Abstract OT1-03-01: Inhibiting fatty acid synthase to improve efficacy of neoadjuvant chemotherapy

Abstract

Abstract Background Human Fatty Acid Synthase (FASN) is the sole cytosolic enzyme responsible for de novo synthesis of long chain fatty acids. Unlike normal tissues, cancer cells require FASN dependent fatty acid synthesis for survival. FASN is overexpressed in 70% of newly diagnosed triple negative breast cancer (TNBC) and associated with significantly shorter disease free and overall survival. In vitro, FASN overexpression induces resistance to multiple DNA damaging agents including doxorubicin and cisplatin. Proton pump inhibitors (PPI), particularly omeprazole can selectively inhibit FASN enzyme activity at a Ki of 3.4umol. Inhibition of FASN activity with PPIs induces apoptosis selectively in cancer cells with minimal effect on non-malignant breast cell lines. PPIs are well tolerated and are FDA approved for a variety of gastro-intestinal disorders. We hypothesize that PPIs will effectively inhibit FASN activity and improve clinical efficacy of neoadjuvant chemotherapy with minimal added toxicity in operable TNBC. Materials and Methods This is a single arm multi -center phase II study of omeprazole 80mg PO BID in combination with standard neoadjuvant anthracycline-weekly taxane chemotherapy (AC-T; Adriamycin 60mg/m2 Cyclophosphamide 600mg/m2 given every q2w with G-CSF or q 3wk x 4 followed by weekly paclitaxel 80mg/m2 x 12) in patients with newly diagnosed clinically stage II or greater TNBC (NCT02595372). Neoadjuvant carboplatin may be offered with weekly paclitaxel at treating physician’s discretion. Patients with prior over the counter or prescription PPI use within 12 months are excluded. An initial core biopsy is performed at baseline, after which patients begin omeprazole monotherapy for a brief period (4-7 days). This is followed by a second research core biopsy and initiation of standard AC-T. PPI is continued until night before definitive surgery. Study follow up ends with definitive surgery and after resolution of known adverse events (<=G1). The primary endpoint is the rate of pCR (defined as no residual invasive disease in breast or axilla) in study patients with FASN expression. Relevant secondary endpoints include rate of pCR in all patients, change in FASN expression, enzymatic activity and downstream target gene expression from baseline to surgery; safety and limited omeprazole PK sampling during the study. Assuming that 70% of newly diagnosed TNBC have FASN expression, a single stage phase II trial to detect a pCR rate of 60% (null= pCR-40%) with 80% power and alpha of 0.10 requires 30 FASN patients (or 42 patients total). This sample size also provides approximately 80% power to identify a change in FASN expression and/or activity of 0.5 SDs using a paired t-test and significance level of 0.05. Conclusion The study enrolled its last participant in May 2019. Six patients are in follow-up who have yet to undergo definitive surgery. Final study patient is anticipated to have surgery in October 2019, with final data analysis planned in the last quarter of 2019. Funding This work has been supported by the Breast Cancer Research Foundation. Citation Format: Sagar Sardesai, Alexandra Thomas, Christopher Gallagher, Filipa Lynce, Yvonne Ottaviano, Tarah Ballinger, Brian P Schneider, Anna Maria Storniolo, Susan Perkins, Jian Tian Zhang, Kathy D Miller. Inhibiting fatty acid synthase to improve efficacy of neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-03-01.