INTRODUCTION: Trastuzumab deruxtecan (T-DXd) is a HER2-directed antibody-drug conjugate indicated for the treatment of unresectable or metastatic HER2-positive breast cancer in patients who have received a prior anti-HER2-based regimen. T-DXd is also indicated for unresectable or metastatic HER2-low breast cancer, following prior chemotherapy in the metastatic setting or recurrent disease within six months of adjuvant chemotherapy. This study aims to evaluate the efficacy and safety of T-DXd in treating HER2-positive and HER2-low metastatic breast cancer (MBC) patients in a real-world clinical setting. In the T-DXd pivotal research, imaging assessments were conducted every six weeks with CT or MRI, but outside of a clinical trial setting, this frequent imaging is practically challenging due to resources and difficulty in reimbursing. In addition to clinical outcome assessments, we sought to review the incidence of pneumonitis in a real-world setting and to assess if the three-monthly response assessment scans would be sufficient to rule out asymptomatic pneumonitis. METHODS: A retrospective analysis was conducted on 100 patients diagnosed with HER2-positive (immunohistochemistry (IHC) 3+ or in situ hybridization (ISH) positive) or HER2-low (IHC 1+ or IHC 2+ and ISH negative) MBC treated with T-DXd at 5.4 mg/kg every 21 days, with standardized dose adjustments as required. Treatment was continued until disease progression or unacceptable toxicity. The median follow-up duration was 15 months. Responses were assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria, and toxicity was determined using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Data analysis was performed using SPSS IBM software version 26 (IBM Corp., Armonk, New York, NY, US). RESULTS: The median age of the patients was 47 years, ranging from 29 to 86 years, with the majority being younger than 65 and predominantly women. All patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 at baseline. Most patients were HER2-positive, while a smaller proportion were classified as HER2-low. A significant number of patients presented with visceral disease, while a smaller subset had brain metastases at the time of baseline evaluation. Nearly half of the patients were hormone receptor-positive (HR+), and more than half had a high Ki-67 index of over 20%. The majority of patients received T-DXd as a second- or third-line treatment. Clinical responses included partial response, complete response, and stable disease. Survival outcomes showed high overall survival rates at 12 and 24 months, with a median progression-free survival (PFS) of 24 months. Only one patient experienced grade 3 pneumonitis, suggesting that 12-weekly imaging assessments may be adequate for monitoring most patients. CONCLUSIONS: Our real-world experience confirms that the efficacy of T-DXd in UAE is consistent with published data from published phase 3 clinical trials. The incidence of clinical pulmonary toxicity is much lower than anticipated, and until further data is available, it may be reasonable to continue using the 12-weekly assessment scans to monitor patients for interstitial lung disease (ILD). Further studies are needed to determine the optimal imaging frequency for monitoring ILD.