原发性肺肿瘤和转移部位的差异分子标志物表明转移性肺腺癌患者的不同可能治疗选择。
Differential molecular markers of primary lung tumors and metastatic sites indicate different possible treatment selections in patients with metastatic lung adenocarcinoma.
机构信息
Department of Oncology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang, People's Republic of China.
Dental Hospital, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Road, Nangang District, Harbin, 150001, Heilongjiang, People's Republic of China.
出版信息
Clin Transl Oncol. 2019 Feb;21(2):197-205. doi: 10.1007/s12094-018-1906-4. Epub 2018 Jun 11.
PURPOSE
Detecting different molecular markers in primary tumors and metastases may provide therapeutic information. Here we investigated differences between primary tumors and four metastatic sites of lung adenocarcinoma in the biomarkers' features and discussed potential therapeutic implications.
METHODS
A total of 228 patients with metastatic lung adenocarcinoma were analyzed for EGFR, KRAS, BRAF and PIK3CA mutations detected by xTAG liquidchip technology (xTAG-LCT), as well as ERCC1, TYMS, RRM1, TUBB3, STMN1, TOP2A and VEGFR1-3 mRNA expression detected by branched DNA-liquidchip technology (bDNA-LCT).
RESULTS
Higher rates of low ERCC1 (35.6 vs. 20.3%, P = 0.0105), RRM1 (23.3 vs. 13.0%, P = 0.0437), STMN1 (72.2 vs. 42.8%, P = 0.0000) and high VEGFR2 (34.4 vs. 18.8%, P = 0.0078) mRNA expression were found in EGFR-mutated tumors, suggesting possible benefit from platinum, gemcitabine, taxanes or VEGFR2 inhibitors. Primary lesions showed low ERCC1 (31.6 vs. 18.5%, P = 0.0271), TYMS (17.6 vs. 7.6%, P = 0.0300), TUBB3 (16.9 vs. 7.6%, P = 0.0415), STMN1 (62.1 vs. 42.9%, P = 0.0065) and high TOP2A (48.7 vs. 33.1%, P = 0.0262) mRNA expression and higher KRAS mutations (25.7 vs. 14.1%, P = 0.0350), suggesting platinum, taxanes, pemetrexed, anti-TOP2A agents and resistant to anti-EGFR therapies. Liver metastases showed absence of low TYMS expression, indicating insensitivity to pemetrexed-based regimen. Pleura metastases harbored higher rates of high VEGFR2 expression (50.0 vs. 19.1%, P = 0.0127). Lymph node metastases presented higher rates of high VEGFR2 expression (37.5 vs. 19.1%, P = 0.0253) and EGFR mutations (59.4 vs. 34.4%, P = 0.0011), suggesting use of anti-VEGFR2 and anti-EGFR therapies.
CONCLUSION
Molecular profiling of 228 lung adenocarcinomas determined a significant difference between biomarkers such as EGFR and KRAS subtypes at primary and metastatic sites. Our results serve as a reference for individual treatment based on different potential targets in metastatic lung adenocarcinoma directed by molecular profiling.
目的
检测原发性肿瘤和转移部位之间的不同分子标志物可能为治疗提供信息。在此，我们研究了肺腺癌原发灶和四个转移部位在生物标志物特征方面的差异，并讨论了潜在的治疗意义。
方法
对 228 例转移性肺腺癌患者进行了 EGFR、KRAS、BRAF 和 PIK3CA 突变检测（xTAG 液体芯片技术，xTAG-LCT），以及 ERCC1、TYMS、RRM1、TUBB3、STMN1、TOP2A 和 VEGFR1-3mRNA 表达检测（分枝 DNA 液体芯片技术，bDNA-LCT）。
结果
EGFR 突变肿瘤中 ERCC1（35.6%比 20.3%，P=0.0105）、RRM1（23.3%比 13.0%，P=0.0437）、STMN1（72.2%比 42.8%，P=0.0000）和 VEGFR2（34.4%比 18.8%，P=0.0078）mRNA 表达较高，提示铂类、吉西他滨、紫杉烷类或 VEGFR2 抑制剂可能有效。原发灶中 ERCC1（31.6%比 18.5%，P=0.0271）、TYMS（17.6%比 7.6%，P=0.0300）、TUBB3（16.9%比 7.6%，P=0.0415）、STMN1（62.1%比 42.9%，P=0.0065）和 TOP2A（48.7%比 33.1%，P=0.0262）mRNA 表达较低，KRAS 突变率较高（25.7%比 14.1%，P=0.0350），提示铂类、紫杉烷类、培美曲塞、抗 TOP2A 药物和抗 EGFR 治疗耐药。肝转移中缺乏 TYMS 低表达，提示对培美曲塞方案不敏感。胸膜转移中 VEGFR2 高表达率较高（50.0%比 19.1%，P=0.0127）。淋巴结转移中 VEGFR2 高表达率较高（37.5%比 19.1%，P=0.0253）和 EGFR 突变率较高（59.4%比 34.4%，P=0.0011），提示抗 VEGFR2 和抗 EGFR 治疗。
结论
对 228 例肺腺癌进行的分子谱分析确定了原发性肿瘤和转移部位之间 EGFR 和 KRAS 亚型等生物标志物的显著差异。我们的结果为基于分子谱分析指导的转移性肺腺癌不同潜在靶点的个体化治疗提供了参考。
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