Patient Characteristics Associated with Growth of Patient-Derived Tumor Implants in Mice (Patient-Derived Xenografts)
Abstract
:Simple Summary
Abstract
1. Background
1.1. Background Findings Associated with Engraftment Success Rate
1.1.1. Tumor Stage
1.1.2. Sample Origin: Metastases
1.1.3. Tumor Type and Subtype
2. Methods
2.1. PDX Generation
- (1)
- PX0: Time elapsed between the moment of patient’s tumor implant in mice, and achievement of tumor growth (reaching a volume of 150 mm3). Because we mean to evaluate potential patient and tumor characteristics on the final success, retrieving those models that achieve a minimum initial growth was required.
- (2)
- PX1: or First Passage: time elapsed between the moment the patient’s tumor implant in mice achieves 150 mm3 and the moment the tumor is retrieved from the model and implanted on a second mouse.
- (3)
- PX2: or Second Passage: time elapsed between the moment of implant in the second mouse, and the moment of implant in the third mouse.
- (4)
- PX3: or Third Passage (coincides with the definition of final engraftment success).
2.2. Statistical Analysis
2.2.1. Assessment of Success or Failure of Engraftment
2.2.2. Comparison of Tumor Growth Rates at Each Step
2.2.3. Associations of Variables with Tumor Growth Rate in Each Passage
- If the coefficient is positive, the correlation is positive; therefore, the higher the variable, the higher the tumor growth rate should be.
- If the coefficient is negative, the correlation is negative; therefore, the higher the variable, the lower the tumor growth rate should be.
3. Results
3.1. Baseline Clinical Characteristics Significantly Correlate with Engraftment Success
3.2. Tumor Growth Rate Increases throughout Passages, and Can Predict Final Success in Engraftment of Pdx Models
ROC Curves for Tumor Growth Rates in the Second Passage
3.3. Baseline Clinical and Histological Variables Can Also Help Predict Engraftment Success
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
BRAF | v-raf murine sarcoma viral oncogene homologue B1 gene |
BRCA | Breast Cancer Gene |
EGFR | Epidermal Growth Factor Receptor gene |
ER | Estrogen Receptors |
Exp | Exponential |
FJD | Fundación Jiménez Díaz |
HER2 | Epidermal Growth Factor Receptor 2 |
HR | Hormone Receptors |
IHC | Immunohistochemistry |
IQR | Interquartile Range |
K-RAS | Kirsten rat sarcoma viral oncogene homolog gene |
LDH | Lactate Dehydrogenase |
MLH1 | MutL Homolog 1 gene |
MLH2 | MutL Homolog 2 gene |
MMRd | Mismatch Repair Deficiency |
MMRp | Mismatch Repair Proficiency |
MSH6 | MutS Homolog 6 gene |
MSI | Microsatellite Instability |
mTGR | Median Tumor Growth Rate |
NGS | Next-Generation Sequencing |
N-RAS | Neuroblastoma RAS gene |
PDXs/PDTXs | Patient-Derived Xenografts |
PMS2 | Postmeiotic Segregation Increased 2 gene |
PR | Progesterone Receptors |
PX1 | Passage 1 |
PX2 | Passage 2 |
PX3 | Passage 3 |
ROC | Receiver Operating Characteristic Curve |
RPMI | Roswell Park Memorial Institute |
START | South Texas Accelerated Research Therapeutics |
TGR/TG | Tumor Growth Rate |
TTG | Time to Tumor Growth |
ULN | Upper Limit of Normality |
V0 | Baseline Tumor Volume |
Vt | Tumor Volume at X time. |
WT | Wild-Type |
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Baseline Patient Characteristics | n (%) | |
---|---|---|
Clinical Characteristics | ||
Sex | Male | 242 (42.9) |
Female | 322 (57.1) | |
Menopausal status | Premenopausal | 49 (8.7) |
Postmenopausal | 273 (48.2) | |
Diabetes Mellitus | Diabetic | 89 (15.8%) |
Non Diabetic | 475 (84.2) | |
Smoking habit | Non smoker | 300 |
Smoker | 264 | |
Chemotherapy < 21 days 1 | Yes | 23 (4%) |
No | 541 (96%) | |
Primary Tumor Baseline Characteristics | ||
Tumor grade | High grade (grade 3) | 196 (34.8%) |
Middle grade (grade 2) | 237 (42%) | |
Low grade (grade 1) | 131 (23.2%) | |
Ki67% | <15 | 45 (8%) |
15–30 | 22 (3.9%) | |
>30 | 91 (16.1%) | |
Total | 158 (28%) | |
MMRd 2 | Proficient | 184 (32.6%) |
Deficient | 29 (5.1%) | |
Total | 213 (37.8%) | |
HER2 expression | HER 2 Amplified | 7 (1.2%) |
HER 2 Negative | 81 (14.4%) | |
Total: | 88 (15,6%) | |
Hormone Receptor Expression | Positive | 62 (11.5%) |
Negative | 19 (3.4%) | |
Total | 84 (14.9%) | |
BRCAm 3 | BRCA mutant | 17 (3%) |
BRCA wild-type | 61 (10.8%) | |
Total | 78 (13.8) | |
Sampling characteristics | ||
Sample source 4 | Primary | 405 (71.8%) |
Metastatic | 159 (28.2) |
Implanted Tumors and Final Growth: Total Numbers | |
---|---|
Tumor Type: | Implanted/Grow n |
CNS | 38/17 |
Bladder | 15/6 |
Breast | 56/11 |
Luminal Subtype | 44/5 |
HER2 Enriched | 4/0 |
TNBC | 8/6 |
Cervix | 12/6 |
CRC | 128/74 |
Endometrial | 28/6 |
Gastric/Gastroesophageal Junction | 11/3 |
Kidney | 49/9 |
NSCLC | 86/20 |
SCLC | 5/3 |
Ovarian | 62/19 |
Pancreas | 8/2 |
Liver | 7/0 |
Head and neck | 9/3 |
Biliary tract | 5/2 |
Other solid tumors | 48/6 |
Passage | Group | Median (P25%, P75%) | Comparison with PX3 | Comparison between PX1 and PX2 |
---|---|---|---|---|
First Passage (PX1) | PX1 | 14.6 (−68.2, 274) | <0.001 | 0.761 |
PX2 | 64.7 (−1.70, 256) | 0.002 | ||
PX1 + PX2 | 48.3 (−54.8, 270) | <0.001 | ||
PX3 | 317 (125, 546) | |||
Second Passage (PX2) | PX2 | 4079 (1538, 8765) | <0.001 | |
PX3 | 12,514 (6544, 23,214) |
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Hernández Guerrero, T.; Baños, N.; del Puerto Nevado, L.; Mahillo-Fernandez, I.; Doger De-Speville, B.; Calvo, E.; Wick, M.; García-Foncillas, J.; Moreno, V. Patient Characteristics Associated with Growth of Patient-Derived Tumor Implants in Mice (Patient-Derived Xenografts). Cancers 2023, 15, 5402. https://doi.org/10.3390/cancers15225402
Hernández Guerrero T, Baños N, del Puerto Nevado L, Mahillo-Fernandez I, Doger De-Speville B, Calvo E, Wick M, García-Foncillas J, Moreno V. Patient Characteristics Associated with Growth of Patient-Derived Tumor Implants in Mice (Patient-Derived Xenografts). Cancers. 2023; 15(22):5402. https://doi.org/10.3390/cancers15225402
Chicago/Turabian StyleHernández Guerrero, Tatiana, Natalia Baños, Laura del Puerto Nevado, Ignacio Mahillo-Fernandez, Bernard Doger De-Speville, Emiliano Calvo, Michael Wick, Jesús García-Foncillas, and Victor Moreno. 2023. "Patient Characteristics Associated with Growth of Patient-Derived Tumor Implants in Mice (Patient-Derived Xenografts)" Cancers 15, no. 22: 5402. https://doi.org/10.3390/cancers15225402
APA StyleHernández Guerrero, T., Baños, N., del Puerto Nevado, L., Mahillo-Fernandez, I., Doger De-Speville, B., Calvo, E., Wick, M., García-Foncillas, J., & Moreno, V. (2023). Patient Characteristics Associated with Growth of Patient-Derived Tumor Implants in Mice (Patient-Derived Xenografts). Cancers, 15(22), 5402. https://doi.org/10.3390/cancers15225402