Biopsia líquida en carcinoma hepatocelular: utilidad del perfil de adn libre circulante y los niveles de citoquinas en el manejo del carcinoma hepatocelular
- Autores: Elena Vargas Accarino
- Directores de la Tesis: Beatriz Mínguez Rosique (dir. tes.), Mar Riveiro Barciela (codir. tes.), Francisco Rodríguez Frías (codir. tes.)
- Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2023
- Idioma: español
- Tribunal Calificador de la Tesis: Joan Genescà Ferrer (presid.), Roser Pinyol Agelet (secret.), María Varela Calvo (voc.)
- Programa de doctorado: Programa de Doctorado en Medicina por la Universidad Autónoma de Barcelona
- Materias:
- Enlaces
- Tesis en acceso abierto en: TDX
- Resumen
Hepatocellular carcinoma is the second leading cause of cancer-related death, and its incidence is increasing globally. Surgery remains as the first therapeutic option for patients with early HCC, but most patients are diagnosed at late clinical stages due to the lack of early symptoms. Curative treatments are only applicable to patients diagnosed at early stages, which are less than half of the patients diagnosed with HCC. In the case of surgical resection, tumor recurrence is close to 70% at 5 years; its prompt detection or a prognostic estimation would be necessary in clinical practice.
Systemic therapies, that are treatment of choice for patients with advanced HCC, are rapidly changing. Immunotherapy, and in particular immune checkpoint inhibitors, have revolutionized the therapeutic landscape of advanced HCC, increasing the expected survival of these patients. However, objective radiological response to these therapies has been reported to occur in around 20% of patients. The precise identification of patients that could benefit from those therapies would optimize the rational use of these drugs, avoiding their potential side effects in patients who a priori will not benefit from them, and so allowing to design the therapeutic strategy in a more rational way, refining the current clinical algorithms.
In the first study we collected tumoral tissue, paired nontumor adjacent tissue and blood samples from 30 HCC patients undergoing curative therapies, to analyze the most prevalent mutations in HCC (TERT promoter, TP53, CTNNB1, AXIN1 and ARID1A) in plasma cfDNA by next-generation sequencing, aiming to elucidate their value as prognostic noninvasive biomarkers. In our study, total amount of cfDNA was related to survival during follow-up. The number of mutated genes or the number of detectable mutations on cfDNA were correlated with recurrence and survival. Moreover, dynamic changes in cfDNA mutations were detected during the follow-up, with increase or appearance of these mutations before radiological detection of HCC recurrence.
In the second study plasma samples from a prospective cohort of 25 advanced HCC patients treated with immune checkpoint inhibitors were collected at the beginning and after 3 months under treatment. Twenty-four inflammatory cytokine levels were analyzed by ELISA as well as the levels of cfDNA, ctDNA and percentage of TERT mutation by ddPCR, at baseline and after 3 months of treatment. Basal cfDNA profiling from 21 of these patients was analyzed by Onco-500 TruSight. Results showed that basal differences in total amount of cfDNA, CTLA-4 and CNV were significantly different between patients with and without radiological response to ICIs treatment. Levels of MCP-1 and TNF-alpha, and total amount cfDNA and ctDNA after three months of ICIs treatment were significantly different in patients presenting radiological response compared to those not presenting stable or progressive disease as best radiological response.
