Hormone receptor-positive (HR+) and human epidermal growth factor receptor-2 negative (HER2-) breast cancers collectively account for 80% of all molecular subtypes of malignant neoplasms in the breast (Orrantia-Borunda et al., 2022; Jin et al., 2023; Torrisi et al., 2023). Recent therapeutic advances have significantly contributed to extending survival rates in this patient population, know to harbor a more favorable molecular profile compared to other subtypes. Stage II disease now boasts a 5-year survival rate exceeding 90%, while stage III and stage IV exhibit rates of 72% and 22%, respectively (Cuyún Carter et al., 2021; Jerzak et al., 2023).

Cyclin-Dependent Kinase (CDK) 4/6 inhibitors, including abemaciclib, palbociclib and ribociclib constitute important components of the current standard first-line treatment for patients with HR+/HER2-metastatic breast cancer (mBC) (Chagaleti et al., 2023; Chang and Lam, 2023; Geisler et al., 2023). The combination of Palbociclib with aromatase inhibitors or fulvestrant has emerged as a pivotal advancement, reshaping the treatment paradigms for HR+/HER2-mBC (Bilgin et al., 2017). Notably, in its approval by the Food and Drug Administration (FDA), it was reported that the administration of Proton Pump Inhibitors (PPI) led to a noteworthy 62% reduction in the area under the plasma concentration-time curve (AUC) (Shin and Sachs, 2008; Numico et al., 2017; Hunter et al., 2023).

PPIs are frequently used in cancer patients, with a prevalence ranging from 20% to 55%, aimed at alleviating gastrointestinal symptoms associated with antineoplastic drugs, such as gastroesophageal reflux disease (Targownik et al., 2007; Smelick et al., 2013; Raoul et al., 2021). The advent of new targeted oral therapies for breast cancer has significantly altered the disease´s natural history. However, challenges arise due to differences in drug absorption between periods of fasting and during meals, as well as the sensitivity of target drugs to pH-dependent solubility. These challenges pose unique scenarios for treatment, which was not the case with standard intravenous chemotherapy (Budha et al., 2012; Mullin and Schrogie, 2013; Wedemeyer and Blume, 2014).

The consideration of drug-drug interaction (DDI) is crucial when evaluating potential causes of therapeutic failure in cancer patients (Budha et al., 2012). PPIs reduce gastric acid secretion by irreversibly binding to the adenosine triphosphatase hydrogen-potassium pump in the parietal cell membrane of the stomach (Smelick et al., 2013; Wedemeyer and Blume, 2014). This interference may affect bioavailability and pharmacokinetics of oral anticancer drugs, particularly those classified as weak bases (Chu et al., 2017; Raoul et al., 2023). Considering that more than half of the oral agents used against cancer fall into that category, the efficacy of these drugs may be compromised among PPI users (Riechelmann and Krzyzanowska, 2019).

Studies have shown that the absorption of palbociclib is highly dependent on gastric pH. Similarly, food intake can influence the absorption of abemaciclib, possibly due to alterations in gastric pH caused by proton pump inhibitors (Bellet et al., 2019; Roncato et al., 2020). In contrast, a ribociclib study demonstrated that gastric pH changes do not affect its bioavailability (Samant et al., 2018). In this systematic review and meta-analysis, we aim to clarify the influence of the use of PPIs on progression-free survival (PFS) in patients with HR-positive, ERBB2-negative mBC treated with CDK 4/6 inhibitors (included palbociclib, ribociclib and abemciclib).

In this systematic review and meta-analysis encompassing 9 studies and 2,737 patients, we examined the outcomes for women with HR+/HER2-advanced breast cancer undergoing treatment with cyclin-dependent kinase (CDK) 4/6 inhibitors, comparing those who used proton pump inhibitors (PPIs) against those who did not. The analysis of palbociclib and ribociclib subgroups was conducted considering their unique mechanisms of action and interactions with proton pump inhibitors (PPIs), highlighting differences in solubility, metabolism, and pharmacokinetic interactions. This is clinically important for assessing the influence of PPI usage on treatment effectiveness and informing individualized therapy choices for patients with advanced breast cancer.

We used the I² for asses the heterogeneity of analysis, Egger’s test for publications bias by the symmetry of funnel plot and the sensibility analysis to evaluate identified the influential studies in heterogeneity and the robustness of findings.

Our results underscore a significant association between non-use of PPIs and an increased likelihood of progression-free survival (PFS) (HR 2.0901; 95% CI 1.410–2.9498; p < 0.001). Subgroup analysis further revealed that the addition of PPIs significantly reduced PFS for patients treated with palbociclib and ribociclib.

CDK 4/6 inhibitors within the CDK4 (INK4)-retinoblastoma (Rb) pathway govern the regulatory phases of the cell cycle, specifically orchestrating progression from G1 (pre-DNA synthesis) to S (DNA synthesis) (Hamilton and Infante, 2016). CDK 4/6 assumes a pivotal role in overseeing the transition from G1 to S through its interaction with D-type cyclins, thereby inducing the phosphorylation of Rb (Wang et al., 2023). Elevated cyclin-dependent kinase 4/6 activity ensues from mutations in CDK 4/6, the depletion of CDK regulators, and the heightened expression of D-type cycling—all converging to instigate the proliferation of cancer cells. CDK 4/6 inhibitors act by attenuating the phosphorylation state of Rb, thereby reducing the concentration of phosphorylated Rb. This reduction creates an environment conducive to the formation of RB-E2F transcription factor complexes, ultimately incapacitating the E2F transcription factors that activate genes essential for the initiation of the S phase and DNA replication (Malumbres and Barbacid, 2009; Wang et al., 2023; Knudsen et al., 2023; Pan et al., 2023).

PPIs represent weak bases characterized by a substituted pyridine with a primary pK ranging from 3.8 to 4.9 coupled with a benzimidazole exhibiting a secondary pKa of approximately 1.0. PPI acts on gastric ATPase through covalent binding (Shin et al., 2006; Srebro et al., 2022). In an acidic environment, they undergo conversion to sulfenic acids or sulfenamides, initiating a reaction that results in the formation of a disulfide bond with a cysteine or multiple cysteines accessible from the luminal surface of ATPase (Proton Pump Inhibitors, 2012). Because of the establishment of disulfide bonds, their inhibitory effects significantly persist longer (Robinson and Horn, 2003).

The interaction between PPIs and antineoplastic drugs is highly variable among cancer patients. Existing studies have indicated that the concurrent use of PPIs can diminish the antitumor effectiveness or certain drugs like capecitabine and pazopanib (van Leeuwen et al., 2014; Raoul et al., 2023). On the other hand, it does not appear to exert a significant influence on the clinical outcomes of patients undergoing treatment with epidermal growth factor receptor (EGFR) inhibitors (Hilton et al., 2013; Kumarakulasinghe et al., 2016; Chu et al., 2017; Moreau-Bachelard et al., 2022).

In our analysis, ta global assessment of patients using CDK 4/6 inhibitors revealed a significant risk of progression associated with the use of PPIs (HR 2.0901; 95% CI; 1.410–2.9498; p < 0.001). These findings parallel results observed in advanced small cell lung cancer (SCLC) treated with programmed death-ligand 1 (PD-L1) inhibitors, where concurrent use of PPIs was linked to a 74.9% increased risk of progression (HR 1.749; 95% CI; 1.285–2.380) and a 58.3% increased risk of death (HR = 1.583, 95% CI; 1.059–2.366) (Zhang et al., 2023).

In the palbociclib group, negative outcomes associated with the use of PPIs were maintained (HR 2.2539; 95% CI 1.3213–3.8446; p = 0.003; I² 83%), with a slight increase in relative risk compared to the overall group. This aligns with a study by Sun et al. (2017) evaluating the interaction of palbociclib with rabeprazole, a PPI. They found that at pH above 4, rabeprazole decreased palbociclib’s area under the curve (AUC) by 62% and its maximum concentration (Cmax) by 80%. These findings support the potential association between PPI use and reduced oral chemotherapy effectiveness (Sun et al., 2017). However, Sun et al. also demonstrated that taking palbociclib with food significantly mitigated the impact of rabeprazole, restoring AUC and Cmax closer to baseline levels. This suggests that dietary strategies may offer a potential intervention to optimize palbociclib exposure in PPI users (Sun et al., 2017).

In the subgroup analysis involving ribociclib, the hazard ratio significantly favored PPI non-users over PPI users (HR 1.74; 95% CI 1.02–2.97; p = 0.04; I² = 40%). However, this ratio is notably lower in comparison to the palbociclib subgroup. This discrepancy can be attributed to the higher solubility of ribociclib at pH levels below 4.5, contrasting with palbociclib, which already shows reduced solubility at or above pH 4 (Samant et al., 2018; Bellet et al., 2019). Another possible explanation lies in the potential interaction between CDK4/6 inhibitors and PPIs, on the CYP2C19 enzyme responsible for metabolizing both substances (Hamilton and Infante, 2016; Imhann et al., 2016; Wang et al., 2023). Studies by Imhann et al. (2016) and Hamilton and Infante (2016) demonstrated that omeprazole inhibits CYP2C19 activity, which was further corroborated by Wang et al. (2023). This inhibition can lead to a significant increase in plasma concentrations of certain CDK4/6 inhibitors, potentially leading to increased efficacy but also raising concerns about drug toxicity. Therefore, further investigation into the specific enzyme interactions and their clinical implications is warranted.

While our study provides valuable insights, certain limitations should be acknowledged. Firstly, the observed high heterogeneity may stem from the diverse types of PPI used, given the variable effectiveness of each (Zhang et al., 2017; He et al., 2022). Unfortunately, due to a lack of detailed data in the studies, we were unable to conduct a specific analysis of the impact of each type of PPI on PFS. Secondly, the absence of data prevented the reporting of additional outcomes of interest, including overall response rate (ORR), complete response (CR), partial response (PR), stable disease (SD), and overall survival (OS). However, it is important to note that these data gaps this did not prevent the drawing of solid conclusions concerning the results analyzed within each group. Further investigations addressing these limitations could provide a more comprehensive understanding of the nuanced relationship between CKD 4/6 inhibitors, PPIs, and varios clinical ouctomes.

This groundbreaking meta-analysis is the first to examine the impact of PPIs on the efficacy of CDK 4/6 inhibitors in women diagnosed with HR+/HER2-metastatic breast cancer. Our results add significant insights to the existing body of literature, substantiating the notion that PPI usage ay adversely influence the efectiveness of CDK 4/6 inhibitors. This discovery emphasizes the need for careful consideration and potential contraindication of PPIs in this specific clinical context, as their use is strongly correlated with a substantial reduction in PFS among women undergoing treatment with palbociclib or ribociclib. Additionally, our conclusion highlights the urgent need for future research, particularly prospective studies, to rigorously validate these findings and explore underlying mechanisms, crucial for optimizing therapeutic strategies in the treatment of metastatic breast cancer.