Large-Cell Neuroendocrine Carcinoma of the Lung: A Focused Analysis of BRAF Alterations and Case Report of a BRAF Non-V600–Mutated Tumor Responding to Targeted Therapy

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Abstract
Purpose: In advanced stages, large-cell neuroendocrine carcinoma of the lung (L-LCNEC) mimics small-cell lung cancer despite its traditional classification as a non–small-cell lung cancer. Here we present a focused analysis of BRAF mutations in this population. Patients and Methods: Comprehensive genomic profiling of tumor tissues was performed from a cohort of 300 patients with biopsy-proven L-LCNEC. Specimens were either from a primary lung lesion or metastatic site. Results: In 13 patients, 14 unique BRAF alterations (amplifications, mutations) were identified. The importance of biomarker-driven therapy is subsequently highlighted with our case of a 69-year-old man diagnosed with metastatic L-LCNEC who did not respond to cisplatin plus etoposide. A significant durable response was then demonstrated with therapy targeted toward a BRAF non-V600E activating mutation (G469R) associated with biomarker response identified through circulating cell-free tumor DNA analysis. A change in clonal allele frequency from nearly 40% to nondetectable was observed. Conclusion: Although uncommon, L-LCNEC does seem to contain activating and therefore actionable alterations. We thus highlight the value of pursuing next-generation sequencing for patients with this disease.

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