This is a prospective non-interventional, multicenter study observing patient reported outcomes as well as real-world efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients with documented Human epidermal growth factor receptor 2 (HER2)-positive, HER2-low or HER2-ultralow unresectable or metastatic breast cancer (BC) receiving T-DXd in line with the applicable summary of product characteristics (SmPC) within routine clinical practice in Germany. In addition, patients will be informed about use of digital healthcare application (DiGA).

Eligible participants will be those patients with documented HER2-positive, HER2-low or HER2-ultralow unresectable or metastatic BC receiving T-DXd treatment in line with the applicable summary of product characteristics (SmPC) within routine clinical practice.

All diagnostic and treatment procedures including visit frequency are at the discretion of the treating physician and not defined by the protocol. T-DXd treatment is considered as a selection criteria. Patients will be informed about use of digital healthcare application (DiGA).

Approximately 800 eligible participants will be enrolled which includes 400 patients in the HER2-positive cohort and 400 patients in the HER2-low/ HER2-ultralow cohort.

Inclusion Criteria:

1. Adults ≥ 18 years old

2. Patients (irrespective of sex and gender) with pathologically documented breast cancer that:

   • is unresectable or metastatic
   • has confirmed HER2+, HER2-low or HER2-ultralow tumor status by local pathology
   • was previously treated with one or more anti-HER2 directed therapy if the tumor is HER2+ OR
   • was previously treated with at least one endocrine therapy in the metastatic setting and is not considered suitable for endocrine therapy as the next line of treatment if the tumor is HR+, HER2-low or HER2-ultralow OR
   • was previously treated with prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy if the tumor is HER2-low.

3. Has documented radiologic progression (during or after most recent treatment)

4. Patient is eligible for T-DXd treatment in line with the specifications mentioned in the ENHERTU® SmPC and is scheduled for T-DXd treatment *

5. Patient is able to read and understand either German or English

6. Signed written informed consent

   • The prescription of the medicinal product is clearly separated from the decision to include the patient in this NIS.

Exclusion Criteria:

1. Start of T-DXd treatment for more than 30 days before enrolment (eCRF registration date)
2. Known hypersensitivity to T-DXd or any of the excipients of the drug
3. Pregnancy or breast feeding
4. Current or planned participation in an interventional clinical trial
5. Current or planned systemic treatment of any tumor other than unresectable or metastatic BC

Patients who have never received any T-DXd dose will be discontinued from the study and will be considered as a late screening failure, no further documentation besides reason and date of discontinuation is needed.

Patients with documented Human epidermal growth factor receptor 2 (HER2)-positive, HER2-low or HER2-ultralow unresectable or metastatic breast cancer (BC) receiving T-DXd in line with the applicable summary of product characteristics (SmPC) within routine clinical practice may participate in this NIS.

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal.

All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure