275P Clinical and molecular impact of neoadjuvant chemotherapy (NACT) or endocrine therapy (NET) on hormone receptor positive (HR+)/HER2-negative (-) breast cancer (BC)

Clinicopathological and molecular features of HR+/HER2- BC associated with response and survival following NACT or NET have been poorly characterized. A total of 186 patients with early-stage HR+/HER2- BC treated with NACT (52.2%) and NET (47.8%) at the Hospital Clinic of Barcelona between 2014-2018 were evaluated. Associations with pathologic complete response (pCR), event-free survival (EFS) and overall survival (OS) were assessed with logistic and Cox regressions, where appropriate. Intrinsic subtypes (IS), risk of relapse (ROR) and selected genes’ expression before and after neoadjuvant treatment (NAT) were assessed with a research-based PAM50. SAM analyses were carried out. Significance was set at p≤0.05 and false discovery rate (FDR)≤5%. The pCR rates following NACT and NET were 18.6% and 3.4%, respectively. NACT (adjusted odds ratio [aOR]: 6.26, p=0.044) and non-Luminal IS (aOR: 8.89, p=0.021) were independently associated to pCR. Both NAT strategies reduced PgR and Ki67 levels significantly (p<0.001 all). After NAT, a significant (p<0.001) larger proportion of tumor samples were Luminal A/Normal-like (95.1% vs 55.3% at baseline) and ROR-low (78.8% vs. 22.9% at baseline). Both treatments induced the upregulation of selected immune genes and Basal-like-related genes/signature and downregulation of Luminal, proliferation and HER2-related genes/signatures (FDR<5% all). At a median follow-up of 64.0 months, 5-year EFS and OS were 90.4% and 95.0% with no significant difference based on NAT strategy (71.9% NET patients did not receive posterior CT). After adjusting for NAT cohort and significant factors at univariate analyses, including IS switch, only reduction of the proliferation signature remained significantly associated with better EFS (p=0.011) and OS (p=0.014). Similar results were observed with reduction of ROR for EFS (p=0.034), but not OS. This study suggests that molecular downstaging induced by NACT or NET follows similar biological patterns and is associated with favorable survival outcomes, supporting molecular-driven neo-/adjuvant strategies, as tested in the ongoing RIBOLARIS phase II trial (NCT05296746).