A large comprehensive analysis of patient-specific alterations of the anaplastic lymphoma kinase (ALK) gene occurring in non-small cell lung cancer (NSCLC) reported at the European Lung Cancer Virtual Congress 2021 (25-27 March) provided additional insight into the landscape of ALK alterations that may guide treatment of NSCLC.
Aakash Desai from the Division of Oncology, MayoClinic in Rochester, MN, USA conducted a study describing the landscape of ALK alterations emphasising that the detection of ALK gene rearrangements in patients with newly diagnosed NSCLC remains critical. Recently, lorlatinib was found to be potent against all known single ALK resistance mutations including ALK G1202R in the CROWN study1. ALK alterations influence treatment decisions among the several other targeted mutations in lung cancer today.
Dr. Desai and co-investigators conducted a comprehensive analysis of patient-specific ALK alterations in NSCLC using the open-source American Association for Cancer Research (AACR) Project GENIE Cohort v8.1. Using cbioportal as a query database, they analysed 11,107 samples from 10,082 patients with lung adenocarcinoma to determine the prevalence of ALK fusions, mutations, and copy number alterations in NSCLC.
ALK fusion upstream partners and co-alterations identified
ALK alterations were detected in 584 (5%) of queried samples. These alterations comprised 354 (60.6%) missense mutations, 265 (45.4%) fusions, 51 (8.7%) truncating mutations, and 1 (0.17%) in-frame mutation.
The investigators excluded all alterations with mutations and copy number alterations that were of unknown significance and found that 284 (2%) of samples still had significant ALK alterations; of these 259 fusions and 25 missenses mutations were identified.
Regarding the 25 missense mutations, just 7 of 284 (2.46%) were mutations with G1202R protein change, 7 of 284 (2.46%) mutations with L1196M, and 4 of 284 with I1171N were identified; however, all of these were identified as oncogenic.
The most common ALK gene upstream partners of identified ALK fusions were EML4 (81.5%), KIF5B (1.5%), and SQSTM1 (1.1%). ALK fusions were found to be significantly co-altered with HSP90AB1 mutations (p = 2.51E-04), IDH2 mutations (p = 0.027), and NRG1 mutations (p = 0.024).
According to the authors, most ALK variants are described as variants of unknown significance (VUS), thus limiting the impact of precision oncology.
They found that ALK fusions occur in 2.6% of lung adenocarcinomas, with EML4 being the most common upstream partner. Meanwhile, G1202R mutations occur only among 0.07% of the ALK alterations.
The investigators also found that heat shock proteins and the Neuregulin-1 pathways may present additional opportunities for future combination targeted therapies in ALK-positive NSCLC.
No external funding was disclosed.
- Shaw AT, Bauer TM, de Marinis F, et al. First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer. N Engl J Med 2020;383:2018-2029. DOI: 10.1056/NEJMoa2027187.
21P – Desai A, Mohammed T, Rakshit S, et al. The landscape of ALK alterations in non-small cell lung cancer. European Lung Cancer Virtual Congress 2021 (25-27 March).