Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York.
Department of Urology, New York Medical College, Valhalla, New York, USA.
Curr Opin Urol. 2019 Sep;29(5):531-539. doi: 10.1097/MOU.0000000000000663.
Recent publications evaluating cytoreductive nephrectomy in the era of targeted therapy emphasize the importance of patient selection. We reviewed the predictive role of genetic alterations in patients with metastatic renal cell carcinoma (mRCC) undergoing cytoreductive nephrectomy.
Studies evaluating the association between genetic alterations and outcomes following systemic treatment for mRCC include mainly patients after cytoreductive nephrectomy. Expression of proangiogenic genes, single nucleotide polymorphisms involving genes of the vascular-endothelial growth factor (VEGF) pathway and somatic mutations of chromatin remodeling genes were associated with response to VEGF-targeted therapy. Outcomes following treatment with mammalian target of rapamycin (mTOR) inhibitors were initially associated with mTOR/TSC1/TSC2 mutations; however, subsequent studies did not validate these findings but rather found an association between loss of PTEN expression and PBRM1 mutations and improved outcomes. Loss of PBRM1 was initially linked to response to immunotherapy; however, larger studies question this association and showed high expression of T-effector gene signature predicted improved outcome. Primary tumors with low intratumor heterogeneity but elevated somatic copy-number alterations were associated with rapid progression at multiple sites.
Genetic alterations may help select patients for cytoreductive nephrectomy and optimize timing of treatment. Intratumor heterogeneity and genetic discordance between primary and metastatic tumors may limit clinical applicability. Future studies should evaluate approaches to overcome these limitations.
最近评估靶向治疗时代细胞减灭性肾切除术的文献强调了患者选择的重要性。我们回顾了转移性肾细胞癌（mRCC）患者细胞减灭性肾切除术后遗传改变的预测作用。
评估基因改变与 mRCC 全身治疗后结局之间关系的研究主要包括接受细胞减灭性肾切除术的患者。促血管生成基因的表达、血管内皮生长因子（VEGF）途径涉及的基因的单核苷酸多态性和染色质重塑基因的体细胞突变与 VEGF 靶向治疗的反应相关。哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂治疗后的结局最初与 mTOR/TSC1/TSC2 突变相关；然而，随后的研究没有验证这些发现，而是发现 PTEN 表达缺失和 PBRM1 突变与改善结局相关。PBRM1 的缺失最初与免疫治疗反应相关；然而，更大的研究对这种关联提出了质疑，并显示 T 效应基因特征的高表达预测了更好的结局。肿瘤内异质性低但体细胞拷贝数改变升高的原发肿瘤与多个部位的快速进展相关。
遗传改变可能有助于选择接受细胞减灭性肾切除术的患者，并优化治疗时机。肿瘤内异质性和原发肿瘤与转移肿瘤之间的遗传差异可能限制了临床应用。未来的研究应评估克服这些限制的方法。
