To date defining the prognostic impact of molecular drivers
To date, defining the prognostic impact of molecular drivers of early-stage NSCLC has been challenging due to the relative rarity of these subsets and the redefinition of comparator arms over time as understanding of the molecular drivers of NSCLC evolved. Indeed, use of molecularly heterogeneous comparator arms likely obscures interpretation of findings from the previously published, early-stage ALK studies. For example, the Lungscape project, a European multi-institutional effort that analyzed prevalence and disease outcomes of resected ALK-positive NSCLC through study of a large biobank of lung adenocarcinomas, reported superior RFS and OS for patients with ALK-positive early-stage NSCLC . In contrast, two separate studies observed an association between ALK-positivity and inferior RFS [4,6]. These latter two studies exclusively evaluated outcomes among never-smokers, whereas the comparator endothelin receptor antagonists in the Lungscape study was predominantly comprised of smokers. Furthermore, these studies assessed ALK-positive and ROS1-postive cancers as a single group and included a mix of genotypes in the comparator cohort. Considering that most lung cancer arises in smokers and the biology of lung cancer among never-smokers is influenced by genotype, establishing the true prognostic relevance of ALK status in early-stage NSCLC will ultimately depend on assessment of disease outcomes of patients with ALK-positive lung cancer relative to other molecularly-defined cohorts, including cohorts that include smokers.
Here, we present results from a large multi-institution study that included three molecularly-defined NSCLC subsets encompassing a spectrum of tobacco exposure. We did not observe a statistical difference when RFS of patients with resected ALK-positive tumors was compared to that of patients with EGFR- mutant NSCLC who had not received an EGFR inhibitor or patients with KRAS-mutant tumors. However, there were numerical differences favoring the non-ALK groups. Our findings are intriguing, but they must be interpreted within the limitations of our study, including the retrospective nature of the analysis, differences in stage distribution across oncogenic drivers, and the small number of ALK-positive patients studied. The frequency of relapse across molecular cohorts despite curative intent therapy highlights the importance of enrolling patients with ALK-positive or EGFR-mutant lung cancer on studies of targeted therapies.
Conflicts of interest
Introduction Targeted therapy is at the forefront of malignant tumor treatment. Over the past decade, the treatment of non-small cell lung cancer (NSCLC) has been revolutionized by the usage of tyrosine kinase inhibitors (TKIs) with the approach to the driven genetic events of the tumor. Anaplastic lymphoma kinase (ALK) gene rearrangements are found in approximately 5%-7% of lung adenocarcinomas . In lung adenocarcinomas, the echinoderm microtubule-associated protein-like 4 (EML4) was the most common fusion partner of ALK rearrangements . To date, at least 21 EML4-ALK variants have been reported in NSCLC . Moreover, other predominant 5′-partners in ALK fusion-positive NSCLC have also been reported, including kinesin family member 5B (KIF5B), TRK-fused gene (TFG), kinesin light chain 1 (KLC1) and so on. The exact frequency and clinical significance of these fusion genes are still being investigated [, , ]. As the first ALK tyrosine kinase inhibitor approved by FDA in 2011 for ALK-rearranged NSCLCs, crizotinib has shown remarkable response in a series of clinical trials [, ]. However, the response magnitude and duration are heterogeneous; also, most patients benefiting from crizotinib will develop acquired resistance. Several studies have reported different response to crizotinib among different ALK variants. However, some of the conclusions are contradictory. Tatsuya Yoshida reported that patients with EML4-ALK variant 1 had a longer progression-free survival (PFS) than those with non-v1 EML4-ALK variants . Heuckmann et al. also tried to analyze different response to ALK inhibitors and reported a different result . In their in vitro study using the Ba/F3 and NIT3T3 cell lines, Heuckmann showed that variant 2 was significantly more sensitive to crizotinib . Tatsuya Yoshida’s study was limited by the small sample size; also, the difference of PFS among non-v1 variants was not reported. Heuckmann’s study was in vitro study, and need to be confirmed in clinical settings with large cohorts. Therefore, study on the association between clinical responses with ALK variant is still needed.