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DNA Checkpoint Gene Mutation as a Biomarker for Immune Checkpoint Inhibitor Therapy in Advanced Biliary Tract Cancer
1Division of Medical Oncology, Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Republic of Korea.
Background/Aim:
The DNA checkpoint (DNACHK) pathway is engaged in signaling the need for cell cycle arrest. This pathway is being actively researched to assess its role in cancer immunotherapy.
Patients And Methods:
A total of 62 patients participated in this study. These patients were treated with immune checkpoint inhibitors (ICIs) for advanced biliary tract cancers (BTCs) from March 2020 to August 2022 at Samsung Medical Center. DNACHK mutated were defined as genomic alterations, such as single nucleotide variants, multi-nucleotide variants, and short insertion and deletions in seven genes; checkpoint kinase 1 (CHEK1), checkpoint kinase 2 (CHEK2), BRCA1, DNA repair-associated (BRCA1), the serine/threonine kinase ATM, the serine/threonine kinase ATR, mediator of DNA damage checkpoint 1 (MDC1) and tumor protein p53 binding protein 1 (TP53BP1). We analyzed the effect of DNACHK mutations on the efficacy of ICIs in advanced BTCs.
Results:
Patient median age at diagnosis was 68.0 years. 10 patients (16.1%) had GB cancer; the remaining patients (n=52, 83.9%) were diagnosed with cholangiocarcinoma. Thirty-seven (59.7%) patients were categorized into the DNACHK wild-type (WT) group and 25 (40.3%) into the DNACHK mutated (MT) group. The most observed DNA checkpoint mutations were ATM mutations (n=14). Patients in the DNACHK MT group had better disease control rate (DCR) than patients in the DNACHK WT (60.0% vs. 48.6%, p=0.53). Median overall survival (OS) was 8.1 months (95% CI 5.1-22.8) in the MT group and 5.6 months (95%CI 3.1-11.0) in the WT group (p=0.33).
Conclusion:
The DNACHK pathway is expected to serve as a potential biomarker for ICI treatment.
Insights
Genomic alterations in the DNA checkpoint (DNACHK) pathway may predict better outcomes for patients with advanced biliary tract cancers receiving immune checkpoint inhibitors (ICIs). This suggests DNACHK mutations could serve as a biomarker for ICI therapy efficacy.
Area of Science:
- Oncology
- Genetics
- Immunotherapy
Background:
- The DNA checkpoint (DNACHK) pathway is crucial for cell cycle arrest signaling.
- This pathway is under investigation for its role in cancer immunotherapy response.
Purpose of the Study:
- To analyze the impact of DNACHK pathway mutations on the efficacy of immune checkpoint inhibitors (ICIs) in patients with advanced biliary tract cancers (BTCs).
Main Methods:
- Genomic alterations in seven key DNACHK genes were identified in 62 advanced BTC patients treated with ICIs.
- Patients were classified into DNACHK wild-type (WT) and mutated (MT) groups.
- The study compared disease control rate (DCR) and overall survival (OS) between the groups.
Main Results:
- The DNACHK mutated (MT) group (40.3% of patients) showed a higher DCR (60.0%) compared to the WT group (48.6%).
- Median overall survival (OS) was longer in the MT group (8.1 months) versus the WT group (5.6 months).
- ATM mutations were the most frequent DNA checkpoint alterations observed.
Conclusions:
- The DNACHK pathway mutations are associated with improved outcomes in advanced BTC patients treated with ICIs.
- The DNACHK pathway shows potential as a predictive biomarker for ICI treatment effectiveness.
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