Hospital Universitario Fundación Alcorcón, Alcorcón, Spain.
Lancet Oncol. 2011 Nov;12(12):1143-50. doi: 10.1016/S1470-2045(11)70266-2. Epub 2011 Oct 17.
Sunitinib is a tyrosine kinase inhibitor with proven efficacy in renal-cell carcinoma, but some patients do not respond or need dose reductions due to toxicity. Because there are no validated molecular predictors of response or toxicity to sunitinib, we aimed to identify genetic markers predictive of outcome and toxic effects.
In our observational, prospective study we enrolled previously untreated adults (≥ 18 years) with clear-cell renal-cell carcinoma at 15 institutions in the Spanish Oncology Genitourinary Group in Spain. Patients received sunitinib according to local practice guidelines. We assessed RECIST response, progression-free survival (PFS), overall survival, and toxicity of sunitinib with 16 key polymorphisms in nine genes: VEGFR2 (rs2305948 and rs1870377), VEGFR3 (rs307826, rs448012, and rs307821), PDGFR-α (rs35597368), VEGF-A (rs2010963, rs699947, and rs1570360), IL8 (rs1126647), CYP3A4 (rs2740574), CYP3A5 (rs776746), ABCB1 (rs1045642, rs1128503, and rs2032582), and ABCB2 (rs2231142). We assessed associations with efficacy and toxicity by use of univariable and multivariable analyses (with clinical factors associated with outcomes as covariates). We adjusted for multiplicity using the Bonferroni method; p values of less than 0·0031 before adjustment were deemed to still be significant after adjustment.
We enrolled 101 patients between Oct 10, 2007, and Dec 13, 2010. 95 of these patients were included in toxicity analyses and 89 in the efficacy analyses. Two VEGFR3 missense polymorphisms were associated with reduced PFS with sunitinib on multivariable analysis: rs307826 (hazard ratio [HR] per allele 3·57, 1·75-7·30; p(unadjusted)=0·00049, p(adjusted)=0·0079) and rs307821 (3·31, 1·64-6·68; p(unadjusted)=0·00085, p(adjusted)=0·014). The CYP3A5*1 (rs776746) high metabolising allele was associated in a multivariable analysis with an increased risk of dose reductions due to toxicity (HR per allele 3·75, 1·67-8·41; p(unadjusted)=0·0014, p(adjusted)=0·022). No other SNPs were associated with sunitinib response or toxicity.
Polymorphisms in VEGFR3 and CYP3A5*1 might be able to define a subset of patients with renal-cell carcinoma with decreased sunitinib response and tolerability. If confirmed, these results should promote interventional studies testing alternative therapeutic approaches for patients with such variants.
Pfizer.
舒尼替尼是一种已被证实对肾细胞癌有效的酪氨酸激酶抑制剂，但由于毒性作用，一些患者无反应或需要减少剂量。由于没有经过验证的对舒尼替尼反应或毒性的分子预测因子，我们旨在确定对结果和毒性有预测作用的遗传标记物。
在我们的观察性、前瞻性研究中，我们在西班牙肿瘤泌尿生殖集团的 15 个机构中招募了之前未经治疗的成年人（≥ 18 岁），他们患有透明细胞肾细胞癌。患者根据当地的实践指南接受舒尼替尼治疗。我们使用 9 个基因中的 16 个关键多态性来评估 RECIST 反应、无进展生存期（PFS）、总生存期和舒尼替尼的毒性：VEGFR2（rs2305948 和 rs1870377）、VEGFR3（rs307826、rs448012 和 rs307821）、PDGFR-α（rs35597368）、VEGF-A（rs2010963、rs699947 和 rs1570360）、IL8（rs1126647）、CYP3A4（rs2740574）、CYP3A5（rs776746）、ABCB1（rs1045642、rs1128503 和 rs2032582）和 ABCB2（rs2231142）。我们使用单变量和多变量分析（将与结局相关的临床因素作为协变量）来评估与疗效和毒性的关联。我们使用 Bonferroni 方法进行多重性调整；调整前 p 值小于 0.0031 仍被认为在调整后具有统计学意义。
我们于 2007 年 10 月 10 日至 2010 年 12 月 13 日期间招募了 101 名患者。其中 95 名患者纳入毒性分析，89 名患者纳入疗效分析。两个 VEGFR3 错义多态性与多变量分析中舒尼替尼的 PFS 降低相关：rs307826（每个等位基因的风险比 3.57，1.75-7.30；未调整 p 值=0.00049，调整后 p 值=0.0079）和 rs307821（3.31，1.64-6.68；未调整 p 值=0.00085，调整后 p 值=0.014）。CYP3A5*1（rs776746）高代谢等位基因与因毒性而减少剂量的风险增加相关（每个等位基因的风险比 3.75，1.67-8.41；未调整 p 值=0.0014，调整后 p 值=0.022）。其他 SNP 与舒尼替尼反应或毒性无相关性。
VEGFR3 和 CYP3A5*1 中的多态性可能能够确定肾细胞癌患者中对舒尼替尼反应和耐受性降低的亚组。如果得到证实，这些结果应促进对具有这些变体的患者进行替代治疗方法的干预性研究。
辉瑞公司。
