Neoadjuvant Trastuzumab, Pertuzumab and Tucatinib Without Chemotherapy in HER2-positive Breast Cancer: the TRAIN-4 Study

Inclusion Criteria:

1. Signed written informed consent
2. Histologically confirmed primary invasive breast cancer
3. Stage II - IIIA primary breast cancer according to TNM-staging (8th edition, AJCC); (largest tumor diameter on DCE-MRI ≥ 2cm (cT2-3) and/or cN1-2 confirmed with FNA orhistology)
4. HER2 overexpression defined as circumferential membrane staining that is complete,intense and in >10% of invasive tumor cells (IHC 3+) on pre-treatment biopsy
5. Known estrogen- and progesterone-receptor expression of the invasive tumor a. ER-negative or PR-negative is defined as <10% of invasive tumor cell nuclei areimmunoreactive in the presence of evidence that the sample can express ER and/or PR
6. WHO performance status 0-1
7. Age ≥ 18 years
8. LVEF ≥50% measured by echocardiography or MUGA
9. Eligible for neoadjuvant treatment
10. Laboratory requirements within 21 days prior to enrollment:
11. Adequate bone marrow function (ANC ≥1.5 x 109/l, platelets ≥100 x 109/l);
12. Adequate hepatic function (ALAT, ASAT and bilirubin ≤2.5 times upper limit ofnormal). Subjects with Gilbert's syndrome may have a total bilirubin ≥2.5 × theULN range, if no evidence of biliary obstruction exists.
13. Adequate renal function: creatinine clearance >50 ml/min estimated using theCockcroft-Gault equation or MDRD equation, or based on a 24-hour urine collectionmeasurement.

Exclusion Criteria:

1. Current pregnancy or breastfeeding
2. Current or previous other malignancy unless treated without systemic therapy and morethan five years ago
3. Psychological, familial, sociological, or geographical condition potentially hamperingcompliance with the study protocol and follow-up schedule
4. Use of a strong CYP3A4 or CYP2C8 inhibitor within five half-lives of the inhibitor, orused a strong CYP3A4 or CYP2C8 inducer within five days prior to first dose of studytreatment
5. Known chronic liver disease
6. History of inflammatory bowel disease or bowel resection
7. Contraindications for MRI
8. Inflammatory breast cancer, cT4 and/or cN3 tumors
9. Occult breast cancer (cT0)