Pharmacogenetic Study of Trabectedin-Induced Severe Hepatotoxicity in Patients with Advanced Soft Tissue Sarcoma
Abstract
:Simple Summary
Abstract
1. Introduction
2. Results
2.1. Patients’ Characteristics and Toxicity Data
2.2. Evaluation of the NGS Data Quality and Building of the Genetic Database
2.3. Pharmacogenetic Association Studies
2.3.1. Primary Analysis Based on Literature-Selected SNPs
2.3.2. Exploratory Analysis
2.3.3. Haplotype Analysis
3. Discussion
4. Materials and Methods
4.1. Patients
4.2. SNP Selection and Genotyping
4.2.1. SNP Selection
4.2.2. Customized Ion Ampliseq Panel for Gene Targeting
4.2.3. Libraries Preparation and Amplification for Next-Generation Sequencing
4.2.4. PGM Sequencing
4.3. Assessment of Liver Toxicity
4.4. Statistical Analyses
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Demographical Characteristics at Baseline | n (%) or (Range) | |
---|---|---|
Total patients included in the pharmacogenetic study | 63 | |
Gender | Male | 31 (49.2%) |
Female | 32 (50.8%) | |
Age | Median (years) | 65 (21.5–82.3) |
Initial arm before crossover | Trabectedin | 31 (49%) |
Best supportive care | 32 (51%) | |
Baseline ECOG performance status | 0 | 30 (47.6%) |
1 | 32 (50.8%) | |
2 | 1 (1.6%) | |
Tumor characteristics at baseline | ||
Histological subtype of soft tissue sarcoma | STS-L: liposarcoma or leiomyosarcoma | 35 (55.6%) |
STS-non L: other subtype | 28 (44.4%) | |
Hepatic metastasis at baseline | Yes | 13 (20.6%) |
No | 50 (79.4%) | |
Prior anticancer treatment before inclusion | ||
Chemotherapy | Yes | 63 (100%) |
No | 0 (0%) | |
Neoadjuvant and/or adjuvant chemotherapy | Yes | 21 (33.3%) |
No | 42 (66.7%) | |
Lines of prior chemotherapy in advanced setting | Median | 1 (0; 3) |
0 | 7 (11.1%) | |
1 | 29 (46%) | |
2 | 22 (34.9%) | |
3 | 5 (7.9%) | |
Common prior chemotherapies in advanced setting | Anthracyclines | 62 (98.4%) |
Ifosfamide | 34 (54%) | |
Gemcitabine | 17 (27%) | |
Dacarbazine | 15 (23.8%) | |
Pazopanib | 10 (15.9%) | |
Cyclophosphamide | 5 (7.9%) | |
Other | 8 (12.7%) | |
Trabectedin treatment after inclusion | ||
Number of cycles administered per patient | Median | 7 (1–33) |
Total dose administered | Mean (mg) | 2.25 (1.35–3.24) |
Treatment modification because of hepatotoxicity | ||
Administration delay | Yes | 6 (10%) |
No | 57 (90%) | |
Dose reduction | Yes | 17 (27%) |
No | 46 (73%) | |
Stop of treatment | Yes | 2 (3%) |
No | 61 (97%) | |
Hepatic side effects recorded during the two first courses of trabectedin | ||
Cytolysis | Grades 0, 1, 2 | 36 (57%) |
Grades 3, 4 | 27 (43%) | |
Cholestasis | Grades 0, 1, 2 | 60 (95%) |
Grades 3, 4 | 3 (5%) | |
Isolated elevation of γ-GT | Grades 0, 1, 2 | 56 (89%) |
Grades 3, 4 | 7 (11%) | |
Overall hepatotoxicity | Grades 0, 1, 2 | 27 (43%) |
Grades 3, 4 | 36 (57%) |
Gene | SNP | Genotype (n) | Severe HAE | % Severe HAE per Genotype | Genotype Comparison 1 | p-Value | OR | 95% CI | FDR |
---|---|---|---|---|---|---|---|---|---|
ABCB1 | rs1128503 c.1236C > T | CC (19) CT (26) TT (14) | Cytolysis | 68.4/34.6/35.7 | CT-TT vs. CC | 0.015 | 0.25 | 0.08–0.80 | 0.147 |
ABCB1 | rs2032582 c.2677G > T,A | GG (18) GT/A (34) TT (11) | Overall hepatotoxicity | 66.7/61.7/27.3 | TT vs. GG-GT | 0.027 | 0.22 | 0.05–0.91 | 0.705 |
ABCC2 | rs17222723 c.3563T > A | TT (51) TA (9) AA (1) | Cytolysis | 50.9/11.1/0 | TA-AA vs. TT | 0.010 | 0.11 | 0.01–0.91 | 0.147 |
ABCC2 | rs2273697 c.1249G > A | GG (40) GA (21) AA (1) | Cytolysis | 32.5/61.9/100 | GA-AA vs. GG | 0.018 | 3.63 | 1.22–10.83 | 0.147 |
ABCC2 | rs2273697 c.1249G > A | GG (40) GA (21) AA (1) | Isolated elevation of γ-GT | 17.5/0/0 | GA-AA vs. GG | 0.044 | N/C | / | 0.811 |
ABCC2 | rs8187707 c.4488C > T | CC (50) CT (8) TT (0) | Cytolysis | 48/12.5/0 | CT vs. CC | 0.045 | 0.15 | 0.02–1.35 | 0.371 |
ABCC4 | rs9516519 c.*3261A > G | TT (42) TG (16) GG (1) | Overall hepatotoxicity | 69/43.8/0 | TG-GG vs. TT | 0.048 | 0.31 | 0.10–1.01 | 0.444 |
ABCG2 | rs7699188 c.-15994C > T | CC (31) CT (19) TT (2) | Cytolysis | 32.3/63.2/50 | CT-TT vs. CC | 0.034 | 3.41 | 1.07–10.87 | 0.212 |
CYP3A5 | rs776746 c.6986A > G | AA (2) AG (14) GG (47) | Overall hepatotoxicity | 0/85.7/51.1 | AA vs. GA vs. GG | 0.012 | 5.75 | 1.16–28.55 | 0.403 |
Gene | SNP | Genotype (n) | Severe HAE | % Severe HAE per Genotype | Genotype Comparison 1 | p-Value | OR | 95% CI | FDR |
---|---|---|---|---|---|---|---|---|---|
ABCC2 | rs17216282 c.4146 + 11G > C | GG (50) GC (10) CC (0) | Cytolysis | 52/10/0 | GC vs. GG | 0.009 | 0.1 | 0.01–0.87 | 0.698 |
ABCC3 | rs2072365 c.2714 + 29C > T | CC (28) CT (29) TT (6) | Overall hepatotoxicity | 39.2/79.3/33.3 | CT vs. CC vs. TT | 0.003 | 5.92 | 1.83–19.20 | 0.242 |
ABCC3 | rs4148415 c.2600-123C > T | CC (27) CT (27) TT (5) | Overall hepatotoxicity | 40.7/85.2/40 | CT vs. CC vs. TT | 0.001 | 8.36 | 2.26–31 | 0.242 |
ABCC4 | rs11568647 c.2213 + 108delC | CC (53) Cdel (6) DelDel (0) | Overall hepatotoxicity | 66/0/0 | Cdel vs. CC | 0.003 | N/C | - | 0.242 |
ABCC4 | rs1751005 c.1727 + 91G > A | GG (43) GA (14) AA (2) | Cytolysis | 55.8/14.3/50 | GA-AA vs. GG | 0.009 | 0.18 | 0.05–0.74 | 0.385 |
Overall hepatotoxicity | 72/28.6/50 | GA-AA vs. GG | 0.004 | 0.18 | 0.05–0.61 | 0.240 | |||
ABCC4 | rs4148553 c.*694C > T | CC (23) CT (31) TT (6) | Cytolysis | 34.8/41.9/100 | TT vs. CC-CT | 0.006 | N/C | - | 0.644 |
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Maillard, M.; Chevreau, C.; Le Louedec, F.; Cassou, M.; Delmas, C.; Gourdain, L.; Blay, J.-Y.; Cupissol, D.; Bompas, E.; Italiano, A.; et al. Pharmacogenetic Study of Trabectedin-Induced Severe Hepatotoxicity in Patients with Advanced Soft Tissue Sarcoma. Cancers 2020, 12, 3647. https://doi.org/10.3390/cancers12123647
Maillard M, Chevreau C, Le Louedec F, Cassou M, Delmas C, Gourdain L, Blay J-Y, Cupissol D, Bompas E, Italiano A, et al. Pharmacogenetic Study of Trabectedin-Induced Severe Hepatotoxicity in Patients with Advanced Soft Tissue Sarcoma. Cancers. 2020; 12(12):3647. https://doi.org/10.3390/cancers12123647
Chicago/Turabian StyleMaillard, Maud, Christine Chevreau, Félicien Le Louedec, Manon Cassou, Caroline Delmas, Laure Gourdain, Jean-Yves Blay, Didier Cupissol, Emmanuelle Bompas, Antoine Italiano, and et al. 2020. "Pharmacogenetic Study of Trabectedin-Induced Severe Hepatotoxicity in Patients with Advanced Soft Tissue Sarcoma" Cancers 12, no. 12: 3647. https://doi.org/10.3390/cancers12123647