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BACKGROUND: Sacituzumab govitecan (SG) is an anti-trop2 antibody-drug conjugate (ADC) approved for human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). However, data on effectiveness of SG and biomarkers remain limited. DNADX is a plasma-only multi-gene signature assay that identifies five tumor subtypes. In previous studies, DNADX subtypes have been associated with clinical outcomes.MATERIALS AND METHODS: This study included patients with MBC treated with SG monotherapy between June 2014 and January 2023. Clinicopathological features and outcomes [time to next treatment (TTNT), overall survival (OS)] were analyzed. An exploratory analysis evaluated the association between DNADX subtypes and outcomes.RESULTS: A total of 121 patients with triple-negative breast cancer (TNBC), 59 with hormone receptor (HR)-positive/HER2-negative MBC, and 4 with HER2-positive MBC at the time of SG initiation were identified. Visceral disease was present in 75% of patients; 23.4% had brain metastases. Patients with TNBC had a median of 3 (range 0-9) prior lines for MBC, including chemotherapy (91%), immunotherapy (53%), and trastuzumab deruxtecan (T-DXd) (3%). Those with HR-positive/HER2-negative MBC had received a median of 5 (range 0-14) prior lines, including chemotherapy (97%), cyclin-dependent kinase 4/6 inhibitors (78%), immunotherapy (25%), and T-DXd (12%). Median TTNT was 4.3 months [95% confidence interval (CI) 3.7-5.0 months] for TNBC and 4.2 months (95% CI 2.8-4.9 months) for HR-positive/HER2-negative MBC. Median OS was 10.4 months (95% CI 8.0-13.3 months) for TNBC and 10.2 months (95% CI 7.0-12.6 months) for HR-positive/HER2-negative MBC. DNADX subtypes were significantly associated with outcomes. The tumor fraction (TF)-low subtype was linked to the longest TTNT and OS, while the proliferative and basal-related subtypes were associated with poorer outcomes.CONCLUSIONS: Outcomes observed with SG were consistent with those reported in the registrational trials. DNADX subtypes were associated with TTNT and OS, underscoring their potential as biomarkers. Improved therapeutic options in the post-ADC setting and better biomarkers for treatment sequencing are urgently needed.