Abstract 569P
Background
Small-cell lung cancer (SCLC) transformation is one of the major mechanisms of Epidermal Growth Factor Receptor tyrosine kinase inhibitors (EGFR-TKIs) resistance. Chemotherapy alone is usually recommended for transformed-SCLC (T-SCLC), but the benefit is minimal. Prior research highlights differences between the biological traits of T-SCLC and primary SCLC or EGFR-mutated lung adenocarcinoma (LUAD). This study aims to elucidate the molecular characteristics of T-SCLC and identify potential treatment modalities.
Methods
We retrospectively collected tissue samples from LUAD, T-SCLC post-EGFR-TKI resistance, and primary SCLC. Multi-omics were performed to clarify the differences between T-SCLC, LUAD, and primary SCLC. Non-negative matrix factorization (NMF) was then used to categorize the molecular subtype of T-SCLC, followed by a survival analysis based on these subtypes.
Results
A study involving 48 patients investigated differences between LUAD, SCLC, and primary SCLC. RNA sequencing revealed distinct gene expression variations, particularly up-regulation in PPM1E, INSM1, and KCNC1 genes in T-SCLC. Pathway analysis linked T-SCLC to the cell cycle and neural differentiation. While certain T-SCLC showed similarities and differences compared to SCLC, with subtypes identified using NMF analysis: LUAD-like and SCLC-like. Notably, the LUAD-like subtype had significantly higher NKX2-1 expression (P < 0.0001) and TTF-1 protein levels (P < 0.001). Treatment approaches were categorized into matched and unmatched groups, delineated by the alignment of specific therapies with corresponding pathologies. The matched group (13 cases) exhibited a significantly prolonged median progression-free survival (PFS) compared to the unmatched group (10 cases) (5.4 months vs. 3.6 months, P = 0.02).
Conclusions
T-SCLC exhibits marked molecular distinctiveness, setting it apart not only from LUAD but also from classical SCLC. This distinction extends to its classification into two discernible 2 molecular subtypes: LUAD-like and SCLC-like. The implementation of individualized therapeutic protocols, aligned with these distinct subtypes, holds the potential to augment PFS.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
J-J. Yang.
Funding
This work was supported by the National Natural Science Foundation of China (Grant/Award no.: 81972164); The High-level Hospital Construction Project (Grant/Award no.: DFJH201809); The National Natural Science Foundation of China (Grant/Award no.: 82102966); Key Lab System Project of Guangdong Science and Technology Department – Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer (Grant/Award no.: 2017B030314120) to YL WU.
Disclosure
All authors have declared no conflicts of interest.
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