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

Inclusion criteria

• Signed written informed consent
• Histologically confirmed primary invasive breast cancer
• 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 or histology)
• HER2 overexpression defined as circumferential membrane staining that is complete, intense and in \>10% of invasive tumor cells (IHC 3+) on pre-treatment biopsy
• 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 are immunoreactive in the presence of evidence that the sample can express ER and/or PR
• WHO performance status 0-1
• Age ≥ 18 years
• LVEF ≥50% measured by echocardiography or MUGA
• Eligible for neoadjuvant treatment
• Laboratory requirements within 21 days prior to enrollment:
• Adequate bone marrow function (ANC ≥1.5 x 109/l, platelets ≥100 x 109/l);
• Adequate hepatic function (ALAT, ASAT and bilirubin ≤2.5 times upper limit of normal). Subjects with Gilbert's syndrome may have a total bilirubin ≥2.5 × the ULN range, if no evidence of biliary obstruction exists.
• Adequate renal function: creatinine clearance \>50 ml/min estimated using the Cockcroft-Gault equation or MDRD equation, or based on a 24-hour urine collection measurement.

Exclusion criteria

• Current pregnancy or breastfeeding
• Current or previous other malignancy unless treated without systemic therapy and more than five years ago
• Psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
• Use of a strong CYP3A4 or CYP2C8 inhibitor within five half-lives of the inhibitor, or used a strong CYP3A4 or CYP2C8 inducer within five days prior to first dose of study treatment
• Known chronic liver disease
• History of inflammatory bowel disease or bowel resection
• Contraindications for MRI
• Inflammatory breast cancer, cT4 and/or cN3 tumors
• Occult breast cancer (cT0)