2199P - Immunohistochemical identification of clinical subtypes and potential therapeutic vulnerabilities of lung carcinoids based on multi-omic analysis

Background

Multi-omic studies have identified three lung carcinoid (LC) subtypes (A1, A2, B) with unique expression for OTP, ASCL1 & HNF1a genes. We developed an immunohistochemical (IHC) panel for LC subtype identification and clinical-pathological correlation.

Methods

IHC was evaluated in a blinded fashion in mRNA-profiled LC (n=5 per A1/A2/B). IHC H-score was scored and positive for OTP/HNF1a if ≥50 & ASCL1 ≥10. Then, surgically resected pathology revised LC (2003-2012) from a Dutch population based cohort using the cancer/pathology registry (n=474) were evaluated including matching metastasis of 20 recurrent LC. Also, potential therapeutic targets (SSRT2a/DLL3) were assessed. Normal lung tissue distant to the primary LC (≈35/type) was screened for neuroendocrine cell hyperplasia (NECH) using OTP/ChrA IHC. Disease free survival (DFS) was calculated and evaluated using log rank test. Clinical caracteristics were compared using chi-square test.

Results

IHC and mRNA expression of matched primary samples were near-identical. IHC identified A1 in 44% and was classified as OTP^HIGH/LOW/ASCL1^HIGH/HNF1a^LOW, A2 in 40% as OTP^HIGH/ASCL1^LOW/HNF1a^HIGH and B in 16% as OTP^LOW/ASCL1^LOW/HNF1a^HIGH/LOW. Patients with A1 LC generally were middle-aged/elderly females with a peripheral tumour (Table). By contrast, in A2 primarily young patients with endobronchial tumours were identified. In B, the rate of recurrence of disease and tumor size were highest. Patients with A2 had significantly longer DFS compared to A1 and B. Matching primary-metastatic tumours showed similar IHC expression patterns for OTP/ASCL1 and HNF1a. SSRT2a was highest in A2-B while DLL3 showed unique expression in A1. NECH was enriched in A1 and this NECH showed an IHC pattern similar to A1 (OTP^HIGH/ASCL1^HIGH). Table: 2199P

Clinical characteristics of LC subtypes

Conclusions

An OTP/ASCL1/HNF1a IHC panel enables separation of molecular LC types into clinically different groups with distinct therapeutic vulnerabilities.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

KWF Dutch Cancer Society, ENETS.

Disclosure

All authors have declared no conflicts of interest.