Inhibiting Fatty Acid Synthase with Omeprazole to Improve Efficacy of Neoadjuvant Chemotherapy in Patients with Operable TNBC.
Citation: Clinical Cancer Research. 27(21):5810-5817, 2021 11 01.PMID: 34400413Institution: MedStar Franklin Square Medical Center | Washington Cancer InstituteForm of publication: Journal ArticleMedline article type(s): Journal ArticleSubject headings: *Fatty Acid Synthases/ai [Antagonists & Inhibitors] | *Neoadjuvant Therapy | *Omeprazole/tu [Therapeutic Use] | *Triple Negative Breast Neoplasms/dt [Drug Therapy] | Adult | Aged | Female | Humans | Middle Aged | Omeprazole/pd [Pharmacology] | Treatment OutcomeYear: 2021ISSN:- 1078-0432
- Gallagher, Christopher:
- https://orcid.org/0000-0002-3846-5052
Item type | Current library | Collection | Call number | Status | Date due | Barcode |
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Journal Article | MedStar Authors Catalog | Article | 34400413 | Available | 34400413 |
CONCLUSIONS: 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. Copyright (c)2021 American Association for Cancer Research.
PATIENTS AND METHODS: 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.
PURPOSE: 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.
RESULTS: 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 IC50 for FASN inhibition observed in preclinical testing; FASN expression significantly decreased with omeprazole monotherapy [mean change 0.12 (SD, 0.25); P = 0.02]. Omeprazole was well tolerated with no grade >= 3 toxicities.
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