53BP1 Accumulation in Circulating Tumor Cells Identifies Chemotherapy-Responsive Metastatic Breast Cancer Patients
Abstract
:1. Introduction
2. Results
2.1. Detection of 53BP1 Signals in CTCs from MBC Patients
2.2. 53 BP1 Accumulates in CTCs from HR+ MBC Patients During Eribulin Treatment
2.3. Reduced Formation of Nuclear 53BP1 Foci in TNBC Cell Lines Does Not Reflect Changes in γH2AX-Labeled DNA Damage
2.4. 53 BP1 Signals Rise in CTCs from MBC Patients with Low Genomic Integrity During Eribulin Treatment
2.5. 53 BP1 Score as a Biomarker for Progression-Free Survival of MBC Patients
3. Discussion
4. Materials and Methods
4.1. Patient Recruitment and Sample Collection
4.2. CTC Enrichment, Immunostaining, and Image Analysis
4.3. Evaluation of Genomic Integrity in Individual CTCs
4.4. Breast Cancer Cell Lines, Cultivation, and Treatment
4.5. Western Blot Analysis
4.6. Quantitative Immunofluorescence Microscopy
4.7. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Immunophenotype | Primary Tumor (N = 63) | Metastases (N = 43) | ||||
---|---|---|---|---|---|---|
Triple-Negative N (%) | Luminal-Like (HR+) N (%) | P-Value 2 | Triple-Negative N (%) | Luminal-Like (HR+) N (%) | P-Value 2 | |
15 (23.8%) | 48 (76.2%) | 14 (32.6%) | 29 (67.4%) | |||
Age (years) | Median (Range) | 0.272 3 | Median (Range) | 0.613 3 | ||
65 (43–78) | 62 (34–81) | 64 (43–78) | 63 (39–75) | |||
BMI (kg/m2) | Median (Range) | 0.116 3 | Median (Range) | 1.000 3 | ||
23.3 (18.0–39.7) | 26.4 (18.4–40.6) | 24.6 (18.6–39.7) | 24.0 (19.4–35.3) | |||
ECOG | N (%) | 0.004 4 | N (%) | 0.035 4 | ||
0 | 4 (26.7%) | 35 (72.9%) | 5 (35.7%) | 22 (75.9%) | ||
1 | 9 (60.0%) | 12 (25.0%) | 7 (50.0%) | 6 (20.7%) | ||
2 | 2 (13.3%) | 1 (2.1%) | 2 (14.3%) | 1 (3.4%) | ||
Histotype | N (%) | 0.549 4 | N (%) | 0.537 4 | ||
Ductal | 11 (73.3%) | 37 (77.1%) | 9 (64.3%) | 23 (79.3%) | ||
Lobular | 1 (6.7%) | 6 (12.5%) | 2 (14.3%) | 3 (10.3%) | ||
Mixed and Other | 3 (20.0%) | 5 (10.4%) | 3 (21.4%) | 3 (10.3%) | ||
Grading | N (%) | 0.004 4 | N (%) | 0.041 4 | ||
1 | 0 (0.0%) | 1 (2.1%) | 0 (0.0%) | 0 (0.0%) | ||
2 | 4 (26.7%) | 31 (64.6%) | 4 (28.6%) | 17 (58.6%) | ||
3 | 11 (73.3%) | 11 (22.9%) | 9 (64.3%) | 9 (31.0%) | ||
Unknown | 0 (0.0%) | 5 (10.4%) | 1 (7.1%) | 3 (10.3%) | ||
Metastatic site—locally advanced 1 | N (%) | 0.028 5 | N (%) | 0.252 5 | ||
Yes | 6 (40.0%) | 6 (12.5%) | 5 (35.7%) | 5 (17.2%) | ||
No | 9 (60.0%) | 42 (87.5%) | 9 (64.3%) | 24 (82.8%) | ||
Metastatic site—bone 1 | N (%) | 0.012 4 | N (%) | 0.507 5 | ||
Yes | 6 (40.0%) | 36 (75.0%) | 8 (57.1%) | 20 (69.0%) | ||
No | 9 (60.0%) | 12 (25.0%) | 6 (42.9%) | 9 (31.0%) | ||
Metastatic site—visceral 1 | N (%) | 0.291 5 | N (%) | 0.055 5 | ||
Yes | 10 (66.7%) | 39 (81.3%) | 8 (57.1%) | 25 (86.2%) | ||
No | 5 (33.3%) | 9 (18.8%) | 6 (42.9%) | 4 (13.8%) | ||
Metastatic site—CNS 1 | N (%) | 0.039 5 | N (%) | 0.094 5 | ||
Yes | 3 (20.0%) | 1 (2.1%) | 3 (21.4%) | 1 (3.4%) | ||
No | 12 (80.0%) | 47 (97.9%) | 11 (78.6%) | 28 (96.6%) | ||
Line of chemotherapeutical treatment (in metastatic setting) | N (%) | 0.741 4 | N (%) | 0.899 4 | ||
1 | 6 (40.0%) | 27 (56.3%) | 8 (57.1%) | 15 (51.7%) | ||
2 | 5 (33.3%) | 13 (27.1%) | 4 (28.6%) | 8 (27.6%) | ||
3 or more | 3 (20.0%) | 8 (16.7%) | 2 (14.3%) | 6 (20.7%) | ||
Unknown | 1 (6.7%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
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Schochter, F.; Werner, K.; Köstler, C.; Faul, A.; Tzschaschel, M.; Alberter, B.; Müller, V.; Neubauer, H.; Fehm, T.; Friedl, T.W.P.; et al. 53BP1 Accumulation in Circulating Tumor Cells Identifies Chemotherapy-Responsive Metastatic Breast Cancer Patients. Cancers 2020, 12, 930. https://doi.org/10.3390/cancers12040930
Schochter F, Werner K, Köstler C, Faul A, Tzschaschel M, Alberter B, Müller V, Neubauer H, Fehm T, Friedl TWP, et al. 53BP1 Accumulation in Circulating Tumor Cells Identifies Chemotherapy-Responsive Metastatic Breast Cancer Patients. Cancers. 2020; 12(4):930. https://doi.org/10.3390/cancers12040930
Chicago/Turabian StyleSchochter, Fabienne, Kim Werner, Cäcilia Köstler, Anke Faul, Marie Tzschaschel, Barbara Alberter, Volkmar Müller, Hans Neubauer, Tanja Fehm, Thomas W.P. Friedl, and et al. 2020. "53BP1 Accumulation in Circulating Tumor Cells Identifies Chemotherapy-Responsive Metastatic Breast Cancer Patients" Cancers 12, no. 4: 930. https://doi.org/10.3390/cancers12040930