Inhibiting Fatty Acid Synthase with Omeprazole to Improve Efficacy of Neoadjuvant Chemotherapy in Patients with Operable TNBC Article (Web of Science)

abstract

  • Abstract 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. 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. 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. 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.

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, Robert E.
  • Dong, Zizheng
  • Liu, Jasmine JingYuan
  • Zhang, Jian-Ting
  • Miller, Kathy D.

publication date

  • 2021

webpage

published in

number of pages

  • 7

start page

  • 5810

end page

  • 5817

volume

  • 27

issue

  • 21