Not all non-small cell lung cancer patients who could benefit from crizotinib are identified by FISH assay
A need to further refine the FDA approved test
- Date : 31 Aug 2012
- Topic : Lung and other thoracic tumours
EML4-ALK fusion gene is present in 2-7% of non-small cell lung cancers. Crizotinib is approved by FDA almost a year ago, and very recently European Medicines Agency recommended granting a conditional approval in patients with ALK+ non-small cell lung cancer. A recent University of Colorado Cancer Centre case study, published in the Journal of Thoracic of Oncology, describes the never before seen case of a patient who has been tested negative for EML4-ALK fusion based on the well defined criteria for FISH assay as approved by FDA, but nevertheless experienced remission after treatment with crizotinib.
Atypical fusion protein
According to paper’s co-author, Dr Fred Hirsch, investigator at the University of Colorado Cancer Centre and professor of medical oncology and pathology at the University of Colorado School of Medicine, this case implies that not all patients who might benefit from crizotinib are captured by the FDA approved FISH assay, and therefore other assays or other criteria for ALK/FISH positivity could be used.
In the news written by Gurth Sundem for the University of Colorado Cancer Centre's Website, the study authors explained that it was by chance that after the patient’s negative result by FISH testing, Dr Hirsch and colleagues chose to study deeper. Besides using FISH to stain sections of chromosomes with the EML4-ALK fusion gene, the team used immunohistochemistry to look for the protein products of this fusion gene – not the faulty plans but the faulty results. In this case, the patient had the EML4-ALK fusion protein but apparently without the typical EML4-ALK fusion gene that should code for it.
The team used next-generation sequencing to discover what, exactly, was going on in the short arm of chromosome number 2, which harbours the EML4-ALK fusion gene. What they found looked less like a pair of clean breaks that reattached in the wrong places, but more like shattered fragments with genetic shards embedded in and around the primary sections. It made the resulting gene look different enough from the typical EML4-ALK fusion gene to avoid detection by the FDA approved FISH assay.
Within two weeks of starting crizotinib, the patient reported improved pain symptoms and energy. Four months after starting the drug, a PET scan was negative. A chest CT scan showed the primary tumour had shrunk by 75%.
According to the study researchers FISH is a valuable assay to check for ALK-positive lung cancer, but they hope this work demonstrates the need to further refine this test.
The University of Colorado Cancer Centre researchers are participating in a larger study comparing different assays for ALK testing to determine which assay or combination of assays identifies the most patients likely to benefit from crizotinib.
Thank you for rating!
You have already rated this page, you can only rate it once!