Distribution of EML4-ALK fusion variants and clinical outcomes in patients with resected non-small cell lung cancer

Hong, Tao; Shi, Liang; Zhou, Anna; Li, Hongxia; Gai, Fei; Zhan, Huichun; Che, Nanying; Liu, Zhe

doi:10.1016/j.lungcan.2020.09.012

Cited by 25 publications

(17 citation statements)

References 36 publications

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“…Even with the relatively narrow profiling focused on mutations of oncogenic drivers employed in this study, therapeutic opportunities emerged for less than half of liquid biopsy-positive cases, while genetic changes not sensitive to currently available therapies were more frequent (Figure S1 and Table S1). Moreover, ctDNA detectability correlated with presence of the high-risk molecular features "short" EML4-ALK fusion variant (mainly variant 3) and TP53 mutations, which were independently associated with worse patient outcome in several retrospective analyses and the randomized phase 3 trial ALTA-1L (33)(34)(35)(36)(37)(38). The association between presence of EML4-ALK V3 and detectability of ALK resistance mutations has also been noted by other investigators (39) and stands in apparent contradiction to the adverse phenotype of V3-positive patients (40).…”

Section: Discussionmentioning

confidence: 98%

Earlier extracranial progression and shorter survival in ALK- rearranged lung cancer with positive liquid rebiopsies

Christopoulos¹,

Dietz²,

Angeles³

et al. 2021

Transl Lung Cancer Res

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Background: Liquid rebiopsies can detect resistance mutations to guide therapy of anaplastic lymphoma kinase-rearranged (ALK + ) non-small-cell lung cancer (NSCLC) failing tyrosine kinase inhibitors (TKI).Here, we analyze how their results relate to the anatomical pattern of disease progression and patient outcome.Methods: Clinical, molecular, and radiologic characteristics of consecutive TKI-treated ALK + NSCLC patients were analyzed using prospectively collected plasma samples and the 17-gene targeted AVENIO kit, which covers oncogenic drivers and all TP53 exons.Results: In 56 patients, 139 instances of radiologic changes were analyzed, of which 133 corresponded to disease progression. Circulating tumor DNA (ctDNA) alterations were identified in most instances of extracranial progression (58/94 or 62%), especially if concomitant intracranial progression was also present (89%, P<0.001), but rarely in case of isolated central nervous system (CNS) progression (8/39 or 21%, P<0.001). ctDNA detectability correlated with presence of "short" echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion variants (mainly V3, E6:A20) and/or TP53 mutations (P<0.05), and presented therapeutic opportunities in <50% of cases. Patients with extracranial progression and positive liquid biopsies had shorter survival from the start of palliative treatment (mean 52 vs. 69 months, P=0.002), regardless of previous and subsequent therapy and initial ECOG performance status. Furthermore, for patients with extracranial progression, ctDNA detectability was associated with shorter next-line progressionfree survival (PFS) (3 vs. 13 months, P=0.003) if they were switched to another systemic therapy (49/86 samples), and with shorter time-to-next-treatment (TNT) (3 vs. 8 months, P=0.004) if they were continued ^ ORCID: 0000-0002-7966-8980.

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Section: Discussionmentioning

confidence: 98%

Earlier extracranial progression and shorter survival in ALK- rearranged lung cancer with positive liquid rebiopsies

Christopoulos¹,

Dietz²,

Angeles³

et al. 2021

Transl Lung Cancer Res

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“…Among the 6 cases (6/18, 33.3%) investigated with DNA sequencing, exon 6 of EML4 fused with exon 20 of ALK in 4 cases, including the two IMTs that we investigated; additionally, exon 4 of EML4 fused with exon 20 of ALK in one case, and the other case involved exon 2 of EML4 and exon 20 of ALK. Some clinical studies have demonstrated that the EML4 (exon 6)-ALK (exon 20) fusion variant (3a/b) is a high-risk feature, conferring accelerated metastatic spread, ALK inhibitor resistance, and worsened prognosis in ALK-positive non-small-cell lung cancer (NSCLC) (22)(23)(24). The 3a/b variants of the EML4-ALK fusion gene were identified by using FISH and Sanger sequencing in a malignant hypopharynx IMT, and strong ALK immunoreactivity was also observed in neoplastic cells (8), which was best illustrated by our cases.…”

Section: Discussionmentioning

confidence: 99%

Case Report: Early Distant Metastatic Inflammatory Myofibroblastic Tumor Harboring EML4-ALK Fusion Gene: Study of Two Typical Cases and Review of Literature

Han

Qiu

et al. 2022

Front. Med.

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Inflammatory myofibroblastic tumor (IMT) is a distinctive neoplasm that frequently arises in the lung and accounts for ~1% of lung tumors. Distant metastatic IMT is extremely rare and has been poorly investigated. This analysis was specifically performed to explore the clinicopathological and genetic features of early distant metastatic IMT. Two typical patients with distant metastatic IMTs were selected, which accounted for 1.13% of all diagnosed IMTs in the last 5 years. One patient was a 55 year-old male, and the other patient was a 56 year-old female. Both primary tumors arose from the lung, and the initial clinical symptoms of the two patients involved coughing. Both of the imaging examinations showed low-density nodular shadows in the lungs with enhancement around the mass. Microscopically, dense arranged tumor cells, prominent cellular atypia, and high mitotic activity with atypical form were more prominent in the metastatic lesions than in the primary lesions. All of the primary and metastatic tumors in both cases showed positive anaplastic lymphoma kinase (ALK) immunostaining and ALK rearrangement via fluorescence in situ hybridization. The EML4 (exon 6)-ALK (exon 20) fusion variant (v3a/b) was identified by using next-generation sequencing (NGS) and was verified by using reverse transcription polymerase chain reaction (RT-PCR). Furthermore, intronic variants of NOTCH1 and synonymous variants of ARAF were also detected via NGS in one IMT for the first time and were verified in all of the primary and metastatic lesions via PCR. Distant metastasis occurred during a short period of time (1 and 2 months) after the first surgery. One patient presented with multiple metastases to the subcutaneous tissue and bone that responded to ALK inhibitor alectinib therapy, and the tumor was observed to regress 10 months after the initial ALK inhibitor therapy. In contrast, the other patient presented with subcutaneous neck metastasis without ALK inhibitor treatment and succumbed to the disease within 3 months after the surgery. This study demonstrated the possible role of EML4-ALKv3a/b in the malignant progression of IMT and proposed certain therapeutic effects of ALK inhibitors on multiple metastatic IMTs.

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“…To support this hypothesis, the frequency of PD-1 high expressers in our study cohort is similar to the response rate for PD-1 blockade in the prospective studies. 10 14 15 Although there are conflicting data as to whether EGFR and ALK wild-type tumor are associated with a worse prognosis after surgical resection and an improved response to checkpoint inhibitors, [43][44][45][46][47][48] our study suggests that the T-cell exhaustion status can be utilized to select patient populations that would be expected to most highly benefit from adjuvant treatment with immune checkpoint inhibitors.…”

Section: Open Accessmentioning

confidence: 91%

Distinct exhaustion features of T lymphocytes shape the tumor-immune microenvironment with therapeutic implication in patients with non-small-cell lung cancer

Kim

et al. 2021

J Immunother Cancer

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BackgroundReinvigoration of T-cell exhaustion with antibodies has shown promising efficacy in patients with non-small-cell lung cancer (NSCLC). However, the characteristics of T-cell exhaustion with regard to tumor-infiltrating lymphocytes (TILs) are poorly elucidated in NSCLC. Here, we investigated the exhaustion status of TILs in NSCLC patients at the intraindividual and interindividual levels.MethodsWe obtained paired peripheral blood, normal adjacent tissues, peritumoral tissues, and tumor tissues from 96 NSCLC patients. Features of T-cell exhaustion were analyzed by flow cytometry. T cells were categorized according to their programmed cell death-1 (PD-1) expression (PD-1high, PD-1int, and PD-1neg cells). Patients were classified based on the presence or absence of discrete PD-1high CD8+ TILs. Production of effector cytokines by CD8+ TILs was measured after T-cell stimulation with or without antibodies against immune checkpoint receptors.ResultsProgressive T-cell exhaustion with marked expression of exhaustion-related markers and diminished production of effector cytokines was observed in PD-1high CD8+ TILs compared with PD-1int and PD-1neg CD8+ TILs. Patients with distinct PD-1high CD8+ TILs (PD-1high expressers) exhibited characteristics associated with a favorable anti-PD-1 response compared with those without these lymphocytes (non-PD-1high expressers). Combined inhibition of dual immune checkpoint receptors further restored effector cytokine production by CD8+ TILs following T-cell stimulation. PD-1high CD8+ T lymphocyte populations in the peripheral blood and tumors were significantly correlated.ConclusionsT-cell exhaustion was differentially regulated among individual patients and was prominent in a subgroup of NSCLC patients who may benefit from PD-1 blockade or combined blockade of other immune checkpoint receptors.

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Distribution of EML4-ALK fusion variants and clinical outcomes in patients with resected non-small cell lung cancer

Cited by 25 publications

References 36 publications

Earlier extracranial progression and shorter survival in ALK- rearranged lung cancer with positive liquid rebiopsies

Earlier extracranial progression and shorter survival in ALK- rearranged lung cancer with positive liquid rebiopsies

Case Report: Early Distant Metastatic Inflammatory Myofibroblastic Tumor Harboring EML4-ALK Fusion Gene: Study of Two Typical Cases and Review of Literature

Distinct exhaustion features of T lymphocytes shape the tumor-immune microenvironment with therapeutic implication in patients with non-small-cell lung cancer

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