The Transcriptomic Portrait of Locally Advanced Breast Cancer and Its Prognostic Value in a Multi-Country Cohort of Latin American Patients
Author
Llera, Andrea Sabina
Abdelhay, Eliana
Artagaveytia, Nora
Daneri-Navarro, Adrian
Müller, Bettina
Velazquez, Carlos
Alcoba, Elsa
Alonso, Isabel
Alves da Quinta, Daniela B.
Binato, Renata
Bravo, Alicia I.
Camejo, Natalia
Carraro, Dirce María
Castro, Mónica
Castro-Cervantes, Juan M.
Cataldi, Sandra
Cayota, Alfonso
Cerda, Mauricio
Colombo, Alicia
Crocamo, Susanne
Del Toro-Arreola, Alicia
Delgadillo-Cisterna, Raúl
Delgado, Lucía
Dreyer-Breitenbach, Marisa
Fejerman, Laura
Fernández, Elmer Andrés
Fernández, Wanda
Franco-Topete, Ramón A.
Gabay, Carolina
Gaete, Fancy
Garibay-Escobar, Adriana
Gómez, Jorge
Greif, Gonzalo
Gross, Thomas G.
Guerrero, Marisol
Henderson, Marianne K.
Lopez-Muñoz, Miguel E.
Lopez-Vazquez, Alejandra
Maldonado, Silvia
Moran-Mendoza, Andrés de J.
Nagai, Maria Aparecida
Oceguera-Villanueva, Antonio
Ortiz-Martínez, Miguel A.
Quintero, Jael
Quintero-Ramos, Antonio
Reis, Rui M.
Retamales, Javier
Rivera-Claisse, Ernesto
Rocha, Darío
Rodriguez, Robinson
Rosales, Cristina
Salas-Gonzalez, Efrain
Sanchotena, Verónica
Segovia, Laura
Sendoya, Juan M.
Silva-Garcia, Aida A.
Trinchero, Alejandra
Valenzuela, Olivia
Vedham, Vidya
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Purposes: Most molecular-based published studies on breast cancer do not adequately represent the unique and diverse genetic admixture of the Latin American population. Searching for similarities and differences in molecular pathways associated with these tumors and evaluating its impact on prognosis may help to select better therapeutic approaches. Patients and Methods: We collected clinical, pathological, and transcriptomic data of a multi-country Latin American cohort of 1,071 stage II-III breast cancer patients of the Molecular Profile of Breast Cancer Study (MPBCS) cohort. The 5-year prognostic ability of intrinsic (transcriptomic-based) PAM50 and immunohistochemical classifications, both at the cancer-specific (OSC) and disease-free survival (DFS) stages, was compared. Pathway analyses (GSEA, GSVA and MetaCore) were performed to explore differences among intrinsic subtypes. Results: PAM50 classification of the MPBCS cohort defined 42·6% of tumors as LumA, 21·3% as LumB, 13·3% as HER2E and 16·6% as Basal. Both OSC and DFS for LumA tumors were significantly better than for other subtypes, while Basal tumors had the worst prognosis. While the prognostic power of traditional subtypes calculated with hormone receptors (HR), HER2 and Ki67 determinations showed an acceptable performance, PAM50-derived risk of recurrence best discriminated low, intermediate and high-risk groups. Transcriptomic pathway analysis showed high proliferation (i.e. cell cycle control and DNA damage repair) associated with LumB, HER2E and Basal tumors, and a strong dependency on the estrogen pathway for LumA. Terms related to both innate and adaptive immune responses were seen predominantly upregulated in Basal tumors, and, to a lesser extent, in HER2E, with respect to LumA and B tumors. Conclusions: This is the first study that assesses molecular features at the transcriptomic level in a multicountry Latin American breast cancer patient cohort. Hormone-related and proliferation pathways that predominate in PAM50 and other breast cancer molecular classifications are also the main tumor-driving mechanisms in this cohort and have prognostic power. The immune-related features seen in the most aggressive subtypes may pave the way for therapeutic approaches not yet disseminated in Latin America. Clinical Trial Registration: ClinicalTrials.gov (Identifier: NCT02326857). Copyright © 2022 Llera, Abdelhay, Artagaveytia, Daneri-Navarro, Müller, Velazquez, Alcoba, Alonso, Alves da Quinta, Binato, Bravo, Camejo, Carraro, Castro, Castro-Cervantes, Cataldi, Cayota, Cerda, Colombo, Crocamo, Del Toro-Arreola, Delgadillo-Cisterna, Delgado, Dreyer-Breitenbach, Fejerman, Fernández, Fernández, Fernández, Franco-Topete, Gabay, Gaete, Garibay-Escobar, Gómez, Greif, Gross, Guerrero, Henderson, Lopez-Muñoz, Lopez-Vazquez, Maldonado, Morán-Mendoza, Nagai, Oceguera-Villanueva, Ortiz-Martínez, Quintero, Quintero-Ramos, Reis, Retamales, Rivera-Claisse, Rocha, Rodríguez, Rosales, Salas-González, Sanchotena, Segovia, Sendoya, Silva-García, Trinchero, Valenzuela, Vedham, Zagame, United States-Latin American Cancer Research Network (US-LACRN) and Podhajcer.Fil: Llera, Andrea Sabina. Fundación Instituto Leloir-CONICET. Molecular and Cellular Therapy Laboratory; Argentina
Fil: Abdelhay, Eliana Saul Furquim Werneck. Instituto Nacional de Câncer. Bone Marrow Transplantation Unit; Brasil
Fil: Artagaveytia, Nora. Universidad de la República. Hospital de Clínicas Manuel Quintela; Uruguay
Fil: Daneri-Navarro, Adrián. Universidad de Guadalajara; México
Fil: Müller, Bettina. Instituto Nacional del Cáncer; Chile
Fil: Velazquez, Carlos. Universidad de Sonora; México
Fil: Alcoba, Elsa B. Hospital Municipal de Oncología María Curie; Argentina
Fil: Alonso, Isabel. Centro Hospitalario Pereira Rossell; Uruguay
Fil: Alves da Quinta, Daniela B. Fundación Instituto Leloir-CONICET. Molecular and Cellular Therapy Laboratory; Argentina
Fil: Alves da Quinta, Daniela B. Universidad Argentina de la Empresa (UADE). Instituto de Tecnología (INTEC); Argentina
Fil: Binato, Renata. Instituto Nacional de Câncer. Bone Marrow Transplantation Unit; Brasil
Fil: Bravo, Alicia Inés. Hospital Regional de Agudos Eva Perón; Argentina
Fil: Camejo, Natalia. Universidad de la República. Hospital de Clínicas Manuel Quintela; Uruguay
Fil: Carraro, Dirce Maria. AC Camargo Cancer Center. Centro Internacional de Pesquisa (CIPE). Laboratory of Genomics and Molecular Biology; Brasil
Fil: Castro, Mónica. Instituto de Oncología Angel Roffo; Argentina
Fil: Castro-Cervantes, Juan M. Hospital de Especialidades CMNO-IMSS; México
Fil: Cataldi, Sandra. Instituto Nacional del Cáncer; Uruguay
Fil: Cayota, Alfonso. Institut Pasteur de Montevideo; Uruguay
Fil: Cerda, Mauricio. Universidad de Chile. Instituto de Neurociencias Biomédicas. Facultad de Medicina. Centro de Informática Médica y Telemedicina. Instituto de Ciencias Biomédicas (ICBM). Integrative Biology Program; Chile
Fil: Colombo, Alicia. Universidad de Chile. Facultad de Medicina y Hospital Clínico. Department of Pathology; Chile
Fil: Crocamo, Susanne. Instituto Nacional de Câncer. Oncology Department; Brasil
Fil: Del Toro-Arreola, Alicia. Universidad de Guadalajara; México
Fil: Delgadillo-Cisterna, Raúl. Hospital de Especialidades CMNO-IMSS; México
Fil: Delgado, Lucía. Universidad de la República. Hospital de Clínicas Manuel Quintela; Uruguay
Fil: Dreyer-Breitenbach, Marisa. Universidade do Estado do Rio de Janeiro. Instituto de Biologia Roberto Alcantara Gomes; Brasil
Fil: Fejerman, Laura. University of California Davis. Department of Public Health Sciences and Comprehensive Cancer Center; Estados Unidos
Fil: Fernández, Elmer A. Universidad Católica de Córdoba. CONICET. Centro de Investigación y Desarrollo en Inmunología y Enfermedades Infecciosas [Centro de Investigación y Desarrollo en Inmunología y Enfermedades Infecciosas (CIDIE); Argentina
Fil: Fernández, Elmer A. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; Argentina
Fil: Fernández, Wanda. Hospital San Borja Arriarán; Chile
Fil: Franco-Topete, Ramón A. Universidad de Guadalajara. Hospital Civil de Guadalajara. Organismo Público Descentralizado (OPD); México
Fil: Gabay, Carolina. Instituto de Oncología Angel Roffo; Argentina
Fil: Gaete, Fancy. Hospital Luis Tisne; Chile
Fil: Garibay-Escobar, Adriana. Universidad de Sonora; México
Fil: Gómez, Jorge. Texas A&M University; Estados Unidos
Fil: Greif, Gonzalo. Institut Pasteur de Montevideo; Uruguay
Fil: Gross, Thomas G. Center for Global Health, National Cancer Institute; Estados Unidos
Fil: Guerrero, Marisol. Hospital San José; Chile
Fil: Henderson, Marianne K. Center for Global Health, National Cancer Institute; Estados Unidos
Fil: Lopez-Muñoz, Miguel E. Universidad de Sonora; México
Fil: Lopez-Vazquez, Alejandra. Universidad de Sonora; México
Fil: Maldonado, Silvina. Hospital Regional de Agudos Eva Perón; Argentina
Fil: Morán-Mendoza, Andrés J. Hospital de Gineco-Obstetricia CMNO-IMSS; México
Fil: Nagai, Maria Aparecida. Sao Paulo University Medical School. Cancer Institute of São Paulo (ICESP). Center for Translational Research in Oncology; Brasil
Fil: Oceguera-Villanueva, Antonio. Instituto Jalisciense de Cancerologia; México
Fil: Ortiz-Martínez, Miguel A. Hospital General Regional No. 1. IMSS; México
Fil: Quintero, Jael. Universidad de Sonora; México
Fil: Quintero-Ramos, Antonio. Universidad de Guadalajara; México
Fil: Reis, Rui M. Hospital de Câncer de Barretos. Molecular Oncology Research Center; Brasil
Fil: Retamales, Javier. Grupo Oncológico Cooperativo Chileno de Investigación; Chile
Fil: Rivera-Claisse, Ernesto. Centro Estatal de Oncologia; México
Fil: Rocha, Darío. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; Argentina
Fil: Rodríguez, Robinson. Hospital Central de las Fuerzas Armadas; Uruguay
Fil: Rosales, Cristina. Hospital Municipal de Oncología María Curie; Argentina
Fil: Salas-González, Efrain. Hospital de Gineco-Obstetricia CMNO-IMSS; México
Fil: Sanchotena, Verónica. Hospital Municipal de Oncología María Curie; Argentina
Fil: Segovia, Laura. Hospital Barros Luco Trudeau; Chile
Fil: Sendoya, Juan Martín. Fundación Instituto Leloir-CONICET. Molecular and Cellular Therapy Laboratory; Argentina
Fil: Silva-García, Aida A. Universidad de Guadalajara. Hospital Civil de Guadalajara. Organismo Público Descentralizado (OPD); México
Fil: Trinchero, Alejandra. Hospital Regional de Agudos Eva Perón; Argentina
Fil: Valenzuela, Olivia. Universidad de Sonora; México
Fil: Vedham, Vidya. National Cancer Institute. Center for Global Health; Estados Unidos