Exploring HER2-low disease: Does it impact breast cancer survival?
Authors: López-Paradís Assumpció , Pous Anna , Bernat-Peguera Adrià , Quiroga Vanesa , Cirauqui Beatriz , Felip Eudald , Bergamino Milana , Ferrando-Diez Angelica , Romeo Marga , Teruel Iris , Martínez-Cardús Anna , Margelí Mireia 
Published: June 2023

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Background: HER-2 low has emerged as a potential new entity in breast cancer (BC). Data of this subset is still limited and prognostic results are controversial, suggesting HER2-low does not represent a distinct biological subtype. HER2-low account for up to 50% of BC, representing a potential therapeutic target with encouraging results in the metastatic setting. Hence, we pretend to analyze clinical characteristics of this subset to elucidate commented points. Methods: Confirmed HER2-negative BC patients (p) diagnosed between 2006-2017 were retrospectively reviewed in a single center study, in ICO-Badalona. HER2-positive and in situ carcinomas were excluded, and p were classified as HER2-low and HER2-0. The prevalence of HER2-low versus HER2-0 among p, originally scored as HER2-negative, was measured. Demographics and clinicopathological characteristics were examined and compared via medical charts/electronic health records. We aim to describe HER2-0/HER2-low populations, and explore its prognostic impact, using Kaplan-Meyer and Cox regression models. Results: From 1451 infiltrating HER2-negative BC p, 87% were hormone receptor (HR)-positive vs 13% triple negative (TNBC). Overall, 43% were HER2-0 and 57% HER2-low (61% IHC 1+ and 39% IHC 2+). Comparing HER2-0 vs HER2-low, the latest showed significant higher proportion of ER-positive (80% vs 91.7%, p = < 0.001) and PR-positive (69.3% vs 79.1%, p = < 0.001) cases, but there were no differences between HER2-low 1+ vs 2+. HER2-0 exhibited higher proportion of TNBC p (20% vs 8.3%, p = 0.001), grade III tumors (28.8% vs 23.5%, p = 0.036) and higher Ki67 median value (26.47% vs 23.88%, p = 0.041). No significant differences were observed in median age at diagnosis, menopausal status, clinical stage, clinical nodal status, histological subtype, time to recurrence, time to local recurrence and overall survival (OS). HER2-low presented longer time to distant recurrence (TDR) compared to HER2-0 (67.8 vs 54.1 months, p = 0.015) and better BC-related OS (19.2 vs 16.3 years, p = 0.033). However, in the multivariate analysis, considering HER2, ER, PR, histological grade and nodal status, PR showed the strongest association with longer TDR (HR: 0.69; 95%CI 0.54-0.89, p = 0.004); and positive nodal status was the strongest factor related to worse BC-related OS (HR: 2.97; CI 2.10-4.21, p = 0.000). No statistical differences in TDR and BC-related OS were observed between HER2 1+ vs 2+ populations. Conclusions: HER2-low was significantly associated to HR-positive disease whereas TNBC, histological grade III and higher Ki67% were more represented in HER2-0 group. Although HER2-0 was related to worse TDR and BC-related OS, these findings could be explained by the presence of an enriched population in worse prognostic features, as suggested by multivariate analysis. New therapies for HER2-0 disease are an unmet medical need.