Tucatinib and Trastuzumab in HER3-mutant and HER2-not Amplified Metastatic Breast Cancer

Inclusion Criteria: * Age ≥ 18 years * Metastatic or unresectable breast cancer * HER2-negative (defined as having an IHC 0+, IHC 1+, or IHC 2+ and ISH non-amplified, per ASCO/CAP guidelines) on last assessable tumor sample * Having received ≥ 2 previous chemotherapy lines for advanced breast cancer: including at least one line of conjugated antibody, at the investigator's discretion or if a germinal BRCA mutation is present, a PARP inhibitor. * Class IV or V somatic ERBB3 mutation as determined on a tumor sample obtained during the molecular screening step * ECOG performance status ≤ 2 (Appendix A) * Evaluable disease, per RECIST v1.1 inclusion criteria * Left ventricular ejection fraction (LVEF) ≥50% as assessed by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) documented within 4 weeks prior to first dose of study treatment * Adequate organ function: 1. Creatinine clearance ≥ 50 mL/min as calculated per institutional guidelines 2. Total bilirubin ≤1.5 X upper limit of normal (ULN), except for patients with known Gilbert's disease, who may enroll if the conjugated bilirubin is ≤1.5 X ULN. 3. Transaminases (aspartate aminotransferase and alanine aminotransferase) ≤ 2.5 X ULN (≤ 5 X ULN if the patient has liver metastases) * Women of childbearing potential (WCBP) must have a negative serum pregnancy test \< 7 days prior to first dose of treatment. A woman is considered of childbearing potential following menarche and until becoming post-menopausal unless permanently sterile. A postmenopausal state is defined as the absence of menses for 12 months without an alternative cause. * WCBP (as defined above) and men with partners of childbearing potential must agree to use a highly effective birth control method during the study and for 3 months after completion of investigational treatment. * Patients should be eligible for the treatment step according to the investigator's opinion. * Patients must be covered by a health insurance plan. * Patients able to provide signed informed consent. Exclusion Criteria: * Having received any prior treatment targeting HER2. Prior treatment with trastuzumab deruxtecan is allowed, per label, in patients with HER2-low metastatic breast cancer (IHC 1+ or 2+, ISH non-amplified) * History of allergic reactions to trastuzumab or tucatinib or chemically similar drugs * Patients who are pregnant, breastfeeding, or planning a pregnancy from time of informed consent until 7 months after the final dose of study drug * Inability to swallow pills or having a significant gastro-intestinal disease or a history of surgery which would preclude the adequate oral absorption of medications * Having used a strong CYP2C8 inhibitor within a duration of 5 half-lives prior to the first dose of study treatment, or have used a strong CYP3A4 or CYP2C8 inducer within 5 days prior to first dose of study treatment (see Appendix B and Appendix C) * Treatment with any systemic anti-cancer therapy (including hormonal therapy), non-central nervous system (CNS) radiation, or experimental agent ≤ 3 weeks prior to the first dose of study treatment, except gonadotropin releasing hormone (GnRH) agonists * Participation in another interventional clinical trial. * Symptomatic and untreated brain metastases or brain metastases requiring urgent treatment, or brain metastases requiring a dose \> 2 mg of dexamethasone (or equivalent) * Whole brain radiotherapy \< 21 days prior to first dose of treatment, stereotactic radiotherapy \< 7 days prior to first dose of treatment * Leptomeningeal metastases * Major surgery (including surgery of brain metastases) \< 21 days prior to first dose of treatment * Evidence within 2 years of the start of study treatment of another malignancy that required systemic treatment * Have known myocardial infarction or unstable angina within 24 weeks prior to first dose of study treatment * Have clinically significant cardiopulmonary disease such as: * Ventricular arrhythmia requiring therapy, * Uncontrolled hypertension (defined as persistent systolic blood pressure \>150 mmHg and/or diastolic blood pressure \> 100 mm Hg on antihypertensive medications) * Any history of symptomatic congestive heart failure * Severe dyspnea at rest (CTCAE v5.0 Grade 3 or above) due to complications of advanced malignancy * Hypoxia requiring supplementary oxygen therapy except when oxygen therapy is needed only for obstructive sleep apnea * Presence of ≥ Grade 2 QTc prolongation on screening ECG * Conditions potentially resulting in drug-induced prolongation of the QT interval or torsade de pointes: * Congenital or acquired long QT syndrome * Family history of sudden death * History of previous drug-induced QT prolongation * Current use of medications with known and accepted associated risk of QT prolongation (see row "Accepted Association" in Appendix D) * Are known carriers of active Hepatitis B or Hepatitis C or have other known chronic liver disease * Are known to be positive for human immunodeficiency virus (HIV) * Altered mental status or psychiatric disorder that, in the opinion of the investigator, would preclude a valid patient informed consent. * Patients who have difficulty undergoing trial procedures for geographic, social or psychological reasons * Person deprived of liberty or under guardianship