The Detection of Stem-Like Circulating Tumor Cells Could Increase the Clinical Applicability of Liquid Biopsy in Ovarian Cancer
Abstract
:1. Introduction
2. Materials and Methods
2.1. The Study Cohort
2.2. Enumeration of Circulating Tumor Cells
2.3. Statistical Processing
3. Results
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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No. | Manufacturer | Product | Usage |
---|---|---|---|
1 | BioLegend, CA, USA | PE anti-human CD45 Antibody Clone 2D1 | CD45 |
2 | BioLegend | PE Mouse IgG1, κ Isotype Ctrl (FC) Antibody clone MOPC-21 | Isotype |
3 | BioLegend | APC anti-human CD44 Antibody Clone BJ18 | CD44 |
4 | BioLegend | APC Mouse IgG1, κ Isotype Ctrl Antibody clone MOPC-21 | Isotype |
5 | Miltenyi biotec, Bergisch Gladbach, Germany | CD133/1 VioBright 667 mouse IgG1 clone AC133 | CD133 |
6 | Miltenyi biotec | VioBright 515 mouse IgG1, Clone IS5-21F5 | Isotype |
7 | Stemcell, Canada | ALDEFLUOR kit #01700 | ALDH |
8 | Invitrogen, CA, USA | CD326 (EpCAM) Monoclonal Antibody PE-Cyanine7 clone 1B7 | EpCAM |
9 | Invitrogen | PE-Cyanine7 mouse/IgG1, kappa clone P3.6.2.8.1 | Isotype |
10 | Abcam, Cambridge, United Kingdom | Mouse Anti-Cytokeratin 8 + 18 + 19 antibody clone 2A4 (ab41825) IgG1 | Primary |
11 | BioLegend | Brilliant Violet 421™ anti-mouse IgG1 Antibody clone RMG1-1 | Secondary |
12 | BioLegend | Alexa Fluor 647 anti-Vimentin Antibody clone 091D3 Mouse IgG2a | Vimentin |
13 | BioLegend | Alexa Fluor 647 anti-mouse IgG2a clone RMG2a-62 | Isotype |
Parameter | Number of Patients (%) |
---|---|
Age—median (IQR Q1–Q3), years—66 (53–70) | |
Serum CA-125 before treatment—median (IQR), U/mL—863 (309–1595) | |
FIGO stage | |
I | 2 (5%) |
III | 22 (58%) |
IV | 14 (37%) |
Ascites at diagnosis | |
yes | 31 (82%) |
no | 7 (18%) |
Histological subtype | |
serous high-grade adenocarcinoma | 16 (42%) |
other subtypes | 4 (11%) |
not determined due to CRS 3 | 5 (13%) |
no histological assessment (only cytological verification) | 13 (34%) |
Chemotherapy | |
neoadjuvant | 31 (82%) |
adjuvant | 7 (18%) |
Cytoreductive surgery within first-line treatment | |
performed | 20 (53%) |
not performed | 18 (47%) |
Maintenance therapy with bevacizumab after first-line CT | |
performed | 12 (32%) |
not performed | 26 (68%) |
Phenotype | EpCAM+CK+ (Median (Min–Max)) | EpCAM+Vimentin- | EpCAM-Vimentin+ | CK-Vimentin+ | CK+Vimentin- | CK+Vimentin+ | Vimentin+ |
---|---|---|---|---|---|---|---|
Before | 0 (0–11) | 25 (9–48) | 59 (15–108) | 50 (14–89) | 218 (112–392) | 6 (2–24) | 59 (20–137) |
During | 1 (0–15) | 28 (12–45) | 57 (40–80) | 48 (24–77) | 217 (101–310) | 5 (0–12) | 79 (50–93) |
Phenotype | CD44+ | CD133+ | CD44+CD133+ | ALDHhigh | ALDHveryhigh | ||
Before | 527 (121–1519) | 101 (15–291) | 1 (0–14) | 90 (50–152) | 12 (1–57) | ||
During | 205 (120–339) | 172 (57–391) | 4 (0–23) | 110 (37–154) | 6 (0–9) | ||
Phenotype | CD44+ALDHhigh | CD44+ALDH veryhigh | CD133+ALDHhigh | CD133+ALDHveryhigh (Median (Min–Max)) | |||
Before | 15 (2–49) | 7 (0–26) | 0 (0–10) | 0 (0–83) | |||
During | 16 (6–49) | 1 (0–5) | 6 (0–26) | 0 (0–300) |
No. | Age | Stage | Histology | CT Regimen | Ascites | Platinum Sensitivity | CD44+CD133+ ALDHhigh Count | CD44+CD133+ ALDHveryhigh Count |
---|---|---|---|---|---|---|---|---|
Patients positive for the cells at baseline | ||||||||
1 | 61 | IV | HGS | NACT | Yes | No | 11 | 34 |
2 | 69 | IV | HGS | NACT | Yes | Yes (M) | 7 | 0 |
3 | 72 | III | NS | NACT | Yes | No | 2 | 2 |
4 | 70 | III | NS | NACT | Yes | No | 2 | 2 |
5 | 64 | III | HGS | NACT | Yes | Yes | 1 | 4 |
6 | 49 | IV | HGS | NACT | Yes | No | 5 | 0 |
Patients positive for the cells during treatment only | ||||||||
7 | 37 | IV | NS | NACT | Yes | Yes (M) | 29 | 44 |
8 | 73 | IV | HGS | NACT | Yes | Yes | 1 | 1 |
9 | 52 | III | HGS | NACT | Yes | Yes | 4 | 7 |
10 | 57 | IV | Clear cell | ACT | No | Yes | 3 | 0 |
Category | Univariable Analysis, HR (95% CI) | Multivariable Analysis, HR (95% CI) |
---|---|---|
FIGO stage | ||
Stage III | ||
Stage IV | 1.13 (0.61–2.10), p = 0.699 | |
Ascites | ||
No ascites | ||
Ascites present | 2.07 (1.03–4.18), p = 0.042 | 1.65 (0.81–3.37), p = 0.169 |
Surgery in first line | ||
Surgery not performed | ||
Surgery performed | 0.14 (0.03–0.67), p = 0.014 | 0.06 (0.01–0.48), p = 0.009 |
Chemotherapy | ||
Adjuvant regimen | ||
Neoadjuvant regimen | 2.06 (1.00–4.25), p = 0.051 | 1.27 (0.47–2.86), p = 0.562 |
Age | 1.01 (0.98–1.04), p = 0.458 | |
Initial serum CA-125 | 1.00 (1.00–1.00), p = 0.619 | |
Initial WBC count in blood | 1.19 (1.01–1.41), p = 0.040 | 1.21 (0.91–1.62), p = 0.195 |
Maintenance after first line | 0.28 (0.11–0.68), p = 0.006 | 0.27 (0.06–1.27), p = 0.096 |
CTC number before treatment | ||
EpCAM+CK+ | 1.01 (0.89–1.15), p = 0.856 | |
EpCAM+vimentin- | 1.00 (1.00–1.01), p = 0.260 | |
EpCAM-vimentin+ | 1.00 (1.00–1.00), p = 0.456 | |
CK-vimentin+ | 1.00 (1.00–1.00), p = 0.484 | |
CK+vimentin- | 1.00 (1.00–1.00), p=0.711 | |
CK+vimentin+ | 1.00 (0.98–1.01), p = 0.727 | |
CD44+ | 1.00 (1.00–1.00), p = 0.377 | |
CD133+ | 1.00 (1.00–1.00), p = 0.885 | |
ALDHhigh | 1.00 (1.00–1.00), p = 0.375 | |
ALDHveryhigh | 1.00 (1.00–1.01), p = 0.080 | |
CD44+CD133+ | 1.01 (0.99–1.03), p = 0.292 | |
CD44+ALDHhigh | 1.00 (0.99–1.00), p = 0.160 | |
CD44+ALDHveryhigh | 1.01 (1.00–1.02), p = 0.175 | |
CD133+ALDHhigh | 1.01 (0.97–1.04), p = 0.764 | |
CD133+ALDHveryhigh | 1.03 (1.01–1.06), p = 0.014 | 1.06 (1.02–1.12), p = 0.010 |
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Gening, S.O.; Abakumova, T.V.; Gafurbaeva, D.U.; Rizvanov, A.A.; Antoneeva, I.I.; Miftakhova, R.R.; Peskov, A.B.; Gening, T.P. The Detection of Stem-Like Circulating Tumor Cells Could Increase the Clinical Applicability of Liquid Biopsy in Ovarian Cancer. Life 2021, 11, 815. https://doi.org/10.3390/life11080815
Gening SO, Abakumova TV, Gafurbaeva DU, Rizvanov AA, Antoneeva II, Miftakhova RR, Peskov AB, Gening TP. The Detection of Stem-Like Circulating Tumor Cells Could Increase the Clinical Applicability of Liquid Biopsy in Ovarian Cancer. Life. 2021; 11(8):815. https://doi.org/10.3390/life11080815
Chicago/Turabian StyleGening, Snezhanna O., Tatyana V. Abakumova, Dina U. Gafurbaeva, Albert A. Rizvanov, Inna I. Antoneeva, Regina R. Miftakhova, Andrey B. Peskov, and Tatyana P. Gening. 2021. "The Detection of Stem-Like Circulating Tumor Cells Could Increase the Clinical Applicability of Liquid Biopsy in Ovarian Cancer" Life 11, no. 8: 815. https://doi.org/10.3390/life11080815