前瞻性多中心验证循环肿瘤细胞中 ALK 重排检测在晚期 NSCLC 患者非侵入性纵向管理中的应用。

Prospective Multicenter Validation of the Detection of ALK Rearrangements of Circulating Tumor Cells for Noninvasive Longitudinal Management of Patients With Advanced NSCLC.

机构信息

Laboratory of Clinical and Experimental Pathology, FHU OncoAge, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France; Hospital-Related Biobank (BB-0033-00025), FHU OncoAge, Centre Hospitalier Universitaire de Nice, Université Côte d'Azur, Nice, France; Institute of Research on Cancer and Ageing of Nice (IRCAN), CNRS, INSERM, FHU OncoAge, Université Côte d'Azur, Nice, France.

Department of Pulmonology, Centre Hospitalier Universitaire Toulouse, Institut Universitaire du Cancer, Université Paul Sabatier, Toulouse, France.

出版信息

J Thorac Oncol. 2021 May;16(5):807-816. doi: 10.1016/j.jtho.2021.01.1617. Epub 2021 Feb 3.

DOI:10.1016/j.jtho.2021.01.1617

PMID:33545389

Abstract

INTRODUCTION

Patients with advanced-stage NSCLC whose tumors harbor an ALK gene rearrangement benefit from treatment with multiple ALK inhibitors (ALKi). Approximately 30% of tumor biopsy samples contain insufficient tissue for successful ALK molecular characterization. This study evaluated the added value of analyzing circulating tumor cells (CTCs) as a surrogate to ALK tissue analysis and as a function of the response to ALKi.

METHODS

We conducted a multicenter, prospective observational study (NCT02372448) of 203 patients with stage IIIB/IV NSCLC across nine French centers, of whom 81 were ALK positive (immunohistochemistry or fluorescence in situ hybridization [FISH]) and 122 ALK negative on paraffin-embedded tissue specimens. Blood samples were collected at baseline and at 6 and 12 weeks after ALKi initiation or at disease progression. ALK gene rearrangement was evaluated with CTCs using immunocytochemistry and FISH analysis after enrichment using a filtration method.

RESULTS

At baseline, there was a high concordance between the detection of an ALK rearrangement in the tumor tissue and in CTCs as determined by immunocytochemistry (sensitivity, 94.4%; specificity 89.4%). The performance was lower for the FISH analysis (sensitivity, 35.6%; specificity, 56.9%). No significant association between the baseline levels or the dynamic change of CTCs and overall survival (hazard ratio = 0.59, 95% confidence interval: 0.24-1.5, p = 0.244) or progression-free survival (hazard ratio = 0.84, 95% confidence interval: 0.44-1.6, p = 0.591) was observed in the patients with ALK-positive NSCLC.

CONCLUSIONS

CTCs can be used as a complementary tool to a tissue biopsy for the detection of ALK rearrangements. Longitudinal analyses of CTCs revealed promise for real-time patient monitoring and improved delivery of molecularly guided therapy in this population.

摘要

简介

肿瘤存在 ALK 基因重排的晚期 NSCLC 患者，从多种 ALK 抑制剂（ALKi）治疗中获益。大约 30%的肿瘤活检样本组织量不足以成功进行 ALK 分子特征分析。本研究评估了分析循环肿瘤细胞（CTC）作为 ALK 组织分析的替代物的附加值，以及作为对 ALKi 反应的一种功能。

方法

我们在法国 9 个中心进行了一项多中心、前瞻性观察研究（NCT02372448），共纳入 203 名 IIIB/IV 期 NSCLC 患者，其中 81 名患者的肿瘤（免疫组化或荧光原位杂交 [FISH]）呈 ALK 阳性，122 名患者的肿瘤石蜡包埋组织标本呈 ALK 阴性。在开始 ALKi 治疗或疾病进展时，分别在基线和 6 周及 12 周采集血样。使用滤过法富集后，通过免疫细胞化学和 FISH 分析评估 CTC 中 ALK 基因重排。

结果

在基线时，免疫细胞化学检测肿瘤组织和 CTC 中 ALK 重排的结果高度一致（敏感性 94.4%，特异性 89.4%）。FISH 分析的性能较低（敏感性 35.6%，特异性 56.9%）。在 ALK 阳性 NSCLC 患者中，基线水平或 CTC 动态变化与总生存期（风险比=0.59，95%置信区间：0.24-1.5，p=0.244）或无进展生存期（风险比=0.84，95%置信区间：0.44-1.6，p=0.591）之间无显著相关性。