The Transcriptomic Portrait of Locally Advanced Breast Cancer and Its Prognostic Value in a Multi-Country Cohort of Latin American Patients

Abstract

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; ArgentinaFil: Abdelhay, Eliana Saul Furquim Werneck. Instituto Nacional de Câncer. Bone Marrow Transplantation Unit; BrasilFil: Artagaveytia, Nora. Universidad de la República. Hospital de Clínicas Manuel Quintela; UruguayFil: Daneri-Navarro, Adrián. Universidad de Guadalajara; MéxicoFil: Müller, Bettina. Instituto Nacional del Cáncer; ChileFil: Velazquez, Carlos. Universidad de Sonora; MéxicoFil: Alcoba, Elsa B. Hospital Municipal de Oncología María Curie; ArgentinaFil: Alonso, Isabel. Centro Hospitalario Pereira Rossell; UruguayFil: Alves da Quinta, Daniela B. Fundación Instituto Leloir-CONICET. Molecular and Cellular Therapy Laboratory; ArgentinaFil: Alves da Quinta, Daniela B. Universidad Argentina de la Empresa (UADE). Instituto de Tecnología (INTEC); ArgentinaFil: Binato, Renata. Instituto Nacional de Câncer. Bone Marrow Transplantation Unit; BrasilFil: Bravo, Alicia Inés. Hospital Regional de Agudos Eva Perón; ArgentinaFil: Camejo, Natalia. Universidad de la República. Hospital de Clínicas Manuel Quintela; UruguayFil: Carraro, Dirce Maria. AC Camargo Cancer Center. Centro Internacional de Pesquisa (CIPE). Laboratory of Genomics and Molecular Biology; BrasilFil: Castro, Mónica. Instituto de Oncología Angel Roffo; ArgentinaFil: Castro-Cervantes, Juan M. Hospital de Especialidades CMNO-IMSS; MéxicoFil: Cataldi, Sandra. Instituto Nacional del Cáncer; UruguayFil: Cayota, Alfonso. Institut Pasteur de Montevideo; UruguayFil: 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; ChileFil: Colombo, Alicia. Universidad de Chile. Facultad de Medicina y Hospital Clínico. Department of Pathology; ChileFil: Crocamo, Susanne. Instituto Nacional de Câncer. Oncology Department; BrasilFil: Del Toro-Arreola, Alicia. Universidad de Guadalajara; MéxicoFil: Delgadillo-Cisterna, Raúl. Hospital de Especialidades CMNO-IMSS; MéxicoFil: Delgado, Lucía. Universidad de la República. Hospital de Clínicas Manuel Quintela; UruguayFil: Dreyer-Breitenbach, Marisa. Universidade do Estado do Rio de Janeiro. Instituto de Biologia Roberto Alcantara Gomes; BrasilFil: Fejerman, Laura. University of California Davis. Department of Public Health Sciences and Comprehensive Cancer Center; Estados UnidosFil: 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); ArgentinaFil: Fernández, Elmer A. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; ArgentinaFil: Fernández, Wanda. Hospital San Borja Arriarán; ChileFil: Franco-Topete, Ramón A. Universidad de Guadalajara. Hospital Civil de Guadalajara. Organismo Público Descentralizado (OPD); MéxicoFil: Gabay, Carolina. Instituto de Oncología Angel Roffo; ArgentinaFil: Gaete, Fancy. Hospital Luis Tisne; ChileFil: Garibay-Escobar, Adriana. Universidad de Sonora; MéxicoFil: Gómez, Jorge. Texas A&M University; Estados UnidosFil: Greif, Gonzalo. Institut Pasteur de Montevideo; UruguayFil: Gross, Thomas G. Center for Global Health, National Cancer Institute; Estados UnidosFil: Guerrero, Marisol. Hospital San José; ChileFil: Henderson, Marianne K. Center for Global Health, National Cancer Institute; Estados UnidosFil: Lopez-Muñoz, Miguel E. Universidad de Sonora; MéxicoFil: Lopez-Vazquez, Alejandra. Universidad de Sonora; MéxicoFil: Maldonado, Silvina. Hospital Regional de Agudos Eva Perón; ArgentinaFil: Morán-Mendoza, Andrés J. Hospital de Gineco-Obstetricia CMNO-IMSS; MéxicoFil: Nagai, Maria Aparecida. Sao Paulo University Medical School. Cancer Institute of São Paulo (ICESP). Center for Translational Research in Oncology; BrasilFil: Oceguera-Villanueva, Antonio. Instituto Jalisciense de Cancerologia; MéxicoFil: Ortiz-Martínez, Miguel A. Hospital General Regional No. 1. IMSS; MéxicoFil: Quintero, Jael. Universidad de Sonora; MéxicoFil: Quintero-Ramos, Antonio. Universidad de Guadalajara; MéxicoFil: Reis, Rui M. Hospital de Câncer de Barretos. Molecular Oncology Research Center; BrasilFil: Retamales, Javier. Grupo Oncológico Cooperativo Chileno de Investigación; ChileFil: Rivera-Claisse, Ernesto. Centro Estatal de Oncologia; MéxicoFil: Rocha, Darío. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; ArgentinaFil: Rodríguez, Robinson. Hospital Central de las Fuerzas Armadas; UruguayFil: Rosales, Cristina. Hospital Municipal de Oncología María Curie; ArgentinaFil: Salas-González, Efrain. Hospital de Gineco-Obstetricia CMNO-IMSS; MéxicoFil: Sanchotena, Verónica. Hospital Municipal de Oncología María Curie; ArgentinaFil: Segovia, Laura. Hospital Barros Luco Trudeau; ChileFil: Sendoya, Juan Martín. Fundación Instituto Leloir-CONICET. Molecular and Cellular Therapy Laboratory; ArgentinaFil: Silva-García, Aida A. Universidad de Guadalajara. Hospital Civil de Guadalajara. Organismo Público Descentralizado (OPD); MéxicoFil: Trinchero, Alejandra. Hospital Regional de Agudos Eva Perón; ArgentinaFil: Valenzuela, Olivia. Universidad de Sonora; MéxicoFil: Vedham, Vidya. National Cancer Institute. Center for Global Health; Estados Unido