1052 Background: The DESTINY-Breast04 trial demonstrated for the first time that trastuzumab deruxtecan (T-DXd), a HER2-targeting antibody-drug conjugate (ADC), benefits patients with HER2-low metastatic breast cancer (mBC). This efficacy in HER2-low disease (45–65% of cases) has spurred research into optimal methods for identifying eligible patients. We propose molecular imaging to explore intra-/interpatient heterogeneity in HER2 mapping of metastatic disease and to identify patients unlikely to benefit from T-DXd. Methods: HER2-low mBC patients with IHC1+ or IHC 2+/FISH ≤ 2.2 scheduled for T-DXd underwent paired HER2-targeted 18 FAlF-HER2-BCH PET/CT (HER2–PET) and 18 FFDG–PET/CT (FDG–PET) at baseline and 2 cycle follow-up. High-uptake was defined as having >50% of tumors with a baseline SUVmax >6.0 on HER2–PET; otherwise, it was low uptake. HER2-PET was defined as nonresponding showed no significant reduction of HER2 uptake (10%) at 2 cycle follow-up. Negative (NPV) and positive predictive values (PPV) of HER2–PET, FDG–PET, early HER2/FDG response, and their combination were assessed to predict morphological response (RECIST 1.1) after two T-DXd cycles and time-to-treatment failure (TTF). Results: In the 32 HER2-low mBC patients analyzed, 24 (75%) had high baseline HER2-PET uptake (SUVmax >6.0), while 8 (25%) had low uptake. Of 24 high-uptake patients, 14 (58.3%) achieved a complete response (CR), 7 (29.2%) initially reached a partial response (PR) after two T-DXd cycles but later developed progressive disease (PD) between cycles 5–10, and 3 (12.5%) experienced PD as early as cycle 2. In the low-uptake group (n=8), one patient (12.5%) with isolated pulmonary metastases maintained stable disease (SD) through 14 cycles, whereas 7 (87.5%) patients with multiple metastases developed rapid PD. Compared with RECIST1.1, respective NPV/PPV for baseline HER2–PET were 87.5%/87.5% for predicting treatment response at 2 cycles. When combining baseline HER2-PET uptake with early 2 cycles, patients with high baseline uptake and a ∆SUVmax >40% had a median TTF of 15.3 months n = 14, 95% confidence interval (CI) 7.7––not calculable, those with high baseline uptake and a 10% < ∆SUVmax <40% a median TTF of 4.8 months n = 7, 95% CI: 3.8–9.8; and patients with a ∆SUVmax <10% a median TTF of only 1.3 months n = 10, 95%CI: 1.3, 3.9. Baseline FDG uptake was not associated with lesion response status, and while trends in ∆SUVmax aligned with those observed in HER2-PET, no clear cutoff value was established in this study. Conclusions: Baseline HER2-PET uptake, especially when combined with early on-treatment ∆SUVmax, not only improves the understanding of tumor heterogeneity but also offers an imaging-guided strategy to personalize management and select patients most likely to benefit from T-DXd in HER2-low mBC. Clinical trial information: NCT06909604 ; NCT04547309 .
Guo et al. (Wed,) studied this question.