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Co-Occurring Alteration of NOTCH and DDR Pathways Serves as Novel Predictor to Efficacious Immunotherapy in NSCLC
Zhimin Zhang1, Yanyan Gu2, Xiaona Su3
1Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China.
Abstract:
Although immune checkpoint inhibitors (ICIs) have shown remarkable benefit for treatment of advanced non-small lung cancer (NSCLC), only a minority of patients can achieve durable responses and the most patients produce an ultra-rapid progressive disease. Here, we collected the availably published datasets and mined the determinants of response to immunotherapy on pathway levels. One hundred six NSCLC patients treated with immunotherapy were combined from Rizvi et al. and Hellman et al. studies (whole exon sequencing). Two independent validation datasets consisted of the MSKCC cohort (targeted sequencing) and data by Anagnostou and colleagues (whole exon sequencing). The Cancer Genome Atlas (TCGA) somatic mutation and gene expression data were applied to explore the immunobiology features. In the first combined cohort, we detected NOTCH pathway altered in 71% patients with durable clinical benefit (DCB) while only 36% among no durable benefit (NDB) (p = 0.005). Compared to NDB group, co-occurrence of NOTCH and at least two DDR (co-DDR) pathway was discovered in DCB group and contributed to a prolonged progression-free survival (PFS) [22.1 vs 3.6 months, p < 0.0001, HR, 0.34, 95% confidence interval (CI), 0.2-0.59]. In two independent datasets, co-occurrence of NOTCH+/co-DDR+ was also validated to be a better immunotherapy efficacy [Cohort 2: 13 vs 6 months, p = 0.034, HR, 0.55, 95% CI, 0.31-0.96; Cohort 3: 21 vs 11 months, p = 0.067, HR, 0.45, 95% CI, 0.18-1.1]. By analyzing TCGA cohort, we found patients with coexisting NOTCH+/co-DDR+ pathway had a higher TMB, more infiltration of CD4+T cells. Overall, co-occurrence of NOTCH and co-DDR pathway reflect a better immunotherapy efficacy in advanced NSCLC. This genomic predictor show promise in stratifying patients that suit for immunotherapy for future clinical practice.
Insights
Identifying NOTCH and DNA Damage Response (DDR) pathway alterations predicts durable responses to immunotherapy in advanced non-small cell lung cancer (NSCLC). This genomic biomarker can help select patients for effective immunotherapy treatment.
Area of Science:
- Genomics and Bioinformatics
- Oncology
- Immunotherapy
Background:
- Immune checkpoint inhibitors (ICIs) offer significant benefits for advanced non-small cell lung cancer (NSCLC), but response rates remain limited.
- Identifying predictive biomarkers for immunotherapy efficacy in NSCLC is crucial for clinical practice.
- Understanding the genomic landscape associated with durable clinical benefit is essential.
Purpose of the Study:
- To identify genomic pathway-level determinants of response to immunotherapy in advanced NSCLC.
- To validate the predictive value of identified pathways in independent patient cohorts.
- To explore the immunobiological features associated with favorable treatment outcomes.
Main Methods:
- Meta-analysis of published NSCLC immunotherapy treatment datasets (whole exon and targeted sequencing).
- Analysis of The Cancer Genome Atlas (TCGA) for somatic mutations and gene expression data.
- Statistical analysis to compare pathway alterations between durable clinical benefit (DCB) and no durable benefit (NDB) groups, and to assess progression-free survival (PFS).
Main Results:
- Alterations in the NOTCH pathway were significantly more frequent in patients with DCB (71%) compared to NDB (36%).
- The co-occurrence of NOTCH pathway alterations and at least two DNA Damage Response (DDR) pathways (co-DDR) was associated with significantly prolonged PFS in the primary cohort (22.1 vs 3.6 months).
- This NOTCH+/co-DDR+ signature was validated in two independent cohorts, showing improved immunotherapy efficacy and correlating with higher tumor mutational burden (TMB) and CD4+ T cell infiltration.
Conclusions:
- The co-occurrence of NOTCH and co-DDR pathway alterations is a promising genomic predictor of better immunotherapy efficacy in advanced NSCLC.
- This finding provides a potential tool for stratifying patients who are likely to benefit from immunotherapy.
- Further clinical validation is warranted to integrate this genomic biomarker into patient selection for immunotherapy.
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