AUTHOR=Llera Andrea Sabina , Abdelhay Eliana Saul Furquim Werneck , Artagaveytia Nora , Daneri-Navarro Adrián , Müller Bettina , Velazquez Carlos , Alcoba Elsa B. , Alonso Isabel , Alves da Quinta Daniela B. , Binato Renata , Bravo Alicia Inés , Camejo Natalia , Carraro Dirce Maria , 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 A. , Fernández Jorge , 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 Silvina , Morán-Mendoza Andrés 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 , Rodríguez Robinson , Rosales Cristina , Salas-González Efrain , Sanchotena Verónica , Segovia Laura , Sendoya Juan Martín , Silva-García Aida A. , Trinchero Alejandra , Valenzuela Olivia , Vedham Vidya , Zagame Livia , United States-Latin American Cancer Research Network (US-LACRN) , Podhajcer Osvaldo L. , Abarca Juan , Acevedo Pamela , Acosta Graciela , Acosta Gissel , Haab Gabriela Acosta , Silva Ana Lilian Acosta , Aghazarian Marta , Aguayo Carola , Aizen Bernardo , Lopez Gustavo Alarcon , Almeida Liz , Alvarez Ana , Andrade Viviane , Angeles-Bueno Wenceslao , Arai Roberto , Barreras Priscila Elvira Arambula , Rubio Ma. Isabel Aramburo , Ardao Gonzalo , Arellano-Jimenez Lilia A. , Arias Claudia , Armisen Ricardo , Aspee Mauricio , Assar Rodrigo , Rascón Itzel Reneé Astiazarán , Astorga Sebastian , Rodriguez Maxwell Aviles , Junior Antônio Bailão , Barragan-Curiel Adolfo E. , Barragan-Ruiz Adelfo , Bermudez Fernanda , Bernachin Julia , Herrera Wilfrido Bernal , Bonet Mara , Brnich Sarah , Bustamante Claudio , Bustamante Miguel Angel , Bustos-Gomez Julio , de J Bustos-Rodriguez Felipe , Jasso Janett Caballero , Calfuman Angie , Marques Antonio Hugo José Froes , Campos Mónica , Cano Soledad , Canton-Romero Juan C. , Cappetta Ricardo , Carmona Paulina , Carrizo Fernando , Carvalho André Lopes , Carvallo Erika , Carzoglio Julio , Casalnuovo Monica , Caserta Benedicta , Castillo Alvaro , Castillo César , Chammas Roger , Zamudio Mario Alberto Chavez , Chia Loreto , Chiarello Elisa , Chirico Daniela , Cisneros-Quirarter Esther , Bautista Minor Raul Cordero , Cornejo Valeria , Villegas Baldemar Corral , Cortés Andrés , Cortés Sandra , Cortes-Sanabria Laura , Zamorano German Salvador Cortez , Corvalan Alejandro , Cruz Adolfo , d'Aurora Alba , Fuente Sandra De la , Peña Soledad De la , Caballero Roberto de Leon , Souza Mirian de , Castillo César Del , Del-Toro-Valero Azucena , Pretoro Mirtha Di , Digonzelli Andrea , Ters Jose El , Escobar Paula , Estolaza Marcela , Evangelista Adriane Feijo , Fanelli Marcelo , Farias Paulo , Fernandez Graciela , Filassi José R. , Filgueiras Natalia , Flaks Diego , Flores-Ayala Edgar G. , Flores-Marquez Maria R. , Hughes David Franco , Franco-Topete Karina , Freire Jimena , Fresno Cristobal , Gabrielli Romina , Gallegos Mario , Gamboa Jorge , Ganiewich Daiana , Garbovesky Carlos , Munguia Ruben Alejandro Garcia , Garcia-Gaeta Ricardo , Garcia-Martinez Alma C. , Gimenez Liliana , Silveira Hector Gómez , Toro Mariana M. Gomez-Del , Gonzalez Marcela , Gonzalez Alicia , González Germán , Mondaca Cesar Osbaldo Gonzalez , Gonzalez-Ramirez Leivy P. , Gonzalez-Ulloa Beatriz , Gorostidy Susana , Grass Mariela , Torres Alfonso G. Guevara , Gutierrez Lorena , Gutierrez-Rubio Susan A. , Hannois Adrián , Hart Andrew , Härtel Steffen , Henriquez Marcos , Guevara Rafael Hernandez , Hernandez-Franco Miriam E. , Herrera-Miramontes Manuel I. , Horton Graciela , Ibañez Gladys , Ipiña Martín , Jalfin Beatriz , Jara Lilian , Jara Raul , Jaramillo Maria Luisa , Javalera-Castro David , Jimenez Maria Eugenia , Ju Hugo , Rusjan Nazareth Juárez , Juneman Karen , Kerr Ligia Maria , Krupelis Alejandra , Larios-Jimenez Flor Esmeralda , Latorre Jose Domingo , Laviña Guillermo , Lavista Fernando , Duarte Irma Leticia León , Lescano Alberto , Lezano Verónica , Lopez Rossana Mendoza , Cervantes Jose Guillermo Lopez , Muñoz Miguel Enrique Lopez , Loria Dora , Luque Alejandra , Maass Alejandro , do Socorro Maciel Maria , Mangone Flavia Rotea , Mansilla Jorge , Marcelain Katherine , Mariani Carolina , Marques Marcia Maria Chiquitelli , Martinez-Arriaga Reyna J. , Martinez-Ramirez Hector R. , Martins Marcela , Maya-Gonzalez Alma G. , Mazzaferri Brenda , Medina-Mora Yadira , Menini Mariana , Míguez Silvia , Milans Soledad , Montes Soledad , Hernández Ana Verónica Morales , Morga-Villela Giberto , Morong Carla , Muñoz Homero , Muse Ignacio Miguel , Mussetti Carina , Mussetti Eduardo , Najar-Acosta Luis J. , Ferreira Elisa Napolitano e , Navarro-Ruiz Nancy E. , Noblía Cristina , Nunes João Soares , Núñez Daniela , Núñez Fabiola , Onari Nilton , Oropeza-De Anda Emma M. , Tirado David Ortega , Bueno de Toledo Osório Cynthia Aparecida , Paiva Carlos Eduardo , Peñaloza Paulina , Peredo-Navarro Miguel , Pereira David , Michel Laura Perez , Pino Francisca , Pino Tania , Pinto Natalia , Pizarro Jessica , Pressa Carlos , Ramirez Enrique , Ramirez-Rosales Gladys E. , Ramis Claudia , Ramos-Ramirez Maritza , Alcantar Adela Rascon , Ravaglio Silvana , Richard Francois , Méndez Omar Rios , Zepeda Ramón Enrique Robles , Rocha Iara Santana , Rodriguez Natalia , Rodriguez Vilma , Rodriguez Maria Teresa , Rodriguez-Gonzalez Diego , Roela Rosemeire A , Romero-Gomez Ana M , Rosales-Sandoval Ana M , Rubio-Plascencia Omar V , Russo Florencia , Sabini Gaciela , Saffie Isabel , Dias Helena Salina , Soto Brenda Guadalupe Samaniego , Martino Julio San , Sanchez-Llamas Benito , Sat-Muñoz Daniel , Savignano Mariana , Neto Cristovam Scapulatempo , Senna Max Mano , Silva Carolina , Silvera Jaime , Small Isabele , Soares Fernando , Soares Iberê , dos Santos Silvana Soares , Mello Evandro Sobrosa de , Sola José Antonio , Sorín Irene , Sosa Alejandra , Sosa Anabella , Sosa Claudio , Soto Sandra , Souza Cristiano de Pádua , Spangenberg Lucía , Steffanof Gustavo , Straminsky Florencia , Tapia Mónica , Tapia-Llanos Raziel O. , Tavares-Macias Geronimo M. , Temperley Guillermo , Terzieff Veronica , Teti Vicente , Tognarelli Javier , Toledo Verónica , Toro Paulina , Torres Roberto , Torres-Palomares Mariana , Roman Rogelio Troyo-San , Urbano Hernan , Vacca Nicolas , Vaimberg Daniel , Peña María Lourdes Valencia , Vaselevich Maria Lujan , Vazquez-Nares Jaime , Velez-Gomez Ezequiel , Venegas-Godinez Laura N. , Vercelli Patricia , Verdugo Ricardo , Aloisio da Costa Vieira René , Vilensky Marta , Villarubias María José , Gómez Manuel Isaac Villegas , Viña Stella , Vornetti Silvia , Watanabe Anapaula Hidemi Uema , Zamorano Carlos , Zapata Luis , Zlatar Zdenka TITLE=The Transcriptomic Portrait of Locally Advanced Breast Cancer and Its Prognostic Value in a Multi-Country Cohort of Latin American Patients JOURNAL=Frontiers in Oncology VOLUME=12 YEAR=2022 URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.835626 DOI=10.3389/fonc.2022.835626 ISSN=2234-943X 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).