Circulating Cell-Free DNA Profiling Predicts the Therapeutic Outcome in Advanced Hepatocellular Carcinoma Patients Treated with Combination Immunotherapy
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Patients and Study Design
2.2. Extraction and Quantitative Measurement of cfDNA
2.3. Library Preparation, Hybridization Capture and Sequencing of cfDNA
2.4. Variant Analysis
2.5. Statistical Analysis
3. Results
3.1. Clinical Outcomes of Atezo/Bev Therapy in u-HCC Patients
3.2. Patients with High Plasma cfDNA Levels Show a Significantly Lower ORR and Shorter PFS and OS Than Those with Low cfDNA Levels
3.3. ctDNA Profiling in u-HCC Patients Treated with Atezo/Bev
3.4. Patients with TERT Promoter ctDNA Show Significantly Shorter OS Than Those without
3.5. TERT ctDNA Mutation and AFP Level Can Be Used to Stratify u-HCC Patients Treated with Combination Immunotherapy Based on Prognosis
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Factor | Unit | Value |
---|---|---|
Age | Years Old | 74 (65–80) |
Gender | Male/Female | 66/19 |
ECOG PS | 0/1 | 76/9 |
Etiology | HBV/HCV/HBV + HCV/alcohol/others | 22/29/2/15/17 |
Child-pugh | 5/6/7 | 41/40/4 |
PT | % | 92 (82–102) |
ALB | g/dL | 3.7 (3.2–3.9) |
T-BIL | mg/dL | 0.7 (0.5–1.0) |
ALBI score | −2.35 (−2.69–−2.02) | |
ALT | U/L | 26 (17–35) |
PLT | ×104/μL | 13.8 (11.2–17.6) |
NLR | 2.4 (1.8–3.6) | |
AFP | ng/mL | 11 (3–887) |
DCP | mAU/mL | 333 (65–2614) |
Prior systemic therapy | Yes/No | 37/48 |
Extrahepatic metastasis | Yes/No | 38/47 |
Macrovascular invasion | Yes/No | 15/70 |
Maximal tumor size | cm | 2.3 (1.6–4.5) |
Intrahepatic tumor number | ≥5/≤4 | 36/49 |
BCLC stage | A/B/C | 6/31/48 |
Observation period | Days | 286 (216–359) |
Factor | Unit | Univariate Analysis | Multivariate Analysis | |||
---|---|---|---|---|---|---|
Hazard Ratio (95% CI) | p Value | Hazard Ratio (95% CI) | p Value | |||
Age | Years Old | ≥70/<70 | 0.96 (0.39–2.39) | 0.939 | ||
Gender | Male/Female | 0.56 (0.23–1.39) | 0.212 | |||
ECOG PS | 0/1 | 0.59 (0.17–2.00) | 0.398 | |||
Etiology | Viral/non-Viral | 1.41 (0.55–3.65) | 0.477 | |||
PT | % | ≥90/<90 | 1.12 (0.43–2.90) | 0.817 | ||
ALB | g/dL | ≥4.0/<4.0 | 0.95 (0.35–2.60) | 0.920 | ||
T-BIL | mg/dL | ≥0.7/<0.7 | 2.26 (0.83–6.18) | 0.112 | ||
ALBI score | ≥−2.27/<−2.27 | 1.30 (0.55–3.09) | 0.546 | |||
ALT | U/L | ≥45/<45 | 0.62 (0.14–2.66) | 0.520 | ||
PLT | ×104/μL | ≥15/<15 | 0.47 (0.16–1.39) | 0.170 | ||
NLR | ≥3.0/<3.0 | 3.98 (1.62–9.78) | 0.003 | 2.42 (0.80–7.36) | 0.119 | |
AFP | ng/mL | ≥400/<400 | 4.79 (1.99–11.54) | 0.001 | 4.90 (1.58–15.13) | 0.006 |
DCP | mAU/mL | ≥200/<200 | 2.96 (1.06–8.25) | 0.038 | 1.72 (0.53–5.57) | 0.365 |
Prior systemic therapy | Yes/No | 0.99 (0.42–2.34) | 0.984 | |||
Extrahepatic metastasis | Yes/No | 0.99 (0.42–2.35) | 0.980 | |||
Macrovascular invasion | Yes/No | 3.61 (1.49–8.76) | 0.005 | 1.85 (0.62–5.59) | 0.273 | |
Intrahepatic tumor number | ≥5/≤4 | 2.29 (0.96–5.46) | 0.061 | |||
BCLC stage | A,B/C | 0.46 (0.18–1.18) | 0.104 | |||
cfDNA | ng/uL | ≥2.23/<2.23 | 2.99 (1.16–7.75) | 0.024 | 2.92 (0.98–8.71) | 0.054 |
TERT | Yes/No | 3.93 (1.63–9.44) | 0.002 | 3.25 (1.14–9.28) | 0.028 |
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Matsumae, T.; Kodama, T.; Myojin, Y.; Maesaka, K.; Sakamori, R.; Takuwa, A.; Oku, K.; Motooka, D.; Sawai, Y.; Oshita, M.; et al. Circulating Cell-Free DNA Profiling Predicts the Therapeutic Outcome in Advanced Hepatocellular Carcinoma Patients Treated with Combination Immunotherapy. Cancers 2022, 14, 3367. https://doi.org/10.3390/cancers14143367
Matsumae T, Kodama T, Myojin Y, Maesaka K, Sakamori R, Takuwa A, Oku K, Motooka D, Sawai Y, Oshita M, et al. Circulating Cell-Free DNA Profiling Predicts the Therapeutic Outcome in Advanced Hepatocellular Carcinoma Patients Treated with Combination Immunotherapy. Cancers. 2022; 14(14):3367. https://doi.org/10.3390/cancers14143367
Chicago/Turabian StyleMatsumae, Takayuki, Takahiro Kodama, Yuta Myojin, Kazuki Maesaka, Ryotaro Sakamori, Ayako Takuwa, Keiko Oku, Daisuke Motooka, Yoshiyuki Sawai, Masahide Oshita, and et al. 2022. "Circulating Cell-Free DNA Profiling Predicts the Therapeutic Outcome in Advanced Hepatocellular Carcinoma Patients Treated with Combination Immunotherapy" Cancers 14, no. 14: 3367. https://doi.org/10.3390/cancers14143367