# Molecular typing of stage IB non-small-cell lung cancer for precision medicine

## TL;DR

This study identifies two subtypes of stage IB non-small-cell lung cancer with different survival outcomes and introduces a biomarker to guide treatment decisions.

## Contribution

A novel molecular classification system and a biomarker (CPD) for risk stratification in stage IB NSCLC.

## Key findings

- Stage IB NSCLC was classified into two subtypes (IB1 and IB2) with distinct disease-free survival rates.
- Carboxypeptidase D (CPD) was identified as a key biomarker distinguishing high- and low-risk patients (AUC=0.874).
- IB1 patients had survival similar to stage IA, while IB2 patients had survival comparable to stage II.

## Abstract

The optimal postoperative management of stage IB non-small-cell lung cancer (NSCLC) remains controversial due to significant heterogeneity. This study aimed to establish a molecular classification for stage IB NSCLC to guide precision medicine.

We performed consensus clustering of transcriptomic profiles from TCGA-NSCLC (training set, n=119) and validated in GSE31210 (n=53). Molecular subtypes were compared with stage IA/II patients for clinical significance. Differentially expressed genes were analyzed using LASSO regression to identify biomarkers. Functional studies were conducted using patient-derived organoids (PDOs), cell lines, and tissue specimens.

Stage IB NSCLC was divided into two subtypes (IB1 and IB2) with significantly different disease-free survival (DFS). IB1 patients showed DFS similar to stage IA, while IB2 patients exhibited DFS comparable to stage II (especially IIB). Carboxypeptidase D (CPD) was identified as a key biomarker capable of distinguishing high- and low-risk patients (AUC=0.874 in validation). CPD was overexpressed in tumor tissues and promoted proliferation and migration in PDOs and cell lines.

This molecular classification effectively stratifies stage IB NSCLC into low-risk (IB1, observation suitable) and high-risk (IB2, adjuvant therapy warranted) subgroups. CPD serves as a promising biomarker for clinical risk stratification.