HemOnc Today's PharmAnalysis
HemOnc Today's PharmAnalysis
Disclosures: Hartzell and Madison report no relevant financial disclosures.
April 24, 2020
4 min read

Proton pump inhibitors may lead to cognitive decline among breast cancer survivors

Disclosures: Hartzell and Madison report no relevant financial disclosures.
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Annelise A. Madison, MA
Annelise A. Madison

Breast cancer survivors often take proton pump inhibitors to manage gastrointestinal symptoms related to their treatment.

Physicians also may recommend longer-term use of proton pump inhibitors (PPIs) to protect the gastric mucosal layer, which can deteriorate as a result of chemotherapy.

These off-label uses of PPIs may lead to cognitive problems for breast cancer survivors, according to results of a study by Annelise A. Madison, MA, a graduate student in clinical psychology at The Ohio State University, and colleagues.

Breast cancer survivors are more susceptible to cognitive decline than the general population, which can affect memory and overall quality of life.

The study by Madison and colleagues, published in Journal of Cancer Survivorship, explored the relationship between PPI use and cognitive decline among this vulnerable population.

The investigators conducted secondary analyses of data from three previously published studies of patients with breast cancer at various points during survivorship. They sought to determine if PPIs influenced survivor-reported cognitive function and predicted that PPI users would have worse cognitive function than nonusers.

Madison acknowledged these are secondary analyses of studies that were originally designed to answer other questions of interest

“But we have seen data from other labs suggesting that PPI users might be at an increased risk for mild cognitive impairment or even dementia,” she told Healio.

“We wanted to look at the relationship between PPI use and self-reported cognitive functioning — including concentration and memory — in these different samples,” she added. “What we found across these samples, and these are women at different stages in treatment and survivorship, was that there was an association that was pretty notable.”

Breast cancer survivors may be more susceptible to PPI-related cognitive decline because the off-label uses by this group tend to be for a longer period than by those who take the drugs for FDA-approved indications. Madison and colleagues wrote that with prolonged use, PPIs can “compromise the gut barrier and enter into the circulation. Once in the bloodstream, PPIs can cross the blood-brain barrier, triggering the buildup of amyloid beta proteins — a biological signature of dementia.”

‘A jumping-off point’

Madison and colleagues analyzed the three studies separately.

PPI users in the first study reported more severe problems with concentration (P = .039) than nonusers, but not more severe memory problems. Similarly, PPI users in the second study reported more severe concentration problems (P = .022) than nonusers, but not memory problems.


The third study, however, showed an association between PPI use and measures of cognitive decline, although in this study PPI users did not report more severe concentration problems than nonusers. Participants who used PPIs reported more severe memory problems (P = .002), poorer overall cognitive function (P = .006), lower quality of life related to cognitive problems (P = .005), greater perceived cognitive impairment (P = .013) and poorer cognitive abilities (P = .046) than nonusers.

“This research is really just a jumping-off point,” Madison said of the study results.

She told Healio that the studies showed breast cancer survivors tend to use PPIs for a longer period than the general public and that survivors are more prone to poor cognitive outcomes regardless of PPI use.

Madison said the results are purely observational and fall short of proving cause and effect. She would like to see a clinical trial that can examine the development of potential cognitive effects due to PPI use by breast cancer survivors over time.

Most PPI clinical trials have been short-term studies that did not look specifically at cognitive problems, which were not expected as a result of PPI treatment, Madison said.

“Further research, especially research that has a PPI control group, would be a really important follow-up to our study,” she said.

“These results are preliminary,” Madison added. “The results are correlations and, because PPI use is not being manipulated, we can’t really say anything about causality.”

‘A new area of exploration’

Jennifer W. Hartzell, PsyD, ABPP-CN
Jennifer W. Hartzell

Jennifer W. Hartzell, PsyD, ABPP-CN — a clinical neuropsychologist with Levine Cancer Institute at Atrium Health whose work focuses on measuring cognition and identifying neurocognitive disorders among patients with cancer and cancer survivors — agreed that further study of PPI use among breast cancer survivors is necessary to confirm the findings.

“This study needs more follow-up before we can interpret the findings as meaningful,” Hartzell told Healio.

Nevertheless, it’s a good starting point for an area of research that lacks outcome data, Hartzell said.

Previous research on PPI use has focused on its contribution to cognitive decline among the elderly, usually those aged older than 75 years, according to Hartzell.

“The relationship between PPI use and cognition warrants further investigation in general, as well as within cancer populations— this is a new area of exploration,” she told Healio.

Hartzell maintained that the analysis by Madison and colleagues is limited by its reliance on self-reported cognitive decline and lack of an objective neuropsychological testing component.


“We have learned from studies examining cognition in breast cancer survivors that self-report of cognitive problems often far exceeds objective measurement of cognitive impairment on standardized neuropsychological tests,” Hartzell said. “That doesn't mean that cognitive problems are not there or are not meaningful — they certainly are — but the level of cancer-related cognitive impairment is generally mild.”

Informing clinical practice

Overprescribing of PPIs may be the biggest takeaway from this research, according to Hartzell.

“Pharmacologic symptom management is inevitable in cancer patients, and is often necessary and beneficial, but cancer patients may be particularly susceptible to overprescribing of preventative drugs. PPIs and other preventative medications may provide relief but may also have adverse health consequences,” she said.

“We’ve seen this unfold over the last decade with cancer pain management and the opioid epidemic. With the long-term risks of PPIs still being equivocal, this work reinforces the importance of conservative prescribing practices in cancer patients,” Hartzell added.

Finding ways to avoid long-term use of PPIs following treatment for breast cancer is something that Madison champions, as well. For example, Madison said strategies that alter health behaviors — such as dietary changes — could be useful in mitigating the gastrointestinal adverse effects of cancer treatments.

“There are not any necessarily critical guidelines that should be implemented as a result of this one study,” Madison said. “But I do think that, based on potential further studies in this area, that hopefully this will help inform clinical practice.” – by Drew Amorosi


Madison AA, et al. J Cancer Surviv. 2020;doi:10.1007/s11764-019-00815-4.

For more information:

Jennifer W. Hartzell, PsyD, ABPP-CN, can be reached at jennifer.hartzell@atriumhealth.org.

Annelise A. Madison, MA, can be reached at annelise.madison@osumc.edu.

Disclosures: Hartzell and Madison report no relevant financial disclosures.