Medicine (Baltimore) 2022 Oct 07;10140:e30913. doi: 10.1097/MD.0000000000030913.

Lung adenocarcinoma harboring complex EML4-ALK fusion and BRAF V600E co-mutation responded to alectinib.

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RATIONALE: The echinoderm microtubule-associated protein-like 4 gene and anaplastic lymphoma kinase gene (EML4-ALK) is the most frequent fusion variant of ALK rearrangements in non-small cell lung cancer (NSCLC). With the widespread application of next-generation sequencing (NGS), more fusions and co-mutations of EML4-ALK have been discovered. Complex co-mutation of EML4-ALK fusions together with BRAF V600E, though rarely occurred, also deserves attention to determine the standard of caring these patients. Herein, we report a case of lung adenocarcinoma harboring a complex ALK fusion that coexisted with a BRAF mutation, as tested by DNA-NGS prior to treatment. PATIENT CONCERNS: A 51-year-old non-smoking man, without any symptoms, was admitted to hospital due to small pulmonary nodules and enlarged supraclavicu larlymph nodes found in health checkup. DIAGNOSIS: He was diagnosed with stage IVB (T4N3M1c) lung adenocarcinoma. BRAF V600E (abundance 3.75%) mutation and a novel thus little-understood EML4-ALK (E13, A5; abundance 2.16%) fusion were identified by DNA-NGS analysis of lymph node biopsy tissue in December 2019. INTERVENTIONS: Darafenib plus trametinib targeted therapy and chemotherapy were given firstly, but tumor progression was not inhibited. The ALK inhibitor alectinib was prescribed then. OUTCOMES: The patient exhibited a rapid disease response to ALK tyrosine kinase inhibitors alectinib with a complete remission of widespread metastatic disease and progression-free survival of more than 26 months, but not to darafenib plus trametinib targeted BRAF V600E therapy. Re-analyzed the patient's DNA-NGS original data, showed it is a rare and complex EML4-ALK (E13, A5, A20) fusion in fact. Additional RNA-NGS analysis showed it verified to be a canonical EML4-ALK (E13, A20) fusion transcript and coexisting with a BRAF V600E mutation. LESSONS: This case suggests that for patients with rare or complex EML4-ALK fusions at DNA level, additional RNA-NGS is necessary to verify its functionality as early as possible. Targeting EML4-ALK firstly may be more preferable despite the coexisting of BRAF V600E.

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