Clinical implications of germline variations for treatment outcome and drug resistance for small molecule kinase inhibitors in patients with non-small cell lung cancer.

Small-molecule kinase inhibitors (SMKIs) represent the cornerstone in the treatment of non-small cell lung cancer (NSCLC) patients harboring genetic driver mutations. Because of the introduction of SMKIs in the last decades, treatment outcomes have drastically improved. Their treatment efficacy, the development of drug resistance as well as untoward toxicity, all suffer from large patient variability. This variability can be explained, at least in part, by their oral route of administration, which leads to a large inter- and intra-patient variation in bioavailability based on differences in absorption. Additionally, drug-drug and food-drug interactions are frequently reported. These interactions could modulate SMKI efficacy and/or untoward toxicity. Furthermore, the large patient variability could be explained by the presence of germline variations in target receptor domains, metabolizing enzymes, and drug efflux transporters. Knowledge about these predictor variations is crucial for handling SMKIs in clinical practice, and for selecting the most optimal therapy. In the current review, the literature search included all SMKIs registered for locally-advanced and metastatic NSCLC by the US Food and Drug Administration (FDA) or European Medicines Agency (EMA) until March 24th, 2022. The BIM deletion showed a significantly decreased PFS and OS for East-Asian patients treated with gefitinib, and has the potential to be clinically relevant for other SMKIs as well. Furthermore, we expect most relevance from the ABCG2 34 G>A and CYP1A1 variations during erlotinib and gefitinib treatment. Pre-emptive CYP2D6 testing before starting gefitinib treatment can also be considered to prevent severe drug-related toxicity. These and other germline variations are summarized and discussed, in order to provide clear recommendations for clinical practice.

Review - The impact of pharmacogenetics on the outcome of immune checkpoint inhibitors.

The development of immune checkpoint inhibitors (ICIs) has a tremendous effect on the treatment options for multiple types of cancer. Nonetheless, there is a large interpatient variability in response, survival, and the development of immune-related adverse events (irAEs). Pharmacogenetics is the general term for germline genetic variations, which may cause the observed interindividual differences in response or toxicity to treatment. These genetic variations can either be single-nucleotide polymorphisms (SNPs) or structural variants, such as gene deletions, amplifications or rearrangements. For ICIs, pharmacogenetic variation in the human leukocyte antigen molecules has also been studied with regard to treatment outcome. This review presents a summary of the literature regarding the pharmacogenetics of ICI treatment, discusses the most important known genetic variations and offers recommendations on the application of pharmacogenetics for ICI treatment.

Effect of the Proton Pump Inhibitor Esomeprazole on the Systemic Exposure of Capecitabine: Results of A Randomized Crossover Trial.

Retrospective data suggest that gastric acid reduction by proton pump inhibitors (PPIs) impairs the dissolution and subsequent absorption of capecitabine, and thus potentially reduces the capecitabine exposure. Therefore, we examined prospectively the effect of esomeprazole on the pharmacokinetics of capecitabine. In this randomized crossover study, patients with cancer were assigned to 2 sequence groups, each consisting of 3 phases: capecitabine with esomeprazole administration 3 hours before (phase A), capecitabine alone (phase B), and capecitabine concomitant with cola and esomeprazole co-administration 3 hours before (phase C). The primary end point was the relative difference (RD) in exposure to capecitabine assessed by the area under the plasma concentration-time curve from zero to infinity (AUC0-inf ) and analyzed by a linear mixed effect model. Twenty-two evaluable patients were included in the analysis. After esomeprazole, there was a 18.9% increase in AUC0-inf of capecitabine (95% confidence interval (CI) -10.0% to 57.0%, P = 0.36). In addition, capecitabine half-life was significantly longer after esomeprazole (median 0.63 hours vs. 0.46 hours, P = 0.005). Concomitant cola did not completely reverse the effects observed after esomeprazole (RD 3.3% (95% CI -16.3 to 27.4%, P = 1.00). Capecitabine exposure is not negatively influenced by esomeprazole cotreatment. Therefore, altered capecitabine pharmacokinetics do not explain the assumed worse clinical outcome of PPI-cotreated patients with cancer.

Tissue Type Differences in ABCB1 Expression and Paclitaxel Tissue Pharmacokinetics in Patients With Esophageal Cancer.

Background: Data from previous work suggests that there is no correlation between systemic (plasma) paclitaxel exposure and efficacy in patients treated for esophageal cancer. In this trial, we investigated ATP-binding cassette efflux transporter expression and intratumoral pharmacokinetics of paclitaxel to identify changes which could be a first sign of chemoresistance. Methods: Patients with esophageal cancer treated with paclitaxel and carboplatin (± concomitant radiotherapy) were included. During the first and last cycle of weekly paclitaxel, blood samples and biopsies of esophageal mucosa and tumor tissue were taken. Changes in paclitaxel exposure and expression of ABCB1 (P-glycoprotein) over time were studied in both tumor tissue and normal appearing esophageal mucosa. Results: ABCB1 was significantly higher expressed in tumor tissue compared to esophageal tissue, during both the first and last cycle of paclitaxel (cycle 1: p < 0.01; cycle 5/6: p = 0.01). Interestingly, ABCB1 expression was significantly higher in adenocarcinoma than in squamous cell carcinoma (p < 0.01). During the first cycle, a trend towards a higher intratumoral paclitaxel concentration was observed compared to the esophageal mucosa concentration (RD:43%; 95%CI: -3% to 111% p = 0.07). Intratumoral and plasma paclitaxel concentrations were significantly correlated during the first cycle (AUC0-48 h: r = 0.72; p < 0.01). Conclusion: Higher ABCB1 expression in tumor tissue, and differences between histological tumor types might partly explain why tumors respond differently to systemic treatment. Resistance by altered intratumoral paclitaxel concentrations could not be demonstrated because the majority of the biopsies taken at the last cycle of paclitaxel did contain a low amount of tumor cells or no tumor.

Influence of Genetic Variation in COMT on Cisplatin-Induced Nephrotoxicity in Cancer Patients.

Cisplatin is a chemotherapeutic agent widely used for multiple indications. Unfortunately, in a substantial set of patients treated with cisplatin, dose-limiting acute kidney injury (AKI) occurs. Here, we assessed the association of 3 catechol-O-methyltransferase (COMT) single nucleotide polymorphisms (SNPs) with increased cisplatin-induced nephrotoxicity. In total, 551 patients were genotyped for the 1947 G>A (Val158Met, rs4680), c.615 + 310 C>T (rs4646316), and c.616 - 367 C>T (rs9332377) polymorphisms. Associations between these variants and AKI grade ≥3 were studied. The presence of a homozygous variant of c.616-367C>T was associated with a decreased occurrence of AKI grade 3 toxicity (p = 0.014, odds ratio (OR) 0.201, 95% confidence interval (CI) (0.047-0.861)). However, we could not exclude the role of dehydration as a potential cause of AKI in 25 of the 27 patients with AKI grade 3, which potentially affected the results substantially. As a result of the low incidence of AKI grade 3 in this dataset, the lack of patients with a COMT variant, and the high number of patients with dehydration, the association between COMT variants and AKI does not seem clinically relevant.