Circulating p16-Positive and p16-Negative Tumor Cells Serve as Independent Prognostic Indicators of Survival in Patients with Head and Neck Squamous Cell Carcinomas
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patient Enrollment
2.2. Tissue Immunohistochemistry Staining for p16 Expression Analysis
2.3. The Isolation and Identification of Circulating Tumor Cells via Microscopy
2.4. Analysis of p16 Expression in Circulating Tumor Cells via Flow Cytometry
2.5. Human Papillomavirus Genotyping
2.6. Statistical Analysis
3. Results
3.1. Patient Enrollment
3.2. The Identification of p16-Positive Circulating Tumor Cells in Cancer Patients
3.3. HPV Genotyping of Cancer Tissues and Circulating Tumor Cells
3.4. Effects of CTCs and p16-Positive CTCs on Survival
4. Discussion
5. Limitations
6. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
Full name | Abbreviations |
head and neck squamous cell carcinomas | HNSCC |
human papillomavirus | HPV |
circulating tumor cells | CTCs |
confidence interval | CI |
concurrent chemoradiotherapy | CCRT |
American Joint Committee on Cancer | AJCC |
response evaluation criteria in solid tumors | RECIST |
complete remission | CR |
partial response | PR |
Stable disease | SD |
progressive disease | PD |
Immunohistochemistry staining | IHC |
Progression-free survival | PFS |
Overall survival | OS |
Eastern Cooperative Oncology Group performance status | ECOG PS |
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Characters | n | % |
---|---|---|
Age (median, range) in years | 55 (37–74) | |
Sex | ||
Female | 8 | 19.5% |
Male | 33 | 80.5% |
Tumor type | ||
Oropharynx | 28 | 68.3% |
Non-oropharynx a | 13 | 31.7% |
ECOG PS | ||
0–1 | 32 | 78.0% |
2 | 9 | 22.0% |
Tumor stage (AJCC 8th edition) b | ||
II | 20 | 48.8% |
III | 5 | 12.2% |
IV | 16 | 39.0% |
T classification | ||
T1-2 | 28 | 68.3% |
T3-4 | 13 | 31.7% |
Lymph node Involvement | ||
Negative (N0) | 11 | 26.8% |
Positive (N1-3) | 30 | 73.2% |
p16 status by IHC staining | 0.0% | |
Negative (0–70%) | 22 | 53.7% |
Positive (>70%) | 19 | 46.3% |
CCRT completion | 41 | 100.0% |
Disease Progression after CCRT | ||
No | 19 | 46.3% |
Yes | 22 | 53.7% |
Cancer-related death c | ||
No | 27 | 65.9% |
Yes | 14 | 34.1% |
Circulating tumor cells (CTCs) detection rate | ||
p16-positive CTCs (p16posEpCAMposHoechstpos) | 21 | 51.2% |
p16-negative CTCs (p16negEpCAMposHoechstpos) d | 20 | 48.8% |
Tissue IHC p16 Negative | Tissue IHC p16 Positive | p-Value | Tissue IHC p16 Negative AND HPV Genotyping Negative | Tissue IHC p16 Positive OR HPV Genotyping Positive | p-Value | |
---|---|---|---|---|---|---|
p16pos CTC Negative | 13 | 7 | 0.155 | 13 | 7 | 0.019 * |
p16pos CTC Positive | 9 | 12 | 6 | 15 |
Progression-Free Survival | Overall Survival | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Univariate Analysis | Multivariate Analysis | Univariate Analysis | Multivariate Analysis * | |||||||||
Factors | p | HR | (95% CI) | p | HR | (95% CI) | p | HR | (95% CI) | p | HR | (95% CI) |
Age | 0.135 | 0.957 | (0.904–1.014) | 0.003 | 0.909 | (0.852–0.969) | 0.338 | 0.973 | (0.920–1.029) | |||
Sex (female vs. male) | 0.262 | 2.328 | (0.532–10.195) | 0.371 | 1.967 | (0.447–8.659) | ||||||
Tumor type (ORX vs. non-ORX) | 0.924 | 0.95 | (0.334–2.707) | 0.415 | 1.524 | (0.553–4.198) | ||||||
T classification (cT1-2 vs. cT3-4) | 0.975 | 0.985 | (0.374–2.592) | 0.548 | 1.350 | (0.506–3.600) | ||||||
N classification | 0.421 | 1.214 | (0.758–1.944) | 0.968 | 0.991 | (0.624–1.574) | ||||||
ECOG PS | 0.171 | 0.377 | (0.093–1.523) | 0.248 | 0.439 | (0.109–1.775) | ||||||
Best response of CCRT (Non-responders vs. responders) | 0.104 | 1.535 | (0.916–2.573) | 0.038 | 1.738 | 1.031–2.927 | 0.114 | 1.499 | (0.907–2.475) | |||
Tissue p16 IHC (Positive vs. negative) | 0.099 | 0.415 | (0.146–1.180) | 0.369 | 0.629 | (0.228–1.731) | ||||||
p16neg CTC (Positive vs. negative) | 0.005 | 4.029 | (1.522–10.668) | 0.003 | 5.497 | 1.818–16.615 | 0.029 | 3.037 | (1.123–8.213) | |||
p16pos CTC (Positive vs. negative) | 0.018 | 0.300 | (0.110–0.816) | 0.003 | 0.176 | 0.056–0.554 | 0.024 | 0.294 | (0.102–0.852) | 0.024 | 0.294 | (0.102–0.852) |
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Chang, P.-H.; Wang, H.-M.; Kuo, Y.-C.; Lee, L.-Y.; Liao, C.-J.; Kuo, H.-C.; Hsu, C.-L.; Liao, C.-T.; Lin, S.H.-C.; Huang, P.-W.; et al. Circulating p16-Positive and p16-Negative Tumor Cells Serve as Independent Prognostic Indicators of Survival in Patients with Head and Neck Squamous Cell Carcinomas. J. Pers. Med. 2021, 11, 1156. https://doi.org/10.3390/jpm11111156
Chang P-H, Wang H-M, Kuo Y-C, Lee L-Y, Liao C-J, Kuo H-C, Hsu C-L, Liao C-T, Lin SH-C, Huang P-W, et al. Circulating p16-Positive and p16-Negative Tumor Cells Serve as Independent Prognostic Indicators of Survival in Patients with Head and Neck Squamous Cell Carcinomas. Journal of Personalized Medicine. 2021; 11(11):1156. https://doi.org/10.3390/jpm11111156
Chicago/Turabian StyleChang, Pei-Hung, Hung-Ming Wang, Yung-Chia Kuo, Li-Yu Lee, Chia-Jung Liao, Hsuan-Chih Kuo, Cheng-Lung Hsu, Chun-Ta Liao, Sanger Hung-Chi Lin, Pei-Wei Huang, and et al. 2021. "Circulating p16-Positive and p16-Negative Tumor Cells Serve as Independent Prognostic Indicators of Survival in Patients with Head and Neck Squamous Cell Carcinomas" Journal of Personalized Medicine 11, no. 11: 1156. https://doi.org/10.3390/jpm11111156
APA StyleChang, P.-H., Wang, H.-M., Kuo, Y.-C., Lee, L.-Y., Liao, C.-J., Kuo, H.-C., Hsu, C.-L., Liao, C.-T., Lin, S. H.-C., Huang, P.-W., Wu, T. M.-H., & Hsieh, J. C.-H. (2021). Circulating p16-Positive and p16-Negative Tumor Cells Serve as Independent Prognostic Indicators of Survival in Patients with Head and Neck Squamous Cell Carcinomas. Journal of Personalized Medicine, 11(11), 1156. https://doi.org/10.3390/jpm11111156