A novel GHR-ALK fusion gene in a patient with metastatic lung adenocarcinoma and its response to crizotinib: a case report

Anaplastic lymphoma kinase ( ALK) rearrangement occurs in approximately 5% of non-small cell lung cancers (NSCLCS), and EML4-ALK is the most commonly observed ALK fusion variant in NSCLC. However, growth hormone receptor ( GHR) as the fusion partner for ALK and the clinical response to ALK tyrosine kinase inhibitors in patients with metastatic lung adenocarcinoma (LUAD) who carry the GHR-ALK variant have not been documented. This case describes a 63-year-old woman diagnosed with metastatic LUAD. Immunohistochemistry revealed positive ALK expression, and the patient was treated with crizotinib. After 3 weeks of treatment, the patient had a partial response. Because of treatment-related adverse events, the dose of crizotinib was reduced. After 3.7 months, computed tomography uncovered disease progression. Next-generation sequencing identified a novel GHR-ALK fusion in the plasma of the patient. The patient was treated again with crizotinib, but the disease progressed again 2 months later. Then, the patient received chemotherapy. She succumbed to her disease 11 months after the initial diagnosis. Our work provides evidence supporting the use of crizotinib in patients with metastatic LUAD harboring GHR-ALK.

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Case Report: A Novel Non-Reciprocal ALK Fusion: ALK-GCA and EML4-ALK Were Identified in Lung Adenocarcinoma, Which May Respond to Alectinib Adjuvant-Targeted Therapy

Frontiers in Oncology ◽

10.3389/fonc.2021.782682 ◽

2022 ◽

Vol 11 ◽

Author(s):

Xiaoqian Zhai ◽

Qiang Wu ◽

Dan Pu ◽

Liyuan Yin ◽

Weiya Wang ◽

...

Keyword(s):

Case Report ◽

Targeted Therapy ◽

Lung Adenocarcinoma ◽

Kinase Inhibitors ◽

Postoperative Radiotherapy ◽

Good Condition ◽

Disease Free Survival ◽

Alk Rearrangement ◽

Lung Cancers ◽

Anaplastic Lymphoma

Anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancers (NSCLCs) have favorable and impressive response to ALK tyrosine kinase inhibitors (TKIs). However, ALK rearrangement had approximately 90 distinct fusion partners. Patients with different ALK fusions might have distinct responses to different-generation ALK-TKIs. In this case report, we identified a novel non-reciprocal ALK fusion: ALK-grancalcin (GCA) (A19: intragenic) and EML4-ALK (E20: A20) by next-generation sequencing (NGS) in a male lung adenocarcinoma patient who was staged as IIIB-N2 after surgery. After a multidisciplinary discussion, the patient received alectinib adjuvant targeted therapy and postoperative radiotherapy (PORT). He is currently in good condition, and disease-free survival (DFS) has been 20 months so far, which has been longer than the median survival time of IIIB NSCLC patients. Our study extended the spectrum of ALK fusion partners in ALK + NSCLC, and we reported a new ALK fusion: ALK-GCA and EML4-ALK and its sensitivity to alectinib firstly in lung cancer. It is vital for clinicians to detect fusion mutations of patients and report timely the newfound fusions and their response to guide treatment.

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CSF rhinorrhea following alectinib treatment for anaplastic lymphoma kinase rearranged lung adenocarcinoma - e contrario

International Journal of Molecular and Immuno Oncology ◽

10.25259/ijmio_20_2020 ◽

2020 ◽

Vol 5 ◽

pp. 127-130

Author(s):

Deepa Shrestha ◽

Raghava Rao Gandra ◽

Ramandeep Singh Virk ◽

Paramjeet Singh ◽

Aditi Mehta ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Skull Base ◽

Anaplastic Lymphoma Kinase ◽

Trauma Surgery ◽

Skull Base Tumors ◽

Alk Rearrangement ◽

Csf Rhinorrhea ◽

Anaplastic Lymphoma ◽

Metastatic Lung

Cerebrospinal fluid (CSF) rhinorrhea is a condition characterized by leakage of CSF from skull base through the nostril(s). It is commonly associated with trauma, surgery, infections of paranasal sinuses/skull base, and intracranial and skull base tumors. Among malignant causes, lung cancer is rarely associated with CSF rhinorrhea. Herein, we report the case of a 51-year-old lady who was initially diagnosed with metastatic lung adenocarcinoma (LUAC) with anaplastic lymphoma kinase (ALK) rearrangement and initiated on treatment with alectinib. She had good clinicoradiological response, but on follow-up developed CSF rhinorrhea that required surgical correction. We also discuss the proposed mechanisms associated with occurrence of CSF rhinorrhea in the setting of metastatic ALK-rearranged LUAC.

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The Prevalence of the EML4-ALK Fusion Gene in Cytology Specimens from Patients with Lung Adenocarcinoma

Pulmonary Medicine ◽

10.1155/2020/3578748 ◽

2020 ◽

Vol 2020 ◽

pp. 1-6

Author(s):

Didik S. Heriyanto ◽

Ika Trisnawati ◽

Evan G. Kumara ◽

Vincent Laiman ◽

Fara S. Yuliani ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Egfr Mutation ◽

Fusion Gene ◽

Small Cell Lung Carcinoma ◽

Alk Rearrangement ◽

Cell Lung Carcinoma ◽

Direct Smear ◽

Nccn Guidelines ◽

Anaplastic Lymphoma ◽

Qrt Pcr

Background. Under the National Comprehensive Cancer Network (NCCN) guidelines for non-small-cell lung carcinoma (NSCLC), anaplastic lymphoma kinase (ALK) gene rearrangement is required to be assessed. However, data showing the prevalence of the ALK rearrangement is still deficient and is not yet available in Indonesia. This study used direct smear preparation from transthoracic needle specimens that are minimally invasive. The main objective of the study is to identify the prevalence of the ALK fusion rearrangement gene in cytological specimens. Materials and Methods. A total of 35 direct smear preparations diagnosed as lung adenocarcinoma and EGFR mutation negative were involved in this study. The samples were taken between 2017 and 2019. These samples were examined for EML4-ALK fusion rearrangement gene using qRT-PCR. The EML4-ALK rearrangement status was determined by qRT-PCR with high-resolution melting (HRM) analysis. Results. A total of 28 (80%) samples were from males, and 7 samples were from females. Seven (20% 95% CI: 8.4%-36.9%) samples were EML4-ALK rearrangement positive. The average age of the patients was 63.5 years old. The most common sites of metastasis in this study were pleural cavity, bone, liver, and CNS. Conclusions. qRT-PCR successfully identified EML4-ALK fusion rearrangement in direct smear preparations of lung adenocarcinoma. Direct smear samples can be used for EML4-ALK rearrangement detection using qRT-PCR. The EML4-ALK rearrangement gene has high prevalence in selected lung adenocarcinoma and EGFR mutation-negative populations. ALK inhibitors in lung cancer can be openly considered for use in Indonesian patients to improve the outcome of this subset of patients.

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Response to crizotinib in advanced ALK-rearranged NSCLCs with different variants and abundance of ALK-fusion alleles.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e20651 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e20651-e20651 ◽

Cited By ~ 1

Author(s):

Jianming Ying ◽

Yan Li ◽

Tongtong Zhang ◽

Wenbin Li ◽

Pu-Yuan Xing ◽

...

Keyword(s):

Clinical Efficacy ◽

High Abundance ◽

P Value ◽

Alk Rearrangement ◽

Lung Cancers ◽

Anaplastic Lymphoma ◽

Baseline Characteristics ◽

Alk Positive ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing

e20651 Background: Anaplastic lymphoma kinase ( ALK) rearrangements are present in approximately 5% of non-small-cell lung cancers (NSCLCs). NSCLCs with ALK-rearrangement can be effectively treated with crizotinib. However, magnitude and duration of responses are found to be heterogeneous. This study explored the clinical efficacy of crizotinib in different ALK variants and abundance levels using next-generation sequencing (NGS). Methods: Among 89 ALK-rearrangement patients treated with crizotinib, 47 patients were identified with tumor specimens that could be evaluated by NGS. We retrospectively evaluated the clinical efficacy of crizotinib in different ALK variants and the abundance of ALK-fusion alleles. Results: The median PFS of the 89 ALK-rearrangement patients was 14.1 months (95%CI: 11.27-18.43 months). Among the 47 patients with NGS results, the most frequent variants were variant 3a/b (29.79%, 14/47), variant 1 (25.53%, 12/47) and variant 2 (14.89%, 7/47). Rare EML4- ALK variants were detected in 6 cases (12.77%). Other new fusion partners were detected in 8 cases (17.02%). Patients with EML4- ALK variant 2 appeared to have longer PFS than other EML4- ALK variants with a borderline p value. Patients were categorized into three groups based on the abundance of ALK-fusion alleles: low-abundance group ( < 35%), middle-abundance group (≥35% and < 55%), and high-abundance group (55%). Middle-abundance group had a better PFS than both low-abundance group and high-abundance group (P = 0.01). After adjusting for other baseline characteristics, abundance levels of ALK-positive alleles and ALKvariant type were identified as important factors for predicting clinical efficacy of crizotinib. Conclusions: Our results indicate prolonged PFS in patients with EML4- ALK variant 2 versus other EML4- ALK patients. The abundance of ALK-fusion alleles also correlated with the extent of benefit from crizotinib treatment.

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Anaplastic lymphoma kinase (ALK) partners identified by next-generation sequencing in Chinese patients with solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.3555 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 3555-3555

Author(s):

Sheng Yang ◽

Fuyu Gong ◽

Guoqiang Wang ◽

Xiaohui He

Keyword(s):

Lung Cancer ◽

Cancer Patients ◽

Solid Tumors ◽

Chinese Patients ◽

Fusion Partner ◽

The Novel ◽

Alk Rearrangement ◽

Lung Cancer Patients ◽

Anaplastic Lymphoma ◽

Generation Sequencing

3555 Background: Anaplastic lymphoma kinase (ALK) rearrangement is a validated therapeutic driver gene in non-small cell lung cancer (NSCLC). More than 30 different fusion partner genes of ALK in NSCLC have been reportedand most of these ALK fusions respond well to ALK inhibitors crizotinib. With the development of next-generation sequencing (NGS), more novel partners for ALK rearrangement have been identified. Here, we aimed to report the landscape of ALK rearrangement in Chinese patients with solid tumors. Methods: Tissue or blood samples were subjected to NGS in a College of American Pathologists-certified and Clinical Laboratory Improvement Amendments-accredited lab for ALK arrangement. Results: In total, we profiled more than 40,000 patients, among which 72 cases with 52 ALK fusion partner, harboring 17 reported partners and 35 novel partners. The average ALK rearrangement patients' age was 53 years (range, 17-76 years). Among all the ALK fusion cases (n = 72), lung cancer were the largest proportion with 77.8% (n = 56), colorectal cancer accounted for, 5.5% (n = 4), liver cancer accounted for 4.2% (n = 3), biliary cancer, melanoma, carcinosarcoma and inflammatory myofibroblastic tumor accounted for 2.8% (n = 2) respectively, and only one case (n = 1) was malignant peritoneal mesothelioma. The most common ALK fusion partners were KIF5B (n = 6), DCTN1 (n = 5) and STRN (n = 5). In 38 cases, 35 novel ALK fusion partners were discovered. The novel CLIP4-ALK, EHBP1-ALK, PLB1-ALK occurred twice in 6 patients, which were two lung cancer patients with CLIP4-ALK fusion, two lung cancer patients with PLB1-ALK fusion, one hepatic cellular cancer patients with EHBP1-ALK, and one melanoma patients with EHBP1-ALK. There were two special lung cancer cases with two ALK fusions. One case detected the novel LRIG1-ALK fusion and novel PLB1-ALK fusion, the other case detected novel GLI3-ALK fusion and reported HIP1-ALK fusion. Conclusions: Novel ALK fusions are detected in patients with not only NSCLC but also other solid tumors. NGS fusion assay is an optional method for screening novel fusions.

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EML4-ALK positive lung adenocarcinoma with skeletal muscle metastasis in the right calf which was treatable with lorlatinib after resistance to treatment with alectinib

BMJ Case Reports ◽

10.1136/bcr-2020-240295 ◽

2021 ◽

Vol 14 (4) ◽

pp. e240295

Author(s):

Hironari Matsuda ◽

Munechika Hara ◽

Shin-Ichiro Iwakami ◽

Kazuhisa Takahashi

Keyword(s):

Skeletal Muscle ◽

Lung Adenocarcinoma ◽

Kinase Inhibitor ◽

Stable Condition ◽

Japanese Woman ◽

Alk Rearrangement ◽

Anaplastic Lymphoma ◽

Resistance To Treatment ◽

Alk Positive ◽

The Right

This report concerns a patient with skeletal muscle metastases due to lung adenocarcinoma harbouring an echinoderm microtubule-associated protein-like-4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangement, who was successfully treated with lorlatinib after resistance to alectinib. A right lower lobectomy based on a diagnosis of lung adenocarcinoma was performed on a 77-year-old Japanese woman. After 7 months of surgical resection, a mass in the right calf was observed. A fine-needle aspiration biopsy from the mass was performed and the mass was diagnosed as metastatic adenocarcinoma harbouring EML4-ALK rearrangement. Alectinib was administered for 10 months. Then, administration of lorlatinib, an ALK tyrosine kinase inhibitor classified as third generation, was initiated after resistance to treatment with alectinib. After starting treatment with lorlatinib, the gastrocnemius tumour diminished and has maintained a stable condition. Our case suggests that EML4-ALK positive lung adenocarcinoma is treatable with lorlatinib after resistance to treatment with alectinib.

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Two different patterns of lung adenocarcinoma with concomitant EGFR mutation and ALK rearrangement

Tumori Journal ◽

10.1177/03008916211005546 ◽

2021 ◽

pp. 030089162110055

Author(s):

Dashi Zhao ◽

Jun Fan ◽

Li Peng ◽

Bo Huang ◽

Yili Zhu ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Egfr Mutation ◽

Growth Factor Receptor ◽

Egfr Mutations ◽

Alk Rearrangement ◽

Molecular Alterations ◽

Anaplastic Lymphoma ◽

Sporadic Cases ◽

Epidermal Growth ◽

Rare Group

Epidermal growth factor receptor ( EGFR) mutations and anaplastic lymphoma kinase ( ALK) rearrangements are considered mutually exclusive in non-small cell lung cancer (NSCLC), especially in lung adenocarcinoma (LUAC). However, sporadic cases harboring concomitant EGFR and ALK alterations have been increasingly reported. There is no consensus opinion regarding the treatment of patients positive for both molecular alterations. NSCLC with EGFR/ ALK coalterations should be separated into two subtypes: unifocal and multifocal LUAC. Here, we present an overview of the available literature regarding this rare group of patients to provide useful suggestions for therapeutic strategies.

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Successful Alectinib Treatment for Carcinoma of Unknown Primary with EML4-ALK Fusion Gene: A Case Report

Current Oncology ◽

10.3390/curroncol28030180 ◽

2021 ◽

Vol 28 (3) ◽

pp. 1938-1945

Author(s):

Keiji Sugiyama ◽

Ai Izumika ◽

Akari Iwakoshi ◽

Riko Nishibori ◽

Mariko Sato ◽

...

Keyword(s):

Lymph Node ◽

Cervical Lymph Node ◽

Kinase Inhibitors ◽

Fusion Gene ◽

Liver Lesion ◽

Lymph Node Biopsy ◽

Unknown Primary ◽

Carcinoma Of Unknown Primary ◽

Anaplastic Lymphoma ◽

Lymph Node Swelling

Gene alteration in anaplastic lymphoma kinase (ALK) is rare, and the efficacy of ALK inhibitors in the treatment of carcinoma of unknown primary (CUP) with ALK alteration remains unclear. The patient was a 56-year-old woman who presented with cervical lymph node swelling. Computed tomography revealed paraaortic, perigastric, and cervical lymph node swelling; ascites; a liver lesion; and a left adrenal mass. A cervical lymph node biopsy was performed, and pathological diagnosis of an undifferentiated malignant tumor was conducted. Finally, the patient was diagnosed with CUP and treated with chemotherapy. To evaluate actionable mutations, we performed a multigene analysis, using a next-generation sequencer (FoundationOne® CDx). It revealed that the tumor harbored an echinoderm microtubule-associated protein-like 4 (EML4) and ALK fusion gene. Additionally, immunohistochemistry confirmed ALK protein expression. Alectinib, a potent ALK inhibitor, was recommended for the patient at a molecular oncology conference at our institution. Accordingly, alectinib (600 mg/day) was administered, and the multiple lesions and symptoms rapidly diminished without apparent toxicity. The administration of alectinib continued for a period of 10 months without disease progression. Thus, ALK-tyrosine kinase inhibitors should be considered in patients with CUP harboring the EML4-ALK fusion gene.

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