转移性肾细胞癌(RCC)患者通常使用血管内皮生长因子(VEGF)抑制剂或雷帕霉素抑制剂的哺乳动物靶标进行治疗。在一项随机试验中,尚未报道体细胞突变与一线靶向治疗结果之间的相关性。
为了评估RECORD-3中肿瘤突变与治疗结果之间的关系,这是一项随机试验,比较了471例转移性肾癌患者中一线依维莫司(mTOR抑制剂)和舒尼替尼(VEGF抑制剂)在进展中的相反顺序。
对来自258例患者的可用肿瘤样本进行了约540×覆盖率的341个癌症基因的靶向测序;220个透明细胞组织学(ccRCC)。
使用Cox比例风险模型和对数秩检验在转移性ccRCC中确定体细胞突变与中位一线无进展生存期(PFS1L)和总生存期之间的关联。
流行突变(≥10%)为VHL(75%),PBRM1(46%),SETD2(30%),BAP1(19%),KDM5C(15%),和PTEN(12%)。用一线依维莫司,PBRM1和BAP1突变与更长(中位数[95%置信区间{CI}]12.8[8.1,18.4]vs5.5[3.1,8.4]mo)和更短(中位数[95%CI]4.9[2.9,8.1]vs10.5[7.3,12.9]mo)PFS1L相关,分别。使用一线舒尼替尼,KDM5C突变与较长的PFS1L相关(中位数[95%CI]20.6[12.4,27.3]vs8.3[7.8,11.0]mo)。基于PBRM1,BAP1和KDM5C突变的转移性ccRCC的分子亚组可能对VEGF或mTOR抑制剂治疗的患者具有预测价值。大多数肿瘤DNA来自原发性肾切除术样本(94%),这可能会影响相关性统计。
PBRM1、BAP1和KDM5C突变影响转移性ccRCC患者靶向治疗的结果。
大规模基因组肾癌研究报告了单个肿瘤之间的新突变和异质性特征。这可能导致不同的临床结果。我们证明了体细胞突变与透明细胞肾细胞癌治疗结果之间的相关性,支持基因组分类在前瞻性研究中的价值。
Metastatic renal cell carcinoma (RCC) patients are commonly treated with vascular endothelial growth factor (VEGF) inhibitors or mammalian target of rapamycin inhibitors. Correlations between somatic mutations and first-line targeted therapy outcomes have not been reported on a randomized
trial.
To evaluate the relationship between tumor mutations and treatment outcomes in RECORD-3, a randomized
trial comparing first-line everolimus (mTOR inhibitor) followed by sunitinib (VEGF inhibitor) at progression with the opposite sequence in 471 metastatic RCC patients.
Targeted sequencing of 341 cancer genes at ∼540× coverage was performed on available tumor samples from 258 patients; 220 with clear cell histology (ccRCC).
Associations between somatic mutations and median first-line progression free survival (PFS1L) and overall survival were determined in metastatic ccRCC using Cox proportional hazards models and log-rank tests.
Prevalent mutations (≥ 10%) were VHL (75%), PBRM1 (46%), SETD2 (30%), BAP1 (19%), KDM5C (15%), and PTEN (12%). With first-line everolimus, PBRM1 and BAP1 mutations were associated with longer (median [95% confidence interval {CI}] 12.8 [8.1, 18.4] vs 5.5 [3.1, 8.4] mo) and shorter (median [95% CI] 4.9 [2.9, 8.1] vs 10.5 [7.3, 12.9] mo) PFS1L, respectively. With first-line sunitinib, KDM5C mutations were associated with longer PFS1L (median [95% CI] of 20.6 [12.4, 27.3] vs 8.3 [7.8, 11.0] mo). Molecular subgroups of metastatic ccRCC based on PBRM1, BAP1, and KDM5C mutations could have predictive values for patients treated with VEGF or mTOR inhibitors. Most tumor DNA was obtained from primary nephrectomy samples (94%), which could impact correlation statistics.
PBRM1, BAP1, and KDM5C mutations impact outcomes of targeted therapies in metastatic ccRCC patients.
Large-scale genomic kidney cancer studies reported novel mutations and heterogeneous features among individual tumors, which could contribute to varied clinical outcomes. We demonstrated correlations between somatic mutations and treatment outcomes in clear cell renal cell carcinoma, supporting the value of genomic classification in prospective studies.