Inclusion Criteria:  Male or female, Age ≥18; Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1; Histologically confirmed HER2 positive breast cancer, with HER2 positive defined by in situ hybridization (ISH), immunohistochemistry (IHC), or fluorescence in situ hybridization (FISH) methodology; Documented isolated brain progression (defined as new or progressive brain metastases with stable or responding systemic disease) under pertuzumab and trastuzumab treatment (with or without taxane) for metastatic disease (There is no limit to the number and size of brain metastasis); Complete local treatment of brain progression (Surgery and/or radiation therapy) should have been completed no more than 12 weeks before inclusion and there is no clinical indication for immediate re-treatment with local therapy in the opinion of the investigator; Able to undergo MRI scanning of the brain; Normal renal function: creatinine <1.5 x upper limit of normal (ULN); Adequate liver function: total bilirubin ≤1.5 ULN (unless documented Gilbert's syndrome); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 ULN (≤5 ULN in the presence of liver metastases); Normal hematological function: Absolute neutrophil count (ANC) ≥1.5 x 10⁹/L; platelets count ≥100 x 10⁹/L; and hemoglobin ≥9.0 g/dL;  Adequate cardiac functions, including:  12 Lead electrocardiograms (ECG) with normal tracing or non-clinically significant changes that do not require medical intervention QT/Corrected QT interval (QTc) ≤470 msec for woman and ≤450 msec for men (mean of replicate values, correction per institutional standard) on the ECG at the screening visit and a normal kalemia Left ventricular ejection fraction (LVEF) ≥50% No history of Torsades de Pointes or other symptomatic QTc abnormality Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to NCI CTCAE version 5.0 Grade 1 or to baseline (except alopecia or others toxicities not considered a safety risk for the patient at investigator's discretion); Stable dose of steroids at the time of enrolment; Women of childbearing potential must have a negative pregnancy test (blood or urine test) within 14 days prior to inclusion; Woman of childbearing potential and male patients must agree to use adequate contraception for the duration of trial participation and up to 7 months after completing treatment/therapy (association of trastuzumab, pertuzumab +/- tucatinib). Hormonal contraceptives such as birth control pills, patches, implants, or injections are not allowed in patients who are hormone receptor positive; Patient must have signed a written informed consent form prior to any trial specific procedures. When the patient is physically unable to give their written consent, a trusted person of their choice, independent from the investigator or the sponsor, can confirm in writing the patient's consent; Patients affiliated to the social security system (or equivalent); Patient must be willing and able to comply with the protocol for the duration of the trial including scheduled visits, treatment plan, laboratory tests, and examinations including follow-up.  Exclusion Criteria:  Radiologic extra-cranial progression under pertuzumab and trastuzumab treatment, at the time of enrolment. The systemic disease must be stable or responding at the time of enrolment; Proven leptomeningeal disease; Any progressive brain lesion between the brain local treatment completion and the enrolment; Poorly controlled seizures (more than 1/week); Clinically significant cardiopulmonary disease; Used of a strong cytochrome P450 (CYP)2C8 inhibitor within 5 half-lives of the inhibitor, or use of a strong CYP3A4 or CYP2C8 inducer within 5 days prior to first dose of study treatment. Use of sensitive CYP3A substrates should be avoided one week before enrollment and during study treatment Previous treatment with a tyrosine kinase inhibitor; Carriers of Hepatitis B or Hepatitis C or have other known chronic liver disease; Positive for human immunodeficiency virus (HIV); Known prior severe hypersensitivity to tucatinib or compounds chemically or/and biologically similar or any component in its formulation; History of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix) unless the patient has been in remission and off all other cancer therapy for at least 3 years; Pregnant women or women who are breast-feeding; Inability to swallow tablets or significant gastrointestinal disease which would preclude the adequate oral absorption of medications; Person deprived of their liberty or under protective custody or guardianship or unable to give informed consent; Participation in another therapeutic trial within the 30 days prior to tucatinib treatment initiation.