The effect of concomitant use of proton pump inhibitors with CDK 4/6 inhibitors on survival in metastatic breast cancer

To evaluate the difference of progression free survival between the patients using concomitant proton pump inhibitors and non-users in the patients using CDK 4/6 inhibitors with HR + and HER2 negative mBC. We included 86 patients with HR + and HER 2 negative mBC treated with CDK 4/6 inhibitors in this study. Patients were divided into two categories according to their status of PPI use. The primary end points was progression free survival (PFS). We compared PPI users and non-users. Forty-five (52.3%) patients used a PPI concomitantly with a CDK 4/6 inhibitor, and 41 (47.7%) did not. The median duration of follow-up was 10.68 (1.94–27.56) months. Of the patients, 50 (58.1%) palbociclib and 36 (41.9%) received ribociclib. The median progression free survival (mPFS) was 10.9 months (95% CI: 7.5–14.27) in the group with concomitant PPI use with a CDK 4/6 inhibitor, whereas the median progression free survival could not be reached in the group without concomitant PPI use (p = 0.04). In addition, concomitant PPI use with palbociclib was associated with a shorter PFS; there was no significant difference between the concomitant PPI users and non-users in terms of PFS in the patients using ribociclib. Palbociclib and ribociclib are weak base drugs so their bioavailability is pH-dependent. PPIs can affect their solubility and their concentration in the plasma. Therefore, we must avoid concomitant use of PPIs and CDK 4/6 inhibitors. If we need to use concomitant PPI and CDK 4/6 inhibitors, we should prefer ribociclib than palbociclib.


Introduction
Proton pump inhibitors (PPIs) are traditionally used to treat acid-related disorders, including peptic ulcer disease and gastroesophageal reflux disease, and are commonly used for symptoms resulting from cancer-related treatments and stress [1,2]. Acid-reducing agents, especially PPIs, are used for approximately 20-33% of all cancer patients [3]. The common use of acid-reducing agents worldwide increases drug-drug interactions for oral anti-cancer treatments due to their pH-dependent solubility [4,5].
Ribociclib and palbociclib are oral, selective cyclindependent kinase 4 and 6 (CDK 4/6) inhibitors that inhibit the progression of cells from the G1 to the S phase, suppressing DNA synthesis [6]. CDK 4/6 inhibitor therapy is used as the first-or second-line treatment concomitantly with fulvestrant or aromatase inhibitors in patients with hormone receptor-positive (HR +) and human epidermal growth factor receptor 2 (HER-2)-negative metastatic breast cancer (mBC) [7][8][9]. Palbociclib and ribociclib are weak base drugs with pH-dependent solubility. The solubility of palbociclib decreases with increasing gastric pH, whereas ribociclib reaches the maximum solubility at a gastric pH below 4.5 [10][11][12][13]. Ribociclib was absorbed after a single oral dose, with time to reach maximum concentration ranging from 0.25 to 4 h in the plasma of human [13]. The mean peak concentration of palbociclib is generally observed between 6 and 12 h following oral administration [14].
PPIs have been associated with intestinal dysbiosis, reduced bacterial diversity, and promotion of T-cell tolerance [15,16]. And may influence the treatment response to immunotherapeutics in several types of cancer [17]. We aimed to investigate the outcomes of the concomitant use of PPIs and CDK 4/6 inhibitors (palbociclib and ribociclib) as second-and later-line treatments in HR + and HER-2-negative mBCs.

Methods
In this study, 180 patients were selected, of whom 74 patients who received CDK 4/6 inhibitors and endocrine therapy as front-line therapy were excluded, as were 10 patients whose data were not available. In addition, 10 patients using drugs with strong CYP3A4 inhibition were excluded. Eighty-six patients with HR + and HER-2 negative mBC treated with endocrine therapy (fulvestrant or aromatase inhibitors) plus CDK4/6 inhibitors (ribociclib or palbociclib) as second or later lines treatment were included in the study. All the patients were female. The study was conducted at three centres between January 2018 and December 2021. Ethics committee approval was obtained (approval no: 2022/3779). The data were obtained retrospectively from the patients' file and the hospital electronic database. The patients receiving CDK4/6 inhibitors were divided into two groups: concomitant PPI users and non-users. The PPIs were rabeprazole (20 mg), esomeprazole (40 mg), pantoprazole (40 mg), and lansoprazole (30 mg). Patients generally used PPI for gastroesophageal reflux, gastritis, ulcer prophylaxis, and dyspepsia. Overall survival (OS) and progression-free survival (PFS) were compared between the groups. OS was defined as the time from diagnosis to death from any cause. PFS was defined as the time from initiation of treatment to disease progression, measured radiologically and with laboratory tests.

Statistical analysis
The data were analysed with SPSS software version15.0 (SPSS Inc., Chicago, IL, USA). The continuous variables were compared between the groups with an independent t test. The chi-square test or Fisher's test were used to compare the categorical variables between the groups. The survival analysis curves were generated using the Kaplan-Meier method and the parameters were compared with the log-rank test. The Cox-regression model was used to identify concurrent PPI use and other risk factors for OS and PFS. A p-value < 0.05 was considered statistically significant. As risk factors for PFS, concomitant PPI use, age, BMI (> 25 vs ≤ 25), comorbidities, bone metastasis, Ki 67, grade 3/4, toxicity, and type of PPI were evaluated by univariate analysis.

Results
A total of 86 patients were included in the study. Forty-five (52.3%) patients used a PPI concomitantly with a CDK 4/6 inhibitor, and 41 (47.7%) did not. Of the patients who received a PPI, 23 (51.1%) received pantoprazole, 12 (26.7%) esomeprazole, 9 (20%) lansoprazole, and 1 (2.2%) rabeprazole. The mean age of the patients was 55.5 ± 12.8 years. The median duration of follow-up was 10.68 (1.94-27.56) months. Of the patients, 50 (58.1%) palbociclib and 36 (41.9%) received ribociclib. With regard to concomitant PPI use, no difference was determined between the CDK 4/6 inhibitors (p = 0.27) ( Table 1). Among the concomitant PPI users and non-users, no difference was found in terms of the use of aromatase inhibitors and fulvestrant (p = 0.66) ( Table 1). Moreover, no difference between the concomitant PPI users and non-users was determined in terms of dose reduction of CDK 4/6 inhibitors, treatment response, any grade-3/4 toxicity, and haematologic and non-haematologic toxicity (all p > 0.05) ( Table 1). Three patients with a QTc > 480 were in the concomitant PPI user group (p = 0.16) and one patient who developed CDK 4/6 inhibitor-associated pneumonitis was in the non-user group (p = 0.5). The characteristics of the study population are presented in Table 1.
The survival curves were generated using Kaplan-Meier analysis. The median progression free survival (mPFS) was 10.9 months (95% CI: 7.5-14.27) in the group with concomitant PPI use with a CDK 4/6 inhibitor, whereas the median progression free survival could not be reached in the group without concomitant PPI use (p = 0.04) (Fig. 1). When compared by the type of CDK 4/6 inhibitor, the mPFS of the patients with concomitant PPI use with ribociclib was 13.7 (95% CI: 8.7-18.8) months, whereas the median value of the group without concomitant PPI use with ribociclib could not be reached (p = 0.6) (Fig. 1). The mPFS of the patients with concomitant PPI use with palbociclib was 10.6 (95% CI: 7.3-13.8) months, whereas the median value of the group without concomitant PPI use with palbociclib could not be reached (p = 0.04) (Fig. 1). mOS was not reached in the study group. The mOS at 12 months of patients using concomitant PPI was 95.4% and that of patients not using concomitant PPI was 94.9% (p = 0.38). Among patients receiving ribociclib, the mOS at 12 months was 77.1% for patients using concomitant PPI and 85.5% for patients not using concomitant PPI (p = 0.74). Among patients receiving palbociclib, the mOS at 12 months was 88.0% in patients using concomitant PPI and 95% in patients not using concomitant PPI (p = 0.27).

Discussion
In the present study, concomitant PPI use with CDK 4/6 inhibitors was found to be a risk factor for a shorter PFS. The mPFS of the patients with concomitant PPI use with CDK 4/6 inhibitors was significantly shorter. In addition, concomitant PPI use with palbociclib was associated with a shorter PFS; there was no significant difference between the concomitant PPI users and non-users in terms of PFS in the patients using ribociclib. Endocrine therapy with CDK 4/6 inhibitors was not found to be associated with PPI use. Among the concomitant PPI users and non-users, the dose reduction and discontinuation of therapy rates of CDK 4/6 inhibitors were similar. Similarly, the rate of response to CDK 4/6 inhibitors was similar among the concomitant PPI users and non-users. The rates of haematologic and non-haematologic toxicities also were similar among the concomitant PPI users and non-users. In a previous study, in the patients receiving CDK 4/6 inhibitors therapy, there was no any difference between the concomitant PPI users and non-user in terms of haematological toxicities [18]. There was no statistically significant difference in the incidence of capecitabine or lapatinib dose reductions, grade 3 or 4 diarrhoea, or any rash between PPI users and non-users [19]. In a review, they mentioned that we need to avoid the concomitant use PPIs with erlotinib, gefitinib, dasatinib, and nilotinib based on label recommendation [20]. CDK 4/6 inhibitors (ribociclib and palbociclib) are weak base drugs and, therefore, their bioavailability is pH-dependent. It has been demonstrated that solubility of palbociclib and ribociclib decreases and the rate of reaching to maximum plasma concentration is altered when the pH becomes above 4.5 and 6.5, respectively [11,12]. It has been shown that solubility of ribociclib increases in the acidic environment [11]. Moreover, pH changes and nutritional status have been shown to have no effect on bioavailability of ribociclib [11]. In our study, no difference was found between mPFS of the concomitant PPI users and non-users receiving ribociclib.
It has been revealed in previous studies that, in metastatic breast cancer patients receiving palbociclib, compared to non-use, concomitant PPI use reduces PFS [18,21]. In addition, these studies demonstrated that concomitant PPI use is an independent risk factor for a shorter PFS [18,21]. Similarly, it was found in our study that concomitant PPI use with palbociclib was associated with a shorter PFS and was an independent risk factor for a shorter PFS.
The limitations of our study include the retrospective design and relatively low number of patients included. However, the distribution between the groups is similar.
In conclusion, in the light of our data, it may be said that preferring ribociclib in patients requiring concomitant PPI use and avoidance from unnecessary concomitant PPI use with palbociclib is necessary in this specific population.
Author contribution Concept -DÇ and MA. Design -DÇ and MA. Supervision -all authors. Data collection and/or processing -all authors. Analysis and/or interpretation -MZK and MA. Literature search -DÇ. Writing -DÇ, MZK, and MA. Critical reviews -all authors.

Declarations
Ethics approval This research was conducted ethically in accordance with the World Medical Association Helsinki Declaration. All patients had to give informed consent before participating in our sensitive study. Ethics approval was obtained from Necmettin Erbakan University Meram Medical Faculty, Konya, Turkey (Ethics Committee No: 2022/3779).