Integration of comprehensive genomic profiling, tumor mutational burden, and PD-L1 expression to identify novel biomarkers of immunotherapy in non-small cell lung cancer
机构:[1]Department of geriatric thoracic surgery, The First Hospital of Kunming Medical University, Kunming City, People's Republic of China外科科室胸外科昆明医科大学附属第一医院[2]Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China华中科技大学同济医学院附属协和医院[3]OrigiMed, Shanghai, People's Republic of China[4]Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China广东省人民医院
Objectives This study aimed to explore the novel biomarkers for immune checkpoint inhibitor (ICI) responses in non-small cell lung cancer (NSCLC) by integrating genomic profiling, tumor mutational burden (TMB), and expression of programmed death receptor 1 ligand (PD-L1). Materials and Methods Tumor and blood samples from 637 Chinese patients with NSCLC were collected for targeted panel sequencing. Genomic alterations, including single nucleotide variations, insertions/deletions, copy number variations, and gene rearrangements, were assessed and TMB was computed. TMB-high (TMB-H) was defined as >= 10 mutations/Mb. PD-L1 positivity was defined as >= 1% tumor cells with membranous staining. Genomic data and ICI outcomes of 240 patients with NSCLC were derived from cBioPortal. Results EGFR-sensitizing mutations, ALK, RET, and ROS1 rearrangements were associated with lower TMB and PD-L1+/TMB-H proportions, whereas KRAS, ALK, RET, and ROS1 substitutions/indels correlated with higher TMB and PD-L1+/TMB-H proportions than wild-type genotypes. Histone-lysine N-methyltransferase 2 (KMT2) family members (KMT2A, KMT2C, and KMT2D) were frequently mutated in NSCLC tumors, and these mutations were associated with higher TMB and PD-L1 expression, as well as higher PD-L1+/TMB-H proportions. Specifically, patients with KMT2C mutations had higher TMB and PD-L1+/TMB-H proportions than wild-type patients. The median progression-free survival (PFS) was 5.47 months (95% CI 2.5-NA) in patients with KMT2C mutations versus 3.17 months (95% CI 2.6-4.27) in wild-type patients (p = 0.058). Furthermore, in patients with NSCLC who underwent ICI treatment, patients with TP53/KMT2C co-mutations had significantly longer PFS and greater durable clinical benefit (HR: 0.48, 95% CI: 0.24-0.94, p = 0.033). TP53 mutation combined with KMT2C or KRAS mutation was a better biomarker with expanded population benefit from ICIs therapy and increased the predictive power (HR: 0.46, 95% CI: 0.26-0.81, p = 0.007). Conclusion We found that tumors with different alterations in actionable target genes had variable expression of PD-L1 and TMB in NSCLC. TP53/KMT2C co-mutation might serve as a predictive biomarker for ICI responses in NSCLC. Implications for Practice Cancer immunotherapies, especially immune checkpoint inhibitors (ICIs), have revolutionized the treatment of non-small cell lung cancer (NSCLC); however, only a proportion of patients derive durable responses to this treatment. Biomarkers with greater accuracy are highly needed. In total, 637 Chinese patients with NSCLC were analyzed using next-generation sequencing and IHC to characterize the unique features of genomic alterations and TMB and PD-L1 expression. Our study demonstrated that KMT2C/TP53 co-mutation might be an accurate, cost-effective, and reliable biomarker to predict responses to PD-1 blockade therapy in NSCLC patients and that adding KRAS to the biomarker combination creates a more robust parameter to identify the best responders to ICI therapy.
基金:
The study was supported by the
National Key R&D Program of
China (Grant No.2016YFC1303800),
Doctoral Research Fund of the first
affiliated Hospital of Kunming Medical
University (Grant No. 2017BS029),
and the Scientific Research Projects
of Institutions of Medical and Health
Institutions in Yunnan Province (Grant
No. 2016NS017).
第一作者机构:[1]Department of geriatric thoracic surgery, The First Hospital of Kunming Medical University, Kunming City, People's Republic of China
共同第一作者:
通讯作者:
通讯机构:[*1]Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences, 106 Zhongshan Er Road, Guangzhou 510080, China.
推荐引用方式(GB/T 7714):
Yunfei Shi,Youming Lei,Li Liu,et al.Integration of comprehensive genomic profiling, tumor mutational burden, and PD-L1 expression to identify novel biomarkers of immunotherapy in non-small cell lung cancer[J].CANCER MEDICINE.2021,10(7):2216-2231.doi:10.1002/cam4.3649.
APA:
Yunfei Shi,Youming Lei,Li Liu,Shiyue Zhang,Wenjing Wang...&Qing Zhou.(2021).Integration of comprehensive genomic profiling, tumor mutational burden, and PD-L1 expression to identify novel biomarkers of immunotherapy in non-small cell lung cancer.CANCER MEDICINE,10,(7)
MLA:
Yunfei Shi,et al."Integration of comprehensive genomic profiling, tumor mutational burden, and PD-L1 expression to identify novel biomarkers of immunotherapy in non-small cell lung cancer".CANCER MEDICINE 10..7(2021):2216-2231