Inclusion Criteria:
* Women or men aged ≥18 years at the time of informed consent.
* Histologically or cytologically confirmed breast cancer with documented HER2-positive status, defined as immunohistochemistry (IHC) 3+ or IHC 2+ with in situ hybridization (ISH) amplification ratio ≥2.0 or average HER2 copy number ≥6.0 signals/cell, per ASCO/CAP guidelines \[31\]. HER2 status may be determined on primary tumour or metastatic biopsy.
* Radiologically confirmed metastatic disease (Stage IV) with first diagnosis of BMs documented on contrast-enhanced magnetic resonance imaging (MRI) of the brain performed within 28 days prior to enrolment.
* Brain metastases amenable to SRS/fSRT, defined as 1 to 10 intracranial lesions with a cumulative planned target volume (PTV) ≤20.0 mL. Individual lesion diameter must not exceed 30 mm in the longest axis.
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1 at screening.
* Stable or decreasing corticosteroid dose equivalent to ≤4 mg/day dexamethasone for a minimum of 5 consecutive days prior to Day 1 of Cycle 1.
* Adequate organ function documented within 14 days prior to enrolment, defined as:
* Absolute neutrophil count (ANC) ≥1.5 × 10⁹/L
* Platelet count ≥100 × 10⁹/L
* Haemoglobin ≥9.0 g/dL (transfusion permitted if stable for ≥7 days)
* Total bilirubin ≤1.5 × upper limit of normal (ULN); ≤3 × ULN if documented Gilbert syndrome Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 × ULN (≤5 × ULN if liver metastases present)
* Estimated creatinine clearance ≥30 mL/min (Cockcroft-Gault formula)
* Left ventricular ejection fraction (LVEF) ≥50% by echocardiography or multigated acquisition (MUGA) scan within 28 days of enrolment
* Adequate pulmonary function defined as oxygen saturation ≥92% on room air at rest and no clinical or radiographic evidence of interstitial lung disease (ILD) or pneumonitis on baseline chest computed tomography (CT) performed within 28 days of enrolment.
* For women of childbearing potential: negative serum pregnancy test within 7 days prior to Day 1 of Cycle 1 and agreement to use highly effective contraception (combined hormonal or intrauterine device or bilateral tubal occlusion or vasectomized partner or sexual abstinence) from screening through at least 7 months after the last dose of T-DXd. For men with female partners of childbearing potential: agreement to use barrier contraception from screening through at least 4 months after the last dose of T-DXd.
* Ability to understand and willingness to sign a written informed consent document in accordance with ICH E6(R2) Good Clinical Practice guidelines and local regulatory requirements \[16\].
* Willingness and ability to comply with scheduled visits, treatment plan, imaging assessments (see Section 8), and laboratory evaluations for the duration of the study.
Exclusion Criteria:
* Prior treatment with T-DXd or any other HER2-directed antibody-drug conjugate employing a topoisomerase I inhibitor payload in the metastatic setting. Patients with metastatic disease who previously received T-DXd in the (neo)adjuvant setting are eligible, provided that at least 24 months have elapsed since the last T-DXd administration and that disease progression did not occur during T-DXd treatment.
* Leptomeningeal carcinomatosis confirmed by cerebrospinal fluid cytology or unequivocal MRI findings (linear or nodular leptomeningeal enhancement with associated clinical symptoms).
* Any prior radiation therapy to the brain.
* Brain metastases requiring urgent neurosurgical intervention (e.g., lesions causing midline shift \>5 mm, obstructive hydrocephalus, or impending herniation).
* Significant cardiovascular disease, including:
* LVEF \<50% at screening History of New York Heart Association (NYHA) Class III or IV congestive heart failure
* Myocardial infarction within 6 months prior to enrolment
* History of non-infectious ILD/pneumonitis requiring systemic corticosteroids, or current ILD/pneumonitis of any grade, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
* Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals at the time of enrolment.
* Known active hepatitis B (HBsAg positive with detectable HBV DNA), active hepatitis C (detectable HCV RNA), or known HIV infection with CD4 count \<200 cells/μL or detectable viral load.
* Active autoimmune disease requiring systemic immunosuppressive therapy (\>10 mg/day prednisone equivalent) within 14 days prior to enrolment. Replacement-dose corticosteroids (e.g., for adrenal insufficiency) and topical, inhaled, or ophthalmic corticosteroids are permitted.
* Major surgical procedure within 28 days prior to enrolment or anticipated need for major surgery during the study treatment period.
* Concurrent malignancy requiring active systemic treatment, with the exception of adequately treated non-melanoma skin cancer, carcinoma in situ of the cervix, or other malignancies in complete remission for ≥3 years.
* Known hypersensitivity to T-DXd, other antibody-drug conjugates, or any excipient of the investigational product formulation (L-histidine, L-histidine hydrochloride monohydrate, sucrose, polysorbate 80).
* Pregnancy, lactation, or intention to become pregnant during the study or within 7 months after the last dose of T-DXd.
* Any condition that, in the investigator's judgment, would compromise the patient's ability to comply with study procedures, confound interpretation of study results, or pose unacceptable risk to the patient.
* Concurrent participation in another interventional clinical trial with an investigational medicinal product. Participation in observational studies or registries is permitted.
