Elsevier

Journal of Thoracic Oncology

Volume 10, Issue 11, November 2015, Pages 1648-1652
Journal of Thoracic Oncology

Brief Report
Clinical Implications of Variant ALK FISH Rearrangement Patterns

https://doi.org/10.1097/JTO.0000000000000665Get rights and content
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Introduction

Break-apart fluorescence in situ hybridization (FISH) is the FDA-approved assay for detecting anaplastic lymphoma kinase (ALK) rearrangements in non–small-cell lung cancer (NSCLC), identifying patients who can gain dramatic benefit from ALK kinase inhibitors. Assay interpretation can be technically challenging, and either splitting of the 5' and 3' probes or loss of the 5' probe constitute rearrangement. We hypothesized that there may be clinical differences depending on rearrangement pattern on FISH.

Methods

An IRB-approved database of NSCLC patients at Dana-Farber Cancer Institute was queried for ALK rearrangement. Clinical characteristics and response to crizotinib were reviewed. Immunohistochemistry (IHC) and targeted next-generation sequencing (NGS) were obtained when available.

Results

Of 1614 NSCLC patients with ALK testing, 82 patients (5.1%) had ALK rearrangement by FISH: 30 patients with split signals, 25 patients with 5' deletion, and 27 patients with details unavailable. Patients with 5' deletion were older (p = 0.01) and tended to have more extensive smoking histories (p = 0.08). IHC was positive for ALK rearrangement in all 27 patients with FISH split signals, whereas three of 21 patients with FISH 5' deletion had negative IHC (p = 0.05). Targeted NGS on two of three cases with discordant FISH and IHC results did not identify ALK rearrangement, instead finding driver mutations in EGFR and KRAS. Patients with 5' deletion treated with crizotinib had a smaller magnitude of tumor response (p = 0.03).

Conclusions

Patients with 5' deletion on ALK FISH harbor features less typical of ALK-rearranged tumors, potentially indicating that some cases with this variant are false positives. Corroborative testing with IHC or NGS may be beneficial.

Key Words

Anaplastic lymphoma kinase rearrangement
Crizotinib
Non-small-cell lung cancer
Fluorescence in situ hybridization

Cited by (0)

Sources of supported are Wong Family Fellowship in Translational Oncology, Harold and Gail Kirstein Lung Cancer Research Fund, 1K23CA157631 (NCI), and R01CA136851. LMS retains board membership with Genentech. MN receives consulting fees from Bristol-Myers Squibb. PAJ has received consulting fees from Pfizer and Chugai Pharmaceuticals. GRO has received consulting fees from AstraZeneca, Sanofi, Clovis, Novartis, Genentech, Boehringer-Ingelheim and honoraria from Chugai.

Disclosure: LMS retains board membership with Genentech. MN receives consulting fees from Bristol-Myers Squibb. PAJ has received consulting fees from Pfizer and Chugai Pharmaceuticals. GRO has received consulting fees from AstraZeneca, Sanofi, Clovis, Novartis, Genentech, Boehringer-Ingelheim and honoraria from Chugai..