55P Clinicopathological and molecular changes induced by neoadjuvant therapy (NAT) in hormone receptor-positive (HR+)/HER2-low vs HER2 0 breast cancer (BC)

HER2-low represents ∼65% of HR+/HER2-negative(-) BC; there is conflicting evidence regarding the potential association with higher pathologic complete response (pCR) and differential prognosis compared to HR+/HER2 0. Moreover, molecular changes induced by NAT have not been studied so far. Patients with HR+/HER2- BC treated with NAT at our institution between 2014-2018 were analyzed. Gene expression was assessed using nCounter. Associations with pCR, event-free survival (EFS) and overall survival (OS) were assessed with logistic and Cox regressions. Paired and unpaired SAM analyses for differential gene expression were performed. Significance was set at p≤0.05 and false discovery rate (FDR)≤5%. Overall, 186 patients were included, 52.2% treated with neoadjuvant chemotherapy (NACT) and 47.8% with endocrine therapy (NET); 62.9% were HER2-low and 37.1% were HER2 0, with no difference in main clinicopathological features and neo/adjuvant treatments administered. Luminal A+B were the most frequent intrinsic subtypes (IS) (84.6%). The pCR rate was 10.1%, similar between HER2-low and HER2 0 (p=0.704). At baseline, HER2-low vs. HER2 0 showed upregulation of ESR1, ERBB2 and GRB7 (FDR<5%). NAT induced a significant reduction of progesterone receptor (p<0.001) and Ki67 (p<0.001), but not TILs (p=0.994), regardless of HER2 status. An upregulation of Basal-like-related genes, CD8A, PDCD1 and CD274, with a downregulation of CD4, Luminal- and proliferation-related genes (FDR<5%) were observed in both cohorts, with no significant post-NAT differences, except for already differentially expressed genes at baseline. A switch towards less aggressive IS (p<0.001; Luminal A+Normal-like increase from 51.8% to 94.7%) and lower risk of relapse (ROR) score (p<0.001; ROR-low increase from 22.9% to 78.8%), was observed regardless of HER2 status. There were no differences in EFS (p=0.335) and OS (p=0.627) based on HER2 status. HER2-low status in HR+ BC was not predictive of pCR nor prognostic. Tailored neo/adjuvant approaches based on pathologic/molecular downstaging merit exploration, but differential strategies based on HER2-low status are not encouraged.