistochemistry for Ki-67, TUNEL, and p-ERK with stratification by Ret expression by immunohistochemistry., Results: Ten patients were enrolled. There was no statistically significant difference in ERK activation compared with placebo (P=0.45); however, ERK activation was reduced 74% compared with pretreatment biopsy with vandetinib treatment (P=0.005) without a significant reduction in the placebo group (-29%, P=0.55). Mean change in Ki-67 after vandetanib treatment was +0.3% compared with +2.0% in placebo treated patients, P=0.72. Mean change in TUNEL was +0.48 apoptotic nuclei per HPF in the vandetanib arm compared with +1.02 in the placebo arm, P=0.32. In vandetanib treated patients, Ki-67 was reduced 0.3% in RET-positive tumors compared with increased 1.0% in RET-negative tumors, P=0.43 and TUNEL was increased 0.77 in RET-positive tumors and 0.2 in RET-negative tumors, P=0.21., Conclusions: In this pilot study, no statistically significant differences on prespecified markers were seen with vandetanib compared with placebo. In accordance with the investigational hypothesis, there was a nonsignificant trend with vandetanib treatment of reduction in p-ERK and increased effects in Ret expressing tumors., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)