CUL4A, ERCC5, and ERCC1 as Predictive Factors for Trabectedin Efficacy in Advanced Soft Tissue Sarcomas (STS): A Spanish Group for Sarcoma Research (GEIS) Study
Abstract
:1. Introduction
2. Results
2.1. Demographic and Pathologic Features
2.2. Expression of DDR-Associated Genes in STS Samples
2.3. Association of BRCA1, CUL4A, ERCC1, and ERCC5 with Clinical Outcome
2.4. CUL4A Protein Expression Analysis
2.5. In Vitro Correlation between Gene Expression and Trabectedin Sensitivity
3. Discussion
4. Methods
4.1. Patients
4.2. Gene Expression of Tumour Samples
4.3. Immunohistochemistry
4.4. Cell Lines
4.5. Determination of Trabectedin IC50 Values
4.6. Gene Expression Determination in Cell Lines
4.7. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Median Age (Range) | 52 (21–72) |
---|---|
Sex: | |
Female | 31 (47%) |
Male | 35 (53%) |
Median tumor Size (mm) (Range) | 90 (2–300) |
Histological Grade: | |
1 | 10 (15.6%) |
2 | 18 (28.1%) |
3 | 36 (56.3%) |
Primary tumor site | |
Extremity | 25 (38.4%) |
Head and neck | 2 (3.1%) |
Trunk wall | 3 (4.6%) |
Retroperitoneum | 15 (23.1%) |
Others | 20 (30.8%) |
Disease type | |
Localized | 38 (62.3%) |
Metastatic | 23 (37.7%) |
Sarcoma subtypes: | |
Leiomyosarcoma | 22 (33.3%) |
Liposarcoma | 12 (18.1%) |
UPS * | 12 (18.1%) |
Fibrosarcoma | 4 (6.1%) |
Haemangiopericytoma | 3 (4.6%) |
MPNST ** | 3 (4.6%) |
Synovial Sarcoma | 3 (4.6%) |
Others *** | 7 (10.6%) |
Experimental Arm | |
Doxorubicin | 34 (51.5%) |
Doxorubicin plus Trabectedin | 32 (48.5%) |
Gene | Median Expression 1 in Whole Series (Range) | Median Expression 1 in Control Arm (Range) | Median Expression 1 in Experimental Arm (Range) |
---|---|---|---|
BRCA1 (n = 64) | 0.52 (0.04–3.75) | 0.47 (0.08–2.97) | 0.59 (0.04–3.75) |
CUL4A (n = 65) | 1.31 (0.10–31.07) | 1.20 (0.24–7.79) | 1.46 (0.10–31.07) |
ERCC1 (n = 64) | 1.18 (0.11–10.82) | 1.14 (0.16–7.70) | 1.22 (0.11–10.82) |
ERCC5 (n = 66) | 0.37 (0.01–7.07) | 0.37 (0.02–1.45) | 0.39 (0.01–7.07) |
Whole Series 1 | ||||
---|---|---|---|---|
Biomarker | Median PFS (Months) (95% CI) | p | Median OS (Months) (95% CI) | p |
BRCA1 (n = 64) | 0.902 | 0.684 | ||
Below median (n = 32) | 4.60 (0.00–9.22) | 22.47 (4.43–40.51) | ||
Above median (n = 32) | 5.70 (3.02–8.38) | 17.47 (12.15–22.78) | ||
CUL4A (n = 65) | 0.173 | 0.343 | ||
Below median (n = 33) | 4.60 (0.25–8.95) | 14.03 (4.68–23.39) | ||
Above median (n = 32) | 5.50 (2.17–8.83) | 21.83 (11.62–32.05) | ||
ERCC1 (n = 64) | 0.696 | 0.406 | ||
Below median (n = 32) | 3.73 (0.30–7.23) | 17.47 (2.99–31.94) | ||
Above median (n = 32) | 5.50 (2.87–8.13) | 17.97 (10.75–25.18) | ||
ERCC5 (n = 66) | 0.559 | 0.593 | ||
Below median (n = 33) | 4.60 (1.15–8.05) | 17.97 (6.89–29.04) | ||
Above median (n = 33) | 5.97 (1.99–9.94) | 17.47 (7.38–27.56) | ||
Control Group 2 | ||||
Biomarker | Median PFS (months) (95% CI) | p | Median OS (months) (95% CI) | p |
BRCA1 (n = 34) | 0.642 | 0.406 | ||
Below median (n = 17) | 5.43 (1.18–9.69) | 8.73 (-) | ||
Above median (n = 17) | 6.03 (0.12–11.95) | 17.97 (11.16–24.77) | ||
CUL4A (n = 33) | 0.626 | 0.994 | ||
Below median (n = 16) | 4.60 (0.00–12.70) | - | ||
Above median (n = 17) | 5.50 (0.97–10.03) | 15.10 (7.41–22.79) | ||
ERCC1 (n = 32) | 0.321 | 0.871 | ||
Below median (n = 16) | 6.93 (3.80–10.07) | 27.03 (0.00–61.26) | ||
Above median (n = 16) | 2.53 (0.18–4.89) | 13.73 (9.96–17.51) | ||
ERCC5 (n = 34) | 0.515 | 0.746 | ||
Below median (n = 17) | 6.93 (4.78–9.09) | - | ||
Above median (n = 17) | 2.60 (0.00–8.02) | 13.73 (9.51–17.96) | ||
Experimental Group 3 | ||||
Biomarker | Median PFS (months) (95% CI) | p | Median OS (months) (95% CI) | p |
BRCA1 (n = 30) | 0.420 | 0.608 | ||
Below median (n = 15) | 1.70 (0.00–4.02) | 14.23 (13.22–15.24) | ||
Above median (n = 15) | 5.70 (0.87–10.54) | 21.07 (10.37–31.77) | ||
CUL4A (n = 32) | 0.038 | 0.059 | ||
Below median (n = 16) | 1.80 (0.00–3.63) | 13.53 (6.25–20.81) | ||
Above median (n = 16) | 6.53 (0.00–13.39) | 22.63 (17.02–28.25) | ||
ERCC1 (n = 32) | 0.006 | 0.295 | ||
Below median (n = 16) | 2.63 (0.41–4.86) | 14.03 (5.73–22.34) | ||
Above median (n = 16) | 8.10 (4.77–11.43) | 21.07 (11.32–30.81) | ||
ERCC5 (n = 32) | 0.039 | 0.521 | ||
Below median (n = 16) | 1.70 (1.05–2.35) | 13.53 (5.94–21.13) | ||
Above median (n = 16) | 7.67 (5.64–9.69) | 21.07 (15.04–27.09) |
Cell line | IC50 (pM) | CUL4A * | ERCC1 * | ERCC5 * |
---|---|---|---|---|
93T449 | 156 | 0.0046 | 0.0179 | 0.0006 |
AA | 107 | 0.0106 | 0.0318 | 0.0007 |
CP0024 | 399 | 0.0099 | 0.0252 | 0.0019 |
HT-1080 | 148 | 0.0083 | 0.0263 | 0.0022 |
SK-UT-1 | 87 | 0.0323 | 0.0685 | 0.0015 |
SW872 | 142 | 0.0124 | 0.0270 | 0.0068 |
SW982 | 90 | 0.0103 | 0.0403 | 0.0022 |
Spearman's rank correlation coefficient (ρ) ** | CUL4A * | ERCC1 * | ERCC5 * | |
Trabectedin IC50 | −0.750 | −0.964 | −0.143 | |
p = 0.052 | p < 0.001 | p = 0.760 |
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Moura, D.S.; Sanchez-Bustos, P.; Fernandez-Serra, A.; Lopez-Alvarez, M.; Mondaza-Hernandez, J.L.; Blanco-Alcaina, E.; Gavilan-Naranjo, A.; Martinez-Delgado, P.; Lacerenza, S.; Santos-Fernandez, P.; et al. CUL4A, ERCC5, and ERCC1 as Predictive Factors for Trabectedin Efficacy in Advanced Soft Tissue Sarcomas (STS): A Spanish Group for Sarcoma Research (GEIS) Study. Cancers 2020, 12, 1128. https://doi.org/10.3390/cancers12051128
Moura DS, Sanchez-Bustos P, Fernandez-Serra A, Lopez-Alvarez M, Mondaza-Hernandez JL, Blanco-Alcaina E, Gavilan-Naranjo A, Martinez-Delgado P, Lacerenza S, Santos-Fernandez P, et al. CUL4A, ERCC5, and ERCC1 as Predictive Factors for Trabectedin Efficacy in Advanced Soft Tissue Sarcomas (STS): A Spanish Group for Sarcoma Research (GEIS) Study. Cancers. 2020; 12(5):1128. https://doi.org/10.3390/cancers12051128
Chicago/Turabian StyleMoura, David S., Paloma Sanchez-Bustos, Antonio Fernandez-Serra, María Lopez-Alvarez, José L. Mondaza-Hernandez, Elena Blanco-Alcaina, Angela Gavilan-Naranjo, Paula Martinez-Delgado, Serena Lacerenza, Paloma Santos-Fernandez, and et al. 2020. "CUL4A, ERCC5, and ERCC1 as Predictive Factors for Trabectedin Efficacy in Advanced Soft Tissue Sarcomas (STS): A Spanish Group for Sarcoma Research (GEIS) Study" Cancers 12, no. 5: 1128. https://doi.org/10.3390/cancers12051128