Association of metabolomics with PD-1 inhibitor plus chemotherapy outcomes in patients with advanced non-small-cell lung cancer
Background Combining immune checkpoint inhibitors (ICIs) with chemotherapy has become a standard treatment for patients with non-small cell lung cancer (NSCLC) lacking driver gene mutations. Reliable biomarkers are essential for predicting treatment outcomes. Emerging evidence from various cancers s...
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BMJ Publishing Group
2024-04-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/4/e008190.full |
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| author | Jun Lu Ying Li Wei Zhang Hua Zhong Fang Hu Liang Zheng Xiaohua Yang Lin Huang Xueyan Zhang Tianqing Chu Baohui Han Yinchen Shen Wei Nie Jianlin Xu Shuyuan Wang Runbo Zhong Xiaoxuan Zheng |
| author_facet | Jun Lu Ying Li Wei Zhang Hua Zhong Fang Hu Liang Zheng Xiaohua Yang Lin Huang Xueyan Zhang Tianqing Chu Baohui Han Yinchen Shen Wei Nie Jianlin Xu Shuyuan Wang Runbo Zhong Xiaoxuan Zheng |
| author_sort | Jun Lu |
| collection | DOAJ |
| description | Background Combining immune checkpoint inhibitors (ICIs) with chemotherapy has become a standard treatment for patients with non-small cell lung cancer (NSCLC) lacking driver gene mutations. Reliable biomarkers are essential for predicting treatment outcomes. Emerging evidence from various cancers suggests that early assessment of serum metabolites could serve as valuable biomarkers for predicting outcomes. This study aims to identify metabolites linked to treatment outcomes in patients with advanced NSCLC undergoing first-line or second-line therapy with programmed cell death 1 (PD-1) inhibitors plus chemotherapy.Method 200 patients with advanced NSCLC receiving either first-line or second-line PD-1 inhibitor plus chemotherapy, and 50 patients undergoing first-line chemotherapy were enrolled in this study. The 200 patients receiving combination therapy were divided into a Discovery set (n=50) and a Validation set (n=150). These sets were further categorized into respond and non-respond groups based on progression-free survival PFS criteria (PFS≥12 and PFS<12 months). Serum samples were collected from all patients before treatment initiation for untargeted metabolomics analysis, with the goal of identifying and validating biomarkers that can predict the efficacy of immunotherapy plus chemotherapy. Additionally, the validated metabolites were grouped into high and low categories based on their medians, and their relationship with PFS was analyzed using Cox regression models in patients receiving combination therapy.Results After the impact of chemotherapy was accounted for, two significant differential metabolites were identified in both the Discovery and Validation sets: N-(3-Indolylacetyl)-L-alanine and methomyl (VIP>1 and p<0.05). Notably, upregulation of both metabolites was observed in the group with a poorer prognosis. In the univariate analysis of PFS, lower levels of N-(3-Indolylacetyl)-L-alanine were associated with longer PFS (HR=0.59, 95% CI, 0.41 to 0.84, p=0.003), and a prolonged PFS was also indicated by lower levels of methomyl (HR=0.67, 95% CI, 0.47 to 0.96, p=0.029). In multivariate analyses of PFS, lower levels of N-(3-Indolylacetyl)-L-alanine were significantly associated with a longer PFS (HR=0.60, 95% CI, 0.37 to 0.98, p=0.041).Conclusion Improved outcomes were associated with lower levels of N-(3-Indolylacetyl)-L-alanine in patients with stage IIIB-IV NSCLC lacking driver gene mutations, who underwent first-line or second-line therapy with PD-1 inhibitors combined with chemotherapy. Further exploration of the potential predictive value of pretreatment detection of N-(3-Indolylacetyl)-L-alanine in peripheral blood for the efficacy of combination therapy is warranted.Statement The combination of ICIs and chemotherapy has established itself as the new standard of care for first-line or second-line treatment in patients with advanced NSCLC lacking oncogenic driver alterations. Therefore, identifying biomarkers that can predict the efficacy and prognosis of immunotherapy plus chemotherapy is of paramount importance. Currently, the only validated predictive biomarker is programmed cell death ligand-1 (PD-L1), but its predictive value is not absolute. Our study suggests that the detection of N-(3-Indolylacetyl)-L-alanine in patient serum with untargeted metabolomics prior to combined therapy may predict the efficacy of treatment. Compared with detecting PD-L1 expression, the advantage of our biomarker is that it is more convenient, more dynamic, and seems to work synergistically with PD-L1 expression. |
| format | Article |
| id | doaj-art-b9a445ffb44c4e5997bab417d9a49d00 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-04-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-b9a445ffb44c4e5997bab417d9a49d002024-11-14T00:40:08ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-04-0112410.1136/jitc-2023-008190Association of metabolomics with PD-1 inhibitor plus chemotherapy outcomes in patients with advanced non-small-cell lung cancerJun Lu0Ying Li1Wei Zhang2Hua Zhong3Fang Hu4Liang Zheng5Xiaohua Yang6Lin Huang7Xueyan Zhang8Tianqing Chu9Baohui Han10Yinchen Shen11Wei Nie12Jianlin Xu13Shuyuan Wang14Runbo Zhong15Xiaoxuan Zheng16Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School Of Medicine, Shanghai, ChinaDepartment of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School Of Medicine, Shanghai, ChinaDepartment of Oral Pathology, Affiliated Stomatological Hospital, Nanjing Medical University, Nanjing, ChinaDepartment of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School Of Medicine, Shanghai, ChinaHangzhou Institute of Medicine (HlM), Chinese Academy of Sciences, Zhejiang, China2 Research Center for Translational Medicine, Tongji University Affilliated East Hospital, Shanghai, ChinaCentral Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School Of Medicine, Shanghai, ChinaDepartment of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School Of Medicine, Shanghai, ChinaDepartment of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School Of Medicine, Shanghai, ChinaDepartment of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School Of Medicine, Shanghai, ChinaDepartment of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School Of Medicine, Shanghai, ChinaDepartment of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School Of Medicine, Shanghai, ChinaDepartment of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, ChinaDepartment of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School Of Medicine, Shanghai, ChinaDepartment of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School Of Medicine, Shanghai, ChinaDepartment of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School Of Medicine, Shanghai, ChinaDepartment of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School Of Medicine, Shanghai, ChinaBackground Combining immune checkpoint inhibitors (ICIs) with chemotherapy has become a standard treatment for patients with non-small cell lung cancer (NSCLC) lacking driver gene mutations. Reliable biomarkers are essential for predicting treatment outcomes. Emerging evidence from various cancers suggests that early assessment of serum metabolites could serve as valuable biomarkers for predicting outcomes. This study aims to identify metabolites linked to treatment outcomes in patients with advanced NSCLC undergoing first-line or second-line therapy with programmed cell death 1 (PD-1) inhibitors plus chemotherapy.Method 200 patients with advanced NSCLC receiving either first-line or second-line PD-1 inhibitor plus chemotherapy, and 50 patients undergoing first-line chemotherapy were enrolled in this study. The 200 patients receiving combination therapy were divided into a Discovery set (n=50) and a Validation set (n=150). These sets were further categorized into respond and non-respond groups based on progression-free survival PFS criteria (PFS≥12 and PFS<12 months). Serum samples were collected from all patients before treatment initiation for untargeted metabolomics analysis, with the goal of identifying and validating biomarkers that can predict the efficacy of immunotherapy plus chemotherapy. Additionally, the validated metabolites were grouped into high and low categories based on their medians, and their relationship with PFS was analyzed using Cox regression models in patients receiving combination therapy.Results After the impact of chemotherapy was accounted for, two significant differential metabolites were identified in both the Discovery and Validation sets: N-(3-Indolylacetyl)-L-alanine and methomyl (VIP>1 and p<0.05). Notably, upregulation of both metabolites was observed in the group with a poorer prognosis. In the univariate analysis of PFS, lower levels of N-(3-Indolylacetyl)-L-alanine were associated with longer PFS (HR=0.59, 95% CI, 0.41 to 0.84, p=0.003), and a prolonged PFS was also indicated by lower levels of methomyl (HR=0.67, 95% CI, 0.47 to 0.96, p=0.029). In multivariate analyses of PFS, lower levels of N-(3-Indolylacetyl)-L-alanine were significantly associated with a longer PFS (HR=0.60, 95% CI, 0.37 to 0.98, p=0.041).Conclusion Improved outcomes were associated with lower levels of N-(3-Indolylacetyl)-L-alanine in patients with stage IIIB-IV NSCLC lacking driver gene mutations, who underwent first-line or second-line therapy with PD-1 inhibitors combined with chemotherapy. Further exploration of the potential predictive value of pretreatment detection of N-(3-Indolylacetyl)-L-alanine in peripheral blood for the efficacy of combination therapy is warranted.Statement The combination of ICIs and chemotherapy has established itself as the new standard of care for first-line or second-line treatment in patients with advanced NSCLC lacking oncogenic driver alterations. Therefore, identifying biomarkers that can predict the efficacy and prognosis of immunotherapy plus chemotherapy is of paramount importance. Currently, the only validated predictive biomarker is programmed cell death ligand-1 (PD-L1), but its predictive value is not absolute. Our study suggests that the detection of N-(3-Indolylacetyl)-L-alanine in patient serum with untargeted metabolomics prior to combined therapy may predict the efficacy of treatment. Compared with detecting PD-L1 expression, the advantage of our biomarker is that it is more convenient, more dynamic, and seems to work synergistically with PD-L1 expression.https://jitc.bmj.com/content/12/4/e008190.full |
| spellingShingle | Jun Lu Ying Li Wei Zhang Hua Zhong Fang Hu Liang Zheng Xiaohua Yang Lin Huang Xueyan Zhang Tianqing Chu Baohui Han Yinchen Shen Wei Nie Jianlin Xu Shuyuan Wang Runbo Zhong Xiaoxuan Zheng Association of metabolomics with PD-1 inhibitor plus chemotherapy outcomes in patients with advanced non-small-cell lung cancer Journal for ImmunoTherapy of Cancer |
| title | Association of metabolomics with PD-1 inhibitor plus chemotherapy outcomes in patients with advanced non-small-cell lung cancer |
| title_full | Association of metabolomics with PD-1 inhibitor plus chemotherapy outcomes in patients with advanced non-small-cell lung cancer |
| title_fullStr | Association of metabolomics with PD-1 inhibitor plus chemotherapy outcomes in patients with advanced non-small-cell lung cancer |
| title_full_unstemmed | Association of metabolomics with PD-1 inhibitor plus chemotherapy outcomes in patients with advanced non-small-cell lung cancer |
| title_short | Association of metabolomics with PD-1 inhibitor plus chemotherapy outcomes in patients with advanced non-small-cell lung cancer |
| title_sort | association of metabolomics with pd 1 inhibitor plus chemotherapy outcomes in patients with advanced non small cell lung cancer |
| url | https://jitc.bmj.com/content/12/4/e008190.full |
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