ARMISEN YAÑEZ, RICARDO AMADO
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ARMISEN YAÑEZ, RICARDO AMADO
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rarmisen@udd.cl
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22956957700

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

2023 , Solange V. Rivas , Evelin González , Alejandro Blanco , Carolina Ibáñez , Alejandro Corvalán , Marcelo Garrido , Gareth Owen , Katherine Marcelain , ARMISEN YAÑEZ, RICARDO AMADO

Abstract 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? Citation Format: Solange V. Rivas, Evelin González, Alejandro Blanco, Carolina Ibáñez, Alejandro Corvalán, Marcelo Garrido, Gareth Owen, Katherine Marcelain, Ricardo Armisén. Disparities in the access to non-small cell lung cancer´s target therapies in Chile [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C018.

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A Molecular Stratification of Chilean Gastric Cancer Patients with Potential Clinical Applicability

2020 , Mauricio P. Pinto , Miguel Córdova-Delgado , Ignacio N. Retamal , Matías Muñoz-Medel , M. Loreto Bravo , Doris Durán , Francisco Villanueva , César Sanchez , Francisco Acevedo , Sebastián Mondaca , Erica Koch , Carolina Ibañez , Héctor Galindo , Jorge Madrid , Bruno Nervi , José Peña , Javiera Torres , Gareth I. Owen , Alejandro H. Corvalán , ARMISEN YAÑEZ, RICARDO AMADO , Marcelo Garrido

Gastric cancer (GC) is a complex and heterogeneous disease. In recent decades, The Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ACRG) defined GC molecular subtypes. Unfortunately, these systems require high-cost and complex techniques and consequently their impact in the clinic has remained limited. Additionally, most of these studies are based on European, Asian, or North American GC cohorts. Herein, we report a molecular classification of Chilean GC patients into five subtypes, based on immunohistochemical (IHC) and in situ hybridization (ISH) methods. These were Epstein–Barr virus positive (EBV+), mismatch repair-deficient (MMR-D), epithelial to mesenchymal transition (EMT)-like, and accumulated (p53+) or undetected p53 (p53−). Given its lower costs this system has the potential for clinical applicability. Our results confirm relevant molecular alterations previously reported by TCGA and ACRG. We confirm EBV+ and MMR-D patients had the best prognosis and could be candidates for immunotherapy. Conversely, EMT-like displayed the poorest prognosis; our data suggest FGFR2 or KRAS could serve as potential actionable targets for these patients. Finally, we propose a low-cost step-by-step stratification system for GC patients. To the best of our knowledge, this is the first Latin American report on a molecular classification for GC. Pending further validation, this stratification system could be implemented into the routine clinic

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Abstract 5293: A molecular classification of gastric cancer in Chilean patients

2020 , Mauricio P. Pinto , Matias Muñoz-Medel , Miguel Cordova-Delgado , Ignacio N. Retamal , Gareth Owen , Maria Loreto Bravo , ARMISEN YAÑEZ, RICARDO AMADO , Marcelo Garrido , POLI HARLOWE, MARIA CECILIA BERTA

Abstract Objective: Incidence and mortality rates of gastric cancer (GC) are characterized by their geographical heterogeneity. In Chile, GC is the leading cause of cancer death. To date, GC patients' response to standard therapies remains limited. A molecular classification of GCs may deliver better stratifications. Herein, we obtained clinical data, protein expression and genetic profiles in a cohort of Chilean patients and present a molecular classification that correlated with overall survival (OS) rates. Methods: A total of 71 patients were included. Clinical data were obtained from medical records; protein expression was analyzed by a Tissue MicroArray. We also performed Next Generation Sequencing to assess p53 status (WT or Mut). Supervised clustering was used to generate a molecular classification. Kaplan-Meier method was used to calculate OS. Hazard ratio was calculated by Cox regression. Results: We defined 5 GC subgroups: Epstein-Barr virus+ (EBV, n=9; 13%), Microsatellite Instable (MSI, n=9; 13%), E-cadherin loss (EMT-like, n=12; 17%). The remaining patients (those MSS-/EBV-/not EMT-like) were classified either as p53 WT (n=21; 30%) or p53 Mutated (n=20; 28%). According to subgroups, 5-year survival rates were: MSI=77,8%; EBV=43.2%; p53WT=43.5%; p53Mut=25% and EMT-like=16.7%. Hazard ratios for p53Mut and EMT-like were 5.1 (IC 95%: 1.16-22.41; p=0.031) and 6.81 (IC 95%: 1.48-31.24; p=0.014), respectively against the MSI group used as reference. This association is maintained in a multivariate model using age, gender and stage. Conclusions: Our study defined 5 GC subgroups. These are associated to OS rates. EMT-like and p53Mut subgroups displayed poorer survival. Future studies should explore actionable targets in these subsets in order to improve their survival. Citation Format: Mauricio P. Pinto, Matias Muñoz-Medel, Miguel Cordova-Delgado, Ignacio N. Retamal, Gareth Owen, Maria Loreto Bravo, Ricardo Armisen, Marcelo Garrido. A molecular classification of gastric cancer in Chilean patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5293.

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Beyond tobacco: genomic disparities in lung cancer between smokers and never-smokers

2024 , GARRIDO MANRIQUEZ, JAVIERA NICOLE , Yanara Bernal , Evelin González , Alejandro Blanco , Gonzalo Sepúlveda-Hermosilla , Matías Freire , Karen Oróstica , RIVAS ARENA, SOLANGE , Katherine Marcelain , Gareth Owen , Carolina Ibañez , Alejandro Corvalan , Marcelo Garrido , Rodrigo Assar , Rodrigo Lizana , Javier Cáceres-Molina , Diego Ampuero , Liliana Ramos , Paola Pérez , Osvaldo Aren , Sara Chernilo , Cristina Fernández , María Loreto Spencer , Jacqueline Flores Aguila , Giuliano Bernal Dossetto , Mónica Ahumada Olea , Germán Rasse , Carolina Sánchez , Maria Galli de Amorim , Thais F. Bartelli , Diana Noronha Nunes , Emmanuel Dias-Neto , Helano C. Freitas , Ricardo Armisén

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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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A case-control study of a combination of single nucleotide polymorphisms and clinical parameters to predict clinically relevant toxicity associated with fluoropyrimidine and platinum-based chemotherapy in gastric cancer

2021 , Miguel Cordova-Delgado , BRAVO CELEDÓN, MARÍA LORETO , Elisa Cumsille , Charlotte N. Hill , Matías Muñoz-Medel , Mauricio P. Pinto , Ignacio N. Retamal , María A. Lavanderos , Juan Francisco Miquel , Maria Rodriguez-Fernandez , Yuwei Liao , Zhiguang Li , Alejandro H. Corvalán , ARMISEN YAÑEZ, RICARDO AMADO , Marcelo Garrido , Luis A. Quiñones , Gareth I. Owen

Abstract Background Fluoropyrimidine plus platinum chemotherapy remains the standard first line treatment for gastric cancer (GC). Guidelines exist for the clinical interpretation of four DPYD genotypes related to severe fluoropyrimidine toxicity within European populations. However, the frequency of these single nucleotide polymorphisms (SNPs) in the Latin American population is low (< 0.7%). No guidelines have been development for platinum. Herein, we present association between clinical factors and common SNPs in the development of grade 3–4 toxicity. Methods Retrospectively, 224 clinical records of GC patient were screened, of which 93 patients were incorporated into the study. Eleven SNPs with minor allelic frequency above 5% in GSTP1, ERCC2, ERCC1, TP53, UMPS, SHMT1, MTHFR, ABCC2 and DPYD were assessed. Association between patient clinical characteristics and toxicity was estimated using logistic regression models and classification algorithms. Results Reported grade ≤ 2 and 3–4 toxicities were 64.6% (61/93) and 34.4% (32/93) respectively. Selected DPYD SNPs were associated with higher toxicity (rs1801265; OR = 4.20; 95% CI = 1.70–10.95, p = 0.002), while others displayed a trend towards lower toxicity (rs1801159; OR = 0.45; 95% CI = 0.19–1.08; p = 0.071). Combination of paired SNPs demonstrated significant associations in DPYD (rs1801265), UMPS (rs1801019), ABCC2 (rs717620) and SHMT1 (rs1979277). Using multivariate logistic regression that combined age, sex, peri-operative chemotherapy, 5-FU regimen, the binary combination of the SNPs DPYD (rs1801265) + ABCC2 (rs717620), and DPYD (rs1801159) displayed the best predictive performance. A nomogram was constructed to assess the risk of developing overall toxicity. Conclusion Pending further validation, this model could predict chemotherapy associated toxicity and improve GC patient quality of life.

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