This is a multicenter, prospective, non-randomized, open-label, pharmacokinetic study, aiming to compare the plasma exposure of the payload (free-DXd) in patients treated by T-DXd for locally advanced or metastatic breast cancer according to their BMI.

The primary objective is to compare plasma exposition of the payload (free-DXd) between overweight or obese (BMI>25) and normal weight (BMI≤25) breast cancer patients during the first 3 cycles of Trastuzumab-Deruxtecan (T-DXd).

A total of 210 patients will have to be enrolled in this study with the following repartition:

N = 105 patients with a BMI ≤ 25 (normal weight patients). N = 105 patients with a BMI > 25 (overweight or obese patients) with at least 30 obese patients (BMI>30).

Inclusion Criteria:

1. Women (or men) aged ≥ 18 years on the day of signing the informed consent with histologically proven breast cancer.

2. Metastatic or locally advanced breast cancer with overexpression/amplification HER2 (IHC +++ or ++ and positive-hybridation in situ) or low HER2 expression (IHC + or ++ and negative-hybridation in situ) and may be ultra-low (in first line, in case of approval).

3. Patient eligible for Trastuzumab-Deruxtecan (T-DXd).

4. Concomitant administration of pertuzumab may be accepted in case of approval in first line for HER2- overexpressed/amplified locally advanced or metastatic breast cancer.

5. Female subjects of childbearing potential must have a negative pregnancy test within 72 hours prior to receiving the first dose of study treatment.

6. Female subjects of childbearing potential must be willing to follow at least one method of contraception or be surgically sterile, or abstain from heterosexual activity for the duration of the study and until 7 months after the last dose of study treatment. Subjects of childbearing potential are those who have not been surgically sterilized and who had menstruation in the last 12 months.

   Note: Abstinence is acceptable if it is the subject's usual lifestyle and preferred method of contraception.

7. Male subjects must agree to use at least one method of contraception for the duration of the study and until 4 months after the last dose of study treatment.

   Note: Abstinence is acceptable if it is the subject's usual lifestyle and preferred method of contraception.

8. Signed written informed consent.

9. Patient able to participate and willing to give informed consent prior performance of any study-related procedures and to comply with the study protocol.

10. Patient affiliated to a Social Health Insurance in France.

Exclusion Criteria:

1. Peripheral venous access making blood samples difficult.
2. Patients unable to receive T-DXd treatment at a dose of 5.4 mg/kg in cycle 1 (whatever the reason)
3. Patients with known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
4. Patients with any other significant medical, psychiatric, or surgical condition, currently uncontrolled by treatment, which may interfere with completion of the study.
5. Patient pregnant, or breast-feeding.
6. Any psychological, familial, geographic or social situation, according to the judgment of investigator, potentially preventing the provision of informed consent or compliance to study procedure.
7. Patient who has forfeited his/her freedom by administrative or legal award or who is under legal protection (curatorship and guardianship, protection of justice).
8. Concurrent participation in an experimental drug study.
9. Patient with a known history of hypersensitivity to the active substance of T-DXd or to any of the excipients listed in the SmPC of T-DXd.
10. Patient with severe hepatic impairment defined by TGO and/or TGP > 5 x ULN and Total bilirubin > 1.5 x ULN.