M Kanai1, T Kawaguchi2, M Kotaka3, K Shinozaki4, T Touyama5, D Manaka6, K Ishigure7, J Hasegawa8, Y Munemoto9, T Matsui10, A Takagane11, H Ishikawa12, S Matsumoto13, J Sakamoto14, S Saji14, T Yoshino15, A Ohtsu16, T Watanabe17, F Matsuda2. 1. Department of Clinical Oncology, Pharmacogenomics, and Palliative Medicine. Electronic address: kanai@kuhp.kyoto-u.ac.jp. 2. Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto. 3. Gastrointestinal Cancer Center, Sano Hospital, Kobe. 4. Division of Clinical Oncology, Hiroshima Prefectural Hospital, Hiroshima. 5. Department of Surgery, Nakagami Hospital, Okinawa. 6. Department of Surgery, Gastrointestinal Center, Kyoto-Katsura Hospital, Kyoto. 7. Department of Surgery, Konan Kosei Hospital Konan, Aichi. 8. Department of Surgery, Osaka Rosai Hospital, Osaka. 9. Department of Surgery, Fukui-ken Saiseikai Hospital, Fukui. 10. Department of Gastroenterological Surgery, Aichi Cancer Center Aichi Hospital, Aichi. 11. Department of Surgery, Hakodate Goryoukaku Hospital, Hokkaido. 12. Department of Gastrointestinal Surgery, Sasebo City General Hospital, Nagasaki. 13. Department of Clinical Oncology, Graduate School of Medicine, Kyoto University, Kyoto. 14. Japanese Foundation for Multidisciplinary Treatment of Cancer, Tokyo. 15. Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba. 16. Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Chiba. 17. Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan.
Abstract
BACKGROUND: Peripheral sensory neuropathy (PSN) is a dose-limiting toxicity of oxaliplatin-based chemotherapy. Several genetic markers have been shown to predict oxaliplatin-induced PSN; however, results remain to be validated in a large-scale and prospective pharmacogenomics study. PATIENTS AND METHODS: Among 882 patients enrolled in the JFMC41-1001-C2 (JOIN trial), which was designed to investigate the tolerability of adjuvant-modified FOLFOX6 (mFOLFOX6) in Japanese Patients with stage II or III colon cancers undergoing curative resection, 465 patients were eligible for this pharmacogenomics analysis. Twelve single-nucleotide polymorphisms (SNPs) were selected based on published data. The effect of each genotype on time to PSN onset was evaluated in all patients (n = 465) using the Cox proportional hazard model. For the association analysis between severity of PSN and 12 SNP markers, 84 patients who failed to complete 12 cycles of mFOLFOX6 from grade 0/1 PSN group were excluded because the termination of the protocol treatment had been caused by reasons other than PSN. RESULTS: Comparison of grade 0/1 PSN with grade 2/3 PSN or grade 3 PSN showed no significant associations with any of the 12 SNP markers after adjustment for total dose of oxaliplatin. Time-to-onset analysis also failed to reveal any significant differences. CONCLUSIONS: Our large-scale and prospective pharmacogenomics study of Japanese patients receiving protocol treatment of adjuvant mFOLFOX6 could not verify a role for any of the 12 SNP markers reported as being significantly associated with PSN. Considering the OR observed in this study (range: 0.76-1.89), further evaluation of these 12 SNP markers in the context of L-OHP-induced PSN is unlikely to be clinically informative.
BACKGROUND:Peripheral sensory neuropathy (PSN) is a dose-limiting toxicity of oxaliplatin-based chemotherapy. Several genetic markers have been shown to predict oxaliplatin-induced PSN; however, results remain to be validated in a large-scale and prospective pharmacogenomics study. PATIENTS AND METHODS: Among 882 patients enrolled in the JFMC41-1001-C2 (JOIN trial), which was designed to investigate the tolerability of adjuvant-modified FOLFOX6 (mFOLFOX6) in Japanese Patients with stage II or III colon cancers undergoing curative resection, 465 patients were eligible for this pharmacogenomics analysis. Twelve single-nucleotide polymorphisms (SNPs) were selected based on published data. The effect of each genotype on time to PSN onset was evaluated in all patients (n = 465) using the Cox proportional hazard model. For the association analysis between severity of PSN and 12 SNP markers, 84 patients who failed to complete 12 cycles of mFOLFOX6 from grade 0/1 PSN group were excluded because the termination of the protocol treatment had been caused by reasons other than PSN. RESULTS: Comparison of grade 0/1 PSN with grade 2/3 PSN or grade 3 PSN showed no significant associations with any of the 12 SNP markers after adjustment for total dose of oxaliplatin. Time-to-onset analysis also failed to reveal any significant differences. CONCLUSIONS: Our large-scale and prospective pharmacogenomics study of Japanese patients receiving protocol treatment of adjuvant mFOLFOX6 could not verify a role for any of the 12 SNP markers reported as being significantly associated with PSN. Considering the OR observed in this study (range: 0.76-1.89), further evaluation of these 12 SNP markers in the context of L-OHP-induced PSN is unlikely to be clinically informative.
Authors: Leonidas Apostolidis; Lars Kowalscheck; Tim Frederik Weber; Tim Godel; Martin Bendszus; Hans-Ulrich Kauczor; Dirk Jäger; Heinz-Peter Schlemmer; Philipp Bäumer Journal: Clin Neuroradiol Date: 2021-09-09 Impact factor: 3.156
Authors: Jennifer G Le-Rademacher; Camden L Lopez; Rahul Kanwar; Brittny Major-Elechi; Alexej Abyzov; Michaela S Banck; Terry M Therneau; Jeff A Sloan; Charles L Loprinzi; Andreas S Beutler Journal: J Neurol Sci Date: 2020-01-14 Impact factor: 3.181
Authors: Araba A Adjei; Camden L Lopez; Daniel J Schaid; Jeff A Sloan; Jennifer G Le-Rademacher; Charles L Loprinzi; Aaron D Norman; Janet E Olson; Fergus J Couch; Andreas S Beutler; Celine M Vachon; Kathryn J Ruddy Journal: Cancers (Basel) Date: 2021-03-03 Impact factor: 6.639