Radium-223 dichloride improves survival and delays symptomatic skeletal events in patients with bone-metastatic castration-resistant prostate cancer; however, therapeutic responses vary considerably among individuals, and predictive germline biomarkers remain undefined. We conducted a prospective multicenter genome-wide association study within the KYUCOG-1901 cohort to identify germline single-nucleotide polymorphisms associated with the clinical efficacy of radium-223.
Among 93 patients with bone-predominant castration-resistant prostate cancer treated with up to six cycles of radium-223, the intronic variant rs1568679 in MEIS2 reached genome-wide significance for association with ≥ 30% decline in prostate-specific antigen (P < 5.0 × 10⁻⁸). Patients carrying the rs1568679 CC genotype exhibited significantly greater prostate-specific antigen decline and significantly longer symptomatic skeletal event-free survival, radiographic progression-free survival, and overall survival compared with those with TT/TC genotypes. In multivariate analyses adjusting for established clinical prognostic factors, the rs1568679 CC genotype remained independently associated with favorable clinical outcomes. Although rs1568679 showed no significant expression quantitative trait loci effect on MEIS2 expression, pathway enrichment analysis of MEIS2-associated regulatory networks revealed strong enrichment of genes involved in DNA repair and genomic stability.
The germline variant rs1568679 in MEIS2 may represent a potential biomarker associated with favorable response to radium-223 in metastatic castration-resistant prostate cancer. These findings suggest that MEIS2-related DNA repair regulation may influence susceptibility to α-particle-induced cytotoxicity and may facilitate biomarker-driven treatment strategies for optimizing Ra-223 therapy.
University Hospital Medical Information Network (UMIN), UMIN000040358, registered 11 May 2020, https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000045641.
EJNMMI research. 2026 Jun 02 [Epub ahead of print]
Tokiyoshi Tanegashima, Masaki Shiota, Atsushi Doi, Shuichi Tatarano, Tomomi Kamba, Tsukasa Igawa, Naoya Masumori, Hirotsugu Uemura, Toshiyuki Kamoto, Katsuyoshi Higashijima, Kensuke Mitsunari, Hiroji Uemura, Takayuki Sumiyoshi, Takuro Isoda, Kousei Ishigami, Shoji Tokunaga, Masatoshi Eto
Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan., Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. ., Division of Biomedical Information Analysis, Medical Research Center for High Depth Omics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan., Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan., Department of Urology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan., Department of Urology, School of Medicine, Kurume University, Kurume, Japan., Department of Urology, Sapporo Medical University School of Medicine, Sapporo, Japan., Department of Urology, Kindai University Faculty of Medicine, Osaka, Japan., Department of Urology, Faculty of Medicine, Miyazaki University, Miyazaki, Japan., Department of Urology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan., Department of Urology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan., Department of Urology, Yokohama City University Graduate School of Medicine, Yokohama, Japan., Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan., Clinical Therapeutic Trial Center, Ehime University Hospital, Touon, Japan.