British journal of clinical pharmacology · 2026
Pharmacogenomic profiling of the efficacy of gemcitabine monotherapy in metastatic pancreatic cancer: Subgroup analysis of the GENESECT study.
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Yokokawa Takashi, Tsuji Daiki, Hatori Masahiro, Kawakami Kazuyoshi, Nakao Masahiko, Yano Takuya, Arakawa Yuichiro, Matsuo Keisuke, Ohashi Yasukata, Ozaka Masato, Sasahira Naoki, Sakata Yasuhiko, Kogure Yuki, Tamaki Shinya, Wada Atsushi, Taki Yusuke, Suzuki Wataru, Kobayashi Kazuo, Ishii Hiroshi, Itoh Kunihiko, Yamaguchi Masakazu, Suzuki Kenichi
Аннотация
AIM: In the GENESECT study, no significant gemcitabine (GEM) metabolism-related germline genetic polymorphisms (GPs) were identified because approximately 70% of patients received combination therapy with nab-paclitaxel, which has metabolic pathways different from GEM. The present study was a sub-analysis including only GEM monotherapy patients.
METHODS: Of 159 patients analysed in the GENESECT study, only GEM-monotherapy patients were selected. The endpoints included carbohydrate antigen 19-9 (CA19-9) response (reduction ≥ 50% from the pretreatment level at 8 weeks), progression-free survival (PFS), and overall survival (OS) in relation to GPs. Analysed genes included those encoding GEM transporters and metabolic enzymes (SLC29A1, ABCC5, CDA, DCK, RRM1/2) and a tumour cell proliferation enzyme (COX-2). Screening and significance levels were set at 10% (univariable) and 5% (multivariable), respectively.
RESULTS: Data for 50 patients were analysed. Genotype AA of ABCC5 1146A>G (rs7636910) showed a higher CA19-9 response rate than AG/GG (52.9% vs. 21.2%, p = 0.023) and remained significant in multivariable analysis (odds ratio: 6.255, p = 0.014). It also tended to be associated with longer PFS, but not significantly (hazard ratio [HR]: 0.464, p = 0.074). By contrast, although CA19-9 responses were not significantly associated with DCK -1205T>C (rs4694362), the TT/TC genotype was significantly associated with prolonged PFS compared with CC (median 127 vs. 48 days, p = 0.002), and this association remained significant in multivariable analysis (HR: 0.153, p = 0.028). No GPs were significantly associated with OS.
CONCLUSION: ABCC5 and DCK might be related to the efficacy of GEM treatment, but further research is needed.
METHODS: Of 159 patients analysed in the GENESECT study, only GEM-monotherapy patients were selected. The endpoints included carbohydrate antigen 19-9 (CA19-9) response (reduction ≥ 50% from the pretreatment level at 8 weeks), progression-free survival (PFS), and overall survival (OS) in relation to GPs. Analysed genes included those encoding GEM transporters and metabolic enzymes (SLC29A1, ABCC5, CDA, DCK, RRM1/2) and a tumour cell proliferation enzyme (COX-2). Screening and significance levels were set at 10% (univariable) and 5% (multivariable), respectively.
RESULTS: Data for 50 patients were analysed. Genotype AA of ABCC5 1146A>G (rs7636910) showed a higher CA19-9 response rate than AG/GG (52.9% vs. 21.2%, p = 0.023) and remained significant in multivariable analysis (odds ratio: 6.255, p = 0.014). It also tended to be associated with longer PFS, but not significantly (hazard ratio [HR]: 0.464, p = 0.074). By contrast, although CA19-9 responses were not significantly associated with DCK -1205T>C (rs4694362), the TT/TC genotype was significantly associated with prolonged PFS compared with CC (median 127 vs. 48 days, p = 0.002), and this association remained significant in multivariable analysis (HR: 0.153, p = 0.028). No GPs were significantly associated with OS.
CONCLUSION: ABCC5 and DCK might be related to the efficacy of GEM treatment, but further research is needed.