Memorial Sloan Kettering Cancer Center, New York, New York, USA.
University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
Nature. 2018 Feb 8;554(7691):189-194. doi: 10.1038/nature25475. Epub 2018 Jan 31.
Somatic mutations of ERBB2 and ERBB3 (which encode HER2 and HER3, respectively) are found in a wide range of cancers. Preclinical modelling suggests that a subset of these mutations lead to constitutive HER2 activation, but most remain biologically uncharacterized. Here we define the biological and therapeutic importance of known oncogenic HER2 and HER3 mutations and variants of unknown biological importance by conducting a multi-histology, genomically selected, 'basket' trial using the pan-HER kinase inhibitor neratinib (SUMMIT; clinicaltrials.gov identifier NCT01953926). Efficacy in HER2-mutant cancers varied as a function of both tumour type and mutant allele to a degree not predicted by preclinical models, with the greatest activity seen in breast, cervical and biliary cancers and with tumours that contain kinase domain missense mutations. This study demonstrates how a molecularly driven clinical trial can be used to refine our biological understanding of both characterized and new genomic alterations with potential broad applicability for advancing the paradigm of genome-driven oncology.
在多种癌症中发现 ERBB2 和 ERBB3（分别编码 HER2 和 HER3）的体细胞突变。临床前模型表明，这些突变中的一部分导致 HER2 持续激活，但大多数仍然具有生物学特征。在这里，我们通过使用泛 HER 激酶抑制剂奈拉替尼（SUMMIT；clinicaltrials.gov 标识符 NCT01953926）进行多组织学、基因组选择的“篮子”试验，定义了已知致癌性 HER2 和 HER3 突变以及具有未知生物学重要性的突变体的生物学和治疗重要性。在 HER2 突变型癌症中的疗效因肿瘤类型和突变等位基因而异，这在一定程度上无法通过临床前模型预测，在乳腺癌、宫颈癌和胆管癌以及含有激酶结构域错义突变的肿瘤中观察到最大的活性。这项研究表明，如何使用分子驱动的临床试验来完善我们对特征明确和新的基因组改变的生物学理解，这对于推进基于基因组的肿瘤学范例具有广泛的适用性。
