PPIs Linked to Worse Outcomes With Widely Used Breast Cancer Drug

Using proton pump inhibitors (PPIs) during treatment with palbociclib (Ibrance) was linked to higher risks of progression and death among patients with breast cancer, according to a retrospective cohort study from South Korea.

Among over 1,300 women, the median clinical progression-free survival (PFS) in the group taking both a PPI and palbociclib was 25.3 months compared with 39.8 months in those who never used a PPI during palbociclib treatment (P<0.001), reported Eui-Kyung Lee, PhD, of Sungkyunkwan University in Suwon, and colleagues.

The difference in overall survival (OS) between the the concomitant and nonconcomitant groups was also statistically significant, even though median OS was not reached in either group, with 1-year OS rates of 83.1% versus 94.0%, and 2-year OS rates of 69.5% versus 89.3%, they noted in JAMA Network Open.

After adjusting for other risk factors, the HR for concomitant use associated with clinical PFS was 1.76 (95% CI 1.46-2.13) and the HR for OS was 2.71 (95% CI 2.07-3.53).

“Most patients with cancer use proton pump inhibitors to mitigate anticancer drug-related gastrointestinal symptoms, such as gastroesophageal reflux disease,” Lee and team wrote. “Proton pump inhibitors irreversibly bind to and inhibit the hydrogen-potassium adenosine triphosphatase pump located on the luminal surface of the parietal cell membrane, reducing the secretion of gastric acid.”

“However, acid suppression negatively affects the oral bioavailability, pharmacokinetics, and clinical effects of orally administered anticancer medications,” they added.

They noted that their results supported those reported in earlier, smaller retrospective studies that showed that a combination of a PPI and palbociclib changed the therapeutic effect in terms of PFS for patients with hormone receptor-positive, HER2-negative advanced and metastatic breast cancer.

“Physicians should be cautious when prescribing PPIs to patients who are receiving palbociclib and should inform patients about the risks of interaction to prevent inadequate prescription of PPI by others,” they urged.

In subgroup analyses, Lee and colleagues found that both clinical PFS and OS in the concomitant group were “consistently poor” in patients receiving endocrine-sensitive and endocrine-resistant treatment.

The median clinical PFS for the nonconcomitant group of patients with endocrine-sensitive treatment was 40.4 months versus 27.2 months for those in the concomitant group (P<0.001), with an adjusted HR of 1.75 (95% CI 1.42-2.15). There was also a substantial difference in clinical PFS between the groups in the endocrine-resistant subgroup (adjusted HR 1.82, 95% CI 1.12-2.94, P=0.03).

The HRs for taking PPIs with palbociclib associated with OS were 2.68 (95% CI 2.01-3.58, P<0.001) and 2.98 (95% CI 1.49-5.96, P=0.006) in the endocrine-sensitive and endocrine-resistant subgroups, respectively.

For this study, Lee and colleagues used nationwide claims data from November 2016 through July 2021 to identify patients with breast cancer receiving palbociclib from November 2017 through July 2020. Patients whose prescriptions for palbociclib and PPI overlapped by at least 33% were classified into a concomitant group. Patients who never received PPI during the palbociclib treatment period were classified into a nonconcomitant group.

After propensity score matching, a total of 1,310 women (344 in the concomitant group and 966 in the nonconcomitant group) were included.

Most of the patients were over 50 years of age (84.6%), with 98.4% experiencing menopause. Palbociclib was combined with nonsteroidal aromatase inhibitors such as anastrozole or letrozole in 84.8% of women, and most had not received chemotherapy (99.1%) or endocrine therapy (94.7%) prior to palbociclib.

Half of the patients in both groups had metastases, with bone metastases being the most common.

Lee and team acknowledged several limitations to their study. For example, they noted that due to the nature of the claims data used, they could not actually confirm whether or not patients took their medications. However, they pointed out that in identifying patients for analysis, only those who received multiple prescriptions for palbociclib together with a PPI for more than a certain period of time were selected.

They also pointed out that it is difficult to measure how much PPI needs to be taken for drug-drug interactions to interfere with the treatment outcome. Thus, they performed a sensitivity analysis by defining the PPI group by different coverage ratios (50%, 67%, and 80%) and still found the “increased risk associated with clinical PFS and OS for taking PPI was robust.”

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