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.
- Li, J.
- Zhang, B.
- Zhang, Y.
- Xu, F.
- Zhang, Z.
- Shao, L.
- Yan, C.
- Ulivi, P.
- Denis, M. G.
- Christopoulos, P.
- Thomas de Montpréville, V.
- Bernicker, E. H.
- van der Wekken, A. J.
- Wang, C.
- Yue, D.
Keywords
- ALK fusion
- Anaplastic lymphoma kinase rearrangement (ALK rearrangement)
- concomitant mutation
- crizotinib
- next-generation sequencing (NGS)
- non-small cell lung cancer (NSCLC)
- (available at http://dx.doi.org/10.21037/tlcr-21-160). Dr. MGD reports grants from
- Takeda and BluePrint Medicine, personal fees from Pfizer, BMS, and Boehringer
- Ingelheim, grants and personal fees from AstraZeneca, outside the submitted work.
- Dr. PC reports grants and personal fees from Novartis, Roche, AstraZeneca, and
- Takeda, personal fees from Pfizer, Chugai and Boehringer, outside the submitted
- work. Dr. AJW reports grants from Astra Zeneca, grants and personal fees from
- Boehringer Ingelheim, Pfizer, Roche, Takeda, outside the submitted work. The other
- authors have no conflicts of interest to declare.
