Abstract PS5-05-17: Real-world effectiveness of Trastuzumab Deruxtecan in HER2-low Metastatic breast cancer: a single-center retrospective study

Abstract Background: Clinical trials of trastuzumab deruxtecan (T-Dxd) have expanded options for HER2-low breast cancer, yet real-world patients often present with poorer prognostic features such as active brain metastases or heavy pretreatment. Robust effectiveness data in routine practice are therefore needed. Methods: This is a retrospective real-world monocentric study conducted by 81 patients with HER2-low advanced breast cancer, who were treated with T-Dxd. Database from the Department of Breast Oncology at Peking University Cancer Hospital was reviewed, spanning March 2023 to January 2025. All patients underwent at least one radiologic response assessment. Results: The median progression-free survival (PFS) was 6.0 months (95%CI, 3.8-8.1). There were 68 HR+(83.95%) and 13 HR- (16.05%) patients included. HR+ disease showed a median PFS of 6.7 months (95%CI, 5.2-8.2) versus 3.4 months (95%CI, 2.1-4.7) in triple-negative breast cancer (TNBC), no statistical significance between these two groups (P=0.062). TNBC patients had a significantly shorter median overall survival (OS) (8.7 months, (95%CI, 2.2-15.2) , P=0.002), while mOS was not reached in HR+ group. Presence of visceral, liver, lung, or CNS lesions did not materially alter PFS (6.0 vs 5.9 months, P=0.906). Among 13 patients (16.05%) with active brain metastases, disease-control rate was 84.62% and 5/6 evaluable patients achieved CNS partial response. Baseline IHC score (HER2 1+ vs 2+) did not affect PFS (5.9 vs 6.0 months, P=0.707). But patients whose metastatic sites showed up-regulated HER2 expression achieved longer PFS (7.0 vs 3.4 months, P=0.015). The cohort had received a median of 4 prior lines of systemic therapy, including a median of 2 chemotherapy regimens. Administering T-Dxd after more than 3 prior chemotherapy lines or after exposure to topoisomerase I/II inhibitors significantly shortened PFS (4.5 vs 7.0 months, P=0.018 and 3.2 vs 6.7 months, P=0.002, respectively). Of the 48 patients who underwent germline BRCA testing, 13 carried BRCA1/2 mutations and 35 were wild type. Although mPFS was numerically longer in the mutant subgroup (7.5 months) than in the wild-type subgroup (4.8 months), the difference was not statistically significant (P = 0.607). Among the 13 BRCA-mutated patients, 10 had previously received PARP inhibitors; their mPFS did not differ from that of PARP-naïve patients (7.5 vs 4.5 months, P = 0.989). PAM-pathway alterations (PIK3CA/AKT/PTEN) were evaluated in 41 patients, with 11 found to be mutant. Median PFS was similar between the PAM-mutated and wild-type groups (6.0 vs 4.2 months, P = 0.065). Conclusions: In routine clinical practice, T-Dxd delivers meaningful disease control for heavily pre-treated HER2-low metastatic breast cancer, including patients with active brain metastases—but its effectiveness is more modest than that seen in randomized trials. Greatest benefit is observed when: (i) metastatic lesions up-regulate HER2 expression, and (ii) T-Dxd is introduced earlier in the chemotherapy sequence. Outcomes are less favorable in triple-negative disease and after prior topoisomerase-targeted therapy, suggesting that biomarker- and timing-guided patient selection could optimize real-world use. Citation Format: Y. Chen, G. Song, H. Li. Real-world effectiveness of Trastuzumab Deruxtecan in HER2-low Metastatic breast cancer: a single-center retrospective study abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-05-17.