Yukari Tsubata

Association of ABCB1 polymorphisms with erlotinib pharmacokinetics and toxicity in Japanese patients with non-small-cell lung cancer

AIMS We analyzed the association of ABCB1 polymorphisms with erlotinib-induced toxicity and the pharmacokinetics in patients with non-small-cell lung cancer. MATERIALS & METHODS After erlotinib 150 mg was administered to 50 patients, ABCB1 polymorphisms were analyzed via either TaqMan(®) assays or direct nucleotide sequencing. Plasma concentrations were measured by HPLC. RESULTS The trough concentration at steady state in patients with the ABCB1 1236TT-2677TT-3435TT genotype was higher compared with others groups (p = 0.021) and patients carrying this genotype had a higher risk of developing higher grade 2 toxicity (p = 0.012). CONCLUSION The present study suggested that the ABCB1 1236TT-2677TT-3435TT genotype was associated with higher plasma concentration and the risk of developing higher toxicity in patients treated with erlotinib.

Erlotinib-induced acute interstitial lung disease associated with extreme elevation of the plasma concentration in an elderly non-small-cell lung cancer patient

We herein describe a case of drug-induced interstitial lung disease (ILD) following treatment with erlotinib. The plasma trough concentration of erlotinib at the time of the ILD diagnosis was extremely elevated compared with the plasma maximum concentration on day 1. We hypothesized that this phenomenon was associated with the pharmacodynamic interaction with a concomitant drug. The present case indicates that erlotinib-induced ILD was associated with a high plasma concentration of erlotinib. Oncologists should be aware of the possibility of ILD induced by erlotinib, especially for patients with co-morbidities.

A retrospective analysis comparing the safety and efficacy of chemotherapy in elderly and non-elderly non-small-cell lung cancer patients.

Aim:  The number of elderly patients with non‐small‐cell lung cancer (NSCLC) is increasing in Japan. We retrospectively analyzed and compared the safety and efficacy of chemotherapy in elderly and non‐elderly NSCLC patients who received chemotherapy at Shimane University Hospital.

Evaluation of the heterogeneous tissue distribution of erlotinib in lung cancer using matrix-assisted laser desorption ionization mass spectrometry imaging

Although drug distribution in tumor tissues has a significant impact on efficacy, conventional pharmacokinetic analysis has some limitations with regard to its ability to provide a comprehensive assessment of drug tissue distribution. Erlotinib is a tyrosine kinase inhibitor that acts on the epidermal growth factor receptor; however, it is unclear how this drug is histologically distributed in lung cancer. We used matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to analyze erlotinib distribution in the tumor and normal lung tissues of a mouse xenograft model and patient with non-small cell lung cancer. LC-MS/MS showed that the erlotinib tissue concentration in the xenograft tumor tissue was clearly lower than that in the normal tissue at the time of maximum blood concentration. MALDI-MSI showed the heterogeneous distribution of erlotinib at various levels in the murine tissues; interestingly, erlotinib was predominantly localized in the area of viable tumor compared to the necrotic area. In the patient-derived tissue, MALDI-MSI showed that there were different concentrations of erlotinib distributed within the same tissue. For drug development and translational research, the imaging pharmacokinetic study used the combination of MALDI-MSI and LC-MS/MS analyses may be useful in tissues with heterogeneous drug distribution.

A Low Crizotinib Concentration in the Cerebrospinal Fluid Causes Ineffective Treatment of Anaplastic Lymphoma Kinase-positive Non-small Cell Lung Cancer with Carcinomatous Meningitis

The central nervous system is a common site of relapse in patients receiving crizotinib, which is presumed to be associated with the low concentration of crizotinib in the cerebrospinal fluid (CSF). Our patient received surgical treatment for anaplastic lymphoma kinase-positive stage IIA lung adenocarcinoma. His cancer recurred with brain metastases and carcinomatous meningitis. We started whole-brain radiation therapy (WBRT) and subsequently administered crizotinib. The concentration of crizotinib on day 15 in the plasma was 158 ng/mL, and that in the spinal fluid was 4.32 ng/mL. WBRT may elevate the CSF/plasma crizotinib concentration ratio; clinicians may therefore consider performing WBRT prior to crizotinib initiation.

The development of a polypoid intrapulmonary bronchogenic cyst in the bronchial lumen: Bronchogenic cyst in the bronchial lumen

Intrapulmonary bronchogenic cysts are rare in adults and most are outside the trachea and bronchi. There are reports of clear link with the trachea, but the cyst itself occurs outside the trachea. Thus, bronchoscopy will not reveal the cause, which often leads to a diagnosis by surgical resection. We herein report an extremely rare case of an intrapulmonary bronchogenic cyst that was located entirely within the left main bronchial lumen. Bronchoscopy revealed a shiny and smooth surface mass with abundant blood vessels in the lumen that blocked the left main bronchus. The patient was successfully treated with bronchoscopic resection and remained stable at 16 months of follow‐up. To our knowledge, this is the first reported case of an intrapulmonary bronchogenic cyst located entirely within the bronchial lumen.

Pleuroparenchymal fibroelastosis after haematopoietic stem cell transplantation without graft-versus-host disease findings: PPFE after HSCT without GVHD findings

Although rare, pleuroparenchymal fibroelastosis (PPFE) is a serious late‐onset complication of haematopoietic stem cell transplantation (HSCT). It remains unclear whether graft‐versus‐host disease (GVHD) is involved in the development of PPFE. We report the case of a patient with PPFE after HSCT. The patient experienced pneumothorax repeatedly despite surgical treatment. A surgical specimen demonstrated PPFE findings, without evidence of GVHD. In this case, development of PPFE was not associated with GVHD, and immunosuppressive therapy did not improve pulmonary function. Surgical biopsy is recommended for precise treatment and elucidation of pathogenesis in each suspected PPFE patient.

Novel drug-resistance mechanisms of pemetrexed-treated non-small cell lung cancer

Pemetrexed (PEM) improves the overall survival of patients with advanced non-small cell lung cancer (NSCLC) when administered as maintenance therapy. However, PEM resistance often appears during the therapy. Although thymidylate synthase is known to be responsible for PEM resistance, no other mechanisms have been investigated in detail. In this study, we explored new drug resistance mechanisms of PEM-treated NSCLC using two combinations of parental and PEM-resistant NSCLC cell lines from PC-9 and A549. PEM increased the apoptosis cells in parental PC-9 and the senescent cells in parental A549. However, such changes were not observed in the respective PEM-resistant cell lines. Quantitative RT-PCR analysis revealed that, besides an increased gene expression of thymidylate synthase in PEM-resistant PC-9 cells, the solute carrier family 19 member1 (SLC19A1) gene expression was markedly decreased in PEM-resistant A549 cells. The siRNA-mediated knockdown of SLC19A1 endowed the parental cell lines with PEM resistance. Conversely, PEM-resistant PC-9 cells carrying an epidermal growth factor receptor (EGFR) mutation acquired resistance to a tyrosine kinase inhibitor erlotinib. Although erlotinib can inhibit the phosphorylation of EGFR and Erk, it is unable to suppress the phosphorylation of Akt in PEM-resistant PC-9 cells. Additionally, PEM-resistant PC-9 cells were less sensitive to the PI3K inhibitor LY294002 than parental PC-9 cells. These results indicate that SLC19A1 negatively regulates PEM resistance in NSCLC, and that EGFR-tyrosine-kinase-inhibitor resistance was acquired with PEM resistance through Akt activation in NSCLC harboring EGFR mutations.

Successful rechallenge with ceritinib after leukocytoclastic vasculitis during ceritinib treatment for non-small cell lung cancer harboring the EML4-ALK fusion protein

Anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors (TKIs) dramatically improve progression-free survival compared to cytotoxic agents. It is therefore important to manage patients with ALK-TKIs until drug resistance occurs. Leukocytoclastic vasculitis (LCV) is a rare complication during cancer treatment and is associated with a variety of factors. Currently, it is unclear whether we should withdraw a treatment when drug-induced LCV develops. We report a 40-year-old man with advanced pulmonary adenocarcinoma harboring the EML4-ALK fusion protein who developed LCV during ceritinib treatment. Four weeks after withdrawing ceritinib, we could successfully perform rechallenge with ceritinib at the normal dose. Rapid and massive tumor apoptosis due to ceritinib treatment may lead to neoantigen release and immune complexes deposition. To the best of our knowledge, we report the first case of LCV in a patient during ALK-TKI treatment. Following this occurrence, we were able to successfully perform rechallenge with ceritinib. Therefore, key drugs used in a patients treatment regimen should not be discontinued without careful evaluation, and we should also consider the possibility of rechallenge.

Population Pharmacokinetics and Adverse Events of Erlotinib in Japanese Patients with Non-small-cell Lung Cancer: Impact of Genetic Polymorphisms in Metabolizing Enzymes and Transporters

Determinants of interindividual variability in erlotinib pharmacokinetics (PK) and adverse events remain to be elucidated. This study with 50 Japanese non-small-cell lung cancer patients treated with oral erlotinib at a standard dose of 150 mg aimed to investigate whether genetic polymorphisms affect erlotinib PK and adverse events. Single nucleotide polymorphisms (SNPs) in genes encoding metabolizing enzymes (CYP1A1, CYP1A2, CYP2D6, CYP3A4, CYP3A5, UGT1A1, UGT2B7, GSTM1, and GSTT1) or efflux transporters (ABCB1, and ABCG2) were analyzed as covariates in a population PK model. The ABCB1 1236C>T (rs1128503) polymorphism, not ABCB1*2 haplotype (1236TT-2677TT-3455TT, rs1128503 TT-rs2032582 TT-rs1045642 TT), was a significant covariate for the apparent clearance (CL/F), with the TT genotype showing a 29.4% decrease in CL/F as compared with the CC and the CT genotypes. A marginally higher incidence of adverse events (mainly skin rash) was observed in the TT genotype group; however, patients with high plasma erlotinib exposure did not always experience skin rash. None of the other SNPs affected PK or adverse events. The ABCB1 genotype is a potential predictor for erlotinib adverse events. Erlotinib might be used with careful monitoring of adverse events in patients with ABCB1 polymorphic variants.