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首页> 外文期刊>Clinical cancer research: an official journal of the American Association for Cancer Research >Optimizing the detection of lung cancer patients harboring anaplastic lymphoma kinase (ALK) gene rearrangements potentially suitable for ALK inhibitor treatment.
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Optimizing the detection of lung cancer patients harboring anaplastic lymphoma kinase (ALK) gene rearrangements potentially suitable for ALK inhibitor treatment.

机译：优化具有间变性淋巴瘤激酶（ALK）基因重排的肺癌患者的检测方法，该基因重排可能适用于ALK抑制剂治疗。

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PURPOSE: Anaplastic lymphoma kinase (ALK) rearrangements, associated with sensitivity to an experimental ALK/MET inhibitor, occur in 3% to 5% of non-small cell lung cancers. Intratumoral fluorescence in situ hybridization (FISH) heterogeneity has been reported. We explored the heterogeneity basis, the requirements for accurately determining ALK FISH positivity, and the effect of enriching the tested population using clinical and molecular factors. EXPERIMENTAL DESIGN: Lung cancer patients were screened by ALK and MET FISH and for EGFR and KRAS mutations. RESULTS: Thirteen ALK-positive cases were identified from 73 screened patients. Gene copy number increases occurred together with classic rearrangements. All positive cases were adenocarcinomas, 12 were EGFR/KRAS wild-type, and 1 had a coexistent EGFR exon 20 mutation. No association with MET amplification occurred. ALK positivity was associated with <10-pack-year smoking status (P = 0.0004). Among adenocarcinomas, without KRAS or EGFR mutations, with <10-pack-year history, 44.8% of cases were ALK positive. ALK FISH positivity was heterogeneous, but mean values in tumor areas from ALK-positive patients (54% of cells; range, 22-87%) were significantly higher than in adjacent normal tissue or tumorormal areas from ALK-negative patients (mean, 5-7%). Contiguous sliding field analyses showed diffuse heterogeneity without evidence of focal ALK rearrangements. One hundred percent sensitivity and specificity occurred when four or more fields ( approximately 60 cells) were counted. CONCLUSIONS: Intratumoral ALK FISH heterogeneity reflects technique, not biology. The clinical activity of ALK/MET inhibitors in ALK-positive patients probably reflects ALK, but not MET, activity. Prescreening by histology, EGFR/KRAS mutations, and smoking status dramatically increases the ALK-positive hit rate compared with unselected series.
机译：目的：间变性淋巴瘤激酶（ALK）重排与对实验性ALK / MET抑制剂的敏感性有关，发生在3％至5％的非小细胞肺癌中。肿瘤内荧光原位杂交（FISH）的异质性已有报道。我们探讨了异质性基础，准确确定ALK FISH阳性的要求以及使用临床和分子因素丰富被测人群的效果。实验设计：通过ALK和MET FISH筛选EGFR和KRAS突变的肺癌患者。结果：从73例筛查患者中鉴定出13例ALK阳性病例。基因拷贝数增加与经典重排一起发生。所有阳性病例均为腺癌，其中12例为EGFR / KRAS野生型，其中1例同时存在EGFR外显子20突变。与MET扩增无关联。 ALK阳性与<10包年吸烟状态相关（P = 0.0004）。在无KRAS或EGFR突变且历史＜10年的腺癌中，有44.8％的病例为ALK阳性。 ALK FISH阳性异质性，但ALK阳性患者的肿瘤区域（细胞的54％;范围为22-87％）的平均值显着高于相邻正常组织或ALK阴性患者的肿瘤/正常区域的平均值（平均值，5-7％）。连续的滑动场分析显示弥散的异质性，没有证据表明ALK发生了重排。当计数四个或更多视野（大约60个细胞）时，发生了100％的敏感性和特异性。结论：瘤内ALK FISH异质性反映了技术而非生物学。 ALK阳性患者中ALK / MET抑制剂的临床活性可能反映了ALK活性，但不反映MET活性。与未选择的系列相比，通过组织学，EGFR / KRAS突变和吸烟状态进行的预筛查显着提高了ALK阳性命中率。

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