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Published on: January 12, 2020
Identification of NOTCH4 mutation as a response biomarker for immune checkpoint inhibitor therapy
Junyu Long1, Dongxu Wang1, Xu Yang1
1Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Background:
Immune checkpoint inhibitor (ICI) therapy elicits durable antitumor responses in patients with many types of cancer. Genomic mutations may be used to predict the clinical benefits of ICI therapy. NOTCH homolog-4 (NOTCH4) is frequently mutated in several cancer types, but its role in immunotherapy is still unclear. Our study is the first to study the association between NOTCH4 mutation and the response to ICI therapy.
Methods:
We tested the predictive value of NOTCH4 mutation in the discovery cohort, which included non-small cell lung cancer, melanoma, head and neck squamous cell carcinoma, esophagogastric cancer, and bladder cancer patients, and validated it in the validation cohort, which included non-small cell lung cancer, melanoma, renal cell carcinoma, colorectal cancer, esophagogastric cancer, glioma, bladder cancer, head and neck cancer, cancer of unknown primary, and breast cancer patients. Then, the relationships between NOTCH4 mutation and intrinsic and extrinsic immune response mechanisms were studied with multiomics data.
Results:
We collected an ICI-treated cohort (n = 662) and found that patients with NOTCH4 mutation had better clinical benefits in terms of objective response rate (ORR: 42.9% vs 25.9%, P = 0.007), durable clinical benefit (DCB: 54.0% vs 38.1%, P = 0.021), progression-free survival (PFS, hazard ratio [HR] = 0.558, P < 0.001), and overall survival (OS, HR = 0.568, P = 0.006). In addition, we validated the prognostic value of NOTCH4 mutation in an independent ICI-treated cohort (n = 1423). Based on multiomics data, we found that NOTCH4 mutation is significantly associated with enhanced immunogenicity, including a high tumor mutational burden, the expression of costimulatory molecules, and activation of the antigen-processing machinery, and NOTCH4 mutation positively correlates activated antitumor immunity, including infiltration of diverse immune cells and various immune marker sets.
Conclusions:
Our findings indicated that NOTCH4 mutation serves as a novel biomarker correlated with a better response to ICI therapy.
Insights
NOTCH4 mutations predict better responses to immune checkpoint inhibitor (ICI) therapy across multiple cancer types. This finding suggests NOTCH4 mutation status can guide immunotherapy treatment decisions.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Immune checkpoint inhibitor (ICI) therapy offers durable antitumor responses in various cancers.
- Genomic mutations can predict ICI therapy efficacy.
- The role of NOTCH homolog-4 (NOTCH4) mutations in immunotherapy remains unclear.
Purpose of the Study:
- To investigate the association between NOTCH4 mutations and response to ICI therapy.
- To evaluate NOTCH4 mutation as a predictive biomarker for ICI therapy outcomes.
Main Methods:
- Tested NOTCH4 mutation's predictive value in discovery and validation cohorts across multiple cancer types.
- Analyzed relationships between NOTCH4 mutation and immune response mechanisms using multiomics data.
Main Results:
- Patients with NOTCH4 mutations showed significantly improved objective response rate (ORR), durable clinical benefit (DCB), progression-free survival (PFS), and overall survival (OS).
- NOTCH4 mutation was validated as a prognostic marker in an independent cohort.
- Multiomics data revealed NOTCH4 mutation is linked to enhanced immunogenicity and activated antitumor immunity.
Conclusions:
- NOTCH4 mutation is a novel biomarker associated with better clinical benefits from ICI therapy.
- NOTCH4 mutation status can potentially guide patient selection for immunotherapy.
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