1. Unraveling the clinicopathological and molecular changes induced by neoadjuvant chemotherapy and endocrine therapy in hormone receptor-positive/HER2-low and HER2-0 breast cancer.
- Author
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Schettini F, Nucera S, Brasó-Maristany F, De Santo I, Pascual T, Bergamino M, Galván P, Conte B, Seguí E, García Fructuoso I, Gómez Bravo R, Rivera P, Rodríguez AB, Martínez-Sáez O, Ganau S, Sanfeliu E, González-Farre B, Vidal Losada MJ, Adamo B, Cebrecos I, Mension E, Oses G, Jares P, Vidal-Sicart S, Mollà M, Muñoz M, and Prat A
- Subjects
- Humans, Female, Middle Aged, Retrospective Studies, Adult, Aged, Receptors, Estrogen metabolism, Receptors, Progesterone metabolism, Prognosis, Biomarkers, Tumor metabolism, Antineoplastic Agents, Hormonal therapeutic use, Antineoplastic Agents, Hormonal pharmacology, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Breast Neoplasms metabolism, Neoadjuvant Therapy methods, Receptor, ErbB-2 metabolism
- Abstract
Background: The characterization and comparison of gene expression and intrinsic subtype (IS) changes induced by neoadjuvant chemotherapy (NACT) and endocrine therapy in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 (HER2)-low versus HR+/HER2-0 breast cancer (BC) has not been conducted so far. Most evidence on the association of HER2 status with pathologic responses and prognosis in HR+/HER2-negative BC is controversial and restricted to NACT-treated disease. Similarly, a temporal heterogeneity in HER2 status has been described only with NACT., Methods: We retrospectively recruited a consecutive cohort of 186 patients with stage I-IIIB HR+/HER2-negative BC treated with neoadjuvant therapy (NAT). Available diagnostic biopsies and surgical samples were characterized for main pathological features, PAM50 IS and ROR-P score, and gene expression. Associations with pathologic complete response, residual cancer burden-0/I, event-free survival (EFS) and overall survival (OS) based on HER2 status were assessed. Pre/post pathologic/molecular changes were analyzed in matched samples., Results: The HER2-low (62.9%) and HER2-0 (37.1%) cohorts did not differ significantly in main baseline features, treatments administered, breast-conserving surgery, pathologic complete response and residual cancer burden-0/I rates, EFS, and OS. NAT induced, regardless of HER2 status, a significant reduction of estrogen receptor/progesterone receptor and Ki67 levels, a down-regulation of PAM50 proliferation- and luminal-related genes/signatures, an up-regulation of selected immune genes, and a shift towards less aggressive IS and lower ROR-P. Moreover, 25% of HER2-0 changed to HER2-low and 34% HER2-low became HER2-0. HER2 shifts were significant after NACT (P < 0.001), not neoadjuvant endocrine therapy (P = 0.063), with consistent ERBB2 mRNA level dynamics. HER2 changes were not associated with EFS/OS., Conclusions: HER2-low and HER2-0 status change after NAT in ∼30% of cases, mostly after NACT. Targeted adjuvant strategies should be investigated accordingly. Molecular downstaging with current chemo/endocrine agents and immunotherapy should not rely on HER2 immunohistochemical levels in HR+/HER2-negative BC. Instead, HER2-low-targeted approaches should be explored to pursue more effective and/or less toxic dimensional downstaging., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2024
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