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Adenoid cystic carcinoma (ACC) is an aggressive tumor with a high propensity for distant metastasis and perineural invasion. This tumor is more commonly found in regions of the head and neck, mainly the salivary glands. In general, the primary treatment modality for ACC is surgical resection and, in some cases, postoperative radiotherapy. However, no effective systemic treatment is available for patients with advanced disease. Furthermore, this tumor type is characterized by recurrent molecular alterations, especially rearrangements involving the MYB, MYBL1, and NFIB genes. In addition, they also reported copy number alterations (CNAs) that impact genes. One of them is C-KIT, mutations that affect signaling pathways such as NOTCH, PI3KCA, and PTEN, as well as alterations in chromatin remodeling genes. The identification of new molecular targets enables the development of specific therapies. Despite ongoing investigations into immunotherapy, tyrosine kinase inhibitors, and anti-angiogenics, no systemic therapy is approved by the FDA for ACC. In this review, we report the genetic and cytogenetic findings on head and neck ACC, highlighting possible targets for therapeutic interventions.
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The MET gene, known as MET proto-oncogene receptor tyrosine kinase, was first identified to induce tumor cell migration, invasion, and proliferation/survival through canonical RAS-CDC42-PAK-Rho kinase, RAS-MAPK, PI3K-AKT-mTOR, and ß-catenin signaling pathways, and its driver mutations, such as MET gene amplification (METamp) and the exon 14 skipping alterations (METex14), activate cell transformation, cancer progression, and worse patient prognosis, principally in lung cancer through the overactivation of their own oncogenic and MET parallel signaling pathways. Because of this, MET driver alterations have become of interest in lung adenocarcinomas since the FDA approval of target therapies for METamp and METex14 in 2020. However, after using MET target therapies, tumor cells develop adaptative changes, favoring tumor resistance to drugs, the main current challenge to precision medicine. Here, we review a link between the resistance mechanism and MET signaling pathways, which is not only limited to MET. The resistance impacts MET parallel tyrosine kinase receptors and signals shared hubs. Therefore, this information could be relevant in the patient's mutational profile evaluation before the first target therapy prescription and follow-up to reduce the risk of drug resistance. However, to develop a resistance mechanism to a MET inhibitor, patients must have access to the drugs. For instance, none of the FDA approved MET inhibitors are registered as such in Chile and other developing countries. Constant cross-feeding between basic and clinical research will thus be required to meet future challenges imposed by the acquired resistance to targeted therapies.
Assuntos
Neoplasias Pulmonares , Fosfatidilinositol 3-Quinases , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Neoplasias Pulmonares/patologia , Éxons , Transdução de SinaisRESUMO
Next-generation sequencing (NGS) is progressively being used in clinical practice. However, several barriers preclude using this technology for precision oncology in most Latin American countries. To overcome some of these barriers, we have designed a 25-gene panel that contains predictive biomarkers for most current and near-future available therapies in Chile and Latin America. Library preparation was optimized to account for low DNA integrity observed in formalin-fixed paraffin-embedded tissue. The workflow includes an automated bioinformatic pipeline that accounts for the underrepresentation of Latin Americans in genome databases. The panel detected small insertions, deletions, and single nucleotide variants down to allelic frequencies of 0.05 with high sensitivity, specificity, and reproducibility. The workflow was validated in 272 clinical samples from several solid tumor types, including gallbladder (GBC). More than 50 biomarkers were detected in these samples, mainly in BRCA1/2, KRAS, and PIK3CA genes. In GBC, biomarkers for PARP, EGFR, PIK3CA, mTOR, and Hedgehog signaling inhibitors were found. Thus, this small NGS panel is an accurate and sensitive method that may constitute a more cost-efficient alternative to multiple non-NGS assays and costly, large NGS panels. This kind of streamlined assay with automated bioinformatics analysis may facilitate the implementation of precision medicine in Latin America.
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The recent identification of rearrangements of neurotrophic tyrosine receptor kinase (NTRK) genes and the development of specific fusion protein inhibitors, such as larotrectinib and entrectinib, have revolutionised the diagnostic and clinical management of patients presenting with tumours with these alterations. Tumours that harbour NTRK fusions are found in both adults and children; and they are either rare tumours with common NTRK fusions that may be diagnostic, or more prevalent tumours with rare NTRK fusions. To assess currently available evidence on this matter, three key Spanish medical societies (the Spanish Society of Medical Oncology (SEOM), the Spanish Society of Pathological Anatomy (SEAP), and the Spanish Society of Paediatric Haematology and Oncology (SEHOP) have brought together a group of experts to develop a consensus document that includes guidelines on the diagnostic, clinical, and therapeutic aspects of NTRK-fusion tumours. This document also discusses the challenges related to the routine detection of these genetic alterations in a mostly public Health Care System.
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Consenso , Glicoproteínas de Membrana/genética , Neoplasias/genética , Proteínas de Fusão Oncogênica/genética , Receptor trkA/genética , Receptor trkB/genética , Receptor trkC/genética , Adulto , Fatores Etários , Benzamidas/uso terapêutico , Criança , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Indazóis/uso terapêutico , Terapia de Alvo Molecular , Neoplasias/diagnóstico , Neoplasias/terapia , Proteínas de Fusão Oncogênica/análise , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sociedades Médicas , EspanhaRESUMO
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with an unfavorable prognosis. Despite the poor prognosis in the majority of patients, no improvements in treatment strategies have been achieved. Therefore, the discovery of new prognostic biomarkers is of enormous interest. Sterol-O-acyl transferase 1 (SOAT1) is involved in cholesterol esterification and lipid droplet formation. Recently, it was demonstrated that SOAT1 inhibition leads to impaired steroidogenesis and cell viability in ACC. To date, no studies have addressed the impact of SOAT1 expression on ACC prognosis and clinical outcomes. We evaluated SOAT1 expression by quantitative real-time polymerase chain reaction and immunohistochemistry in a tissue microarray of 112 ACCs (Weiss score ≥ 3) from adults treated in a single tertiary center in Brazil. Two independent pathologists evaluated the immunohistochemistry results through a semiquantitative approach (0-4). We aimed to evaluate the correlation between SOAT1 expression and clinical, biochemical and anatomopathological parameters, recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS). SOAT1 protein expression was heterogeneous in this cohort, 37.5% of the ACCs demonstrated a strong SOAT1 protein expression (score > 2), while 62.5% demonstrated a weak or absent protein expression (score ≤ 2). Strong SOAT1 protein expression correlated with features of high aggressiveness in ACC, such as excessive tumor cortisol secretion (p = 0.01), an advanced disease stage [European Network for the Study of Adrenal Tumors (ENSAT) staging system 3 and 4 (p = 0.011)] and a high Ki67 index (p = 0.002). In multivariate analysis, strong SOAT1 protein expression was an independent predictor of a reduced OS (hazard ratio (HR) 2.15, confidence interval (CI) 95% 1.26-3.66; p = 0.005) in all patients (n = 112), and a reduced RFS (HR 2.1, CI 95% 1.09-4.06; p = 0.027) in patients with localized disease at diagnosis (n = 83). Our findings demonstrated that SOAT1 protein expression has prognostic value in ACC and reinforced the importance of investigating SOAT1 as a possible therapeutic target for patients with ACC.
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RESUMEN Fundamento: El cáncer de pulmón de células no pequeñas es el cáncer de origen epitelial que más muertes provoca; por lo que el estudio de nuevas terapias es una prioridad investigativa en Cuba; para ello se realizaron estudios multicéntricos que evaluaron entre otros aspectos, el perfil de seguridad del nimotuzumab y racotumomab, anticuerpos monoclonales de origen cubano en el tratamiento de esta enfermedad. Objetivo: Evaluar el perfil de seguridad del nimotuzumab y racotumomab en pacientes con cáncer de pulmón de células no pequeñas avanzado después de la primera línea de tratamiento oncoespecífico. Metodología: Se diseñó un estudio multicéntrico, prospectivo, longitudinal en 32 pacientes adultos con cáncer de pulmón de células no pequeñas avanzado después de la primera línea del tratamiento oncoespecífico en la provincia Sancti Spíritus entre junio del 2014 a junio del 2015. Resultados: De los 6 pacientes que recibieron nimotuzumab y 26 pacientes que recibieron racotumomab, en estadio tumoral IIIB o IV, el 75 % entró al estudio con buen estado clínico. El 66 % de ellos no presentó efectos adversos, entre los que se presentaron está, dolor en el sitio de inyección, torácico y la fiebre, todos de intensidad leve o moderada. No se encontraron diferencias significativas entre las proporciones de eventos adversos leves en ambos grupos de sujetos. No se reportaron eventos adversos severos. Todos los eventos se clasificaron en no serios, no graves y del 98.33 % de ellos el paciente se recuperó sin ayuda médica. Conclusiones: Los resultados sugieren que los productos empleados son seguros, expresado en la baja frecuencia de aparición de eventos adversos, la generalidad de ellos leves no graves/no serios, sin que dejaran secuela en los pacientes(AU)
ABSTRACT Background: Non-small cell lung cancer is the cancer of epithelial origin that causes most of deaths; so the study of new therapies is a research priority in Cuba; thus, multicenter studies are carried out which evaluate, among other aspects, the safety profile of nimotuzumab and racotumomab, monoclonal antibodies of Cuban origin in the treatment of this disease. Objective: To evaluate the safety profile of nimotuzumab and racotumomab in patients with advanced non-small cell lung cancer after the first-line of oncospecific treatment. Methodology: A multicenter, prospective, longitudinal study was designed in 32 adult patients with advanced non-small cell lung cancer after the first-line of oncospecific treatment in Sancti Spíritus province from June 2014 to June 2015. Results: The six patients who received nimotuzumab and the twenty-six patients who received racotumomab, in tumor stage IIIB or IV, 75 % participated in the study with good clinical conditions. The 66% of them did not present adverse effects, among which there were, pain at the location of injection, thoracic pain and fever, all of mild or moderate intensity. No significant differences were found between the proportions of mild adverse events in both groups of subjects. No severe adverse events were reported. All events were classified as non-serious, non-very serious and 98.33 % of them recovered without medical help. Conclusions: The results suggest that the products used are safe, expressed in the low frequency of occurrence of adverse events, the generality of them mild non-very serious / non-serious, without no sequel in patients(AU)
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Carcinoma Pulmonar de Células não Pequenas , Anticorpos MonoclonaisRESUMO
RESUMEN Fundamento: El cáncer de pulmón de células no pequeñas es el cáncer de origen epitelial que más muertes provoca; por lo que el estudio de nuevas terapias es una prioridad investigativa en Cuba; para ello se realizaron estudios multicéntricos que evaluaron entre otros aspectos, el perfil de seguridad del nimotuzumab y racotumomab, anticuerpos monoclonales de origen cubano en el tratamiento de esta enfermedad. Objetivo: Evaluar el perfil de seguridad del nimotuzumab y racotumomab en pacientes con cáncer de pulmón de células no pequeñas avanzado después de la primera línea de tratamiento oncoespecífico. Metodología: Se diseñó un estudio multicéntrico, prospectivo, longitudinal en 32 pacientes adultos con cáncer de pulmón de células no pequeñas avanzado después de la primera línea del tratamiento oncoespecífico en la provincia Sancti Spíritus entre junio del 2014 a junio del 2015. Resultados: De los 6 pacientes que recibieron nimotuzumab y 26 pacientes que recibieron racotumomab, en estadio tumoral IIIB o IV, el 75 % entró al estudio con buen estado clínico. El 66 % de ellos no presentó efectos adversos, entre los que se presentaron está, dolor en el sitio de inyección, torácico y la fiebre, todos de intensidad leve o moderada. No se encontraron diferencias significativas entre las proporciones de eventos adversos leves en ambos grupos de sujetos. No se reportaron eventos adversos severos. Todos los eventos se clasificaron en no serios, no graves y del 98.33 % de ellos el paciente se recuperó sin ayuda médica. Conclusiones: Los resultados sugieren que los productos empleados son seguros, expresado en la baja frecuencia de aparición de eventos adversos, la generalidad de ellos leves no graves/no serios, sin que dejaran secuela en los pacientes.
ABSTRACT Background: Non-small cell lung cancer is the cancer of epithelial origin that causes most of deaths; so the study of new therapies is a research priority in Cuba; thus, multicenter studies are carried out which evaluate, among other aspects, the safety profile of nimotuzumab and racotumomab, monoclonal antibodies of Cuban origin in the treatment of this disease. Objective: To evaluate the safety profile of nimotuzumab and racotumomab in patients with advanced non-small cell lung cancer after the first-line of oncospecific treatment. Methodology: A multicenter, prospective, longitudinal study was designed in 32 adult patients with advanced non-small cell lung cancer after the first-line of oncospecific treatment in Sancti Spíritus province from June 2014 to June 2015. Results: The six patients who received nimotuzumab and the twenty-six patients who received racotumomab, in tumor stage IIIB or IV, 75 % participated in the study with good clinical conditions. The 66% of them did not present adverse effects, among which there were, pain at the location of injection, thoracic pain and fever, all of mild or moderate intensity. No significant differences were found between the proportions of mild adverse events in both groups of subjects. No severe adverse events were reported. All events were classified as non-serious, non-very serious and 98.33 % of them recovered without medical help. Conclusions: The results suggest that the products used are safe, expressed in the low frequency of occurrence of adverse events, the generality of them mild non-very serious / non-serious, without no sequel in patients.