RIVAS VERA, SOLANGE VERÓNICA
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RIVAS VERA, SOLANGE VERÓNICA
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rivas.sole@gmail.com
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57189370030

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2023 2023 2022 2022 2021 2021 2020 2020 0.0 0.0 0.5 0.5 1.0 1.0 1.5 1.5 2.0 2.0 2.5 2.5 3.0 3.0

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Abstract C018: Disparities in the access to non-small cell lung cancer´s target therapies in Chile

2023 , RIVAS VERA, SOLANGE VERÓNICA , GONZÁLEZ, EVELYN , BLANCO MARTÍNEZ, ALEJANDRO , Carolina Ibáñez , Alejandro Corvalán , Marcelo Garrido , Gareth Owen , Katherine Marcelain , ARMISEN YAÑEZ, RICARDO AMADO

Comprehensive next-generation sequencing (NGS) panels designed to identify the tumor mutational profile are becoming the standard care to prescribe target therapies in developed countries. In non-small cell lung cancer (NSCLC), this approach significantly impacts the patient´s clinical results, measured as progression-free survival and/or overall survival, compared to conventional chemotherapies. However, as Latin American patients tend to experience more significant health disparities because of structural, sociodemographic, and psychosocial factors, in this work, our purpose is to measure the disparities in the access to NSCLC´s target therapies, specifically in Chile. DNAs and RNAs from 1643 NSCLC samples from Chile, Brazil, and Peru were sequenced to assess the mutational status in fifty-two cancer genes. After an NGS quality control, variants were called and annotated using the Variant Effect Predictor, Annovar, COSMIC, and OncoKB, to categorize somatic mutations. The following analysis focused on today’s actionable genes in NSCLC, with FDA-approved target therapies (EGFR, KRAS, ALK, MET, ERBB2, BRAF, ROS1, and RET). In this analysis, 46.5% of tumors evidenced driver mutations (764/1643); interestingly, from this subset, 86.9% showed one driver variant, 11.2% two drivers, 1.4% three drivers, and 0.5% evidenced between 4-6 driver mutations. However, 19.4% (495/1643) evidenced actionable variants. The most mutated genes and the most common actionable variants were 15.3% EGFR (37% EGFR L858R), followed by 4.9% KRAS (100% KRAS G12C), 4.5% ALK (95.4% EML4-ALK fusion), 3% MET (100% MET exon 14 skipping), and 2.3% ERBB2. Finally, 1.5% BRAF, 1% ROS1 gene fusions and 0.9% RET gene fusions. Considering the target therapies approved by Chile´s Instituto de Salud Publica until October 2021, and if all these patients were diagnosed in Chile, only 64% would receive a targeted drug. EGFR is the gene with more target therapies validated in Chile, although drugs against exon twenty insertion have not been approved yet. Chile does not account for any targeted treatment for patients with alterations in KRAS, MET, RET and ERBB2; although the FDA approved a specific drug against KRAS G12C very recently (May 28, 2021), different is the case of MET because the first inhibitor, crizotinib, was FDA approved four years ago. Interestingly, in 2021, two inhibitors against the most common MET alteration were FDA approved, but none have been approved in Chile yet. In Chile, almost all target therapies have been validated against EGFR, ALK, and BRAF; however, patients with KRAS, MET, RET, and ERBB2 cannot access specific drugs, so in these cases, the recommended therapeutic option is chemotherapy. It is important to note that the target drugs approval only ensures the availability of the drug in Chile. Still, few of the target drugs are part of financed drugs by the Chilean health system, so the question is, how could we increase the national access to existing target therapies?

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Ski Is Required for Tri-Methylation of H3K9 in Major Satellite and for Repression of Pericentromeric Genes: Mmp3, Mmp10 and Mmp13, in Mouse Fibroblasts

2020 , Claudio Cappelli , Hugo Sepulveda , Solange Rivas , Víctor Pola , Ulises Urzúa , Gerardo Donoso , Eduardo Sagredo , David Carrero , Emmanuel Casanova-Ortiz , Alfredo Sagredo , Marisel González , Marcia Manterola , Gino Nardocci , ARMISEN YAÑEZ, RICARDO AMADO , Martin Montecino , Katherine Marcelain

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MET Signaling Pathways, Resistance Mechanisms, and Opportunities for Target Therapies

2022 , RIVAS VERA, SOLANGE VERÓNICA , Arnaldo Marín , Suraj Samtani , Evelin González-Feliú , ARMISEN YAÑEZ, RICARDO AMADO

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 β-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.

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Concordance Analysis of ALK Gene Fusion Detection Methods in Patients with Non–Small-Cell Lung Cancer from Chile, Brazil, and Peru

2021 , Gonzalo Sepúlveda-Hermosilla , Matías Freire , Alejandro Blanco , Javier Cáceres , Rodrigo Lizana , Liliana Ramos , Rodrigo Assar Cuevas , Diego Ampuero , Osvaldo Aren , Sara Chernilo , María L. Spencer , Giuliano Bernal , Jacqueline Flores , Germán Rasse , Carolina Sánchez , Katherine Marcelain , RIVAS VERA, SOLANGE VERÓNICA , Gabriela P. Branco , María Galli de Amorim , Diana N. Nunes , Emmanuel Dias-Neto , Helano C. Freitas , Cristina Fernández , Paola Pérez , ARMISEN YAÑEZ, RICARDO AMADO , Luiz Araujo , Luis Pires , Nils Skare , Gustavo Girotto , Manuela Zereu , Helano Freitas , Hakaru Tadokoro , Ana Caroline Gelatti , Jose Fernando Moura , Clarissa Mathias , Pedro Rafael De Marchi , Fernando Silva , Mayler Olombrada Nunes de Santos , Marianna Deway Andrade Dracoulakis , Renata Pinho Costa , Luciana Castro , Paulo Guilherme de Oliveira Salles , Clodoaldo Zago Campos , Maria Andrade Livia , Sara Chernilo , Osvaldo Arén Frontera , Eduardo Yanez Ruiz , Monica Ahumada Olea , Giuliano Bernal , Loreto Spencer , Alejandro Ortega Vasquez , German Rasse , Juan Bertoglio , Jose David Zorrilla Silvera , Hernan Moron Escobar , Luis Riva Gonzalez , Luis Alberto Mas Lopez , José Luis Fernando Hurtado De Mendoza Acurio , Giovanna Victoria Abrill Mendoza , Alfredo Aguilar , Gerardo Campos Siccha , Ricardo Sanchez Sevillano , Cristina Fernández , Sylvia Chandía , Pablo Araos , Ana Mejías , Francisca Angulo , Carolina Sánchez , Jessica Troncoso , David Jara , Marcela Astete , María Jesús Galleguillos , Emmanuel Dias-Neto , Helano Carioca Freitas , María Galli de Amorim , Diana Noronha Nunes , Gabriela Branco , Marina Eloi , Melissa Pizzi , Jordana Silva , Thais F. Bartelli , Katherine Marcelain , Jessica Toro , Luciana Oliveira-Cruz , Daniela Diez

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Total mutational load and clinical features as predictors of the metastatic status in lung adenocarcinoma and squamous cell carcinoma patients

2022 , Karen Y. Oróstica , Juan Saez-Hidalgo , Pamela R. de Santiago , RIVAS VERA, SOLANGE VERÓNICA , Sebastian Contreras , Gonzalo Navarro , Juan A. Asenjo , Álvaro Olivera-Nappa , ARMISEN YAÑEZ, RICARDO AMADO

Abstract Background Recently, extensive cancer genomic studies have revealed mutational and clinical data of large cohorts of cancer patients. For example, the Pan-Lung Cancer 2016 dataset (part of The Cancer Genome Atlas project), summarises the mutational and clinical profiles of different subtypes of Lung Cancer (LC). Mutational and clinical signatures have been used independently for tumour typification and prediction of metastasis in LC patients. Is it then possible to achieve better typifications and predictions when combining both data streams? Methods In a cohort of 1144 Lung Adenocarcinoma (LUAD) and Lung Squamous Cell Carcinoma (LSCC) patients, we studied the number of missense mutations (hereafter, the Total Mutational Load TML) and distribution of clinical variables, for different classes of patients. Using the TML and different sets of clinical variables (tumour stage, age, sex, smoking status, and packs of cigarettes smoked per year), we built Random Forest classification models that calculate the likelihood of developing metastasis. Results We found that LC patients different in age, smoking status, and tumour type had significantly different mean TMLs. Although TML was an informative feature, its effect was secondary to the "tumour stage" feature. However, its contribution to the classification is not redundant with the latter; models trained using both TML and tumour stage performed better than models trained using only one of these variables. We found that models trained in the entire dataset (i.e., without using dimensionality reduction techniques) and without resampling achieved the highest performance, with an F1 score of 0.64 (95%CrI [0.62, 0.66]). Conclusions Clinical variables and TML should be considered together when assessing the likelihood of LC patients progressing to metastatic states, as the information these encode is not redundant. Altogether, we provide new evidence of the need for comprehensive diagnostic tools for metastasis.

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El cáncer de pulmón de células no pequeñas en la era de la medicina de precisión

2022 , RIVAS VERA, SOLANGE VERÓNICA , ARMISEN YAÑEZ, RICARDO AMADO

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Neutralizing antibodies induced by homologous and heterologous boosters in CoronaVac vaccines in Chile

2023 , ACEVEDO ROMO, JOHANNA PATRICIA , Mónica L. Acevedo , Aracelly Gaete-Argel , ARAOS BRALIC, RAFAEL IGNACIO , Cecilia Gonzalez , Daniela Espinoza , Pablo Pizarro , RIVAS VERA, SOLANGE VERÓNICA , Stephan Jarpa , Ricardo Soto-Rifo , Alejandro Jara , Fernando Valiente-Echeverría

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ADAR1 Transcriptome editing promotes breast cancer progression through the regulation of cell cycle and DNA damage response

2020 , Eduardo A. Sagredo , Alfredo I. Sagredo , Alejandro Blanco , Pamela Rojas De Santiago , RIVAS VERA, SOLANGE VERÓNICA , Rodrigo Assar , Paola Pérez , Katherine Marcelain , ARMISEN YAÑEZ, RICARDO AMADO

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NTRK genomic alterations in Latin-American cancer patients.

2021 , CARVAJAL HAUSDORF, DANIEL EDUARDO , Claudio Salas , Katherine Marcelain , Francisco Perez , Evelin Feliu , Kurt Schalper , Solange Rivas , ARMISEN YAÑEZ, RICARDO AMADO

e15088 Background: The neurotrophic receptor tyrosine kinase genes NTRK1-3 encode the tropomyosin receptor kinase proteins TRKA, TRKB, and TRKC, respectively. TRK fusions lead to overexpression of the chimeric protein, resulting in constitutively active, ligand-independent downstream signaling. NTRKs act as oncogenes, they can be targeted, and it is estimated that they are present in up to 0.3% of tumors. The incidence of actionable alterations in these genes is currently unknown in Latin-American patients. We investigated the presence of NTRK1-3 mutations/rearrangements in 3 independent patient series from several tertiary hospitals from Chile, Brazil and Peru. Methods: 1795 FFPE tumor samples from multiple institutions divided in 3 series were analyzed using 2 NGS panels: Oncomine Focus Assay (OFA; 52 genes) and Oncomine Comprehensive Assay (OCA; 161 genes. Data on NTRK1-3 SNVs, indels, CNVs and fusions was obtained. Bioinformatic workflows were used to study the biologic significance of these alterations. Results: Using OCA (series 1-2), 31 somatic variants were found in gastric, CRC, gallbladder, lung and pancreatic cases out of 300 patients. From these, 13 were located in the tyrosine kinase domain. Using OFA, no NTRK alteration were detected (series 3, 1495 NSCLC cases). Conclusions: NTRK alterations are rare events in Latin-American cancer patients. In 3 series including 1,795 patients, 31 somatic variants were detected. No NTRK fusions or CNVs were identified. The presence of NTRK mutations in the tyrosine kinase domain warrants further research into their potential to benefit from FDA/EMA-approved targeted therapies. [Table: see text]

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