TTF-1 and c-MYC-defined Phenotypes of Large Cell Neuroendocrine Carcinoma and Delta-like Protein 3 Expression for Treatment Selection.

The standard treatment regimen has not yet been established for advanced pulmonary large cell neuroendocrine carcinoma (LCNEC) because of its rarity. LCNEC can be subdivided into 2 mutually exclusive molecular subgroups: STK11/KEAP1 and TP53 mutated with high neuroendocrine expression and transcriptional profile of ASCL1high/DLL3high/NOTCHlow (non-small cell lung carcinoma, NSCLC-like) or RB1 and TP53 mutated with reduced neuroendocrine markers and transcriptional pattern of ASCL1low/DLL3low/NOTCHhigh (small cell lung cancer, SCLC-like). Model-based clustering shows that SCLC has subdivided into 2 major proteomic subsets defined by either TTF-1high/c-MYClow or TTF-1low/c-MYChigh, which may correspond to 2 mutually exclusive molecular subgroups: NSCLC-like or SCLC-like, respectively. We herein investigated whether TTF-1 and c-MYC could be applied to LCNEC to identify distinct subsets immunohistochemically and assessed DLL3 expression in these subsets. The protein expression profile may be useful to select patients for potential efficacy of targeted therapies including aurora kinase inhibitors for MYC alterations or anti-DLL3 antibody-drug conjugates. TTF-1 and c-MYC expression was mutually exclusive in 25 of 27 (93%) cases; TTF-1+/c-MYC- in 10, TTF-1-/c-MYC+ in 15, and TTF-1+/c-MYC+ in 2. DLL3 expression was seen in 15 of 27 cases (56%). All 12 TTF-1+ LCNEC cases were positive for DLL3. Three of 15 (20%) TTF-1-/c-MYC+ cases showed DLL3 positivity. LCNEC could be separated into 2 subsets proteomically defined by TTF-1 and c-MYC expression, which may be suitable to guide treatment selection including aurora kinase inhibitors for c-MYC+ cases. TTF-1 positivity can serve as a surrogate marker for DLL3, but caution is necessary as 20% of TTF-1- cases showed DLL3 positivity.