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

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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
Name of journal: Clinical cancer research : an official journal of the American Association for Cancer ResearchAbstract: 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.All authors: Althouse SK, Ballinger TJ, Bauchle A, Dong Z, Gallagher C, Liu JY, Lynce F, Masters AR, Miller KD, Ottaviano YL, Perkins SM, Sardesai SD, Schneider BP, Storniolo AM, Stratford RE Jr, Thomas A, Zhang JTOriginally published: Clinical Cancer Research. 2021 Aug 16Fiscal year: FY2022Digital Object Identifier: ORCID: Date added to catalog: 2021-11-01
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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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