PPI Added to Chemo Improves Breast Tumor Response Rate

Reflux Drug for Triple-Negative Disease

Nick Mulcahy

May 29, 2020

The proton pump inhibitor (PPI) omeprazole may be a useful addition to treatment for triple-negative breast cancer, as it boosted the expected rate of tumor disappearance among women with early-stage disease, according to the results of a phase 2 trial.

The trial results are presented online at the 2020 virtual annual meeting of the American Society of Clinical Oncology.

The rationale behind the approach includes the fact that PPIs inhibit fatty acid synthase (FASN), an enzyme overexpressed in 70% of newly diagnosed triple-negative breast cancers (TNBC) and associated with poor prognosis.

In the study, omeprazole, a generic drug for gastroesophageal reflux, was added to standard chemotherapy. Both were given to 42 women as neoadjuvant treatment in the weeks before breast surgery at five US centers in the single-arm study.

The pathologic complete response (pCR) rate was 71% in the study population, which is higher than the typical 40% seen in patients treated with standard AC-T (adriamycin and cyclophosphamide plus a taxane), said lead author Sagar Sardesai, MBBS, a medical oncologist at Ohio State Comprehensive Cancer Center in Columbus.

"It's exciting," said Sardesai in an interview with Medscape Medical News. "Overall, triple-negative patients who achieve a pCR have a very good outcome."

That complete disappearance of the tumor is a surrogate for overall survival in TNBC and patients who achieve it have a greatly reduced risk of recurrence or death, he explained.

Natalie Berger, MD, medical oncologist, Icahn School of Medicine at Mount Sinai, New York City, said the study's pCR rates were "much higher" than expected and "intriguing and hypothesis generating."

But Berger, who was not involved in the study, wanted to see more data.

"Having a non-chemotherapeutic agent to offer our patients with TNBC that improves pCR rates without added toxicity would be an exciting finding, but we need a larger randomized study," she said in an email.

The researchers, who include high-profile breast cancer specialist Kathy Miller, MD, of Indiana University, are seeking a National Cancer Institute or Department of Defense grant to mount a 100-plus patient randomized trial.

Potential Drug Target for Some Years

Sardesai explained that FASN, which is an enzyme, helps generate fatty acids that are a key to cancer cell survival. FASN is primarily found in hormone-dominated tissue such as those of the endometrium, prostate, and breast.

PPIs "selectively inhibit FASN activity and induce apoptosis in breast cancer cell lines with minimal effect on non-malignant cells," write the study authors in their meeting abstract.

The only other known agent known to inhibit FASN is the weight loss drug orlistat, which is poorly absorbed by the body and unlikely to impact cancer cells, Sardesai said.

FASN has been a potential drug target in TNBC for 10 to 15 years, but the first clinical evidence of efficacy in solid tumors was only seen in the last 5 years, he commented.

In 2015, Chinese investigators reported that the PPI esomeprazole in combination with chemotherapy produced a 5-month improvement in progression-free survival (vs chemo alone) among a subset of 15 TNBC patients in a randomized trial of 97 patients with a variety of breast cancer types.

No Added Toxicity, But Some Unexpected Findings

The study was conducted in patients with early-stage, operable TNBC (with and without baseline FASN expression) and no prior PPI use within 12 months.

All patients started daily high-dose omeprazole 4 to 7 days prior to start of AC-T neoadjuvant chemotherapy (the addition of carboplatin was allowed per physician discretion) and continued until surgery.

The primary endpoint was pCR, defined as no residual invasive disease in breast or axilla, in patients with baseline FASN expression (FASN+).

The pCR rate was 71.4% in the 28 FASN+ patients and 71.8% in all 42 enrolled patients. The researchers had targeted a pCR rate of 60% in the FASN+ patients.

Also, among the subset of 15 patients who received carboplatin with AC-T, the pCR was 73%.

These two findings both have limitations, commented Berger.

She pointed out that it is "unexplained" as to why the pCR rates were similar among the FASN+ patients and the total population (including 14 FASN– patients); the pCR rate would be expected to be lower in the total population, she suggested.

Further, it was also unexplained as to why there were similar pCR rates with or without carboplatin; other research has demonstrated improved pCR rates in patients receiving additional carboplatin (compared to AC-T alone) but at the cost of increased toxicity, she said.

Sardesai said that omeprazole was well tolerated with no known grade 3 or 4 toxicities and that the chemotherapy toxicity was similar to prior studies of AC-T. PPIs have side effects if taken for longer than a year, including a higher risk of infections, osteoporosis, and low magnesium, he also commented.

"Omeprazole can be safely administered in doses that inhibit FASN. The addition of high-dose omeprazole to neoadjuvant AC-T yields a promising pCR rate without adding toxicity," the authors conclude in their abstract.

Sardesai also highlighted the fact that using a PPI for breast cancer is an example of drug repurposing. The approach offers a way of rapid drug development because PPIs have complete safety and pharmacokinetics data available, he said. "If we can prove the efficacy, the treatment can move forward quickly and be available in clinical practice much sooner than with traditional drug development."

The study was funded by the Breast Cancer Research Foundation. Sardesai has financial ties to Novartis and Immunomedics. Other study authors have ties to industry. Berger has disclosed no relevant financial relationships.

American Society of Clinical Oncology (ASCO) 2020: Abstract 584

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