Lung cancer with translocation in the anaplastic lymphoma kinase gene: a disease within a disease.

Nonsmall cell lung cancer (NSCLC) is a heterogeneous disease, of which our knowledge regarding specific molecular subtypes is rapidly increasing. Oncogenic mutations in the epidermal growth factor receptor (EGFR) and KRAS genes account for nearly 15% and 22%, respectively, of all cases of adenocarcinoma, the most common histological subtype. A recent addition to this list is rearrangements in the anaplastic lymphoma kinase (ALK) gene, which are noted in approximately 7% of patients with adenocarcinoma of the lung. The discovery of ALK gene rearrangement has been rapidly followed by development of ALK inhibitors and has recently culminated in the approval of crizotinib by the US Food and Drug Administration (FDA) for the treatment of patients with advanced stage, ALK-positive NSCLC. ALK gene rearrangements are associated with certain clinical phenotypes such as never-smoker, adenocarcinoma histology, and younger age. In particular, the presence of signet-ring features on light microscopy is more common with this subtype of NSCLC. Beyond this, our knowledge of the clinical characteristics of ALK-positive patients is limited and is only beginning to emerge. In this issue of Cancer, Doebele and colleagues report on an important study that compared the clinical characteristics of patients with ALK-positive NSCLC to those of patients with EGFR or KRASmutation or none of the 3 events (triple negative). Patients with ALK-positive tumors had nearly 5-fold higher prevalence of pleural and/or pericardial involvement compared with patients in the other groups. In addition, the total number of metastatic lesions was higher for ALK-positive patients. The data were collected retrospectively from a limited sample size of approximately 200 patients in total, of whom 41 had ALK-positive disease. In addition, the types of imaging studies obtained in these patients were variable and reflected the real world practice outside of a clinical trial protocol. It is unlikely that the detection of pleural or pericardial metastases would be much different between a conventional computed tomography (CT) scan and a positron emission tomography/CT scan. However, the observed prevalence of brain metastasis could have been influenced by the type of imaging study used. In addition, a higher proportion of patients with triple-negative NSCLC had not undergone an imaging study of the brain. Therefore, it is not possible to make conclusions about differences in brain metastasis based on the genotype of lung cancer. Despite these limitations, the results are important for several reasons. Pleural and pericardial involvement is often associated with disabling symptoms in patients with lung cancer. Malignant involvement of the pleura is often difficult to measure by Response Evaluation Criteria in Solid Tumors and could be a confounding factor for determination of objective response in patients treated with ALK inhibitors. Appropriate management of pleural or pericardial disease by either interventional approaches and/or initiation of systemic therapy with crizotinib would be helpful for effective palliation. These clinical features could also form a part of a clinical enrichment strategy for screening for ALK status in NSCLC patients. Although we believe that routine testing of all lung cancer specimens for common treatable oncogenic events will be done in the not too distant future, a clinical enrichment strategy will continue to play an important role in the daily practice in many parts of the world. The presence of retinal metastasis in 2 patients with ALKpositive disease is another finding that needs further evaluation in larger cohorts of patients. Given that visual disturbances are known to occur with crizotinib treatment, it is important for practicing physicians to be aware of the possibility of