吉非替尼长期应答者（LTR）——癌症干细胞样细胞的故事？来自德国吉非替尼扩展使用项目（EAP）中接受治疗的长期应答者的分子分析的见解。

The gefitinib long-term responder (LTR)--a cancer stem-like cell story? Insights from molecular analyses of German long-term responders treated in the IRESSA expanded access program (EAP).

机构信息

Department of Thoracic Oncology, Thoraxklinik/University of Heidelberg, Amalienstr 5, 69126 Heidelberg, Germany.

出版信息

Lung Cancer. 2012 Jul;77(1):183-91. doi: 10.1016/j.lungcan.2012.03.003. Epub 2012 Apr 7.

DOI:10.1016/j.lungcan.2012.03.003

PMID:22483783

Abstract

BACKGROUND

In selected patients with advanced non-small cell lung cancer (NSCLC) the EGFR (epidermal growth factor receptor) tyrosine kinase inhibitor (TKI) gefitinib (IRESSA) shows response rates of ≥ 70% and a significant prolongation of progression free survival (PFS). However, cogent biomarkers predicting long-term response to EGFR-TKIs are yet lacking. Cancer stem-like cells (CSC) are thought to play a pivotal role in tumor regeneration and appear to be influenced by the EGFR-pathway. This makes them a promising candidate for predicting long-term response to EGFR-TKIs.

MATERIALS AND METHODS

We analyzed pre-therapeutic tissue specimens of a rare and specific subset of previously treated German patients with advanced NSCLC who experienced ≥ 3 year response to gefitinib within the International IRESSA EAP. 11/20 identified long-term responders (LTRs) had appropriate tissue specimens available. Those were analyzed for EGFR and k-ras (Kirsten rat sarcoma) mutations, EGFR and c-met (met proto-oncogene) amplifications and protein expression of EGFR, E-cadherin/vimentin and the CSC antigens CD133 and BCRP1 (breast cancer resistance protein 1). The results were compared to primary resistant patients (RPs) and intermediate responders (IRs) showing a median response of 8.6 months.

RESULTS

Each group consisted of 6 women and 5 men, with 1 squamous cell carcinoma (SCC) and 10 adenocarcinoma (AC). Along the LTRs, all but the SCC had EGFR mutations, whereas the RPs had no EGFR, but k-ras mutations in 5/11 cases. 8/11 IRs had EGFR and 3/11 k-ras mutations, of which 2 occurred concomitantly. One patient of each group had an EGFR and/or c-met amplification. EGFR and E-cadherin/vimentin expression was not different between the groups, whereas CD133 was expressed only in 4/10 LTRs and BCRP1 predominantly in responders. The LTRs showed a substantially longer mean PFS to previous therapies, a substantially lower number of metastatic sites and almost exclusively pulmonary or pleural metastasis.

CONCLUSION

LTRs display established properties of EGFR-TKI responders. Antigens characterizing CSC might identify a fraction of LTRs and matter of interest for further evaluation.

摘要

背景

在某些晚期非小细胞肺癌（NSCLC）患者中，表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）吉非替尼（IRESSA）的反应率≥70%，无进展生存期（PFS）显著延长。然而，目前尚缺乏有力的预测 EGFR-TKI 长期反应的生物标志物。癌症干细胞样细胞（CSC）被认为在肿瘤再生中起着关键作用，并且似乎受 EGFR 通路的影响。这使它们成为预测 EGFR-TKI 长期反应的有希望的候选者。

材料和方法

我们分析了先前接受过治疗的德国晚期 NSCLC 患者的罕见且特定亚组的治疗前组织标本，这些患者在国际 IRESSA EAP 中接受吉非替尼治疗后≥3 年。11/20 名确定的长期缓解者（LTR）有合适的组织标本。对这些标本进行了 EGFR 和 k-ras（Kirsten 大鼠肉瘤）突变、EGFR 和 c-met（原癌基因 met）扩增以及 EGFR、E-钙粘蛋白/波形蛋白和 CSC 抗原 CD133 和 BCRP1（乳腺癌耐药蛋白 1）的蛋白表达分析。结果与原发性耐药患者（RPs）和中间缓解者（IRs）进行了比较，后者的中位缓解时间为 8.6 个月。

结果

每个组均由 6 名女性和 5 名男性组成，其中 1 例为鳞状细胞癌（SCC），10 例为腺癌（AC）。除 SCC 外，所有 LTR 均有 EGFR 突变，而 RPs 则没有 EGFR，但有 11 例中有 5 例存在 k-ras 突变。8/11 IRs 有 EGFR 和 3/11 k-ras 突变，其中 2 例同时存在。每组各有 1 例患者有 EGFR 和/或 c-met 扩增。EGFR 和 E-钙粘蛋白/波形蛋白的表达在各组之间没有差异，而 CD133 仅在 10 例 LTR 中的 4 例中表达，BCRP1 主要在缓解者中表达。LTR 以前的治疗有较长的 PFS 平均值，转移部位数量较少，几乎完全为肺或胸膜转移。