Impact of ABCB1 single-nucleotide variants on early, extremely severe neutropenia induced by paclitaxel/nanoparticle albumin-bound paclitaxel in patients with gastric cancer

Akimitsu Maeda; Keitaro Matsuo; Hitoshi Ando; Jun-Ichi Morishige; Kei Muro; Kosaku Uchida; Masahiro Tajika

doi:10.1111/bcp.16359

Impact of ABCB1 single-nucleotide variants on early, extremely severe neutropenia induced by paclitaxel/nanoparticle albumin-bound paclitaxel in patients with gastric cancer

Br J Clin Pharmacol. 2024 Dec 2. doi: 10.1111/bcp.16359. Online ahead of print.

Authors

Akimitsu Maeda¹, Keitaro Matsuo^{2

3}, Hitoshi Ando⁴, Jun-Ichi Morishige⁴, Kei Muro⁵, Kosaku Uchida¹, Masahiro Tajika⁶

Affiliations

¹ Department of Pharmacy, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan.
² Division of Cancer Epidemiology and Prevention, Aichi Cancer Center, Nagoya, Aichi, Japan.
³ Division of Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
⁴ Department of Cellular and Molecular Function Analysis, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan.
⁵ Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan.
⁶ Department of Endoscopy, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan.

PMID: 39622587
DOI: 10.1111/bcp.16359

Abstract

Aims: Paclitaxel and nanoparticle albumin-bound (nab)-paclitaxel can cause early, extremely severe neutropenia, occasionally leading to fatal outcomes. As paclitaxel is a substrate of P-glycoprotein, this study aimed to investigate the impact of ABCB1 single-nucleotide variants, which encode P-glycoprotein, on early, extremely severe neutropenia in patients receiving paclitaxel/nab-paclitaxel plus ramucirumab as second-line therapy for unresectable advanced/recurrent gastric cancer.

Methods: We analysed patients treated at Aichi Cancer Center Hospital from January 2018 to August 2023, with DNA samples stored in the Cancer BioBank Aichi. The impact of ABCB1 variants T1236C (rs1128503), G2677T/A (rs2032582) and C3435T (rs1045642) on early, extremely severe neutropenia was examined. Neutropenia was defined as a decline in neutrophil count to <100/μL within 28 days of therapy initiation. Firth's logistic regression evaluated the association between the ABCB1 C3435T (rs1045642) TT genotype and early, extremely severe neutropenia, adjusted for age, sex, baseline neutrophil count, and serum albumin and aspartate aminotransferase levels.

Results: Of the 203 eligible patients, 5 (2%) experienced neutropenia with neutrophil counts of <100/μL. The odds ratio for neutrophil counts of <100/μL was 28.1 (95% confidence interval 2.8-283.3) in patients with the ABCB1 C3435T (rs1045642) TT genotype.

Conclusion: The ABCB1 C3435T (rs1045642) TT genotype was significantly associated with early, extremely severe neutropenia in patients receiving paclitaxel/nab-paclitaxel. Evaluating this genotype status may help predict those at increased risk for early, extremely severe neutropenia.

Keywords: P‐glycoprotein; anticancer drugs; chemotherapy; genetic polymorphism; pharmacogenomics.