In preliminary laboratory science studies, the investigators show that proton pump
inhibitors (PPIs) effectively inhibit human fatty acid synthase (FASN) and breast cancer
cell survival. A preliminary retrospective study shows that PPI usage in breast cancer
patients during chemotherapy significantly improved overall survival. The impact was most
striking in patients with triple negative breast cancer (TNBC). Thus, PPIs may be
repositioned as safe and effective breast cancer drugs to enhance the effect of
chemotherapy.
Many of the hurdles that slow progress from target, to lead compound, to investigational
agent, to standard therapy are not barriers for the PPIs. The PPIs are FDA-approved,
chronically used, and well tolerated so the investigators can move quickly from the
laboratory to a proof of concept clinical trial. Incorporating the PPIs into standard care
will require more than the investigators propose here, but the investigators have already
plotted the additional steps needed to truly impact patient care. If successful, the data
gathered in this proposal will lend support to and guide development of a definitive
randomized trial.
Primary Objective
Estimate the rate of pathologic complete response (pCR) in patients with triple negative
breast cancer and FASN expression treated with standard neoadjuvant chemotherapy (NAC) in
combination with high dose omeprazole.
Secondary Objectives
- Quantify the number of patients with newly diagnosed TNBC with tumors that express
FASN.
- Estimate the rate of pCR in patients with triple negative breast cancer (irrespective
of FASN status) treated with standard NAC in combination with high dose omeprazole.
- Describe the safety of incorporating high dose omeprazole with standard NAC.
- Estimate the biologic activity of high dose omeprazole in modulating FASN expression
and activity.
This is a single arm Phase II study. Patients should begin therapy within 7 working days of
study entry. Patients will be treated with omeprazole 80 mg orally twice a day (BID)
beginning 4-7 days prior to chemotherapy and continuing until surgery. After the brief
period of omeprazole monotherapy, patients will begin standard neoadjuvant chemotherapy with
doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) for 4 cycles followed by paclitaxel
(80 mg/m2) weekly x 12. Doxorubicin and cyclophosphamide (AC) may be administered on a
classical every 3 week or dose dense every 2 week (with growth factor support) schedule at
the treating physician's discretion. Routine incorporation of carboplatin is not
recommended, however use of carboplatin (AUC 6 on week 1, 4, 7, and 10) with paclitaxel is
allowed at the treating investigator's discretion. Chemotherapy will be adjusted based on
toxicity according to standard treatment guidelines. Patients with overt disease progression
during AC should move immediately to paclitaxel therapy. Patients with disease progression
during paclitaxel should proceed immediately to surgery.
Inclusion Criteria
1. Newly diagnosed triple negative breast cancer (TNBC) clinical stage Ic, II, or III
- ER and PR < 10%
- HER2 negative based on one of the following:
- IHC 0 or 1+
- IHC 2+ and FISH negative
- IHC 2+ and FISH equivocal and no indication for HER2 targeted therapy based
on the treating investigators discretion (i.e., HER2: CEP17 ratio < 2.0 or
HER2 total copy number <6)
2. Planned neoadjuvant treatment with anthracycline and taxane containing chemotherapy
3. 18 years old at the time of informed consent
4. ECOG Performance Status 0-1
5. Ability to provide written informed consent and HIPAA authorization
6. Women of childbearing potential definition must have a negative pregnancy test within
14 days of registration. All women (regardless of sexual orientation, having
undergone a tubal ligation, or remaining celibate by choice) are considered to have
childbearing potential unless they meet one of the following criteria:
- Prior hysterectomy or bilateral oophorectomy;
- Has not had menses at any time in the preceding 24 consecutive months
7. Adequate organ function for anthracycline and taxane based therapy
- LVEF > LLN based on cardiac ECHO or MUGA
- Hgb > 8.5
- ANC > 1,000
- Platelets > 100,000
- Creatinine < 1.5
- T. bili < 1.3
- AST < 2.5 x ULN
Exclusion Criteria
1. Use of prescription PPIs within 12 months prior to study entry [Dexlansoprazole
(Dexilant), Pantoprazole (Protonix), Rabeprazole (Aciphex), Esomeprazole (Nexium),
Lansoprazole (Prevacid), Omeprazole (Prilosec, Zegerid)]
2. Use of OTC PPIs within 6 months prior to study entry [Esomeprazole (Nexium),
Lansoprazole (Prevacid), Omeprazole (Prilosec, Zegerid)]
3. Use of Orlistat or any other known FASN inhibitor within 6 months prior to study
entry
4. Nursing mothers are excluded
5. Known hypersensitivity to any component of the formulation or substituted
benzimidazoles
6. Prior osteoporotic fracture
Minimum Eligible Age: 18 Years
Maximum Eligible Age: N/A
Eligible Gender: Both
