1] Departments of Bioengineering and Therapeutic Sciences, University of California at San Francisco, San Francisco, CA, USA [2] Institute for Human Genetics, University of California at San Francisco, San Francisco, CA, USA.
1] Institute for Human Genetics, University of California at San Francisco, San Francisco, CA, USA [2] Department of Epidemiology and Biostatistics, University of California at San Francisco, San Francisco, CA, USA.
Pharmacogenomics J. 2014 Aug;14(4):336-42. doi: 10.1038/tpj.2014.2. Epub 2014 Feb 11.
Peripheral neuropathy is a common dose-limiting toxicity for patients treated with paclitaxel. For most individuals, there are no known risk factors that predispose patients to the adverse event, and pathogenesis for paclitaxel-induced peripheral neuropathy is unknown. Determining whether there is a heritable component to paclitaxel-induced peripheral neuropathy would be valuable in guiding clinical decisions and may provide insight into treatment of and mechanisms for the toxicity. Using genotype and patient information from the paclitaxel arm of CALGB 40101 (Alliance), a phase III clinical trial evaluating adjuvant therapies for breast cancer in women, we estimated the variance in maximum grade and dose at first instance of sensory peripheral neuropathy. Our results suggest that paclitaxel-induced neuropathy has a heritable component, driven in part by genes involved in axon outgrowth. Disruption of axon outgrowth may be one of the mechanisms by which paclitaxel treatment results in sensory peripheral neuropathy in susceptible patients.
周围神经病变是紫杉醇治疗患者常见的剂量限制毒性。对于大多数人来说，没有已知的风险因素使患者易患这种不良事件，紫杉醇引起的周围神经病变的发病机制尚不清楚。确定紫杉醇引起的周围神经病变是否具有遗传成分，对于指导临床决策将是有价值的，并且可能为该毒性的治疗和机制提供深入了解。利用来自于CALGB 40101（Alliance）的紫杉醇臂的基因型和患者信息，这是一项评估女性乳腺癌辅助治疗的 III 期临床试验，我们估计了首次出现感觉周围神经病变的最大等级和剂量的变异。我们的结果表明，紫杉醇引起的神经病变具有遗传成分，部分是由涉及轴突生长的基因驱动的。轴突生长的中断可能是紫杉醇治疗导致易感患者出现感觉周围神经病变的机制之一。
