Expression of p16, Ki-67, and Bcl-2 in Head and Neck Squamous Cell Carcinoma Treated whit Chemoradiotherapy
Abstract
Introduction: Squamous cell carcinoma of the head and neck is the seventh most common cancer worldwide, and in Cuba, it is the fifth leading cause of cancer incidence and the sixth leading cause of cancer death. It represents a significant social and health problem.
Objective: Evaluar the efficacy and safety of hypofractionated radiotherapy compared with normofractionated radiotherapy.
Methods: The prognostic and predictive utility of the biomarkers p16, Ki-67, and Bcl-2 was evaluated in 75 patients using immunohistochemistry. Their association with clinical response and survival was analyzed in a multinational, randomized, non-inferiority, phase III clinical trial. The trial's objective was to evaluate the efficacy and safety of hypofractionated radiotherapy compared to normofractionated radiotherapy. Patients were not randomized based on the expression of these biomarkers.
Results: Median survival did not reach nine years in patients expressing p16, while it was four years in p16-negative patients. The absence of Bcl-2 was associated with better survival (6.3 years vs. 3.8 years when Bcl-2 was positive). The combination of p16 positivity and Bcl-2 negativity correlated with a better clinical response and a five- year overall survival rate of 66.7 %. In contrast, p16 negativity and Bcl-2 positivity increased the risk of treatment resistance more than sevenfold and was associated with lower survival. Ki-67 expression ≤ 20 % showed a trend toward improved survival, but this was not statistically significant.
Conclusions: The p16 and Bcl-2 biomarkers proved useful as prognostic and predictive markers in this context, relevant for personalized treatment of patients with head and neck cancers treated with chemoradiotherapy.
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1. Mendenhall MM, Dziegiecki P, Dunn L. General principles in the management of head and neck cancer. In: DeVita VT, Rosenberg SA, editors. Cancer: principles and practice of oncology. 12th ed. Philadelphia: Wolters Kluwer; 2023 [acceso 17/05/2022]. Disponible en: https://user-biackli.cld.bz/9788419663085-DeVita-Cancer-12ed
2. Ministerio de Salud Pública. Anuario estadístico de Cuba 2021. La Habana: Dirección Nacional de Registros Médicos y Estadísticas de Salud; 2022 [acceso 17/05/2022]. Disponible en: https://instituciones.sld.cu/fatesa/files/2022/11/Anuario-Estad%C3%ADstico-de-Salud-2021.-Ed-2022.pdf
3. Zavala AM, Morales-Pinargote MM, Quimiz-Lino MB. Virus del papiloma humano: una actualización al diagnóstico y la prevención. Dominio Cienc. 2022;8(2):402-19. DOI: https://doi.org/10.23857/dc,v8i2.2652
4. Nogues BS, Scott F, Collin M, Zapanta PE. Human papillomavirus-associated head and neck cancer. J Am Board Fam Med. 2021;34(4). DOI: https://doi.org/10.3122/jabfm.2021.04.200588
5. Silva FF, Caponio VC, Camolesi GC, Padín-Iruegas ME, Lorenzo-Pouso AI, Lima KC, et al. Correlation of Bcl-2 expression with prognosis and survival in patients with head and neck cancer: A systematic review and meta-analysis. Crit Rev Oncol Hematol. 2023;187:104021. DOI: https://doi.org/10.1016/j.critrevonc.2023.104021
6. Gadbail A, Sarode S, Chaudhary M, Gondivkar S, Tekade S, Yuwana T, et al. Ki67 labelling Index predicts clinical outcome and survival in oral squamous cell carcinoma. J Appl Oral Sci. 2021;29:e20200751. DOI: https://dx.doi.org/10.1590/1678-7757-2020-0751
7. Uxa S, Castillo-Binder P, Kohler R, Stangner K, Müller GA, Engeland K. Ki-67 gene expression. Cell Death Differ. 2021 [acceso 17/05/2022];28:3357-70. Disponible en: https://share.google/z5mJI2saxMTtY4bDf
8. Wang T, Xue L, Li Z, Hong Z, Hu N, Li Y, et al. A novel nomogram model based on Ki-67 characteristic expression to predict prognosis in head and neck squamous cell carcinoma. Front Oncol. 2024;14:1376498. DOI: https://dx.doi.org/10.3389/fonc.2024.1376498.
9. Kurihara C, Kerpel-Fronius S, Becker S, Chan A, Nagaty Y, Naseem S, et al. Declaration of Helsinki: ethical norm in pursuit of common global goals. Front Med. 2024;11:1360653. DOI: https://dx.doi.org/10.3389/fmed.2024.1360653
10. Mylly M, Nissi L, Huusko T, Routila J, Vaittinen S, Irjala H, et al. Epidemiological study of p16 incidence in head and neck squamous cell carcinoma 2005–2015 in a representative Northern European population. Cancers (Basel). 2022;14(22):5717. DOI: https://dx.doi.org/10.3390/cancers14225717
11. Berdugo J, Rooper LM, Chiosea SI. RB1, p16, and human papillomavirus in oropharyngeal squamous cell carcinoma. Head Neck Pathol. 2021;15:10-7. DOI: https://doi.org/10.1007/s12105-021-01317-5
12. Anwar SL, Dwianingsih EK, Lestari SP, Sugandhi W, Cahyono R, Pradana GD. High P16INK4A expression, keratinizing features, and surgical margin-free status are associated with improved survival in patients with oral squamous cell carcinomas. Asian Pac J Cancer Prev. 2024;25(3):857-64. DOI: https://dx.doi.org/10.31557/APJCP.2024.25.3.857
13. Doll C, Steffen C, Beck-Broichsitter B, Riedel D, Smeets R, Heiland M, et al. The prognostic significance of p16 and its role as a surrogate marker for human papilloma virus in oral squamous cell carcinoma: an analysis of 281 cases. Anticancer Res. 2022;42(5):2405-13. DOI: https://dx.doi.org/10.21873/anticnres.15719
14. Shi J, Wang L, Yao N, Li L, Liu M, Lv M, et al. The effect of HPV DNA and p16 status on the prognosis of patients with hypopharyngeal carcinoma: a meta-analysis. BMC Cancer. 2022;22:658. DOI: https://dx.doi.org/10.1186/s12885-022-09769-w
15. Benzerdjeb N, Tantot J, Blanchet C, Philouze P, Devouassoux-Shisheboran M, Garin D, et al. Oropharyngeal squamous cell carcinoma: p16/p53 immunohistochemistry as a strong predictor of HPV tumour status. Histopathology. 2021;79(3):381-90. DOI: https://dx.doi.org/10.1111/his.14309
16. Xue DY, Shangguan H, Zhang BH, Luo XY. Expression of p16 and Ki67 in laryngeal squamous cell carcinoma and their clinical significance. Front Oncol. 2024;14:1430830. DOI: https://dx.doi.org/10.3389/fonc.2024.1430830
17. Cirauqui Cirauqui B. Factores pronósticos y predictivos de respuesta en pacientes con carcinoma escamoso de cabeza y cuello [Tesis]. Barcelona: Universitat Autònoma de Barcelona; 2021 [acceso 17/05/2022]. Disponible en: https://hdl.handle.net/10803/672595
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Copyright (c) 2026 Misleidy Nápoles Morales, Xiomara Escobar Pérez, Jenny Carolina Ávila Pérez, Janet Lamadrid García, Johannes René Méstre Cabello, Carlos Frómeta Neira, Ariel Ventura Díaz, Adriana Carr Pérez, Ramón de Jesús Ropero Toirac, María Elena Faxas García, Amilcar Duquesne Alderete

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