535 Background: The KATHERINE trial established adjuvant T-DM1 as standard of care (SoC) treatment for patients with HER2+ eBC and residual invasive disease (RD) following neoadjuvant therapy. Recently, DESTINY-Breast05 (DB-05) demonstrated reduced recurrence risk with T-DXd vs. T-DM1 in a high-risk subset. While KATHERINE included any RD, DB-05 restricted eligibility to high-risk patients (inoperable at presentation or ypN+ at surgery). In this analysis, we aim to estimate the prevalence and associated outcomes of patients with HER2+ eBC and RD meeting eligibility for DB-05 vs. KATHERINE in a US real-world setting. Methods: This retrospective cohort study utilized the nationwide Flatiron Health electronic health record-derived de-identified database. We included patients diagnosed with stage I–III HER2+ eBC (Jan 1, 2011–Sept 30, 2025) who completed pertuzumab-based neoadjuvant therapy and surgery. RD status was determined via pathology reports. KATHERINE eligibility required any RD in breast/axillary nodes. DB-05 eligibility required high-risk RD: operable at presentation with node-positive disease at surgery (ypN1–3; “DB-05-operable”) or inoperable at presentation (cT4 or cT1–3/cN2–3; “DB-05-inoperable”). Distant recurrence-free survival (DRFS) and overall survival (OS) were estimated at 3 years post-surgery. The analysis was conducted on complete cases only. Results: The cohort included 9561 patients with HER2+ eBC and RD after neoadjuvant therapy. Overall, 9447 (99%) met KATHERINE eligibility. Conversely, only 4567 (48%) met DB-05 high-risk criteria: 3241 (34%) DB-05-operable and 1326 (14%) DB-05-inoperable. DB-05-ineligible patients mostly presented with cT1–3/cN0–1 disease and had RD confined to the breast (ypN0). In the overall study population, with a median follow-up for DRFS of 44 months, 3-year DRFS and 3-year OS were 88% and 94%, respectively. Patients eligible only for KATHERINE (i.e. DB-05-ineligible) experienced relatively favorable outcomes, with a 3-year DRFS of 94% and 3-year OS of 97%; conversely, DB-05-eligible patients experienced a 3-year DRFS of 82% and 3-year OS of 91%. Within the DB-05-eligible population, the poorest outcomes were observed if patients had inoperable disease at baseline, with a 3-year DRFS of 73% and 3-year OS of 86%. Conclusions: Approximately half of the patients with RD did not meet DB-05 high-risk criteria yet would have been eligible for KATHERINE. While T-DXd may become a new option for high-risk patients, T-DM1 remains a SoC for those with operable disease at baseline and node-negative RD at surgery. As ADCs were not widely available for eBC during the study period, these outcomes do not reflect ADCs’ treatment effect, and modern 3-year DRFS may possibly exceed 94% for this population.
Tarantino et al. (Wed,) studied this question.