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    EGFR基因
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    EGFR基因检测涵盖但不限于exon19del，L858R，T790M，exon20ins，G719X，E709K，S768I，L861Q，L792H，G796R，C797S等突变以及拷贝数扩增。
    携带某些EGFR突变（如19号外显子缺失，L858R，L861，G719，S768等）的肿瘤对一/二代EGFR-TKI敏感。携带某些EGFR突变（如T790M）的肿瘤可能对一/二代EGFR-TKI耐药，但对三代EGFR-TKI敏感。携带EGFR20号外显子插入突变的肿瘤可能对现有EGFR-TKI都不敏感，针对性TKI正在早期研发中。携带EGFR扩增的肺鳞癌可能对抗-EGFR抗体敏感。

    突变丰度指在该位点所有的等位基因中，突变的等位基因的占比（相对野生型等位基因）。例如，突变丰度40%意为该位点含有40%的突变等位基因和60%的野生型等位基因。
    EGFR是一个表皮生长因子受体，为跨膜酪氨酸受体激酶的一种。EGFR突变是肺癌中一个最主要的分子亚型。该基因的激活性突变可以促进细胞的异常增殖、分化以及血管增生，并能抑制肿瘤细胞的凋亡。据TCGA与COSMIC数据库报导，EGFR突变占西方非小细胞肺癌患者的10～20％。这一比例在东亚，女性，无吸烟史肺腺癌患者中尤其高，可以达到50%左右。

    图一：EGFR信号传导通路

    临床上多见的EGFR突变集中出现在18到21号外显子中，这段序列编码EGFR的激酶区域。2004年开始的多项研究发现，肺癌中EGFR突变与EGFR靶向抑制剂疗效密切相关。国际上多个大型临床试验已证实EGFR突变肺癌患者是小分子抑制剂gefitinib（吉非替尼，易瑞沙）、erlotinib（厄洛替尼，特罗凯）、icotinib（埃克替尼，凯美纳）的敏感人群。EGFR突变检测已经被写入美国国家综合癌症网络（NCCN）的肺癌治疗指南。EGFR突变还存在于其他肿瘤。EGFR变异形式还包括EGFR拷贝数增加和高表达，这些变异在临床药物特别是单克隆抗体中的研究正在进行中。
    EGFR的突变多为杂合性的，常见的EGFR突变包括以下几种：


    图二：EGFR基因上的常见突变分布


    参考文献：
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    5. Paz-Ares L, Socinski MA, Shahidi J, Hozak RR, Soldatenkova V, Kurek R, Varella-Garcia M, Thatcher N, Hirsch FR.(2016).Correlation of EGFR-expression with safety and efficacy outcomes in SQUIRE: a randomized, multicenter, open-label, phase III study of gemcitabine-cisplatin plus necitumumab versus gemcitabine-cisplatin alone in the first-line treatment of patients with stage IV squamous non-small-cell lung cancer. Ann Oncol.27(8):1573-9.
    6. Kwak, E. L., Bang, Y. J., Camidge, D. R., Shaw, A. T., Solomon, B., Maki, R. G., Ou, S. H., Dezube, B. J., Janne, P. A., Costa, D. B., et al. (2010). Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. The New England journal of medicine 363, 1693-1703.
    7. Drilon, A., Wang, L., Hasanovic, A., Suehara, Y., Lipson, D., Stephens, P., Ross, J., Miller, V., Ginsberg, M., Zakowski, M. F., et al. (2013). Response to Cabozantinib in patients with RET fusion-positive lung adenocarcinomas. Cancer discovery 3, 630-635.
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    10. Solomon, B. J., Mok, T., Kim, D. W., Wu, Y. L., Nakagawa, K., Mekhail, T., Felip, E., Cappuzzo, F., Paolini, J., Usari, T., et al. (2014). First-line crizotinib versus chemotherapy in ALK-positive lung cancer. The New England journal of medicine 371, 2167-2177.
    11. Frampton, G. M., Ali, S. M., Rosenzweig, M., Chmielecki, J., Lu, X., Bauer, T. M., Akimov, M., Bufill, J. A., Lee, C., Jentz, D., et al. (2015). Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer discovery 5, 850-859.
    12. Gautschi, O., Milia, J., Cabarrou, B., Bluthgen, M. V., Besse, B., Smit, E. F., Wolf, J., Peters, S., Fruh, M., Koeberle, D., et al. (2015). Targeted Therapy for Patients with BRAF-Mutant Lung Cancer: Results from the European EURAF Cohort. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 10, 1451-1457.
    13. Hyman, D. M., Puzanov, I., Subbiah, V., Faris, J. E., Chau, I., Blay, J. Y., Wolf, J., Raje, N. S., Diamond, E. L., Hollebecque, A., et al. (2015). Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations. The New England journal of medicine 373, 726-736.
    14. Janne, P. A., Yang, J. C., Kim, D. W., Planchard, D., Ohe, Y., Ramalingam, S. S., Ahn, M. J., Kim, S. W., Su, W. C., Horn, L., et al. (2015). AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. The New England journal of medicine 372, 1689-1699.
    15. Paik, P. K., Drilon, A., Fan, P. D., Yu, H., Rekhtman, N., Ginsberg, M. S., Borsu, L., Schultz, N., Berger, M. F., Rudin, C. M., and Ladanyi, M. (2015). Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping. Cancer discovery 5, 842-849.
    16. Sequist, L. V., Soria, J. C., Goldman, J. W., Wakelee, H. A., Gadgeel, S. M., Varga, A., Papadimitrakopoulou, V., Solomon, B. J., Oxnard, G. R., Dziadziuszko, R., et al. (2015). Rociletinib in EGFR-mutated non-small-cell lung cancer. The New England journal of medicine 372, 1700-1709.
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    19. Mengoli MC, Barbieri F, Bertolini F, Tiseo M, Rossi G.(2016).K-RAS mutations indicating primary resistance to crizotinib in ALK-rearranged adenocarcinomas of the lung: Report of two cases and review of the literature. Lung Cancer.93:55-8.
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    • 药优 管理员 2020-06-07 20:02 20:021楼

      与野生型EGFR（EGFR-WT）相比，具有EGFR突变（EGFR-mut）的晚期NSCLC患者的无进展生存期较长。然而，EGFR突变以及突变亚型在早期肺癌预后中的意义尚不清楚。Takamochi及其同事开展了一项研究探讨EGFR-mut和特异性EGFR-mut在手术切除肺腺癌患者预后中的价值。
      他们回顾性分析了939例患者的资料，发现与EGFR-WT相比，EGFR-mut患者的5年总生存期（OS）较长相关。点突变（21号外显子 L858R点突变（L858R）与19号外显子缺失（19-del））对患者的预后并无影响。


      该研究值得我们进行探讨。首先，该研究纳入的肺腺癌（45％ EGFR-mut）患者的数量（939）较多。其次，研究者排除了围手术期治疗的患者，有助于确定不接受酪氨酸激酶抑制（TKI）治疗患者中EGFR-mut的预后作用。作者的研究纠正了荟萃分析的结果即EGFR-mut与患者的预后差相关，在荟萃分析中纳入的研究大多样本量小，检验效能不足。
      但是，在16项研究中最大的两项研究报告显示，EGFR-mut与患者的生存获益相关。 D'Angelo和同事报道了具有EGFR突变的I-III期肺腺癌在OS上具有优势。该研究中很大一部分患者接受辅助细胞毒性化疗和EGFR-TKI治疗。
      Izar及其同事报道的307例患者表明，EGFR-mut与改善患者OS和无病生存期相关。该研究中没有患者接受辅助TKI或细胞毒性化疗。尽管在人口统计学，分期和辅助治疗方面存在差异，但是基于EGFR检测和分层的结论比较相似。


      ENSURE研究（厄洛替尼 vs 细胞毒性化疗）发现19-del 相比L858R在PFS上具有显著优势。一项小型回顾性研究发现相比L-858R，19-del可改善患者的OS。Takamochi及其同事报道222例（53％）L858R与161例（39％）19-del患者相比并无生存优势。14例（3％）患者存在T790M突变，且常伴有额外的突变。


      EGFR-mut的临床意义：首先，几乎所有患者多会出现TKI耐药。第一代TKI可逆性结合，而第三代TKI不可逆地结合酪氨酸激酶结构域，亲和力>100倍。随着第三代TKI的研究报道，点突变的治疗意义和预后价值可能会发生变化。
      由于“复杂的致癌机制”研究者推测，不同于依赖于特定驱动基因突变的EGFR-mut，EGFR-WT肿瘤中可能同时存在多个驱动基因突变的。另外，与吸烟者相比，非吸烟者性腺癌中出现新抗原表位的频率的较低。这意味着慢性吸烟会导致数千种体细胞突变，可能影响多种致癌途径，从而减少靶向单一突变的机会。


      Takamochi及其同事建议将EGFR状态纳入未来分期指南。鉴于TKI治疗的迅速发展和肺癌分子生物学知识的增加，分期系统中亚分类可能需要不断的改进，将来应在分期中得到充分反映。


      参考文献：
      1. Fukuoka M, Wu YL, Thongprasert S, et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol. 2011;29(21):2866-2874.
      2. Zhang Z, Wang T, Zhang J, et al. Prognostic value of epidermal growth factor receptor mutations in resected nonsmall cell lung cancer: a systematic review with meta-analysis. PLoS One. 2014;9(8):e106053.
      3. D'Angelo SP, Janjigian YY, Ahye N, et al. Distinct clinical course of EGFR-mutant resected lung cancers: results of testing of 1118 surgical specimens and effects of adjuvant gefitinib and erlotinib. J Thorac Oncol.
      2012;7(12):1815-1822.
      4. Wu YL, Zhou C, Liam CK, et al. First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the phase III, randomized, open-label, ENSURE study. Ann Oncol. 2015;26(9):1883-1889.
      5. Riely GJ, Pao W, Pham D, et al. Clinical course of patients with non-small cell lung cancer and epidermal growth factor receptor exon 19 and exon 21 mutations treated with gefitinib or erlotinib. Clin Cancer Res. 2006;12(3 Pt 1):839-844.
      6. Lawrence MS, Stojanov P, Polak P, et al. Mutational heterogeneity in cancer and the search for new cancer associated genes. Nature. 2013;499(7457):214-218.
      7. Campbell JD, Alexandrov A, Kim J, et al. Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas. Nat Genet. 2016;48(6):607-616.


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