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IASLC ATLAS OF ALK TESTING IN LUNG CANCER
the ALK FISH break-apart assay (Abbott Molecular). However, no requirement for a specific test for ALK screening has been established. Many studies have confirmed a high diagnostic specificity and sensitivity for ALK IHC compared with ALK FISH, and many guidelines already include recommendations for using ALK IHC to screen for ALK gene rearrangement in large populations of people with NSCLC and verifying positive results on IHC with ALK FISH for treatment eligibility. RT-PCR is not currently recommended for ALK screening.
What Is the Most Optimal Screening-Diagnosis Paradigm for Treatment with an ALK Inhibitor?
Although ALK IHC screening has been adopted in many countries, it remains unclear which test results should be verified with ALK FISH. Some guidelines recommend that all tumors that test positively on ALK IHC should be tested on ALK FISH, whereas others suggest that FISH be used to verify IHC results of 1+ and 2+. More detailed clinical-diagnostic associations in terms of response and outcome related to ALK inhibitor therapy is required before the optimal screening-diagnosis paradigm can be determined. Until such additional detailed correlative analysis results are available, the authors recommend that all IHC-positive tumors be verified with ALK FISH. However, there is an increasing number of reports of patients with tumors that are ALK FISH negative but IHC positive who have a good response to crizotinib therapy. In such cases, these negative results on ALK FISH may be true-negative or may be false-negative results because of a borderline or atypical FISH pattern. More in-depth analysis of these cases is ongoing and will help answer important questions.
Where Are We Going in the Future?
From a therapeutic point of view, several second-generation ALK inhibitors are currently in clinical development, as are dual ALK/EGFR inhibitors, with very encouraging results. Only future studies can tell what diagnostic assay will be associated with the best clinical outcomes. The ALK FISH assay is today the criterion standard for eligibility for treatment with crizotinib and is also being used in clinical studies with next-generation ALK inhibitors. However, treatment correlations with other assays, such as IHC and PCR are under investigation, and the screening-diagnosis paradigm may change in the future. Also, the introduction of new multiplex assays, particularly NGS technologies, needs to be validated both for screening and treatment eligibility of patients with NSCLC for ALK targeted therapy.
Conclusion
As illustrated throughout this Atlas, the diagnostics of ALK gene rearrangement are still developing. In the next couple of years, the diagnostic schema may change, and emergence of new targeted drugs may facilitate that transition. However, we are confident that we can now properly treat the few patients who have NSCLC with this gene alteration. All professionals in this field should ensure that all patients who may potentially benefit from ALK-targeted therapy receive optimal treatment.