Toulouse University Hospital, Paul Sabatier Toulouse University, Toulouse, France.
Aix-Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France.
J Thorac Oncol. 2017 Jun;12(6):963-973. doi: 10.1016/j.jtho.2017.02.001. Epub 2017 Feb 9.
Little is known about the prevalence, prognosis, and response to treatment of advanced NSCLC harboring multiple genomic alterations.
The French Biomarkers France database, which includes 17,664 patients, was used. The prevalence of multiple alterations, their associations, their impact on prognosis (overall survival [OS]), and their response to targeted or conventional treatments (progression-free survival [PFS] and objective response rate) were assessed and compared with those of patients harboring single or no mutation.
We identified 162 patients (0.9%) with double alterations and three with triple mutations. Multiple molecular alterations preferentially involved KRAS (67.3%), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA) (53.3%), and EGFR (42.4%). Patients with multiple alterations were more likely to be male (56.4%), be never-smokers (25.8 versus 34.7%, p < 0.001), and exhibit adenocarcinomas (83.6%). OS did not differ between single and multiple alterations. Patients with EGFR/KRAS and EGFR/PIK3CA mutations experienced worse PFS than did patients with only EGFR mutations (7.1 and 7.1 versus 14.9 months, p = 0.02 and 0.002, respectively). Concomitant mutations in patients harboring anaplastic lymphoma receptor tyrosine kinase gene (ALK) rearrangement bore little impact on OS (17.7 versus 20.3 months, p = 0.57) or PFS (10.3 versus 12.1 months, p = 0.93). Patients harboring KRAS mutations plus another alteration had an OS time (13.4 versus 11.2 months, p = 0.28), PFS time (6.4 versus 7.2 months, p = 0.78), and objective response rate under first-line chemotherapy (41.7% versus 37.2%) similar to those of patients harboring KRAS mutations only.
With almost 1% of patients harboring multiple alterations, the dogma of mutually exclusive mutations should be reconsidered. Although double mutations do not decrease OS, they do alter PFS under first-line treatment for patients with EGFR mutations. Among limited numbers of patients, therapies targeting the dominant oncogene seem to usually remain active.
关于同时存在多种基因改变的晚期 NSCLC 的患病率、预后和治疗反应，目前知之甚少。
使用了包含 17664 名患者的法国生物标志物法国数据库。评估了多种改变的患病率、它们之间的关联、它们对总生存期（OS）的影响以及它们对靶向或常规治疗（无进展生存期 [PFS] 和客观缓解率）的反应，并与仅存在单种或无突变的患者进行了比较。
我们发现 162 名患者（0.9%）存在双重改变，3 名患者存在三重突变。多种分子改变优先涉及 KRAS（67.3%）、磷脂酰肌醇-4,5-二磷酸 3-激酶催化亚单位α基因（PIK3CA）（53.3%）和 EGFR（42.4%）。存在多种改变的患者更可能为男性（56.4%）、从不吸烟者（25.8%比 34.7%，p<0.001），并且表现为腺癌（83.6%）。单种和多种改变之间的 OS 无差异。存在 EGFR/KRAS 和 EGFR/PIK3CA 突变的患者的 PFS 不如仅存在 EGFR 突变的患者（7.1 和 7.1 比 14.9 个月，p=0.02 和 0.002）。存在间变性淋巴瘤激酶受体酪氨酸激酶基因（ALK）重排的同时突变对 OS（17.7 比 20.3 个月，p=0.57）或 PFS（10.3 比 12.1 个月，p=0.93）几乎没有影响。存在 KRAS 突变加另一种改变的患者的 OS 时间（13.4 比 11.2 个月，p=0.28）、PFS 时间（6.4 比 7.2 个月，p=0.78）和一线化疗的客观缓解率（41.7%比 37.2%）与仅存在 KRAS 突变的患者相似。
近 1%的患者存在多种改变，相互排斥突变的教条应该重新考虑。虽然双重突变不会降低 OS，但它们确实会改变 EGFR 突变患者一线治疗下的 PFS。在有限数量的患者中，针对优势致癌基因的治疗似乎通常仍然有效。
