Inhibiting Fatty Acid Synthase with Omeprazole to Improve Efficacy of Neoadjuvant Chemotherapy in Patients with Operable TNBC

Fatty acid synthase (FASN) is overexpressed in 70% of operable triple-negative breast cancer (TNBC) and is associated with poor prognosis. Proton pump inhibitors selectively inhibit FASN activity and induce apoptosis in TNBC cell lines. Patients with operable TNBC were enrolled in this single-arm ph...

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Published in:Clinical cancer research 2021-11, Vol.27 (21), p.5810-5817
Main Authors: Sardesai, Sagar D, Thomas, Alexandra, Gallagher, Christopher, Lynce, Filipa, Ottaviano, Yvonne Lynn, Ballinger, Tarah Jean, Schneider, Bryan P, Storniolo, Anna Maria, Bauchle, Amber, Althouse, Sandra K, Perkins, Susan M, Masters, Andrea R, Stratford, Jr, Robert E, Dong, Zizheng, Liu, Jing-Yuan, Zhang, Jian-Ting, Miller, Kathy D
Format: Article
Language:English
Subjects:
Adult
Aged
Fatty Acid Synthases - antagonists & inhibitors
Female
Humans
Middle Aged
Neoadjuvant Therapy
Omeprazole - pharmacology
Omeprazole - therapeutic use
Treatment Outcome
Triple Negative Breast Neoplasms - drug therapy
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Summary:Fatty acid synthase (FASN) is overexpressed in 70% of operable triple-negative breast cancer (TNBC) and is associated with poor prognosis. Proton pump inhibitors selectively inhibit FASN activity and induce apoptosis in TNBC cell lines. Patients with operable TNBC were enrolled in this single-arm phase II study. Patients began omeprazole 80 mg orally twice daily for 4-7 days prior to neoadjuvant anthracycline-taxane-based chemotherapy (AC-T) and continued until surgery. The primary endpoint was pathologic complete response (pCR) in patients with baseline FASN overexpression (FASN+). Secondary endpoints included pCR in all surgery patients, change in FASN expression, enzyme activity, and downstream protein expression after omeprazole monotherapy, safety, and limited omeprazole pharmacokinetics. Forty-two patients were recruited with a median age of 51 years (28-72). Most patients had ≥cT2 (33, 79%) and ≥N1 (22, 52%) disease. FASN overexpression prior to AC-T was identified in 29 of 34 (85%) evaluable samples. The pCR rate was 72.4% [95% confidence interval (CI), 52.8-87.3] in FASN+ patients and 74.4% (95% CI, 57.9-87.0) in all surgery patients. Peak omeprazole concentration was significantly higher than the IC for FASN inhibition observed in preclinical testing; FASN expression significantly decreased with omeprazole monotherapy [mean change 0.12 (SD, 0.25); = 0.02]. Omeprazole was well tolerated with no grade ≥ 3 toxicities. FASN is commonly expressed in early TNBC. Omeprazole can be safely administered in doses that inhibit FASN. The addition of omeprazole to neoadjuvant AC-T yields a promising pCR rate that needs further confirmation in randomized studies.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-21-0493