Division of Oncology, Saint Luke's Cancer Institute, Kansas City, Missouri, USA
Center for Precision Oncology, Saint Luke's Cancer Institute, Kansas City, Missouri, USA.
Oncologist. 2019 Dec;24(12):e1303-e1314. doi: 10.1634/theoncologist.2018-0845. Epub 2019 Jul 10.
The oncogenic role amplification is well established in breast and gastric cancers. This has led to the development of a well-known portfolio of monoclonal antibodies and kinase inhibitors targeting the ERBB2 kinase. More recently, activating mutations in the gene have been increasingly reported in multiple solid cancers and were shown to play an oncogenic role similar to that of amplification. Thus, mutations define a distinct molecular subtype of solid tumors and serve as actionable targets. However, efforts to target mutation has met with limited clinical success, possibly because of their low frequency, inadequate understanding of the biological activity of these mutations, and difficulty in separating the drivers from the passenger mutations. Given the current impetus to deliver molecularly targeted treatments for cancer, there is an important need to understand the therapeutic potential of mutations. Here we review the distribution of mutations in different tumor types, their potential as a novel biomarker that defines new subsets in many cancers, and current data on preclinical and clinical efforts to target these mutations. IMPLICATIONS FOR PRACTICE: A current trend in oncology is to identify novel genomic drivers of solid tumors and developing precision treatments that target them. amplification is an established therapeutic target in breast and gastric cancers, but efforts to translate this finding to other solid tumors with amplification have not been effective. Recently the focus has turned to targeting activating mutations. The year 2018 marked an important milestone in establishing mutation as an important actionable target in multiple cancer types. There have been several recent preclinical and clinical studies evaluating mutation as a therapeutic target with varying success. With increasing access to next-generation sequencing technologies in the clinic, oncologists are frequently identifying activating mutations in patients with cancer. There is a significant need both from the clinician and bench scientist perspectives to understand the current state of affairs for mutations.
致癌作用扩增在乳腺癌和胃癌中已得到充分证实。这导致了针对 ERBB2 激酶的一系列著名的单克隆抗体和激酶抑制剂的开发。最近，在多种实体瘤中越来越多地报道了基因中的激活突变，并显示出与扩增相似的致癌作用。因此，突变定义了一个独特的实体瘤分子亚型，并作为可操作的靶点。然而，针对突变的努力仅取得了有限的临床成功，这可能是由于其频率较低、对这些突变的生物学活性的理解不足以及难以将驱动突变与乘客突变区分开来。鉴于目前为癌症提供分子靶向治疗的动力，重要的是要了解突变的治疗潜力。在这里，我们回顾了不同肿瘤类型中突变的分布，它们作为许多癌症中新亚群定义的新型生物标志物的潜力，以及针对这些突变的临床前和临床努力的当前数据。
肿瘤学的一个当前趋势是确定实体瘤的新基因组驱动因素，并开发针对它们的精确治疗方法。扩增是乳腺癌和胃癌中已确立的治疗靶点，但将这一发现转化为其他扩增的实体瘤的努力尚未取得成效。最近，焦点已转向靶向激活突变。2018 年标志着在多个癌症类型中确立突变作为重要可操作靶标的重要里程碑。最近有几项针对突变作为治疗靶点的临床前和临床研究，取得了不同程度的成功。随着下一代测序技术在临床上的广泛应用，肿瘤学家经常在癌症患者中发现激活突变。无论是从临床医生还是基础科学家的角度来看，都需要了解突变的现状。
