Abstract
ObjectiveThe choice of adjuvant therapy for early stage lung adenocarcinoma (LUAD) remains controversial. Identifying the metabolism characteristics leading to worse prognosis may have clinical utility in offering adjuvant therapy.MethodsThe gene expression profiles of LUAD were collected from 22 public datasets. The patients were divided into a meta-training cohort (n = 790), meta-testing cohort (n = 716), and three independent validation cohorts (n = 345, 358, and 321). A metabolism-related gene pair index (MRGPI) was trained and validated in the cohorts. Subgroup analyses regarding tumor stage and adjuvant chemotherapy (ACT) were performed. To explore potential therapeutic targets, we performed in silico analysis of the MRGPI.ResultsThrough machine learning, MRGPI consisting of 12 metabolism-related gene pairs was constructed. MRGPI robustly stratified patients into high- vs low-risk groups in terms of overall survival across and within subpopulations with stage I or II disease in all cohorts. Multivariable analysis confirmed that MRGPI was an independent prognostic factor. ACT could not improve prognosis in high-risk patients with stage I disease, but could improve prognosis in the high-risk patients with stage II disease. In silico analysis indicated that B3GNT3 (overexpressed in high-risk patients) and HSD17B6 (down-expressed in high-risk patients) may make synergic reaction in immune evasion by the PD-1/PD-L1 pathway. When integrated with clinical characteristics, the composite clinical and metabolism signature showed improved prognostic accuracy.ConclusionsMRGPI could effectively predict prognosis of the patients with early stage LUAD. The patients at high risk may get survival benefit from PD-1/PD-L1 blockade (stage I) or combined with chemotherapy (stage II).
Highlights
Lung cancer is the leading cause of cancer-related death worldwide [1], and early stage lung cancer accounts for about 17% [2]
The Kaplan–Meier curve showed the patients in the high-risk group presented with a significantly worse overall survival (OS) in the meta-training cohort [hazard ratio (HR): 3.584, 95% confidence interval (CI): 2.755–4.663, P < 0.001, Supplementary Figure S2C]
Univariable Cox analysis indicated that metabolismrelated gene pair index (MRGPI) was a prognostic factor for OS, and multivariable Cox analysis confirmed that MRGPI was independently associated with OS (Figure 3 and Supplementary Table S2)
Summary
Lung cancer is the leading cause of cancer-related death worldwide [1], and early stage lung cancer accounts for about 17% [2]. Lung adenocarcinoma (LUAD) is the most common histologic subtype of lung cancer [3]. Surgical resection plus lymph node dissection or sampling is the standard treatment for stage I LUAD [4]. Some patients will still suffer from disease relapse and death, and the 5-year overall survival ranges from 68 to 92% [5]. According to the National Comprehensive Cancer Network (NCCN) guidelines, adjuvant systemic treatment is only considered for high-risk patients [4]. The benefit of adjuvant systemic treatment for stage I LUAD remains controversial
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