Concomitant mutation status of ALK-rearranged non-small cell lung cancers and its prognostic impact on patients treated with crizotinib

Jingjing Li, Bin Zhang, Yu Zhang, Feng Xu, Zhenfa Zhang, Lin Shao, Chunhe Yan, Paola Ulivi, Marc G. Denis, Petros Christopoulos, Vincent Thomas de Montpreville, Eric H. Bernicker, Anthonie J. van der Wekken, Changli Wang, Dongsheng Yue*

*Corresponding author for this work

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    Abstract

    Background: In non-small cell lung cancer (NSCLC), anaplastic lymphoma kinase (ALK) rearrangement characterizes a subgroup of patients who show sensitivity to ALK tyrosine kinase inhibitors (TKIs). However, the prognoses of these patients are heterogeneous. A better understanding of the genomic alterations occurring in these tumors could explain the prognostic heterogeneity observed in these patients.

    Methods: We retrospectively analyzed 96 patients with NSCLC with ALK detected by immunohistochemical staining (VENTANA anti-ALK(D5F3) Rabbit Monoclonal Primary Antibody). Cancer tissues were subjected to next-generation sequencing using a panel of 520 cancer-related genes. The genomic landscape, distribution of ALK fusion variants, and clinicopathological characteristics of the patients were evaluated. The correlations of genomic alterations with clinical outcomes were also assessed.

    Results: Among the 96 patients with immunohistochemically identified ALK fusions, 80 (83%) were confirmed by next-generation sequencing. TP53 mutation was the most commonly co-occurring mutation with ALK rearrangement. Concomitant driver mutations [2 Kirsten rat sarcoma viral oncogene homolog (KRAS) G12, 1 epidermal growth factor receptor (EGFR) 19del, and 1 MET exon 14 skipping] were also observed in 4 adenocarcinomas. Echinoderm microtubule associated protein-like 4 (EML4)-ALK fusions were identified in 95% of ALK-rearranged patients, with 16.2% of them also harboring additional non-EML4- ALK fusions. Nineteen non-EML4 translocation partners were also discovered, including 10 novel ones. Survival analyses revealed that patients concurrently harboring PIK3R2 alterations showed a trend toward shorter progression-free survival (6 vs. 13 months, P=0.064) and significantly shorter overall survival (11 vs. 32 months, P=0.004) than did PIK3R2-wild-type patients. Patients with concomitant alterations in PI3K the signaling pathway also had a shorter median overall survival than those without such alterations (23 vs. 32 months, P=0.014), whereas progression-free survival did not differ significantly.

    Conclusions: The spectrum of ALK-fusion variants and the landscape of concomitant genomic alterations were delineated in 96 NSCLC patients. Our study also demonstrated the prognostic value of concomitant alterations in crizotinib-treated patients, which could facilitate improved stratification of ALK-rearranged NSCLC patients in the selection of candidates who could optimally benefit from therapy.

    Original languageEnglish
    Pages (from-to)1525-1535
    Number of pages12
    JournalTranslational lung cancer research
    Volume10
    Issue number3
    DOIs
    Publication statusPublished - Mar-2021

    Keywords

    • Anaplastic lymphoma kinase rearrangement (ALK rearrangement)
    • ALK fusion
    • concomitant mutation
    • next-generation sequencing (NGS)
    • non-small cell lung cancer (NSCLC)
    • crizotinib
    • ANAPLASTIC LYMPHOMA KINASE
    • SURVIVAL
    • GENE
    • DISCOVERY
    • VARIANTS
    • EFFICACY
    • PREDICT
    • GENOME
    • FISH
    • EGFR

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