Unraveling the clinicopathological and molecular changes induced by neoadjuvant chemotherapy and endocrine therapy in hormone receptor-positive/HER2-low and HER2-0 breast cancer

Background The characterization and comparison of gene expression (GE) and intrinsic subtypes (IS) changes induced by neoadjuvant chemotherapy (NACT) and endocrine therapy (NET) in hormone receptor-positive(HR+)/HER2-low vs. 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 intrinsic subtypes (IS) and risk-of-relapse (ROR)-P score, and GE. Associations with pathologic complete response (pCR), residual cancer burden (RCB)-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 (BCS), pCR and RCB-0/I rates, EFS and OS. NAT induced, regardless of HER2 status, a significant reduction of ER/PgR and Ki67, a downregulation of PAM50 proliferation- and luminal-related genes/signatures, an upregulation 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 NET (p=0.063), with consistent ERBB2 mRNA level dynamics. HER2 changes were not associated to EFS/OS. Conclusions HER2 status changes after NAT in ∼1/4 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. Highlights Hormone receptor-positive (HR+)/HER2-low and HER2-0 breast cancer (BC) showed similar post-neoadjuvant surgical outcomes. Neoadjuvant therapy (NAT) induced a shift towards less aggressive subtypes and ROR-P classes regardless of HER2 status. All NAT strategies induced a downregulation of proliferation- and luminal biology-related genes, regardless of HER2 status. NAT induced changes in HER2 status, with a discordance rate of 34% and HER2-low showing higher instability than HER2-0. HER2 status at baseline, after surgery and its dynamics were not significantly associated to long-term outcomes.