Metabolite normalization with local radiotherapy following breast tumor resection

The aims of this study were to investigate changes in energy balance-associated metabolites associated with radiotherapy in patients with breast cancer, and to relate these changes to the clinical and pathological response-to-treatment. We studied 151 women with breast cancer who received radiotherapy following surgical excision of the tumor. Blood was obtained before and after the irradiation procedure. The control group was composed of 44 healthy women with a similar age distribution to that of the patients. We analyzed the concentrations of metabolites involved in glycolysis, citric acid cycle and amino acid metabolism using targeted quantitative metabolomics. Post-surgery, pre-radiotherapy, patients had major alterations in the serum concentrations of products of glycolysis, citric acid cycle and amino acid metabolism. The strongest alterations were decreases in serine, leucine and isoleucine concentrations. Alterations in metabolite levels were partially, or totally, reversed after irradiation; the concentrations of serine, leucine and isoleucine approached equivalence to those of the control group. Estrogen receptor-positive patients were those with lower concentrations, while triple negative patients had higher concentrations of these amino acids. The normalization of the amino acids serine, leucine and isoleucine concentrations could be clinically relevant because the normalization of these energy-balance metabolites would suggest that residual micro-metastatic disease had been effectively diminished by the radiotherapy, and may be an indicator of its efficacy.

本研究旨在探究乳腺癌患者放疗过程中与能量平衡相关的代谢物变化，并将此类变化与临床及病理治疗应答相关联。我们纳入151名经手术切除肿瘤后接受放疗的女性乳腺癌患者，分别于放疗前后采集血液样本。对照组由44名年龄分布与患者组匹配的健康女性组成。我们采用靶向定量代谢组学（targeted quantitative metabolomics）技术，分析了参与糖酵解（glycolysis）、三羧酸循环（citric acid cycle）及氨基酸代谢的代谢物浓度。术后放疗前，患者血清中糖酵解、三羧酸循环及氨基酸代谢产物的浓度已发生显著改变，其中最为突出的异常为丝氨酸、亮氨酸及异亮氨酸的浓度降低。放疗后，上述代谢物水平的异常得到了部分或完全逆转，丝氨酸、亮氨酸及异亮氨酸的浓度趋近于对照组水平。雌激素受体阳性（estrogen receptor-positive）患者的上述氨基酸浓度更低，而三阴性（triple negative）乳腺癌患者的该类氨基酸浓度更高。血清丝氨酸、亮氨酸及异亮氨酸浓度恢复正常具有重要临床意义，因为这类能量平衡代谢物的正常化提示放疗已有效清除残留的微转移性病灶，或可作为放疗疗效的预测指标。