Are Anaplastic Lymphoma Kinase Gene Rearrangements in Non-small Cell Lung Cancer Prognostic, Predictive, or Both?

Abstract

Many aspects of the clinical and pathological phenotype of non-small cell lung cancer (NSCLC) harboring rearrangements in the anaplastic lymphoma kinase (ALK) gene have been characterized following the description of the EML4-ALK fusion gene in NSCLC in 2007.1,2 These tumors most frequently occur in younger, never or light smokers with adenocarcinoma, are almost always mutually exclusive with EGFR or KRAS mutations, and demonstrate exquisite sensitivity to treatment with the ALK inhibitor crizotinib.3 However, there are few published data regarding the natural history and clinical outcomes of ALK-positive NSCLC. Two reports in this issue of the Journal of Thoracic Oncology, conducted in different patient populations using different methods to detect ALK rearrangements, provide apparently conflicting conclusions about the prognostic significance of ALK gene rearrangements in NSCLC and raise questions about the optimal method to detect ALK gene rearrangements in clinical samples. In the first study, Wu et al. performed a retrospective analysis using reverse transcription polymerase chain reaction (RT-PCR) to detect ALK gene rearrangements in cell pellets derived from malignant pleural effusions in 116 EGFR wild-type, Taiwanese patients with stage IIIB/IV NSCLC. Thirty-nine patients (34%) were found to have ALK gene rearrangements and, in contrast to other studies, these patients did not differ from ALK-negative patients with respect to age or smoking history. Wu et al. observed better median survival in the ALK-positive patients compared with the EGFR wild-type, ALK-negative patients (14.7 versus 10.3 months, p 0.009). In the second study, Yang et al. screened 300 never smokers from the Mayo Clinic Lung Cancer Cohort with a two-staged process involving immunohistochemistry (IHC) using the commercially available monoclonal ALK1 antibody (Dako, Capinteria, Ca) followed by fluorescence in situ hybridization (FISH) using break-apart probes (Vysis, Des Plaines, IL). In this cohort of predominantly early-stage tumors (191/300 stage I/II, 62/300 stage II, and 47/300 stage IV), 22 patients (8.2%) were determined to be ALK-positive by FISH. No overall survival data are presented, but using a composite end point of 5-year progression-free survival (PFS) and recurrence-free survival, adjusted for stage and treatment modality, Yang et al. found inferior outcomes in the ALK-positive cohort, with a twofold increase in the risk of experiencing disease progression or recurrence within 5 years in ALK-positive compared with ALK-negative patients. How do these articles with apparently contradictory findings fit in with what is known about clinical outcomes in this patient population? Of note, assessment of the predictive and prognostic significance of ALK gene rearrangements in NSCLC is limited by the fact that, with the exception of one prospective, single-arm study,3 the published data are limited to relatively small retrospective studies. Furthermore, the possibility of ascertainment bias cannot be excluded because of potential differences in the populations