Great stuff in this week's NEJM!
Today's (October 28, 2010) New England Journal of Medicine has no less than three articles reporting the use of small molecule ALK tyrosine kinase inhibitor crizotinib (PF-02341066, Pfizer) in non-small-cell lung cancers harboring the oncogenic fusion gene EML4-ALK and in a patient with ALK-rearrangement positive inflammatory myofibroblastic tumor, a distinctive but uncommon soft tissue neoplasm.
Pathologists should be familiar with these articles--at least so you can suggest appropriate testing for ALK rearrangement but also that you might "shine" at your next Tumor Conference ; ) BTW, the article by Kwak et al. presents in paper form the data that rocked this past summer's ASCO Annual Meeting regarding crizotinib.
Of interest to pathologists is how the EML4-ALK rearrangements were identified. Importantly, Kwak et al prospectively evaluated about 1500 NSCLC formalin-fixed, paraffin-embedded tumor samples by FISH using an ALK break-apart probe. The study also included a retrospective analysis on the FISH-positive cases using RT-PCR for specific EML4-ALK fusions and immunohistochemistry using anti-ALK antibodies. Note that the authors did not use ALK-rearrangement-specific antibodies that have recently become available. Mino-Kenudson and colleagues recently reported their experience in Clinical Cancer Research using a highly sensitive antibody for ALK-rearrangement by IHC. The availability of these mutation-specific antibodies could make IHC a preferred (and cheaper, more widely available) method for screening to replace FISH.
In this same issue, Choi and colleagues report report the discovery of two secondary mutations within the kinase domain of EML4-ALK in tumor cells isolated from a patient during the relapse phase of treatment with an ALK inhibitor that appear to confer resistance against two different ALK inhibitors (!). Curiously, each mutation developed independently in subclones of the tumor.
Finally, Butrynski and colleagues report a sustained partial response to the crizotinib in a patient with an ALK-translocated inflammatory myofibroblastic tumor (IMT) indicating the biological role for ALK signaling in tumors with ALK rearrangement and a therapeutic strategy for crizotinib in ALK-rearranged IMTs.
Drs. Bengt Hallberg and Ruth Palmer provide an insightful editorial which should also be read (at a minimum).
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