Molecular and clinical analysis of Chinese patients with anaplastic lymphoma kinase (ALK)‐rearranged non‐small cell lung cancer

Abstract

Anaplastic lymphoma kinase (ALK) fusions have been recognized as a therapeutic target in non‐small cell lung cancer (NSCLC). However, molecular signatures and clinical characteristics of the Chinese population with ALK‐rearranged NSCLC are not well elucidated. In the present study, we carried out targeted next‐generation sequencing on tissue and plasma ctDNA samples in 1688 patients with NSCLC. Overall, ALK fusions were detected in 70 patients (4.1%), and the frequencies of ALK fusions detected in tissue and plasma samples were 5.1% and 3.3%, respectively. Additionally, the prevalence of breakpoint locations for EML4‐ALK fusions in ctDNA was significantly correlated with that in tumor tissues (R2 = .91, P = .045). According to age, the incidence rates of ALK fusions among young (age <45 years), middle‐aged (between 45 and 70 years) and elderly (>70 years) patients were significantly different (P < .001). In 70 ALK‐rearranged cases, coexistence of epidermal growth factor receptor (EGFR) alterations and ALK fusions was detected in 12 cases (17.1%) and EGFR mutations tended to coexist with non‐EML4‐ALK rearrangements. Notably, novel ALK fusion partners, including TRIM66, SWAP70, WNK3, ERC1, TCF12 and FBN1 were identified in the present study. Among EML4‐ALK fusion variants, patients with variant V1 were younger than patients with variant V3 (P = .023), and TP53 mutations were more frequently concurrent with variant V3 compared with variant V1 (P = .009). In conclusion, these findings provide new insights into the molecular‐clinical profiles of patients with ALK‐rearranged NSCLC that may improve the treatment strategy of this population.

Longitudinal therapy monitoring of ALK-positive lung cancer by combined copy number and targeted mutation profiling of cell-free DNA

“…Moreover, t-MAD scores correlate with established molecular features of higher risk, i.e. with the presence of TP53 mutations and the EML4-ALK variant 3, which themselves portend worse survival, both in carefully controlled retrospective [ 5 , [54] , [55] , [56] ] and prospective trials [57] . While the EML4-ALK variant does not change during the disease, TP53 mutations do emerge under treatment, and their appearance is a marker of increased risk [6] .…”

Going beneath the tip of the iceberg. Identifying and understanding EML4-ALK variants and TP53 mutations to optimize treatment of ALK fusion positive (ALK+) NSCLC

“…EML4 is located on chromosome 2p21 and contains 26 exons. To date, fusion breakpoints in exons 2, 3,6,7,8,10,13,14,15,16,17,18,19,20,21 and 23 of EML4 have been identified in EML4-ALK+ NSCLC [5][6][7][8][9][10][11]. Additionally, small deletions and insertions have been identified at the fusion junctional points of EML4-ALK [5][6][7][8][9][10][11].…”

“…With the increasing adoption of nextgeneration sequencing (NGS), we now know that there are potentially more than 90 fusion partners identified in ALK+ NSCLC [4]. Despite the large number of fusion partners identified in ALK+ NSCLC, EML4-ALK still accounts for approximately 85% of the fusion variants in ALK+ NSCLC [5][6][7][8][9][10][11].…”

Driver gene alterations in lung adenocarcinoma: Demographic features of 2544 Chinese cases

“…20,21 The current view of a high incidence of ALK fusion in younger NSCLC patients is perceived by the public, but current data are insufficient for a large population-based study which is representative of participants of all ages for more precise validation. 7 In our study, of the 1244 samples involved in the detection of ROS1 fusions, 22 (10 males, and 12 females) were positive. In the ⩽ 50-year-old age group, the prevalence of ROS1 fusions was up to 10%, much higher than the average reported.…”

“…The prevalence of ROS1 fusions in NSCLC ranges from 0.9% to 3.9% in previous studies. [4][5][6][7][8] Although many published studies described EGFR mutations, ALK, or ROS1 fusions in clinical practice, evidence about the prevalence of these mutations or fusions in Chinese lung adenocarcinoma (LUAD) individuals of different genders and ages is insufficient. To understand the relationship between driver gene variations and age and gender in this population, we conducted this retrospective, non-interventional, single-center cohort study of LUAD patients in Beijing, China.…”