Biological Sciences, Sunnybrook Research Institute, Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
J Mammary Gland Biol Neoplasia. 2012 Dec;17(3-4):229-39. doi: 10.1007/s10911-012-9266-0. Epub 2012 Sep 26.
Viewed as a whole, the aggregate outcomes of a number of positive randomized phase III clinical trial results evaluating the VEGF-pathway targeting antiangiogenic drug bevacizumab, with or without concurrent chemotherapy, in metastatic breast cancer patients have been disappointingly modest. In the case of antiangiogenic tyrosine kinase inhibitors (TKIs) the results have been negative. Nevertheless, several findings indicate antiangiogenic drugs, especially bevacizumab, are active and can lead to demonstrable clinical benefit in some patients, thus stimulating research into developing strategies to significantly improve their efficacy and reduce toxicity. Some of these initiatives include: 1) discovery and validation of predictive markers that can prospectively identify patients more likely to benefit from antiangiogenic therapy; 2) recognition that the nature of the chemotherapy partner or backbone can strongly impact outcomes when combined with antiangiogenic drugs such as bevacizumab, and thus developing what may be improved combination chemotherapy partner regimens, e.g. metronomic chemotherapy; 3) evaluating prospectively in more depth whether subtypes of the disease-especially triple negative or inflammatory breast cancer-are more responsive to antiangiogenic therapy than other subtypes; 4) evaluating new agents that inhibit angiogenesis in a VEGF-independent manner and other types of drug that can be effectively combined with antiangiogenics, e.g. c-met inhibitors; 5) uncovering the basis of resistance or relapse/progression on the therapy with antiangiogenic drugs; 6) development of improved predictive preclinical breast cancer models for therapy testing, e.g. treatment of mice with established multi-organ breast cancer metastatic disease or genetically engineered mouse models of breast cancer, or mice bearing patient derived breast cancer tissue xenografts.
总的来说，许多评估 VEGF 通路靶向抗血管生成药物贝伐珠单抗（联合或不联合化疗）在转移性乳腺癌患者中的阳性随机 III 期临床试验结果的综合结果令人失望。在抗血管生成酪氨酸激酶抑制剂（TKI）的情况下，结果是阴性的。然而，一些研究结果表明，抗血管生成药物，尤其是贝伐珠单抗，具有活性，可以在一些患者中产生明显的临床获益，从而刺激了研究开发策略以显著提高其疗效并降低毒性。其中一些举措包括：1）发现和验证预测标志物，这些标志物可以前瞻性地识别更有可能从抗血管生成治疗中获益的患者；2）认识到当与贝伐珠单抗等抗血管生成药物联合使用时，化疗伙伴或骨干的性质可以强烈影响结果，因此开发出可能改进的联合化疗伙伴方案，例如节拍化疗；3）更深入地前瞻性评估疾病的亚型，尤其是三阴性或炎性乳腺癌，是否比其他亚型对抗血管生成治疗更敏感；4）评估以 VEGF 非依赖性方式抑制血管生成的新药物和其他可以与抗血管生成药物有效结合的药物，例如 c-met 抑制剂；5）揭示抗血管生成药物治疗耐药性或复发/进展的基础；6）开发用于治疗测试的改进的预测性乳腺癌临床前模型，例如用已建立的多器官乳腺癌转移性疾病或基因工程乳腺癌小鼠模型或携带患者来源的乳腺癌组织异种移植的小鼠进行治疗。
