Background: Trastuzumab–deruxtecan (T-DXd), a new-generation antibody drug conjugate, has greatly improved the survival and clinical benefit rates of patients affected by advanced HER2-positive/HER2-low breast cancer according to the results of controlled clinical trials with a manageable safety profile. Data from randomized clinical trials can provide valuable information for the management of patients in everyday clinical practice, including those who would typically be excluded from such trials due to not meeting the inclusion criteria. Methods: In this narrative review, we describe and discuss real-world studies in the literature on the use of T-Dxd in HER2-positive and HER2-low MBC patients, providing a critical analysis of the specific settings of clinical interest. Results: Using a PubMed search, we identified nine real-world studies on T-DXd that are available in the literature. A total of 7146 patients have been included in these retrospective studies. A total of 5/9 studies also included HER2-low MBC patients. In the majority of cases, patients had high disease burden with lung and liver involvement. We then reviewed and discussed clinical areas of interest, including heavily pretreated patients, poor performance status, HER2-positive versus HER2-low disease, brain metastasis, elderly patients, lung toxicity, safety profile, and dose modifications. Conclusions: Our analysis confirms the activity of the drug described in real-world studies and shows a favorable safety profile, with manageable adverse effects.

PREDICT v2.2 is a prognostic tool used to estimate 5- and 10-year overall survival (OS) rates in early-stage breast cancer (BC). While it has been validated in several populations, limited data exist on its performance in cohorts derived from randomized clinical trials. This study analyzed individual data from patients with early-stage BC enrolled in five phase III randomized clinical trials conducted by the Gruppo Italiano Mammella (GIM) and Mammella InterGruppo (MIG) between 1992 and 2012. Patients with stage IV disease, prior neoadjuvant therapy, or missing data were excluded. PREDICT v2.2 was used to calculate 5- and 10-year OS predictions. Observed survival was derived using Kaplan-Meier estimates, and the model's calibration and discriminatory accuracy were evaluated. Among the 6205 patents included, the median predicted 5-year OS was 87.1%, while the observed 5-year OS was 93.0%, resulting in an underestimation of 5.6% [95% confidence interval (CI) 5.0% to 6.3%]. Similarly, the predicted 10-year OS was 73.8%, compared with an observed OS of 82.1%, with an underestimation of 8.3% (95% CI 7.2% to 9.4%). Discrimination was moderate, with area under the curve values of 66.2% (95% CI 63.5% to 68.9%) at 5 years and 63.9% (95% CI 61.7% to 66.1%) at 10 years. Subgroup analyses revealed that underestimations were more pronounced in patients with human epidermal growth factor 2-positive tumors, larger tumor sizes, or older age. PREDICT v2.2 underestimates 5- and 10-year OS in a clinical trial-derived population of early-stage BC patients. Despite reasonable accuracy, its performance is influenced by specific patient and tumor characteristics. Regular updates are necessary to ensure its applicability in contemporary clinical practice.