Abstract OT3-06-03: ABC-SE, <u>A</u>dvanced <u>B</u>reast <u>C</u>ancer – <u>S</u>tatins and <u>E</u>ndocrine treatment
Authors: S Borgquist, M Ekholm, M Feldt, T Schyman, S Zackrisson, A Bosch
Journal: Cancer Research (2018)

Abstract Full Title: A randomized, open-label, multi-center, phase II study to compare the efficacy and tolerability of atorvastatin 40 mg in addition to endocrine treatment in patients with estrogen receptor (ER) positive advanced breast cancer with focus on mechanisms of resistance. Background: The majority of metastatic breast cancer patients progress during endocrine therapy and eventually become resistant to treatment. Understanding how metastatic cancer cells adapt to different therapies is key for the development of improved treatment regimens. The effectiveness of endocrine therapy in ER+ tumors may be influenced by cholesterol through the cholesterol metabolite oxysterol 27-hydroxycholesterol, which acts as an ER ligand, harboring the ability to regulate ER-dependent tumor growth. Statin-mediated inhibition of the cholesterol pathway has been demonstrated to induce anti-neoplastic effects in both breast cancer cells and human breast cancer. Hence the goal of this study is to both understand the mechanisms of resistance to endocrine treatment and test the hypothesis that addition of statins will enhance the efficacy of endocrine treatment. Trial Design: A multi-center randomized, open-labelled, phase II trial in the first and second line metastatic treatment setting, comparing standard endocrine treatment (letrozole) with letrozole +/- atorvastatin (1:1). Upon progression in the first line setting, and as part of the translational studies of mechanisms of resistance to endocrine therapy, the patients receive second line endocrine treatment using fulvestrant. Eligibility criteria: 1) Patients diagnosed with ER positive/HER2 negative metastatic breast cancer, including locally advanced stage IV disease, requiring systemic endocrine treatment. 2) No Previous treatment for metastatic breast cancer, unless being considered for direct entry to the second part of the study with fulvestrant. Specific aims: To test the clinical efficacy of adding statins to endocrine treatment in advanced breast cancer. Primary endpoint: Clinical benefit rate, defined as the proportion of all randomly assigned patients who have the best overall response; complete response, partial response, or stable disease for at least 24 weeks following first-line letrozole treatment alone or in combination with atorvastatin. Translational endpoint: To elucidate mechanisms of resistance to endocrine treatment alone or in combination with statins in ER+ metastatic breast cancer. Statistical Methods:The primary endpoint of clinical benefit rate will be compared in the two groups using a logistic regression model where the odds ratios and associated 95% CIs and p-values will be reported. The secondary endpoint, progression-free-survival, will be analyzed in crude analysis using the Kaplan-Meier and Log-Rank test as well as the Cox regression hazards analysis with the latter allowing for confounder-controlled multivariate analysis. Present accrual and target accrual: The trial started recruiting as of October 10, 2016. The target accrual is 126 patients, whereof 17 are presently included in the trial. Contact information for people with a specific interest in the trial: Signe.Borgquist@med.lu.se Citation Format: Borgquist S, Ekholm M, Feldt M, Schyman T, Zackrisson S, Bosch A. ABC-SE, Advanced Breast Cancer – Statins and Endocrine treatment [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-06-03.