Abstract PD13-01: Site(s) of Distant Recurrence after Neoadjuvant Therapy for Patients With High-Risk Early-Stage Breast Cancer (BC): Analysis of Data from the I-SPY2 Trial

Abstract Background: The incidence of central nervous system (CNS) metastases varies with BC subtype, but there is limited data about clinical and molecular predictors of CNS vs non-CNS recurrence risk after neoadjuvant chemotherapy (NACT). Here we present patterns of distant recurrence among patients (pts) in the I-SPY2 trial. Methods: This analysis included 2023 pts with molecularly high-risk stage II and III BC who enrolled in the I-SPY2 trial from 2010-2022 with event-free survival (EFS) data (as of 6/22/25). We analyzed type of recurrence (local vs distant) and site(s) of initial distant recurrence (CNS-only, both CNS- and non-CNS, or non-CNS only). We used a competing risk (Fine-Gray) model to estimate cumulative incidence of site-specific relapse at five years and assessed associations with clinical/molecular subtype, clinical staging (cT, cN), and response to NACT by Residual Cancer Burden (RCB) class. Results: Among 2023 evaluable pts, at a median follow up of 4.7 yrs there were 361 EFS events, most of which were distant recurrences (n=259, 72%). Of the pts with distant recurrences, most had initial non-CNS events (180/259, 69%), 36 pts had initial simultaneous CNS- and non-CNS events (36/259, 14%), and 43 pts had initial CNS-only events (43/259, 17%). Table 1 summarizes the cumulative incidence of initial CNS- and/or non-CNS recurrences at 5 years by clinical/molecular features. Rates of CNS-only recurrence were low and similar across clinical and response predictive subtypes (p=0.47 and =0.19 respectively). Risk of distant recurrence increased in pts with larger tumors and node positive disease at both CNS- and non-CNS sites (see Table 1). Rates of initial non-CNS recurrence increased with the amount of residual disease at surgery, with lowest rates in pts with RCB-0 and highest rates in pts with RCB-III (p