Clinical, pathologic, and biologic features associated with BRAF mutations in non-small cell lung cancer.
Clinical, pathologic, and biologic features associated with BRAF mutations in non-small cell lung cancer.
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DOI：
10.1158/1078-0432.ccr-13-0657
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发表时间：
2013-08-15
期刊：
影响因子：
--
通讯作者：
Jänne PA
中科院分区：
文献类型：
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作者：
Cardarella S;Ogino A;Nishino M;Butaney M;Shen J;Lydon C;Yeap BY;Sholl LM;Johnson BE;Jänne PA
BRAF突变在非小细胞肺癌（NSCLC）的一个子集中发现。我们研究了携带BRAF突变的NSCLC患者的临床特征和治疗结果。使用DNA测序，我们成功地筛选了883例NSCLC患者在2009年7月1日至2012年7月16日之间的BRAF突变。比较有和无BRAF突变患者的基线特征和治疗结局。野生型对照包括BRAF、KRAS、EGFR和ALK无体细胞改变的NSCLC患者。体外研究评估了从NSCLC患者中鉴定的选定非V600 E BRAF突变的生物学特性。在筛选的883例肿瘤中，36例（4%）携带BRAF突变（V600 E：18例;非V600 E：18例），257例为BRAF、EGFR、KRAS和ALK阴性野生型。36名BRAF突变患者中有29名是吸烟者。BRAF突变型和野生型患者之间没有区别的临床特征。BRAF突变和野生型肿瘤的晚期NSCLC患者显示，含铂联合化疗的缓解率和无进展生存期（PFS）相似，总生存期无差异。在BRAF队列中，与非V600 E突变的患者相比，V600 E突变肿瘤患者接受铂类化疗的PFS较短，尽管这没有达到统计学显著性（4.1 vs 8.9个月; P=0.297）。我们发现了5个以前未在NSCLC中报道的BRAF突变;其中2个与BRAF激酶活性增加相关。BRAF突变发生在4%的NSCLC中，一半是非V600 E。正在进行前瞻性试验，以验证BRAF作为NSCLC的治疗靶点。
BRAF mutations are found in a subset of non-small cell lung cancers (NSCLCs). We examined the clinical characteristics and treatment outcomes of patients with NSCLC harboring BRAF mutations. Using DNA sequencing, we successfully screened 883 NSCLC patients for BRAF mutations between 7/1/09 and 7/16/12. Baseline characteristics and treatment outcomes were compared between patients with and without BRAF mutations. Wild type controls consisted of NSCLC patients without a somatic alteration in BRAF, KRAS, EGFR, and ALK. In vitro studies assessed the biological properties of selected non-V600E BRAF mutations identified from NSCLC patients. Of 883 tumors screened, 36 (4%) harbored BRAF mutations (V600E: 18; non-V600E: 18) and 257 were wild type for BRAF, EGFR, KRAS, and ALK negative. Twenty-nine of the 36 BRAF mutant patients were smokers. There were no distinguishing clinical features between BRAF mutant and wild type patients. Advanced NSCLC patients with BRAF mutations and wild type tumors showed similar response rates and progression-free survival (PFS) to platinum-based combination chemotherapy and no difference in overall survival. Within the BRAF cohort, patients with V600E mutated tumors had a shorter PFS to platinum-based chemotherapy compared to those with non-V600E mutations, although this did not reach statistical significance (4.1 versus 8.9 months; P=0.297). We identified five BRAF mutations not previously reported in NSCLC; two of the five were associated with increased BRAF kinase activity. BRAF mutations occur in 4% of NSCLCs and half are non-V600E. Prospective trials are ongoing to validate BRAF as a therapeutic target in NSCLC.