Circulating Tumor Cell Enumeration for Serial Monitoring of Treatment Outcomes for Locally Advanced Esophageal Squamous Cell Carcinoma
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Patients and Sample Collection
2.2. CTC Enrichment and Enumeration
2.3. Cell Spiking Experiments for Reproducibility of Recovery Rate
2.4. Statistical Analysis
3. Results and Discussion
3.1. Patients Characteristics
3.2. Resectable Patients Treated by Pre-Surgery Treatment Had Higher CTC Counts
3.2.1. Patients Treated by Neoadjuvant CTRT Associated with High CTC Level at 3-Month Post-Surgery
3.2.2. Proof-of-Concept Experiment: More CTCs Released into Azygos Vein Blood Versus Peripheral Blood in Patients Treated by Neoadjuvant CTRT Followed by Curative Surgery
3.2.3. Early Predictive and Prognostic Biomarkers for Pre-Surgery CTRT Treatment Efficacy
3.3. Longitudinal CTC Enumeration Analysis from Baseline to 3-Year Post-Surgery along Course of Curative Treatment
3.3.1. Dynamics of Epithelial CTC Counts at Baseline, during and Post-Treatment
3.3.2. Comparing Longitudinal Dynamics of Epithelial and Total CTC Counts
3.4. Pre-Surgery CTC Clusters Associated with Earier Disease Relapse
3.5. Serial CTC Enumeration at Multiple Timepoints Is Associated with Adverse Outcome
3.5.1. CTC Analysis at Baseline
3.5.2. Serial CTC Analysis at Post-Surgery Follow-Up
3.6. COX Regression Analysis of Independent Prognostic Role of Serial CTC Status
3.7. Longitudinal Monitoring of CTC Changes in Response to CTRT and Surgery
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Clinical Parameters | Patients (n = 86) | CTC1E (n = 60) | CTC3E (n = 43) | CTC4E (n = 63) | CTC5E (n = 58) | CTC1E+M (n = 59) | CTC3E+M (n = 43) | CTC4E+M (n = 63) | CTC5E+M (n = 58) | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
≥2 | <2 | ≥2 | <2 | ≥3 | <3 | ≥3 | <3 | ≥2 | <2 | ≥2 | <2 | ≥3 | <3 | ≥3 | <3 | ||
Median age (range) | 69 ± (30–87) | cp = 0.119 | |||||||||||||||
<69 | 41 (47.7%) | 6 | 19 | 7 | 19 | 4 | 26 | 3 | 24 | 8 | 17 | 9 | 17 | 6 | 24 | 6 | 21 |
≥69 | 45 (52.3%) | 5 | 30 | 1 | 16 | 5 | 28 | 0 | 31 | 9 | 26 | 5 | 13 | 8 | 25 | 3 | 28 |
Sex | |||||||||||||||||
Male | 64 (74.4%) | 10 | 35 | 7 | 25 | 6 | 41 | 2 | 42 | 14 | 31 | 12 | 21 | 9 | 38 | 7 | 37 |
Female | 22 (25.6%) | 1 | 14 | 1 | 10 | 3 | 13 | 1 | 13 | 3 | 12 | 2 | 9 | 5 | 11 | 2 | 12 |
G category a | |||||||||||||||||
GX | 36 (41.9%) | 4 | 22 | 4 | 17 | 3 | 21 | 3 | 20 | 7 | 19 | 5 | 16 | 5 | 19 | 4 | 19 |
G1/G2 | 38 (44.2%) | 5 | 21 | 3 | 15 | 4 | 27 | 0 | 27 | 7 | 19 | 7 | 12 | 6 | 25 | 4 | 23 |
G3 | 12 (14.0%) | 2 | 6 | 1 | 3 | 2 | 6 | 0 | 8 | 3 | 5 | 2 | 2 | 3 | 5 | 1 | 7 |
Tumor Location | |||||||||||||||||
Upper/Middle | 57 (66.3%) | 8 | 32 | 6 | 23 | 5 | 35 | 2 | 32 | 13 | 27 | 10 | 20 | 7 | 33 | 6 | 28 |
Lower | 29 (33.7%) | 3 | 17 | 2 | 12 | 4 | 19 | 1 | 23 | 4 | 16 | 4 | 10 | 7 | 16 | 3 | 21 |
Stage b | |||||||||||||||||
Early: I + II | 28 (32.6%) | 5 | 18 | 1 | 11 | 2 | 21 | 1 | 22 | 6 | 17 | 3 | 9 | 3 | 20 | 3 | 20 |
Late: III + IV | 54 (62.8%) | 5 | 30 | 7 | 21 | 7 | 29 | 2 | 30 | 10 | 25 | 11 | 18 | 11 | 25 | 6 | 26 |
Unknown | 4 (4.7%) | - | - | - | - | - | - | - | - | ||||||||
pT (n = 73) | cp = 0.156 | ||||||||||||||||
0–2 | 33 (45.2%) | 7 | 21 | 1 | 18 | 2 | 29 | 0 | 21 | 7 | 14 | 4 | 15 | 4 | 27 | 2 | 19 |
3–4 | 40 (54.8%) | 4 | 17 | 4 | 12 | 6 | 25 | 3 | 32 | 9 | 19 | 7 | 10 | 9 | 22 | 7 | 28 |
pN (n = 73) | cp = 0.069 | ||||||||||||||||
0 | 39 (53.4%) | 5 | 23 | 1 | 19 | 5 | 27 | 2 | 25 | 11 | 17 | 6 | 14 | 7 | 25 | 4 | 23 |
1–3 | 34 (46.6%) | 1 | 20 | 5 | 11 | 3 | 26 | 1 | 27 | 6 | 15 | 6 | 11 | 6 | 23 | 5 | 23 |
Treatment | cp = 0.126 | cp = 0.008 | |||||||||||||||
CRT ± surgery | 54 (62.8%) | 7 | 22 | 8 | 35 | 6 | 31 | 3 | 32 | 8 | 23 | 14 | 30 | 11 | 26 | 9 | 26 |
Upfront surgery | 32 (37.2%) | 4 | 27 | NA | NA | 3 | 23 | 0 | 23 | 9 | 20 | NA | NA | 3 | 23 | 0 | 23 |
Distant Metastasis | |||||||||||||||||
No | 77 (89.5%) | 11 | 44 | 7 | 32 | 9 | 49 | 2 | 50 | 9 | 44 | 13 | 27 | 14 | 44 | 7 | 45 |
Yes | 9 (10.5%) | 0 | 5 | 1 | 3 | 0 | 5 | 1 | 5 | 0 | 5 | 1 | 3 | 0 | 5 | 2 | 4 |
Models | Variables | PFS | OS | ||||
---|---|---|---|---|---|---|---|
HR (95% CI) | p-Value | Concordance | HR (95% CI) | p-Value | Concordance | ||
CP a | pT (3 + 4 vs. 1 + 2 ref) (n = 73) | 4.097 (1.79–9.36) | 8.0 × 10−4 | 0.696 | 3.190 (1.28–7.98) | 0.013 | 0.655 |
CTC1 b | pT (3 + 4 vs. 1 + 2 ref) (n = 49) Sex | 3.319 (1.23–9.0) 8.408 (1.65–42.94) | 0.018 0.011 | 0.782 | - - | - - | 0.76 |
Baseline CTC1 level (≥2 CTCE vs. <2 CTCE ref) (≥2 CTCE+M vs. <2 CTCE ref) | 6.99 (2.10–23.22) 19.162 (4.72–77.74) | 2.0 × 10−4 0.0015 3.6 × 10−5 | 3.665 (1.34–10.04) 8.719 (2.69–28.25) | 5.0 × 10−4 0.012 3.1 × 10−4 | |||
CTC3-CRT c | pT (3 + 4 vs. 1 + 2 ref) (n = 35) Sex:strata(tgroup1) | 5.90 (1.48–23.51) 0.03 (0.002–0.45) | 0.012 0.012 | 0.793 | 4.648 (0.90–23.99) 0.130 (0.01–1.30) | 0.067 0.082 | 0.737 |
CTC3E count at the end of CTRT (≥2 vs. <2 CTCs ref) (≥3 vs. <3 CTCs ref) | 3.652 (1.1–12.14) N/A |
0.035 N/A | N/A 3.50 (0.67–18.35) | N/A 0.139 | |||
CTC4 d | pT (3 + 4 vs. 1 + 2 ref) (n = 62) | 3.222 (1.23–8.46) | 0.017 | 0.776 | - | - | 0.676 |
Sex:strata(tgroup1) | 0.07 (0.006–0.70) | 0.024 | - | - | |||
CTC4 count at post-surgery 1M (≥3 CTCE vs. <3 CTCE ref) (≥3 CTCE+M vs. <3 CTCE ref) | 1.822 (0.67–4.98) 7.56 (3.39–23.91) | 4.0 × 10−4 0.242 5.8 × 10−4 | 1.536 (0.48–4.88 2.902 (0.79–10.62) | 0.1 0.467 0.107 | |||
CTC5 e | pT (3 + 4 vs. 1 + 2 ref) (n = 56) | 6.792 (2.04–22.58) | 0.002 | 0.797 | - | - | 0.802 |
CTC5 count at post-surgery 3M (≥3 CTCE vs. <3 CTCE ref) (≥3 CTCE+M vs. <3 CTCE ref) | 3.641 (1.00–13.25) 9.946 (3.49–28.34) | 9.0 × 10−6 0.0499 1.7 × 10−5 | 5.821 (1.52–22.32) 9.366 (3.11–28.18) | 4.0 × 10−5 0.01 6.9 × 10−5 | |||
CTC3/4 f | pT (3 + 4 vs. 1 + 2 ref) (n = 62) | 3.086 (1.16–8.22) | 0.024 | 0.783 | - | - | 0.739 |
Change of pre-surgery/CTC4 Others vs. favorable change (<3 CTCE) pre-surgery/CTC4 ref) | 3.638 (1.71–7.75) | 8.3 × 10−4 | 3.019 (1.34–6.82) | 0.008 | |||
CTC3/5 g | pT (3 + 4 vs. 1 + 2 ref) (n = 56) | 4.259 (1.47–12.32) | 0.007 | 0.803 | - | - | 0.783 |
Change of pre-surgery/CTC5 Others vs. favorable change (<3 CTCE) pre-surgery/CTC5 ref) | 6.662 (2.92–15.21) | 6.7 × 10−6 | 3.913 (1.66–9.21) | 0.002 | |||
CTC3CL h | pT (3 + 4 vs. 1 + 2 ref) (n = 63) | 3.639 (1.48–8.93) | 0.005 | 0.749 | 3.022 (1.14–8.03) | 0.027 | 0.662 |
- | - | ||||||
CTC clusters (Yes vs. No ref) | 2.539 (0.94–6.89) | 0.068 |
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Ko, J.M.Y.; Lam, K.O.; Kwong, D.L.W.; Wong, I.Y.-H.; Chan, F.S.-Y.; Wong, C.L.-Y.; Chan, K.K.; Law, T.T.; Chiu, K.W.H.; Lam, C.C.S.; et al. Circulating Tumor Cell Enumeration for Serial Monitoring of Treatment Outcomes for Locally Advanced Esophageal Squamous Cell Carcinoma. Cancers 2023, 15, 832. https://doi.org/10.3390/cancers15030832
Ko JMY, Lam KO, Kwong DLW, Wong IY-H, Chan FS-Y, Wong CL-Y, Chan KK, Law TT, Chiu KWH, Lam CCS, et al. Circulating Tumor Cell Enumeration for Serial Monitoring of Treatment Outcomes for Locally Advanced Esophageal Squamous Cell Carcinoma. Cancers. 2023; 15(3):832. https://doi.org/10.3390/cancers15030832
Chicago/Turabian StyleKo, Josephine Mun Yee, Ka On Lam, Dora Lai Wan Kwong, Ian Yu-Hong Wong, Fion Siu-Yin Chan, Claudia Lai-Yin Wong, Kwan Kit Chan, Tsz Ting Law, Keith Wan Hang Chiu, Candy Chi Shan Lam, and et al. 2023. "Circulating Tumor Cell Enumeration for Serial Monitoring of Treatment Outcomes for Locally Advanced Esophageal Squamous Cell Carcinoma" Cancers 15, no. 3: 832. https://doi.org/10.3390/cancers15030832