Kazuhiro Yamamoto1, Kazuaki Shinomiya2, Takeshi Ioroi3, Sachi Hirata3, Kenichi Harada4, Manabu Suno5, Tatsuya Nishioka3, Manabu Kume3, Hiroo Makimoto3, Tsutomu Nakagawa3,6, Takeshi Hirano3,6, Toshinori Bito7, Chikako Nishigori7, Hideaki Miyake4, Masato Fujisawa4, Midori Hirai3,6. 1. Department of Pharmacy, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan. yamakz@med.kobe-u.ac.jp. 2. Department of Clinical Psycho-Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, 1-1-1 Tsushima-naka, Okayama, 700-8530, Japan. 3. Department of Pharmacy, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan. 4. Division of Urology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan. 5. Department of Oncology Pharmaceutical Care & Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, 1-1-1 Tsushima-naka, Okayama, 700-8530, Japan. 6. Division of Pharmacokinetics, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan. 7. Division of Dermatology, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
Abstract
BACKGROUND: Signal transducer and activator of transcription (STAT)3 is a reported mediator of molecular-targeted drug-induced keratinocyte toxicity. AIM: Our purpose was to assess the association of single nucleotide polymorphisms (SNPs) in STAT3 with hand-foot skin reactions (HFSR) in patients with metastatic renal cell carcinoma (mRCC) treated with multiple tyrosine kinase inhibitors (mTKIs). PATIENTS AND METHODS: Sixty-five Japanese patients with clear cell renal cell carcinoma who were treated with any mTKI at Kobe University Hospital were retrospectively genotyped to elucidate a potential association between STAT3 polymorphisms and HFSR development. RESULTS: The final analysis included 60 patients. HFSR was observed in 46 patients. The GG, GC, and CC genotypes at rs4796793 were found in 9, 27, and 24 patients, respectively. Three other STAT3 polymorphisms exhibited tight linkage disequilibrium with rs4796793. A significant association was found between the rs4796793 allele and HFSR [G vs. C; odds ratio [OR], 4.33; 95 % confidence interval [CI], 1.80-10.45; P = 0.001]. The GG genotype had the highest OR compared with GC + CC genotypes (OR, 10.75; 95 % CI, 2.38-48.07; P = 0.001). In a time-to-event Kaplan-Meier analysis, a statistically significant difference was observed between the GC + CC and the GG genotypes (P = 0.009). CONCLUSIONS: The rs4796793 genotype appears to be a novel factor for mTKI-induced HFSR in patients with mRCC. Prospective translational trials with larger numbers of patients are required to confirm our results. This research suggests a potential benefit of STAT3 polymorphism screening in patients treated with mTKIs.
BACKGROUND:Signal transducer and activator of transcription (STAT)3 is a reported mediator of molecular-targeted drug-induced keratinocyte toxicity. AIM: Our purpose was to assess the association of single nucleotide polymorphisms (SNPs) in STAT3 with hand-foot skin reactions (HFSR) in patients with metastatic renal cell carcinoma (mRCC) treated with multiple tyrosine kinase inhibitors (mTKIs). PATIENTS AND METHODS: Sixty-five Japanese patients with clear cell renal cell carcinoma who were treated with any mTKI at Kobe University Hospital were retrospectively genotyped to elucidate a potential association between STAT3 polymorphisms and HFSR development. RESULTS: The final analysis included 60 patients. HFSR was observed in 46 patients. The GG, GC, and CC genotypes at rs4796793 were found in 9, 27, and 24 patients, respectively. Three other STAT3 polymorphisms exhibited tight linkage disequilibrium with rs4796793. A significant association was found between the rs4796793 allele and HFSR [G vs. C; odds ratio [OR], 4.33; 95 % confidence interval [CI], 1.80-10.45; P = 0.001]. The GG genotype had the highest OR compared with GC + CC genotypes (OR, 10.75; 95 % CI, 2.38-48.07; P = 0.001). In a time-to-event Kaplan-Meier analysis, a statistically significant difference was observed between the GC + CC and the GG genotypes (P = 0.009). CONCLUSIONS: The rs4796793 genotype appears to be a novel factor for mTKI-induced HFSR in patients with mRCC. Prospective translational trials with larger numbers of patients are required to confirm our results. This research suggests a potential benefit of STAT3 polymorphism screening in patients treated with mTKIs.
Authors: Bernard Escudier; Tim Eisen; Walter M Stadler; Cezary Szczylik; Stéphane Oudard; Michael Siebels; Sylvie Negrier; Christine Chevreau; Ewa Solska; Apurva A Desai; Frédéric Rolland; Tomasz Demkow; Thomas E Hutson; Martin Gore; Scott Freeman; Brian Schwartz; Minghua Shan; Ronit Simantov; Ronald M Bukowski Journal: N Engl J Med Date: 2007-01-11 Impact factor: 91.245