Department of Medical Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China.
Department of Pathology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
PLoS One. 2014 Jan 3;9(1):e84501. doi: 10.1371/journal.pone.0084501. eCollection 2014.
This study aimed to elucidate clinical significance of anaplastic lymphoma kinase (ALK) rearrangement in selected advanced non-small cell lung cancer (NSCLC), to compare the application of different ALK detection methods, and especially evaluate a possible association between ALK expression and clinical outcomes in crizotinib-treated patients.
ALK status was assessed by fluorescent in situ hybridization (FISH), immunohistochemistry (IHC) and quantitative RT-PCR (qRT-PCR) in 173 selected advanced NSCLC patients. Clinicopathologic data, genotype status and survival outcomes were analyzed. Moreover, the association of ALK expression with clinical outcomes was evaluated in ALK FISH-positive crizotinib-treated patients including two patients with concurrent epidermal growth factor receptor (EGFR) mutation.
The positivity detection rate of ALK rearrangement by FISH, IHC and qRT-PCR was 35.5% (59/166), 35.7% (61/171), and 27.9% (34/122), respectively. ALK rearrangement was observed predominantly in young patients, never or light smokers, and adenocarcinomas, especially with signet ring cell features and poor differentiation. Median progression-free survival (PFS) of crizotinib-treated patients was 7.6 months. The overall survival (OS) of these patients was longer compared with that of crizotinib-naive or wild-type cohorts, but there was no significant difference in OS compared with patients with EGFR mutation. ALK expression did not associate with PFS; but, when ALK expression was analyzed as a dichotomous variable, moderate and strong ALK expression had a decreased risk of death (P = 0.026). The two patients with concomitant EGFR and ALK alterations showed difference in ALK expression, response to EGFR and ALK inhibitors, and overall survival.
Selective enrichment according to clinicopathologic features in NSCLC patients could highly improve the positivity detection rate of ALK rearrangement for ALK-targeted therapy. IHC could provide more clues for clinical trial design and therapeutic strategies for ALK-positive NSCLC patients including patients with double genetic aberration of ALK and EGFR.
本研究旨在阐明间变性淋巴瘤激酶（ALK）重排在选定的晚期非小细胞肺癌（NSCLC）中的临床意义，比较不同 ALK 检测方法的应用，并特别评估 ALK 表达与克唑替尼治疗患者临床结局之间的可能关联。
通过荧光原位杂交（FISH）、免疫组织化学（IHC）和实时定量 RT-PCR（qRT-PCR）检测 173 例选定的晚期 NSCLC 患者的 ALK 状态。分析临床病理数据、基因型状态和生存结局。此外，还评估了 ALK 阳性的克唑替尼治疗患者中 ALK 表达与临床结局的关系，包括 2 例同时存在表皮生长因子受体（EGFR）突变的患者。
FISH、IHC 和 qRT-PCR 检测 ALK 重排的阳性检出率分别为 35.5%（59/166）、35.7%（61/171）和 27.9%（34/122）。ALK 重排在年轻患者、从不或轻度吸烟患者以及腺癌中更为常见，尤其是具有印戒细胞特征和低分化的腺癌。克唑替尼治疗患者的中位无进展生存期（PFS）为 7.6 个月。与克唑替尼初治或野生型患者相比，这些患者的总生存期（OS）更长，但与 EGFR 突变患者的 OS 无显著差异。ALK 表达与 PFS 无关；但当 ALK 表达作为二分类变量进行分析时，中度和强 ALK 表达降低了死亡风险（P=0.026）。同时存在 EGFR 和 ALK 改变的 2 例患者在 ALK 表达、对 EGFR 和 ALK 抑制剂的反应以及总生存期方面存在差异。
根据 NSCLC 患者的临床病理特征进行选择性富集可以显著提高 ALK 靶向治疗的 ALK 重排阳性检出率。IHC 可为 ALK 阳性 NSCLC 患者（包括同时存在 ALK 和 EGFR 双重基因异常的患者）的临床试验设计和治疗策略提供更多线索。
