Lung adenocarcinoma with brain metastasis detected dual fusion of LOC399815-ALK and ALK-EML4 in combined treatment of Alectinib and CyberKnife: A case report

Abstract

Introduction: The anaplastic lymphoma kinase (ALK) gene fusion occurs in approximately 3% to 7% of nonsmall cell lung cancer (NSCLC), in which occurs approximately 23% to 31% of brain metastasis patients in poor prognosis. ALK tyrosine kinase inhibitors have shown efficacy in treating ALK-positive (ALK+) NSCLC. More than 90 distinct subtypes of ALK fusions have been identified through sequencing technique and would lead to significant differences in clinical efficacy, it is necessary to guide clinical treatment effectively by gene detection.

Patient concerns: A 56-year-old nonsmoking female admitted to hospital due to cough, expectoration, and chest pain. Chest computed tomography revealed a space-occupying lesion in the upper left lobe (5.0 cm × 2.4 cm × 2.9 cm), multiple enlarged lymph nodes in mediastinum 3A and 5 (largest size 1.5 cm × 1.4 cm), and evidence of thoracic vertebral metastasis, brain magnetic resonance imaging also showed brain metastasis.

Diagnoses: Lung adenocarcinoma with brain metastasis.

Interventions: The patient initially received conventional first-line chemotherapy, which led to a deteriorated condition. Blood-base liquid biopsy by next-generation sequencing resulted in double ALK fusions, in which with a neo-partner of lncRNA (LOC399815-ALK). Following subsequent treatment with Alectinib and stereotactic radiotherapy (CyberKnife) was subsequently employed to manage the brain metastatic lesions, resulting in a substantial decreased in both the number and size of tumor lesions.

Outcomes: The patient's response to therapy efficacy resulted in a substantial decreased in both the number and size of tumor lesions that assessed comprehensively evaluated through computed tomography imaging and ctDNA sequencing. Patient's condition has been under control for over 29 months.

Conclusion: Liquid biopsy may reveal the rare fusion forms of ALK, precisely guiding personalized treatment, and providing a reference method for longitudinal monitoring and efficacy evaluation of ALK-tyrosine kinase inhibitors in NSCLC patients.

Figure 1.

Dynamic chest CT scan (up), brain MRI imaging (down) and treatment timeline of patients during treatment. Chest CT and brain MRI at initial diagnosis (A). After 4 cycles of pemetrexed combined with carboplatin treatment, the size of left upper lung lesions decreased, but the number of brain lesions increased (B). After 4 cycles of carboplatin/docetaxel combined with bevacizumab treatment, the size of the left upper lung lesion was stable, but the brain lesion continued to deteriorate (C). Four months target therapy of treatment with Alectinib, the size of the left upper lung lesions was reduced, the brain lesions was significantly reduced in number and size (D). After 8 months of treatment with Alectinib, the left upper lung lesions remained unchanged. However, the number and size of brain lesions increased again (E). Take Alectinib orally combined with CyberKnife for 7 months, the left upper lung lesion was continually shrunk, the number and size of brain lesions were reduced (F). After 29 months of treatment with Alectinib combined with CyberKnife, the left upper lung lesions stayed stable, number of brain lesions increased slightly, but no local enhancement was found on enhanced MRI (G). CT = computed tomography, MRI = magnetic resonance imaging.

Figure 2.

NGS and immunohistochemical findings of the lung-tumor-tissue samples. (A) ALK gene and the LOC399815 gene map to chromosome 2 and 10, break point of LOC399815 at chr10 124,655,019 and is ligated to a position of chr2 294,468,648 of ALK, giving rise to the LOC399815–ALK fusion. (B) ALK gene and the EML4 gene map to chromosome 2, break point of EML4 at chr2 42,497,866 and is ligated to chr2 29,895,383 of ALK, giving rise to the ALK-EML4 fusion. (C) Hematoxylin and eosin stain of lung biopsy. (D) Immunohistochemistry (IHC) stain with anti-ALK antibody of lung biopsy. ALK = anaplastic lymphoma kinase, NGS = Next-generation sequencing.