Department of Oncology, ASST Fatebenefratelli-Sacco, Via Giovanni Battista Grassi, 74 20157, Milan, Italy.
Unit of Clinical Pharmacology, Department of Laboratory Medicine, ASST Fatebenefratelli-Sacco, Milan, Italy.
Cancer Chemother Pharmacol. 2019 Apr;83(4):803-808. doi: 10.1007/s00280-019-03794-6. Epub 2019 Feb 22.
Platinum-based doublets are the standard chemotherapy for lung cancer. The identification of markers associated with drug toxicity may improve the success of the treatment. Single nucleotide polymorphisms (SNPs) mapping into the genes involved in platinum transport or detoxification may explain the occurrence of toxicities. In this study, we evaluated the role of three SNPs in predicting the onset of adverse events for lung cancer patients receiving cisplatin or carboplatin in adjuvant, neo-adjuvant and metastatic settings.
Eighty-two patients affected by non-small-cell and small-cell lung cancer treated with cisplatin- or carboplatin-based chemotherapy (stage II-IV) were enrolled. Before genetic analysis, patients signed a written informed consent. DNA was extracted from peripheral blood samples and genotypes were determined by real-time PCR. We selected and analyzed three SNPs: ABCB1 c.3435C>T/rs1045642, ABCC2 -24C>T/rs717620 and GSTP1 c.313A>G/rs1695. Patient characteristics and genotypes were correlated with hematological, gastrointestinal and renal toxicity as recorded by Common Terminology Criteria for Adverse Event (CTCAE) v4.03. No neurological toxicity was observed in our patients.
Variant alleles were present in 53% of patients for ABCB1 c.3435C >T, 18.3% for ABCC2 -24C> T, and 34.8% for GSTP1 c.313A>G. Heterozygous CT at ABCB1 c.3435 was associated to a lower risk of hematological toxicity compared to homozygous CC (OR = 0.20; 95% CI 0.05, 0.69; p = 0.01). Similar results were observed by genetic dominant model (CT + TT vs CC) and hematological toxicity (OR = 0.26; 95% CI 0.09, 0.79; p = 0.02). No other significant associations were found between toxicity and SNPs. Multivariate analysis confirmed an independent value for the ABCB1 c.3435 C >T polymorphism.
The present study reveals that ABCB1 c.3435C>T polymorphism influences platinum toxicity. The T allele seems to exert a protective effect on the development of toxicities. Further studies, such as epigenetic regulation ones, are needed to validate and shed more light on this association.
铂类双药是肺癌的标准化疗药物。鉴定与药物毒性相关的标志物可以提高治疗的成功率。单核苷酸多态性（SNP）映射到参与铂类转运或解毒的基因中，可能解释毒性的发生。在这项研究中，我们评估了三个 SNP 在预测接受顺铂或卡铂辅助、新辅助和转移性治疗的非小细胞和小细胞肺癌患者不良事件发生中的作用。
纳入 82 例接受顺铂或卡铂为基础的化疗（Ⅱ-Ⅳ 期）的非小细胞和小细胞肺癌患者。在进行基因分析之前，患者签署了书面知情同意书。从外周血样本中提取 DNA，并通过实时 PCR 确定基因型。我们选择并分析了三个 SNP：ABCB1 c.3435C>T/rs1045642、ABCC2-24C>T/rs717620 和 GSTP1 c.313A>G/rs1695。根据常见不良事件术语标准（CTCAE）v4.03 记录的患者特征和基因型与血液学、胃肠道和肾毒性相关。在我们的患者中未观察到神经毒性。
ABCB1 c.3435C>T 的变异等位基因在 53%的患者中存在，ABCC2-24C>T 的变异等位基因在 18.3%的患者中存在，GSTP1 c.313A>G 的变异等位基因在 34.8%的患者中存在。与纯合 CC 相比，ABCB1 c.3435 的杂合 CT 与较低的血液学毒性风险相关（OR=0.20；95%CI 0.05，0.69；p=0.01）。在遗传显性模型（CT+TT 与 CC）和血液学毒性中也观察到相似的结果（OR=0.26；95%CI 0.09，0.79；p=0.02）。在毒性和 SNP 之间未发现其他有意义的关联。多变量分析证实 ABCB1 c.3435C>T 多态性具有独立价值。
本研究表明 ABCB1 c.3435C>T 多态性影响铂类毒性。T 等位基因似乎对毒性的发展具有保护作用。需要进一步的研究，如表观遗传调控研究，以验证和进一步阐明这种关联。
