Liquid Biopsy Serial Monitoring of Treatment Responses and Relapse in Advanced Esophageal Squamous Cell Carcinoma
Abstract
:1. Introduction
2. Results
2.1. Patient Characteristics
2.2. Role of CTC Enumeration for Prediction and Prognosis of Interim Reassessment, Progression-Free and Overall- Survival
2.2.1. Serial CTC Enumeration
2.2.2. Baseline CTC Enumeration Is Not Associated with Interim Reassessment, Progression-Free and Overall- Survival
2.2.3. CTC Enumeration at Pre-Cycle III Chemotherapy Is Associated with Adverse Outcome
2.3. Role of cfDNA Levels for Prediction and Prognosis of Interim Reassessment, Progression-Free and Overall- Survival
2.3.1. Serial cfDNA Levels
2.3.2. Baseline and CT Pre-Cycle III cfDNA Levels Are Associated with Overall Survival
2.4. Early Prediction of Disease Progression for Patients with Unfavorable Changes of CTC Counts from Baseline to Pre-Cycle III
2.5. Early Prediction for Disease Relapse for Patients with Integration of Unfavorable Changes of CTC Counts and cfDNAs from Baseline to Pre-Cycle III
2.6. COX Regression Analysis of Independent Prognostic Role of CTC and cfDNA Values
3. Discussion
4. Materials and Methods
4.1. Study Population
4.2. CTC Enrichment and Enumeration
4.3. cfDNA Isolation and Quantification
4.4. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Parameters | Patients (n = 57) | CTC1 | CTC2 | cfDNA1 d Median ± SD | cfDNA2 d Median ± SD | ||
---|---|---|---|---|---|---|---|
≥3 | 0–2 | ≥3 | 0–2 | ||||
Median age (range) | 63 (49–76) | ||||||
<63 | 28 (49%) | 6 | 22 | 7 | 15 | 3425 ± 2496 | 2311 ± 3231 |
≥63 | 29 (51%) | 9 | 18 | 7 | 16 | 2577 ± 6914 | 2171 ± 6482 |
Sex | |||||||
Male | 49 (86%) | 13 | 34 | 12 | 27 | 3116 ± 3690 | 2176 ± 4665 |
Female | 8 (14%) | 2 | 6 | 2 | 4 | 4186 ± 11004 | 2755 ± 8598 |
G category a | |||||||
GX | 1 (1.8%) | - | - | - | - | ||
G2 | 34 (59.6%) | 8 | 24 | 8 | 20 | 2663 ± 3975 | 2176 ± 5316 |
G3 | 22 (38.6%) | 6 | 16 | 6 | 11 | 3682 ± 7054 | 2065 ± 5616 |
Tumor location | |||||||
Upper | 9 (27.3%) | 4 | 4 | 3 | 5 | 2580 ± 1719 | 2447 ± 1326 |
Middle | 26 (41.8%) | 5 | 21 | 6 | 12 | 3171 ± 2201 | 2167 ± 3283 |
Lower | 19 (30.9%) | 5 | 13 | 5 | 13 | 2220 ± 8927 | 1939 ± 6789 |
Unknown | 3 (5.3%) | - | - | - | - | ||
Stage b | |||||||
III | 14 (24.6%) | 5 | 9 | 4 | 5 | 2111 ± 6785 | 3598 ± 7188 |
IV | 42 (73.7%) | 10 | 30 | 10 | 25 | 3137 ± 5113 | 2167 ± 5054 |
Unknown | 1 (1.8%) | - | - | - | - | ||
Previous treatment | |||||||
No | 27 (47.4%) | 7 | 20 | 6 | 12 | 3171 ± 4662 | 3069 ± 6395 |
Yes | 30 (52.6%) | 8 | 20 | 8 | 19 | 3116 ± 5911 | 1954 ± 4513 |
Distant Metastasis | |||||||
No | 15 (26.3%) | 5 | 10 | 4 | 6 | 2111 ± 6785 | 3598 ± 7188 |
Yes | 42 (73.7%) | 10 | 30 | 10 | 25 | 3137 ± 5113 | 2167 ± 5054 |
Synchronous metastasis | 15 (35.7%) | 4 | 11 | 3 | 8 | 3679 ± 3077 | 2429 ± 6126 |
Metachronous metastasis | 27 (64.3%) | 6 | 19 | 7 | 17 | 2954 ± 6018 | 2048 ± 4650 |
Metastasis to one site | 25 (43.9%) | 8 | 16 | 4 | 14 | 3130 ± 6484 | 1954 ± 6432 |
Metastasis to ≥2 sites | 17 (29.8%) | 2 | 14 | 6 | 11 | 3143 ± 2142 | 2171 ± 2581 |
Site of Metastasis | |||||||
Liver | 12 (21.1%) | 1 | 10 | 3 | 9 | 3130 ± 2515 | 2176 ± 3063 |
Lung | 13 (22.8%) | 4 | 8 | 5 | 5 | 2791 ± 8211 | 2167 ± 8013 |
Lymph node | 33 (57.9%) | 6 | 25 | 7 | 22 | 3123 ± 1997 | 2048 ± 2550 |
Others c | 11 (19.4%) | - | - | - | - |
Variables | Univariate Analysis | Multivariate Analysis b | ||
---|---|---|---|---|
HR (95% CI) | p-Value | HR (95% CI) | p-Value | |
(A) Interim Reassessment (n = 52) | ||||
Age | 1.003 (0.95–1.06) | 0.906 | - | - |
Gender (F vs. M ref) | 1.553 (0.52–4.62) | 0.428 | - | - |
L cat (Others vs. Lower ref) | 0.886 (0.40–1.96) | 0.766 | - | - |
G cat (G3 vs. G2 ref) | 0.615 (0.29–1.41) | 0.251 | - | - |
Previous treatment (Yes vs. no ref) | 0.882 (0.40–1.93) | 0.753 | - | - |
Stage at CTC blood collection (IV vs. III ref) | 0.262 (0.11–0.62) | 0.002 | - | - |
Primary tumor resected at CTC blood collection (n = 50) (Yes vs. no ref) | 0.548 (0.22–1.34) | 0.201 | - | - |
Metastasis Meta vs. Syn ref (n = 38) | 1.310 (0.48–3.55) | 0.596 | - | - |
LN metastasis (Yes vs. no ref) | 0.392 (0.18–0.84) | 0.016 | - | - |
Lung metastasis (Yes vs. no ref) | 1.333 (0.54–3.32) | 0.537 | - | - |
Liver metastasis (Yes vs. no ref) | 0.715 (0.24–2.09) | 0.541 | - | - |
Baseline CTC count (3 vs. 0–2 ref) (n = 50) | 2.072 (0.87–4.95) | 0.101 | - | - |
Pre-cycle III CTC count (3 vs. 0–2 ref) (n = 42) | 3.426 (1.32–8.87) | 0.011 | 3.426 (1.32–8.87) | 0.011 |
Baseline log cfDNA * (n = 39) | 4.980 (0.91–27.22) | 0.064 | - | - |
Pre-cycle III log cfDNA * (n = 35) | 2.241 (0.77–6.53) | 0.139 | - | - |
(B) Progression-free survival (PFS) (n = 54) | ||||
Age | 0.956 (0.91–1.00) | 0.062 | - | - |
Gender (F vs. M ref) | 0.969 (0.45–2.08) | 0.935 | - | - |
L cat (Others vs. Lower ref) (n = 53) | 1.286 (0.70–2.35) | 0.414 | - | - |
G cat (G3 vs. G2 ref) (n = 53) | 0.867 (0.48–1.56) | 0.633 | - | - |
Previous Treatment (Yes vs. no ref) | 0.561 (0.30–1.05) | 0.071 | - | - |
Stage at CTC blood collection (IV vs. III ref) | 0.430 (0.22–0.85) | 0.016 | - | - |
Primary tumor resected at CTC blood collection (n = 51) (Yes vs. no ref) | 0.373 (0.19–0.75) | 0.005 | 0.402 (0.19–0.87) | 0.02 |
Metastasis (Meta vs. Syn ref) (n = 40) | 0.517 (0.25–1.08) | 0.080 | - | - |
LN metastasis (Yes vs. no ref) | 0.618 (0.35–1.11) | 0.106 | - | - |
Lung metastasis (Yes vs. no ref)) | 1.167 (0.60–2.25) | 0.646 | - | - |
Liver metastasis (Yes vs. no ref) | 0.449 (0.21–0.98) | 0.043 | - | - |
Baseline CTC count (≥3 vs. 0–2 CTCs ref) (n = 52) | 1.349 (0.69–2.63) | 0.380 | - | - |
Pre-cycle III CTC count (≥3 vs. 0–2 CTCs ref) (n = 43) | 3.680 (1.73–7.81) | 0.001 | 4.014 (1.81–8.88) | 0.001 |
Baseline log cfDNA * (n = 47) | 1.959 (0.67–5.76) | 0.222 | - | - |
Pre-cycle III log cfDNA * (n = 40) | 1.681 (0.70–4.06) | 0.249 | - | - |
(C) Overall survival (OS) (n = 57) | ||||
Age | 0.940 (0.89–0.99) | 0.027 | 0.932 (0.87–0.99) | 0.032 |
Gender (F vs. M ref) | 0.886 (0.38–2.04) | 0.776 | - | - |
L cat (Others vs. Lower ref) (n = 56) | 1.884 (0.89–3.99) | 0.097 | - | - |
G cat (G3 vs. G2 ref) (n = 53) | 0.821 (0.43–1.57) | 0.552 | - | - |
Previous Treatment (Yes vs. no ref) | 0.534 (0.28–1.02) | 0.056 | - | - |
Stage at CTC blood collection (IV vs. III ref) (n = 56) | 0.620 (0.30–1.27) | 0.192 | - | - |
Primary tumor resected at CTC blood drawn (n = 53) (Yes vs. no ref) | 0.584 (0.29–1.17) | 0.127 | - | - |
Metastasis (Meta vs. Syn ref) (n = 42) | 0.565 (0.27–1.21) | 0.140 | - | - |
LN metastasis (Yes vs. no ref) | 0.926 (0.48–1.78) | 0.821 | - | - |
Lung metastasis (Yes vs. no ref) | 1.002 (0.46–2.20) | 0.997 | - | - |
Liver metastasis (Yes vs. no ref) | 0.784 (0.37–1.67) | 0.529 | - | - |
Baseline CTC count (≥3 vs. 0–2 CTCs ref) (n = 55) | 0.973 (0.44–2.14) | 0.946 | - | - |
Pre-cycle III CTC count (≥3 vs. 0–2 CTCs ref) (n = 45) | 3.576 (1.63–7.84) | 0.001 | - | - |
Baseline log cfDNA * (n = 48) | 8.338 (2.42–28.7) | 0.001 | - | - |
Pre-cycle III log cfDNA * (n = 41) | 5.451 (1.74–17.1) | 0.004 | - | - |
Change of cfDNA1/2 (n = 40) | - | - | ||
Group 0 (Other combinations, n = 21) | Reference | |||
Group 1 (High cfDNA1 & cfDNA2, n = 19) | 4.444 (1.85–10.68) | 0.001 | ||
Change of CTC1/2 (n = 43) | - | - | ||
Group 0 (Low CTC1 & CTC2, n = 22) | Reference | 0.012 | ||
Group 1 (Other combinations, n = 16) | 3.103 (1.11–8.65) | 0.089 | ||
Group 2 (High CTC1 & CTC2, n = 5) | 6.178 (1.87–20.4) | 0.004 | ||
Combined changes of CTC and cfDNA a | ||||
(n = 44) | ||||
Group 0 (n = 12) | Reference | 0.001 | 0.002 | |
Group 1 (n = 22) | 3.103 (1.11–8.65) | 0.030 | 6.008 (1.27–28.5) | 0.008 |
Group 2 (n = 8) | 6.178 (1.87–20.4) | 0.030 | 9.520 (1.81–50.0) | 0.008 |
Group 3 (n = 2) | 53.07 (7.02–401) | 1.2 × 10−4 | 81.958 (7.95–845) | 2.2 × 10−4 |
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Ko, J.M.Y.; Ng, H.Y.; Lam, K.O.; Chiu, K.W.H.; Kwong, D.L.W.; Lo, A.W.I.; Wong, J.C.; Lin, R.C.W.; Fong, H.C.H.; Li, J.Y.K.; et al. Liquid Biopsy Serial Monitoring of Treatment Responses and Relapse in Advanced Esophageal Squamous Cell Carcinoma. Cancers 2020, 12, 1352. https://doi.org/10.3390/cancers12061352
Ko JMY, Ng HY, Lam KO, Chiu KWH, Kwong DLW, Lo AWI, Wong JC, Lin RCW, Fong HCH, Li JYK, et al. Liquid Biopsy Serial Monitoring of Treatment Responses and Relapse in Advanced Esophageal Squamous Cell Carcinoma. Cancers. 2020; 12(6):1352. https://doi.org/10.3390/cancers12061352
Chicago/Turabian StyleKo, Josephine Mun Yee, Hoi Yan Ng, Ka On Lam, Keith Wan Hang Chiu, Dora Lai Wan Kwong, Anthony Wing Ip Lo, Jean Chrysei Wong, Roger Chia Wei Lin, Henry Chun Hung Fong, Jason Ying Ki Li, and et al. 2020. "Liquid Biopsy Serial Monitoring of Treatment Responses and Relapse in Advanced Esophageal Squamous Cell Carcinoma" Cancers 12, no. 6: 1352. https://doi.org/10.3390/cancers12061352