Discussion
cancer, tumor, HER2-overexpressing mBC
CANCER, TUMOR
We report converging evidence that HER2 expression is a determinant of T-DXd efficacy. Specifically, the PFS rates were significantly different across the three cohorts of patients; T-DXd uptake was different according to HER2 levels; and HER2 expression decreased at resistance. A previous study suggested that HER2 quantitative continuous score (QCS) could potentially predict outcome to T-DXd in patients with HER2-low mBCAlthough T-DXd anti-tumor activity increased when HER2 expression was high, modest anti-tumor activity was also observed in patients with HER2 IHC 0. This suggests that very low levels of HER2 could allow uptake of T-DXd and/or that drug efficacy could be partially mediated by HER2-independent mechanisms. A study that involved 18 pathologists showed a low level of concordance (26%) to score HER2 IHC 0 and 1+ (ref. Although numbers are small and should be interpreted cautiously, the confirmed objective response was slightly lower in patients with HER2-overexpressing mBC who became HER2-low after baseline biopsy. This finding could be relevant to interpret the DB-02 and DB-03 studies where patients received multiple lines of prior anti-HER2 therapies.While efficacy of second-generation ADCs, such as T-DM1, was strongly associated with target expressionWe observed a lower median PFS in the DAISY trial than in previously reported studies testing the efficacy of T-DXd. PFS was longer in the DB-02 (ref. The safety profile of T-DXd in our study was similar to previous reportsPreclinical data showed that T-DXd increased tumor-infiltrating dendritic cells and CD8Although HER2 expression substantially decreased at the time of resistance to T-DXd, there is no robust evidence that a reduction of T-DXd uptake is the dominant mechanism of resistance in the present study. Indeed, T-DXd was still distributed in the cancer cells in four of six patients at the time of resistance. Unfortunately, no quantitative comparison of T-DXd uptake could be done during treatment and at resistance. In a case report, resistance to sacituzumab govitecan, an ADC targeting TROP2, was associated with Our trial has several limitations. We did not include negative controls for HER2 expression assessment at resistance; the number of samples analyzed was small; and there was no validation cohort for several of the translational objectives.The present study suggests that HER2 is a determinant of sensitivity to T-DXd, although modest anti-tumor activity was also observed in a small subset of patients whose cancer did not express HER2, suggesting other mechanisms of action. Resistance to T-DXd may occur at different levels, potentially involving decrease of HER2 expression, alterations of the cytotoxic effect of DXd and the tumor microenvironment. These data indicate that precision medicine approaches based on molecular analyses will be necessary to optimize treatment after resistance to T-DXd.