Optimizing targeted therapeutic development: analysis of a colorectal cancer patient population with the BRAFV600E mutation
Optimizing targeted therapeutic development: analysis of a colorectal cancer patient population with the BRAFV600E mutation
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DOI：
10.1002/ijc.25555
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发表时间：
2011-05-01
影响因子：
6.4
通讯作者：
Desai, Jayesh
中科院分区：
文献类型：
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作者：
Tie, Jeanne;Gibbs, Peter;Desai, Jayesh
BRAF（V600 E）突变在10%的结直肠癌（CRC）中发现。因此，这种突变的低频率使其成为药物开发的一个具有挑战性的目标，除非可以定义具有较高BRAF（V600 E）发生率的患者子集。了解原发性-转移对之间的一致性以及BRAF（V600 E）对结果的影响也将有助于最佳药物开发。我们从525例年龄（< 70 and >≥ 70岁）、性别和肿瘤位置（右侧、左侧和直肠）均匀匹配的患者（I-IV期）中选择原发性CRC，并选择81对原发性转移癌。BRAF（V600 E），KRAS突变和微卫星不稳定性（MSI）进行了测定，并与临床特征和患者的结果。在多变量分析中，患者年龄（p = 0.04）、女性（p = 0.0005）和右侧肿瘤位置（p < 0.0001）的增加与BRAF（V600 E）独立相关。BRAF（V600 E）的患病率在患有KRAS野生型右侧结肠癌的老年（年龄> 70岁）女性中（50%）显著高于KRAS队列（10%）。BRAF（V600 E）与转移性CRC的总生存率较低相关（HR = 2.02; 95% CI 1.26-3.26），在接受化疗的患者中尤其明显，并且与MSI状态无关。BRAF状态在所有原发性肿瘤和匹配的转移瘤中是一致的（79对野生型和2对突变型）。临床病理和分子特征可以识别BRAF（V600 E）患病率较高的CRC患者。BRAF（V600 E）野生型原发性肿瘤患者在转移灶中似乎不会获得突变，而BRAF（V600 E）与转移性患者的预后较差相关。我们的发现是及时的，将有助于为BRAF（V600 E）抑制剂在CRC中的合理开发提供信息。
BRAF(V600E) mutations are found in 10% of colorectal cancers (CRCs). The low frequency of this mutation therefore makes it a challenging target for drug development, unless subsets of patients with higher rates of BRAF(V600E) can be defined. Knowledge of the concordance between primary-metastasis pairs and the impact of BRAF(V600E) on outcome would also assist in optimal drug development. We selected primary CRCs from 525 patients (stages I-IV) evenly matched for age (< 70 and >= 70), gender and tumor location (right, left and rectum), and 81 primary-metastasis pairs. BRAF(V600E), KRAS mutation and microsatellite instability (MSI) were determined and correlated with clinical features and patient outcomes. In multivariate analyses, increasing patient age (p = 0.04), female gender (p = 0.0005) and right-sided tumor location (p < 0.0001) were independently associated with BRAF(V600E). The prevalence of BRAF(V600E) was considerably higher in older (age > 70) females with KRAS wild-type right-sided colon cancers (50%) compared to the unselected cohort (10%). BRAF(V600E) was associated with inferior overall survival in metastatic CRC (HR = 2.02; 95% CI 1.26-3.26), particularly evident in patients treated with chemotherapy, and is independent of MSI status. BRAF status was concordant in all primary tumors and matched metastases (79 wild-type pairs and two mutant pairs). Clinicopathological and molecular features can identify CRC patients with a higher prevalence of BRAF(V600E). Patients with BRAF(V600E) wild-type primary tumor do not appear to acquire the mutation in their metastases, and BRAF(V600E) is associated with poorer outcomes in metastatic patients. Our findings are timely and will help inform the rational development of BRAF(V600E) inhibitors in CRC.