KRAS Mutations Predict Response and Outcome in Advanced Lung Adenocarcinoma Patients Receiving First-Line Bevacizumab and Platinum-Based Chemotherapy
KRAS Mutations Predict Response and Outcome in Advanced Lung Adenocarcinoma Patients Receiving First-Line Bevacizumab and Platinum-Based Chemotherapy
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DOI：
10.3390/cancers11101514
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发表时间：
2019-10-01
期刊：
影响因子：
5.2
通讯作者：
Dome, Balazs
中科院分区：
文献类型：
--
作者：
Ghimessy, Aron Kristof;Gellert, Aron;Dome, Balazs
贝伐单抗联合铂类化疗已广泛应用于晚期肺腺癌的治疗。虽然KRAS(V-Ki-ras2 Kirsten鼠肉瘤病毒癌基因同源)突变是人类LADC中最常见的基因改变，其促进血管生成的作用已被证实，但其在上述背景下的预后和预测作用尚不清楚。回顾分析了501例接受一线铂类化疗(CHT)联合或不联合贝伐单抗(Bev)的高加索人IIIB-IV期LADC患者的KRAS外显子2突变状态与包括无进展生存期和总生存期(分别为PFS和OS)在内的临床病理变量的关系。排除了EGFR(表皮生长因子受体)突变病例。在247例Bev/CHT和254例CHT患者中，KRAS基因突变分别为95例(38.5%)和75例(29.5%)。在BEV/CHT组中，KRAS突变与吸烟(p=0.008)和女性(p=0.002)相关。我们发现在CHT组中，KRAS突变患者和KRAS野生型肿瘤患者的OS没有差异(p=0.6771)。值得注意的是，与KRAS野生型患者相比，KRAS突变肿瘤患者对BEV/CHT的反应显示出显著的PFS(p=0.0255)和OS(p=0.0186)。在BEV/CHT组中，KRAS突变是较短的PFS(风险比，0.597；p=0.011)和OS(风险比，0.645；p=0.012)的独立预测因子。接受Bev/CHT治疗的G12D KRAS突变患者的PFS(3.7月比G12/13x组的8.27个月；p=0.0032)和OS(7.2月比G12/13x组的16.1月；p=0.0144)明显缩短。在这项单中心的回顾性研究中，接受BEV/CHT治疗的KRAS突变LADC患者表现出比KRAS野生型晚期LADC患者更差的PFS和OS。G12D突变可能定义了不适合BEV抗血管生成治疗的KRAS突变LADC患者的子集。
Bevacizumab, combined with platinum-based chemotherapy, has been widely used in the treatment of advanced-stage lung adenocarcinoma (LADC). Although KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) mutation is the most common genetic alteration in human LADC and its role in promoting angiogenesis has been well established, its prognostic and predictive role in the above setting remains unclear. The association between KRAS exon 2 mutational status and clinicopathological variables including progression-free survival and overall survival (PFS and OS, respectively) was retrospectively analyzed in 501 Caucasian stage IIIB-IV LADC patients receiving first-line platinum-based chemotherapy (CHT) with or without bevacizumab (BEV). EGFR (epidermal growth factor receptor)-mutant cases were excluded. Of 247 BEV/CHT and 254 CHT patients, 95 (38.5%) and 75 (29.5%) had mutations in KRAS, respectively. KRAS mutation was associated with smoking (p = 0.008) and female gender (p = 0.002) in the BEV/CHT group. We found no difference in OS between patients with KRAS-mutant versus KRAS wild-type tumors in the CHT-alone group (p = 0.6771). Notably, patients with KRAS-mutant tumors demonstrated significantly shorter PFS (p = 0.0255) and OS (p = 0.0186) in response to BEV/CHT compared to KRAS wild-type patients. KRAS mutation was an independent predictor of shorter PFS (hazard ratio, 0.597; p = 0.011) and OS (hazard ratio, 0.645; p = 0.012) in the BEV/CHT group. G12D KRAS-mutant patients receiving BEV/CHT showed significantly shorter PFS (3.7 months versus 8.27 months in the G12/13x group; p = 0.0032) and OS (7.2 months versus 16.1 months in the G12/13x group; p = 0.0144). In this single-center, retrospective study, KRAS-mutant LADC patients receiving BEV/CHT treatment exhibited inferior PFS and OS compared to those with KRAS wild-type advanced LADC. G12D mutations may define a subset of KRAS-mutant LADC patients unsuitable for antiangiogenic therapy with BEV.