Abstract OT1-01-01: The NEO-LET-EXE-trial: An intra-patient cross-over trial to explore the "lack of cross-resistance" between steroidal and non-steroidal aromatase inhibitors

Abstract

Abstract Background. The aromatase inhibitor letrozole and the aromatase inactivator exemestane currently belong to the most widely used antihormonal drugs for breast cancer worldwide. Both compounds are strongly suppressing estradiol levels in postmenopausal patients with breast cancer. However, in the metastatic setting, these drugs may be used after another, causing new responses in selected patients following switching to the alternative drug after progressing on the first choice. This well-known “lack of cross resistance” has been recognized for some time and is documented by several trials. However, the precise explanation for this clinical observation is still unknown. The solution may potentially lead us to a novel strategy to treat hormone-sensitive breast cancer. Trial design. NEO-LET-EXE is a neoadjuvant, randomized, open-label, intra-patient cross-over trial . Eligibility criteria. Postmenopausal patients suffering from estrogen receptor (ER) positive (>50%), HER-2 negative, locally advanced breast cancer, suitable for neoadjuvant/presurgical antihormonal therapy, may be enrolled. Age: 18+ (no upper limit). Specific aims. To explain the phenomenon of a lack of cross-resistance between steroidal and non-steroidal aromatase inhibitors in vivo. Sequential tumor biopsies and blood samples, obtained at baseline and following 2 months of therapy with each drug given in sequence, will be used to perform a comprehensive exploration of the consequences of each drug therapy. The influence on plasma and tissue steroids (estrogens, androgens, etc.) will be compared. In addition, whole genome sequencing, whole exome sequencing, epigenetics, proteomics and plasma analysis (cytokines, tumor DNA fragments, etc.) will be performed. Statistical methods. Data will be analyzed using mixed effects models. Present accrural and target accrural. 49 out of planned 100 patients have been enrolled so far. The last patient is expected to enter the trial in Q4 2019. Citation Format: Bahrami N, Sauer T, Loeng M, Gravdehaug B, Engebretsen SS, Aljabri B, Bemanian V, Lindstrøm JC, Lüders T, Kristensen VN, Geisler J. The NEO-LET-EXE-trial: An intra-patient cross-over trial to explore the "lack of cross-resistance" between steroidal and non-steroidal aromatase inhibitors [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-01-01.