Department of Neurosurgery, Wake Forest Baptist Medical Center, Medical Center Boulevard, Winston-Salem, NC, 7157-1082, USA.
Curr Treat Options Oncol. 2013 Dec;14(4):514-27. doi: 10.1007/s11864-013-0248-2.
Molecular subtyping of tumors and treatment with specifically targeted therapy is a rapidly developing trend in oncology. Genetic and protein biomarkers impact biological behavior, patient prognosis, and inform treatment options. Select examples include EGFR mutations in primary non-small cell lung cancers, Her2 overexpression in breast cancer, and BRAF mutations in melanoma. Systemic benefit is emphasized in targeted therapies; yet lung cancer, breast cancer, and melanoma comprise the most common diagnoses in patients with brain metastases making the effectiveness of targeted therapies in the treatment and/or prevention of brain metastases relevant.Emerging evidence suggests efficacy for targeted therapy in the setting of brain metastases. Randomized, phase III clinical trials indicate targeted HER2 treatment with lapatinib and capecitabine in brain metastases from breast cancer increases the time to progression and decreases the frequency of CNS involvement at progression. Phase II trials and retrospective reviews for gefitinib and erlotinib demonstrate these agents may have a role in both the chemoprevention of brain metastases and, in combination with WBRT, treatment for non-small cell lung cancer (NSCLC) brain metastases. Dabrafenib and other BRAF inhibitors have demonstrated improved survival in patients with brain metastases from melanoma in a recent phase II clinical trial. Further data that support the use of these agents are the subject of several active clinical trials. Challenges and future directions for targeted therapies in brain metastases include both better characterization and drug design with respect to central nervous system distribution. Limited published data demonstrate suboptimal CNS distribution of currently available targeted chemotherapeutic agents. Increasing systemic dosing, alternate delivery methods, and new compounds with improved CNS distribution are being pursued. Additionally, eventual resistance to targeted therapies poses a challenge; however, research is showing resistance mutations are conserved and relatively predictable creating opportunities for second-line therapies with additional targeted drugs. Newer targeted therapies represent an additional chemotherapeutic option for the treatment and/or prevention of brain metastases in patients with an appropriate molecular profile.
肿瘤的分子亚型分类和针对特定靶点的治疗是肿瘤学中一个迅速发展的趋势。遗传和蛋白生物标志物影响着生物学行为、患者预后，并为治疗方案提供信息。例如，非小细胞肺癌中的 EGFR 突变、乳腺癌中的 Her2 过表达和黑色素瘤中的 BRAF 突变。靶向治疗强调的是系统性获益；然而，肺癌、乳腺癌和黑色素瘤是脑转移患者最常见的诊断，因此靶向治疗在脑转移的治疗和/或预防中的有效性与脑转移相关。新出现的证据表明靶向治疗在脑转移中的有效性。随机、III 期临床试验表明，针对乳腺癌脑转移的靶向 HER2 治疗，即拉帕替尼和卡培他滨，可延长进展时间并降低进展时中枢神经系统受累的频率。吉非替尼和厄洛替尼的 II 期临床试验和回顾性研究表明，这些药物可能在脑转移的化学预防以及与全脑放疗联合治疗非小细胞肺癌脑转移方面发挥作用。达布拉非尼和其他 BRAF 抑制剂在一项最近的 II 期临床试验中显示出改善了脑转移患者的生存。还有几项正在进行的临床试验，支持这些药物的使用。靶向治疗在脑转移中的挑战和未来方向包括对中枢神经系统分布的更好的特征描述和药物设计。有限的已发表数据表明，目前可用的靶向化疗药物在中枢神经系统中的分布不理想。正在增加全身剂量、替代给药方法和具有改善中枢神经系统分布的新化合物。此外，最终对靶向治疗的耐药性是一个挑战；然而，研究表明耐药性突变是保守的且相对可预测的，这为使用其他靶向药物的二线治疗创造了机会。新型靶向治疗为具有适当分子特征的脑转移患者的治疗和/或预防提供了另一种化疗选择。
