PIK3CA Mutation Associates with Improved Outcome in Breast Cancer
PIK3CA Mutation Associates with Improved Outcome in Breast Cancer
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DOI：
10.1158/1078-0432.ccr-09-0632
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发表时间：
2009-08-15
影响因子：
11.5
通讯作者：
Moynahan, Mary Ellen
中科院分区：
文献类型：
--
作者：
Kalinsky, Kevin;Jacks, Lindsay M.;Moynahan, Mary Ellen
目的：在乳腺癌中，PIK3CA基因的体细胞突变很常见。由于中等规模的研究得出了不同的结果，这些激活突变的预后意义仍不确定。我们的目的是确定PIK3CA突变在乳腺癌中的预后意义。
实验设计：对来自590例已知生存状态的患者的福尔马林固定石蜡包埋的原发性乳腺肿瘤存档样本进行基因分型以检测PIK3CA突变，这些患者的中位随访时间为12.8年且肿瘤＞1厘米。评估了突变率以及突变位点与临床病理特征之间的关联。使用卡普兰 - 迈耶法或竞争风险方法分析无进展生存期、总生存期和乳腺癌特异性生存期。
结果：在32.5%的乳腺癌中发现了PIK3CA突变。PIK3CA突变与诊断时年龄较大、激素受体阳性、HER2阴性、较低的肿瘤分级和分期以及淋巴结阴性显著相关。PIK3CA突变肿瘤患者的总生存期（P = 0.03）和乳腺癌特异性生存期（P = 0.004）有显著改善。对PIK3CA突变位点特异性关联的分析显示，H1047R激酶结构域突变与淋巴结阴性高度相关（P = 0.007），而螺旋结构域热点突变与诊断时年龄较大相关（P = 0.004）。
结论：本研究确定了PIK3CA突变的积极预后意义。这项工作具有临床相关性，因为它将显著影响针对磷脂酰肌醇3 - 激酶靶向治疗的临床试验设计。未来的工作可能会确定一类年龄较大的乳腺癌患者，对其可减少治疗。（《临床癌症研究》2009年；15(16):5049 - 59）
Purpose: In breast cancer, somatic mutations in the PIK3CA gene are common. The prognostic implication of these activating mutations remains uncertain as moderately sized studies have yielded variable outcomes. Our aim was to determine the prognostic implications of PIK3CA mutations in breast cancer.Experimental Design:Archival formalin-fixed paraffin-embedded primary breasttumors, from 590 patients selected for known vital status with a median follow-up of 12.8 years and a tumor >1 cm, were genotyped for PIK3CA mutations. Mutation rates and associations between mutation site and clinicopathologic characteristics were assessed. Progression-free survival, overall survival, and breast cancer-specific survival were examined using Kaplan-Meier or competing risk methodology.Results: PIK3CA mutation is identified in 32.5% of breast cancers. PIK3CA mutation significantly associates with older age at diagnosis, hormone receptor positivity, HER2 negativity, lower tumor grade and stage, and lymph node negativity. Patients with PIK3CA mutated tumors have significant improvement in overall survival (P = 0.03) and breast cancer-specific survival (P = 0.004). Analysis for PIK3CA mutation site-specific associations reveals that the H1047R kinase domain mutation highly associates with node negativity (P = 0.007), whereas helical domain hotspot mutations associate with older age at diagnosis (P = 0.004).Conclusion: This study defines the positive prognostic significance of PIK3CA mutations. This work is clinically relevant, as it will significantly affect the design of clinical trials planned for phosphatidylinositol 3-kinase-targeted therapy. Future work may define a population of older age breast cancer patients in whom therapy can be minimized. (Clin Cancer Res 2009;15(16):5049-59)