Subscribe to RSS
DOI: 10.1055/s-0044-1787301
Comparing Genomic Profiles of ALK Fusion-Positive and ALK Fusion-Negative Nonsmall Cell Lung Cancer Patients
Abstract
Background Anaplastic lymphoma kinase (ALK) fusion events account for 3 to 7% of genetic alterations in patients with nonsmall cell lung cancer (NSCLC). This study aimed to explore the landscape of ALK fusion-positive and ALK fusion-negative in a large cohort of NSCLC patients.
Methods The formalin-fixed paraffin-embedded specimens of NSCLC patients who underwent next-generation sequencing from 2020 to 2023 in Yinfeng Gene Technology Co., Ltd. Clinical laboratory were included in this study.
Results In the current study, a total of 180 (3.20%) patients tested positive for ALK fusions in 5,622 NSCLC samples. Within the ALK-positive cohort, a total of 228 ALK fusions were identified. Furthermore, five novel ALK fusion partners, including DAB1-ALK, KCMF1-ALK, KIF13A-ALK, LOC643770-ALK, and XDH-ALK were identified. In cases with ALK fusion-positive, TP53 alterations were the most prevalent (26.3%), followed by CDKN2A (8.4%), epidermal growth factor receptor (EGFR, 5.6%), and ALK (5.6%). By contrast, EGFR alterations were most prevalent (51%) in patients with ALK fusion-negative NSCLC, followed by TP53 (42.7%), KRAS (11.6%), and CDKN2A (11.3%). A total of 10 cases where ALK fusion co-occurred with EGFR mutations were also identified. Notably, the ALK fusion positivity rate was higher in younger patients (p < 0.0001) and in female patients (p = 0.0429). Additionally, positive ALK test results were more prevalent in patients with high programmed death-ligand 1 expression, especially when applying a 50% cutoff.
Conclusions Collectively, these findings offer valuable genomic insights that could inform the personalized clinical care of patients with NSCLC harboring ALK fusions within the context of precision medicine.
#
Introduction
Lung cancer is the main contributor to cancer-related mortality across the globe, with nonsmall cell lung cancer (NSCLC) encompassing >80% of all diagnosed cases.[1] [2] Within the population of patients with NSCLC, an estimated 2 to 7% exhibit anaplastic lymphoma kinase (ALK) gene rearrangements, resulting in the abnormal expression and oncogenic activation of ALK.[3] [4] The most prevalent and canonical ALK gene arrangement in NSCLC is the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion, wherein various EML4 breakpoints fuse in-frame with the kinase domain of ALK.[5] Notably, >15 distinct EML4-ALK fusion variants have been identified in NSCLC, with v1, v2, and v3a/b being the most frequently encountered variants.[6] In addition to these, certain ALK fusions, although less prevalent in NSCLC, have been reported, classified as noncanonical ALK fusions. These include kinesin family member 5B (KIF5B)-ALK, TRK-fused gene (TFG)-ALK, kinesin light chain 1 (KLC1)-ALK, striatin (STRN)-ALK, and TNFAIP3 interacting protein 2 (TNIP2)-ALK.[7] [8] [9] [10] It is noteworthy that some ALK fusions are predominantly found in other types of cancers.
In recent years, numerous clinical trials have been conducted to explore treatments targeting specific molecular mechanisms, such as ALK fusion. Small molecule inhibitors designed for ALK fusion, including crizotinib, alectinib, brigatinib, and lorlatinib, have been approved by the U.S. Food and Drug Administration for various cancer types.[11] [12] [13] Despite these advancements, it is noteworthy that a subset of patients with ALK-positive NSCLC (10–40%) fail to respond to ALK tyrosine kinase inhibitors (TKIs). This emphasizes the clinical importance of further stratifying patients with ALK-positive NSCLC based on their response to TKIs. While there is potential benefit in identifying ALK fusions, it remains uncertain whether tumors with ALK fusions constitute a distinct, albeit rare, subtype that should be detected early for targeted therapy. With the continued development of next-generation sequencing (NGS) technologies, obtaining the genomic landscape of patients with cancer has become more affordable and accessible. In the current study, the aim was to unveil the genomic landscape of ALK fusion-positive tumors in 180 NSCLC patients who underwent sequencing. The aim was to elucidate their genomic mutation patterns and characteristics, which could notably contribute to the development of more precise and effective treatment strategies.
#
Materials and Methods
Clinical Specimens
The formalin-fixed paraffin-embedded (FFPE) specimens of NSCLC patients who underwent NGS from 2020 to 2023 in Yinfeng Gene Technology Co., Ltd. were included. The diagnosis of the specimens was confirmed by hematoxylin and eosin staining by an independent pathologist. The specimens were required to have a percentage of tumor cells over 20% and a size ≥1 mm for further analysis.
#
DNA Extraction and Next-Generation Sequencing
The DNA extraction process involved a microdissection technique for precise dissection of tissue blocks. Genomic DNA was then extracted from FFPE samples using the QIAamp DNA FFPE Tissue Kits (Qiagen GmbH, 56404). The quality of the isolated genomic DNA was assessed through the measurement of DNA concentration, using Qubit DNA Assay Kits and a Qubit 2.0 Fluorometer (Thermo Fisher Scientific, Inc.), as well as through 1% agarose gel electrophoresis to evaluate DNA degradation. To create DNA fragments in the range of 180 to 280 bp hydrodynamic shearing was executed on 0.6 g of genomic DNA using the M220 Focused-ultrasonicator (Covaris, LLC). Subsequently, sequencing libraries were prepared according to the manufacturer's instructions, employing the Agilent SureSelect Human All Exon V6 kit (Agilent Technologies, Inc. 5190-8863). For the purpose of target enrichment, the constructed libraries were hybridized with custom-designed biotinylated oligonucleotide probes (Roche Diagnostics). Following this, the index-coded library samples were clustered using the Illumina cBot Cluster Generation System (Illumina, Inc.) and the DNA libraries were sequenced with the use of an Illumina HiSeq 2000 system (Illumina, Inc.).
#
Statistical Analysis
In the current study, the association of ALK fusions with age and sex was examined through the Fisher's exact test and the Mann–Whitney U test. Furthermore, the relationship between genomic characteristics and the proportion of programmed death-ligand 1 (PD-L1) expression was assessed using the Fisher's exact test with the cutoff values set at 1 and 50%. It is noteworthy that all statistical tests were conducted as two-sided tests. p < 0.05 was considered to indicate a statistically significant difference.
#
#
Results
Characteristics of Patients with ALK Fusions
A total of 5,622 patients diagnosed with NSCLC who had undergone tissue-based NGS with 500 cancer gene panel were included in the current analysis. Among them, 180 (3.2%) patients were identified as having ALK fusions. The median age of the patients was 58 years, with an age range 26 to 82; 48% of the patients were men. The majority of patients had lung adenocarcinoma (177 cases; 98.3%), whereas a small number had lung squamous cell carcinoma (two cases; 1.1%) and lung adenosquamous carcinoma (one case; 0.6%). Among the 180 patients with ALK fusions, 65 (36.1%) patients had evaluable microsatellite instability (MSI) status, and no patients with high MSI were detected. Furthermore, 54 (30%) patients had evaluable tumor mutational burden (TMB) status, with only two (1.1%) patients presenting with high TMB ([Table 1]). The cutoff for MSI was 29 (13.5%) based on the evaluation of 55 microsatellite markers, and the cutoff for TMB was nine mutations per megabase for the panels. Notably, NGS was conducted on 180 pairs of tumor and white blood cell samples, and all samples that passed the histology quality control yielded sufficient DNA quantities for NGS analysis.
Abbreviations: H, high; L, low; MSI, microsatellite instability; MSS, microsatellite stable; N/A, not applicable; TMB, tumor mutational burden.
#
Molecular Features of ALK Fusion-Positive Patients
Using NGS, a total of 180 patients who harbored ALK fusions were identified and categorized into the ALK fusion-positive group, whereas those without ALK fusions constituted the ALK fusion-negative group. Among the ALK cohort, although a total of 228 ALK fusions were identified, 43 (25%) patients exhibited simultaneous occurrences of ≥2 distinct ALK fusions ([Table 2]). The predominant fusion partner within the present cohort was EML4, accounting for 70% (160/228) of cases followed by KLC1 (2.2%; 5/228), KIF5B (2.2%; 5/228), and HIP1 (0.9%; 2/228). In the ALK fusion-positive patients, various EML4-ALK variants were identified, including variant 1 (E13; A20; 35.0%; 56/160), variant 2 (E20; A20; 9.4%; 15/160), variant 3 (E6; A20; 41.8%; 67/160), variant 5 (E2; A20; 4.4%; 7/160), and other variants (9.4%; 15/160; [Fig. 1A, B]).
In addition to EML4-ALK fusions, the cohort of the current study also revealed the presence of other ALK fusion partners. It is noteworthy that novel variants, including intergenic fusions, have been extensively analyzed due to their potential marked clinical implications for fusion carriers.[14] Consequently, these novel variants, particularly intergenic fusions, have garnered considerable attention as they may represent potential targetable variants. In the present study, a total of five ALK intergenic fusions were identified ([Table 3]). Typically, fusions involving intergenic regions were considered unlikely to produce functional fusion transcripts. However, emerging evidence suggests that intergenic fusions may also lead to the generation of functional fusion proteins after transcription, potentially involving mechanisms such as chromothripsis and alternative splicing.[14] For five cases where RNA-based NGS assays were unsuccessful due to limited materials, further investigation is warranted. Furthermore, among these cases, it is noteworthy that two patients, CLIP4 (intergenic)-ALK (intergenic, exon14) and MTA3 (intergenic)-ALK (intergenic, exon20), also carried the canonical EML4-ALK fusion (exon6; exon20; [Table 3]).
Additionally, five novel ALK fusion partners were identified ([Table 3]). These novel fusions included KCMF1-ALK ([Fig. 2A]), XDH-ALK ([Fig. 2B]), KIF13A-ALK ([Fig. 2C]), LOC643770-ALK ([Fig. 2D]), and DAB1-ALK ([Fig. 3A]). Notably, one patient with an XDH-ALK fusion (exon23; exon19) was found to concurrently possess the canonical EML4-ALK fusion (exon13; exon20; [Table 3]). However, a previous study[15] reported that patients with NSCLC and complex ALK fusions could potentially have better treatment outcomes to ALK TKI therapy. Furthermore, a novel DAB1-ALK fusion variant was identified in a patient with pulmonary adenosquamous carcinoma ([Fig. 3A]). To the best of our knowledge, the present study is the first to report a DAB1-ALK fusion in patients with NSCLC. To confirm the presence of the ALK fusion, pathology and immunohistochemistry (IHC) were performed on puncture tissue samples. The results validated the existence of the ALK fusion in adenosquamous carcinoma samples ([Fig. 3B, C]).
#
Differences of Mutant Genes between Patients with ALK Fusion-Positive and Patients with ALK Fusion-Negative Nonsmall Cell Lung Cancer
In the present analysis of 180 ALK fusion-positive cases, TP53 alterations were the most prevalent (26.3%), followed by CDKN2A (8.4%), epidermal growth factor receptor (EGFR, 5.6%), and ALK (5.6%). Other noteworthy genomic alterations include MET (4.5%), PTEN (2.8%), ERBB2 (2.8%), KRAS (2.2%), and BRAF (2.2%). Among the ALK fusion-positive cases, a total of 55 variations were identified in TP53, encompassing 30 missense mutations, 10 nonsense mutations, five splice mutations, five frameshift mutations, four copy number loss mutations, and one deletion mutation. Additionally, patients with ALK fusion-positive NSCLC exhibited 15 variations in CDKN2A, including 14 copy number loss mutations and one missense mutation. Moreover, MET displayed eight variations in the eight cases, consisting of two missense mutations (p.Q812E, p.A1363T), five copy number gain mutations and one intron mutation. In the five cases with variations in ERBB2, there were five variations, including four missense mutations (p.N125S, p.G603S, p.S310F, p.D1144H) and one frameshift mutation (p.N125S). Furthermore, BRAF manifested four variations, including three missense mutations (p.I582V, p.E695Q, p.V600E) and one copy number gain mutation. The concurrent presence of ALK-positive NSCLC and EGFR mutations is an infrequently observed clinical phenomenon, suggesting the potential for concurrent targeting of ALK and EGFR as an effective therapeutic approach for these patients. The current study revealed 10 cases where ALK fusion co-occurred with EGFR mutations, with three cases involving EML4-ALK fusion and EGFR p.L858R co-mutations, and one case featuring EML4-ALK fusion and EGFR p.E746_A750del co-mutation ([Fig. 4A]).
Comparatively, when patients with ALK fusion-negative NSCLC were examined, EGFR alterations were shown to be the most prevalent (51%), followed by TP53 (42.7%), KRAS (11.6%), and CDKN2A (11.3%). Other genomic alterations included PIK3CA (10.1%), ERBB2 (7.5%), MET (6.7%), NF1 (5.5%), and PTEN (4.3%; [Fig. 4B]).
In the present cohort of patients with ALK fusion-positive tumor, five patients were identified as carrying germline mutations in five different cancer predisposition genes. These mutations included two pathogenic alterations in RAD50 (c.1969 + 1G > A) and BRCA1 (c.3841C > T), two likely pathogenic alterations in BRCA2 (c.2180C > G) and FANCL (c.96 + 2T > A), and one mutation of uncertain significance in SLX4 (c.2854_2855delGCinsAT). Additional clinical details and the distribution of these germline mutations in the patient cohort are provided in [Table 4].
#
Age, Sex, and PD-L1 Expression in ALK Fusion-Positive Tumors
Among the 180 patients with ALK fusion, there were 93 and 87 female and male patients, respectively, with a median age of 58 years (range, 26–82 years). Notably, patients with NSCLC carrying ALK fusion-positive tumors were significantly younger than those with ALK fusion-negative tumors (p < 0.0001; [Fig. 5A]). This observation aligns with a previous study.[16] Regarding sex differences, a higher relative proportion of women was observed among patients with ALK fusion-positive tumors compared with those with ALK fusion-negative tumors (p = 0.0429; [Fig. 5B]). However, a previous study[17] reported that there were no significant differences in ALK fusion between men and women.
The upregulation of the ALK fusion protein has been shown to elevate PD-L1 expression, and immunotherapy with anti-PD-1 monoclonal antibodies has demonstrated efficacy in both crizotinib-sensitive and resistant NSCLC cells.[18] Therefore, an assessment of PD-L1 expression within the present cohort was conducted, which consisted of a total of 2,210 eligible patients after the exclusion of those lacking PD-L1 expression data. PD-L1 IHC was performed using the Dako22C3 antibody. In the current comprehensive study, a statistically significant increase was observed in the prevalence of ALK-positive test results among patients exhibiting high PD-L1 expression levels, as determined by a 1% cutoff (p = 0.0116; [Fig. 5C]). Furthermore, when applying a 50% cutoff, ALK fusion-positive tumors exhibited significantly elevated PD-L1 expression compared with ALK fusion-negative tumors (p < 0.0001; [Fig. 5D]). These findings suggest a potential association between increased PD-L1 expression in ALK fusion-positive tumors and poorer progression-free survival (PFS) following TKI therapy.
#
Copy Number Variations in Patients with ALK Fusions
Copy number variations (CNVs) were identified in 61% (111/180) of the samples in the present study cohort. Notably, approximately 11% of the patients in the cohort exhibited CNVs in CDKN2A, a potential candidate contributing to tumorigenesis and disease progression.[18] Furthermore, previous studies have shown association of CNVs in CDKN2A, CDKN2B, MCL1, MDM2, and IRS2 with prognosis.[19] [20] [21] [22] CNVs in CDKN2A, CDKN2B, MYC, MDM2, and CCND1 were also detected in fusion-positive samples from the Memorial Sloan Kettering Cancer Center database. Within the present study cohort, it was observed that CNVs in CDKN2A and CDKN2B exhibited a notably high frequency ([Fig. 6]).
#
#
Discussion
In the era of precision medicine, the genomic profiles of patients can play a pivotal role in tailoring treatment strategies. For patients with ALK fusion-positive NSCLC, a detailed genomic profile can elucidate the fusion partner and rearranged breakpoint. In the present study, NGS technologies were used to identify ALK rearrangement events in 180 Chinese patients with NSCLC. Consistent with previous studies, EML4 is the most common ALK fusion partner, with the fusion occurring in the three predominant variants.[6] Notably, the present study reports the discovery of five novel ALK fusion partners: DAB1, KCMF1, KIF13A, LOC643770, and XDH. This suggests that NGS-based assessment for ALK fusions is accurate and comprehensive, offering unique advantages in detecting previously unknown ALK fusion partners and precisely identifying breakpoints compared with traditional methods like fluorescence in situ hybridization and IHC.
EGFR mutations and ALK fusions are the two pivotal driver mutations in NSCLC. Traditionally, EGFR mutations and EML4-ALK translocations were considered to be mutually exclusive.[23] [24] Nonetheless, a growing body of evidence suggests that concurrent mutations, although infrequent, can occur.[25] [26] This phenomenon can be attributed to two situations. First, tumor heterogeneity, where distinct tumor cell clones individually carry either an EGFR mutation or an ALK fusion.[27] Second, the same tumor cell clone harbors both an EGFR mutation and an ALK rearrangement.[28] [29] In the current study, 10 patients with EGFR/ALK co-mutations were identified. Among them, three cases involved EML4-ALK fusion and EGFR p.L858R co-mutations, whereas one case featured EML4-ALK fusion and an EGFR p.E746_A750del co-mutation. However, there is limited information available regarding the effects of pharmaceutical treatment on these concurrent mutations. A recent study suggested that EML4-ALK rearrangements could serve as a rare, acquired resistance mechanism following EGFR-TKI treatment.[30] Nevertheless, there are also studies indicating a more common acquisition of EGFR mutations following ALK-TKI therapy.[30]
Moreover, Christopoulos et al[31] reported that concurrent TP53 mutations serve as a robust prognostic indicator in patients with ALK fusion-positive NSCLC.[31] The authors further indicated that the EML4-ALK fusion variant V3 was linked to a more aggressive phenotype and inferior overall survival (OS) due to the early failure of various therapeutic approaches. Additionally, they observed that patients positive for both V3 and TP53 alterations faced a notably high risk of death, with an OS of approximately 2 years. In the present dataset of 180 ALK fusion-positive samples, TP53 alterations were the most prevalent co-mutations, occurring in 26.3% of cases. Consequently, these patients may be independently associated with increased metastatic potential, shorter responses to TKI treatment, and poorer OS in ALK lung adenocarcinoma. Both of these markers hold the potential to aid in selecting cases for more aggressive management and guiding the development of novel therapeutic strategies.
The data of the present study revealed significantly higher PD-L1 expression in tumors with ALK fusions, particularly when using a 5% cutoff compared with fusion-negative tumors. Several studies have demonstrated an association between high tumor PD-L1 expression and poorer PFS in response to ALK-TKIs.[32] [33] [34] [35] [36] A prior study indicated that PD-L1 expression status alone did not markedly impact the OS of patients with ALK-positive NSCLC.[37] Nevertheless, a previous study found that high baseline PD-L1 expression was associated with shorter OS in ALK-rearranged lung adenocarcinoma.[36] In another recent study, patients with high PD-L1 expression were found to exhibit an immunosuppressive status in the tumor microenvironment (TME). The characteristics of the TME may aid in identifying patients who would derive greater benefits from ALK-TKIs.[38]
However, the current study also has several limitations. First, complete and detailed patient clinicopathological characteristics, as well as treatment details, including the survival status of all patients with ALK fusion-positive NSCLC were not collected. Second, the functional properties of these novel ALK fusion proteins and their potential impact on TKI therapy remain unexplored, and further investigation is required. By conducting an analysis of the protein structure and functional sequences of ALK, significant ALK fusion variants can potentially be identified.
Despite the aforementioned limitations, the present study represents a comprehensive analysis of ALK fusions in a substantial cohort of Chinese patients with NSCLC. The current study outcome contributes valuable genomic information for personalized clinical management in the era of precision medicine for patients with ALK fusions.
#
#
Conflict of Interest
None declared.
Acknowledgments
Authors thank to the support of Yinfeng Gene Technology Co., Ltd. in next-generation sequencing and bioinformatics data arrangement.
Author Contributions
W.X. collected and organized the data. J.Y. wrote the manuscript. H.L. prepared the figures. L.L. and J.L. critically revised the manuscript for intellectual content. All authors contributed to the article and approved the submitted version.
Availability of Data and Materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
-
References
- 1 Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc 2008; 83 (05) 584-594
- 2 de Groot PM, Wu CC, Carter BW, Munden RF. The epidemiology of lung cancer. Transl Lung Cancer Res 2018; 7 (03) 220-233
- 3 Soda M, Choi YL, Enomoto M. et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007; 448 (7153): 561-566
- 4 Solomon B, Varella-Garcia M, Camidge DR. ALK gene rearrangements: a new therapeutic target in a molecularly defined subset of non-small cell lung cancer. J Thorac Oncol 2009; 4 (12) 1450-1454
- 5 Hallberg B, Palmer RH. Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology. Nat Rev Cancer 2013; 13 (10) 685-700
- 6 He Y, Sun LY, Gong R. et al. The prevalence of EML4-ALK variants in patients with non-small-cell lung cancer: a systematic review and meta-analysis. Biomarkers Med 2019; 13 (12) 1035-1044
- 7 Takeuchi K, Choi YL, Togashi Y. et al. KIF5B-ALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer. Clin Cancer Res 2009; 15 (09) 3143-3149
- 8 Rikova K, Guo A, Zeng Q. et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 2007; 131 (06) 1190-1203
- 9 Togashi Y, Soda M, Sakata S. et al. KLC1-ALK: a novel fusion in lung cancer identified using a formalin-fixed paraffin-embedded tissue only. PLoS One 2012; 7 (02) e31323
- 10 Feng T, Chen Z, Gu J, Wang Y, Zhang J, Min L. The clinical responses of TNIP2-ALK fusion variants to crizotinib in ALK-rearranged lung adenocarcinoma. Lung Cancer 2019; 137: 19-22
- 11 Rodig SJ, Shapiro GI. Crizotinib, a small-molecule dual inhibitor of the c-Met and ALK receptor tyrosine kinases. Curr Opin Investig Drugs 2010; 11 (12) 1477-1490
- 12 Markham A. Brigatinib: first global approval. Drugs 2017; 77 (10) 1131-1135
- 13 Kuang S, Leighl NB. Lorlatinib in ALK-rearranged lung cancer. Cancer Cell 2021; 39 (01) 25-27
- 14 Li W, Liu Y, Li W, Chen L, Ying J. Intergenic breakpoints identified by DNA sequencing confound targetable kinase fusion detection in NSCLC. J Thorac Oncol 2020; 15 (07) 1223-1231
- 15 Kang J, Zhang XC, Chen HJ. et al. Complex ALK fusions are associated with better prognosis in advanced non-small cell lung cancer. Front Oncol 2020; 10: 596937
- 16 Zhao R, Zhang J, Han Y. et al. Clinicopathological features of ALK expression in 9889 cases of non-small-cell lung cancer and genomic rearrangements identified by capture-based next-generation sequencing: a Chinese retrospective analysis. Mol Diagn Ther 2019; 23 (03) 395-405
- 17 Ke L, Xu M, Jiang X, Sun X. Epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase/oncogene or c-ros oncogene 1 (ALK/ROS1) fusions inflict non-small cell lung cancer (NSCLC) female patients older than 60 years of age. Med Sci Monit 2018; 24 (24) 9364-9369
- 18 Ota K, Azuma K, Kawahara A. et al. Induction of PD-L1 expression by the EML4-ALK oncoprotein and downstream signaling pathways in non-small cell lung cancer. Clin Cancer Res 2015; 21 (17) 4014-4021
- 19 Chen WS, Bindra RS, Mo A. et al. CDKN2A copy number loss is an independent prognostic factor in HPV-negative head and neck squamous cell carcinoma. Front Oncol 2018; 8: 95
- 20 Yin J, Li Y, Zhao H. et al. Copy-number variation of MCL1 predicts overall survival of non-small-cell lung cancer in a Southern Chinese population. Cancer Med 2016; 5 (09) 2171-2179
- 21 Sawada R, Maehara R, Oshikiri T. et al. MDM2 copy number increase: a poor prognostic, molecular event in esophageal squamous cell carcinoma. Hum Pathol 2019; 89: 1-9
- 22 Huang F, Chang H, Greer A. et al. IRS2 copy number gain, KRAS and BRAF mutation status as predictive biomarkers for response to the IGF-1R/IR inhibitor BMS-754807 in colorectal cancer cell lines. Mol Cancer Ther 2015; 14 (02) 620-630
- 23 Gainor JF, Varghese AM, Ou SH. et al. ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1,683 patients with non-small cell lung cancer. Clin Cancer Res 2013; 19 (15) 4273-4281
- 24 Li Y, Li Y, Yang T. et al. Clinical significance of EML4-ALK fusion gene and association with EGFR and KRAS gene mutations in 208 Chinese patients with non-small cell lung cancer. PLoS One 2013; 8 (01) e52093
- 25 Popat S, Vieira de Araújo A, Min T. et al. Lung adenocarcinoma with concurrent exon 19 EGFR mutation and ALK rearrangement responding to erlotinib. J Thorac Oncol 2011; 6 (11) 1962-1963
- 26 Tiseo M, Gelsomino F, Boggiani D. et al. EGFR and EML4-ALK gene mutations in NSCLC: a case report of erlotinib-resistant patient with both concomitant mutations. Lung Cancer 2011; 71 (02) 241-243
- 27 Marusyk A, Almendro V, Polyak K. Intra-tumour heterogeneity: a looking glass for cancer?. Nat Rev Cancer 2012; 12 (05) 323-334
- 28 Ulivi P, Puccetti M, Capelli L. et al. Molecular determinations of EGFR and EML4-ALK on a single slide of NSCLC tissue. J Clin Pathol 2013; 66 (08) 708-710
- 29 Yang JJ, Zhang XC, Su J. et al. Lung cancers with concomitant EGFR mutations and ALK rearrangements: diverse responses to EGFR-TKI and crizotinib in relation to diverse receptors phosphorylation. Clin Cancer Res 2014; 20 (05) 1383-1392
- 30 Imamura F, Inoue T, Kimura M, Nishino K, Kumagai T. A long-term survivor of non-small-cell lung cancer harboring concomitant EGFR mutation and ALK translocation. Respir Med Case Rep 2016; 19: 137-139
- 31 Christopoulos P, Kirchner M, Bozorgmehr F. et al. Identification of a highly lethal V3+ TP53+ subset in ALK+ lung adenocarcinoma. Int J Cancer 2019; 144 (01) 190-199
- 32 Yoneshima Y, Ijichi K, Anai S. et al. PD-L1 expression in lung adenocarcinoma harboring EGFR mutations or ALK rearrangements. Lung Cancer 2018; 118: 36-40
- 33 Kim SJ, Kim S, Kim DW. et al. Alterations in PD-L1 expression associated with acquisition of resistance to ALK inhibitors in ALK-rearranged lung cancer. Cancer Res Treat 2019; 51 (03) 1231-1240
- 34 Yang CY, Liao WY, Ho CC. et al. Association of programmed death-ligand 1 expression with fusion variants and clinical outcomes in patients with anaplastic lymphoma kinase-positive lung adenocarcinoma receiving crizotinib. Oncologist 2020; 25 (08) 702-711
- 35 Li M, Hou X, Chen J. et al. ALK fusion variant 3a/b, concomitant mutations, and high PD-L1 expression were associated with unfavorable clinical response to second-generation ALK TKIs in patients with advanced ALK-rearranged non-small cell lung cancer (GASTO 1061). Lung Cancer 2022; 165: 54-62
- 36 Zhou Y, Song L, Xu Q. et al. Investigation on the survival implications of PD-L1 expression status in ALK− rearranged advanced non-small cell lung cancer treated with first-line crizotinib. Lung Cancer 2022; 167: 58-64
- 37 Chang GC, Yang TY, Chen KC. et al. ALK variants, PD-L1 expression, and their association with outcomes in ALK-positive NSCLC patients. Sci Rep 2020; 10 (01) 21063
- 38 Tian X, Li Y, Huang Q, Zeng H, Wei Q, Tian P. High PD-L1 expression correlates with an immunosuppressive tumour immune microenvironment and worse prognosis in ALK-rearranged non-small cell lung cancer. Biomolecules 2023; 13 (06) 991
Address for correspondence
Publication History
Article published online:
13 June 2024
© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
-
References
- 1 Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc 2008; 83 (05) 584-594
- 2 de Groot PM, Wu CC, Carter BW, Munden RF. The epidemiology of lung cancer. Transl Lung Cancer Res 2018; 7 (03) 220-233
- 3 Soda M, Choi YL, Enomoto M. et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007; 448 (7153): 561-566
- 4 Solomon B, Varella-Garcia M, Camidge DR. ALK gene rearrangements: a new therapeutic target in a molecularly defined subset of non-small cell lung cancer. J Thorac Oncol 2009; 4 (12) 1450-1454
- 5 Hallberg B, Palmer RH. Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology. Nat Rev Cancer 2013; 13 (10) 685-700
- 6 He Y, Sun LY, Gong R. et al. The prevalence of EML4-ALK variants in patients with non-small-cell lung cancer: a systematic review and meta-analysis. Biomarkers Med 2019; 13 (12) 1035-1044
- 7 Takeuchi K, Choi YL, Togashi Y. et al. KIF5B-ALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer. Clin Cancer Res 2009; 15 (09) 3143-3149
- 8 Rikova K, Guo A, Zeng Q. et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 2007; 131 (06) 1190-1203
- 9 Togashi Y, Soda M, Sakata S. et al. KLC1-ALK: a novel fusion in lung cancer identified using a formalin-fixed paraffin-embedded tissue only. PLoS One 2012; 7 (02) e31323
- 10 Feng T, Chen Z, Gu J, Wang Y, Zhang J, Min L. The clinical responses of TNIP2-ALK fusion variants to crizotinib in ALK-rearranged lung adenocarcinoma. Lung Cancer 2019; 137: 19-22
- 11 Rodig SJ, Shapiro GI. Crizotinib, a small-molecule dual inhibitor of the c-Met and ALK receptor tyrosine kinases. Curr Opin Investig Drugs 2010; 11 (12) 1477-1490
- 12 Markham A. Brigatinib: first global approval. Drugs 2017; 77 (10) 1131-1135
- 13 Kuang S, Leighl NB. Lorlatinib in ALK-rearranged lung cancer. Cancer Cell 2021; 39 (01) 25-27
- 14 Li W, Liu Y, Li W, Chen L, Ying J. Intergenic breakpoints identified by DNA sequencing confound targetable kinase fusion detection in NSCLC. J Thorac Oncol 2020; 15 (07) 1223-1231
- 15 Kang J, Zhang XC, Chen HJ. et al. Complex ALK fusions are associated with better prognosis in advanced non-small cell lung cancer. Front Oncol 2020; 10: 596937
- 16 Zhao R, Zhang J, Han Y. et al. Clinicopathological features of ALK expression in 9889 cases of non-small-cell lung cancer and genomic rearrangements identified by capture-based next-generation sequencing: a Chinese retrospective analysis. Mol Diagn Ther 2019; 23 (03) 395-405
- 17 Ke L, Xu M, Jiang X, Sun X. Epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase/oncogene or c-ros oncogene 1 (ALK/ROS1) fusions inflict non-small cell lung cancer (NSCLC) female patients older than 60 years of age. Med Sci Monit 2018; 24 (24) 9364-9369
- 18 Ota K, Azuma K, Kawahara A. et al. Induction of PD-L1 expression by the EML4-ALK oncoprotein and downstream signaling pathways in non-small cell lung cancer. Clin Cancer Res 2015; 21 (17) 4014-4021
- 19 Chen WS, Bindra RS, Mo A. et al. CDKN2A copy number loss is an independent prognostic factor in HPV-negative head and neck squamous cell carcinoma. Front Oncol 2018; 8: 95
- 20 Yin J, Li Y, Zhao H. et al. Copy-number variation of MCL1 predicts overall survival of non-small-cell lung cancer in a Southern Chinese population. Cancer Med 2016; 5 (09) 2171-2179
- 21 Sawada R, Maehara R, Oshikiri T. et al. MDM2 copy number increase: a poor prognostic, molecular event in esophageal squamous cell carcinoma. Hum Pathol 2019; 89: 1-9
- 22 Huang F, Chang H, Greer A. et al. IRS2 copy number gain, KRAS and BRAF mutation status as predictive biomarkers for response to the IGF-1R/IR inhibitor BMS-754807 in colorectal cancer cell lines. Mol Cancer Ther 2015; 14 (02) 620-630
- 23 Gainor JF, Varghese AM, Ou SH. et al. ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1,683 patients with non-small cell lung cancer. Clin Cancer Res 2013; 19 (15) 4273-4281
- 24 Li Y, Li Y, Yang T. et al. Clinical significance of EML4-ALK fusion gene and association with EGFR and KRAS gene mutations in 208 Chinese patients with non-small cell lung cancer. PLoS One 2013; 8 (01) e52093
- 25 Popat S, Vieira de Araújo A, Min T. et al. Lung adenocarcinoma with concurrent exon 19 EGFR mutation and ALK rearrangement responding to erlotinib. J Thorac Oncol 2011; 6 (11) 1962-1963
- 26 Tiseo M, Gelsomino F, Boggiani D. et al. EGFR and EML4-ALK gene mutations in NSCLC: a case report of erlotinib-resistant patient with both concomitant mutations. Lung Cancer 2011; 71 (02) 241-243
- 27 Marusyk A, Almendro V, Polyak K. Intra-tumour heterogeneity: a looking glass for cancer?. Nat Rev Cancer 2012; 12 (05) 323-334
- 28 Ulivi P, Puccetti M, Capelli L. et al. Molecular determinations of EGFR and EML4-ALK on a single slide of NSCLC tissue. J Clin Pathol 2013; 66 (08) 708-710
- 29 Yang JJ, Zhang XC, Su J. et al. Lung cancers with concomitant EGFR mutations and ALK rearrangements: diverse responses to EGFR-TKI and crizotinib in relation to diverse receptors phosphorylation. Clin Cancer Res 2014; 20 (05) 1383-1392
- 30 Imamura F, Inoue T, Kimura M, Nishino K, Kumagai T. A long-term survivor of non-small-cell lung cancer harboring concomitant EGFR mutation and ALK translocation. Respir Med Case Rep 2016; 19: 137-139
- 31 Christopoulos P, Kirchner M, Bozorgmehr F. et al. Identification of a highly lethal V3+ TP53+ subset in ALK+ lung adenocarcinoma. Int J Cancer 2019; 144 (01) 190-199
- 32 Yoneshima Y, Ijichi K, Anai S. et al. PD-L1 expression in lung adenocarcinoma harboring EGFR mutations or ALK rearrangements. Lung Cancer 2018; 118: 36-40
- 33 Kim SJ, Kim S, Kim DW. et al. Alterations in PD-L1 expression associated with acquisition of resistance to ALK inhibitors in ALK-rearranged lung cancer. Cancer Res Treat 2019; 51 (03) 1231-1240
- 34 Yang CY, Liao WY, Ho CC. et al. Association of programmed death-ligand 1 expression with fusion variants and clinical outcomes in patients with anaplastic lymphoma kinase-positive lung adenocarcinoma receiving crizotinib. Oncologist 2020; 25 (08) 702-711
- 35 Li M, Hou X, Chen J. et al. ALK fusion variant 3a/b, concomitant mutations, and high PD-L1 expression were associated with unfavorable clinical response to second-generation ALK TKIs in patients with advanced ALK-rearranged non-small cell lung cancer (GASTO 1061). Lung Cancer 2022; 165: 54-62
- 36 Zhou Y, Song L, Xu Q. et al. Investigation on the survival implications of PD-L1 expression status in ALK− rearranged advanced non-small cell lung cancer treated with first-line crizotinib. Lung Cancer 2022; 167: 58-64
- 37 Chang GC, Yang TY, Chen KC. et al. ALK variants, PD-L1 expression, and their association with outcomes in ALK-positive NSCLC patients. Sci Rep 2020; 10 (01) 21063
- 38 Tian X, Li Y, Huang Q, Zeng H, Wei Q, Tian P. High PD-L1 expression correlates with an immunosuppressive tumour immune microenvironment and worse prognosis in ALK-rearranged non-small cell lung cancer. Biomolecules 2023; 13 (06) 991