Exclusion criterion 10 (inadequate bone marrow function) was deleted. This criterion is used for (dis)continuation of chemotherapy, not for (dis)continuation of trastuzumab. Safety lab was determined at screening, but bone marrow function was not used for in/exclusion. The sample size was corrected from 150 to 128. Trastuzumab SC vials were added as IMP because vials were used as back-up in case of SID failure. Furthermore, a description on how to handle SID failure was added. Text was added to indicate that also HCP could return the SID to the hospital. Text was added to indicate that the ICF had to be signed within 28 days to first dose. Visit windows were added to Protocol Section 4.4.2.1, and the time point for completion of the questionnaires was clarified and a time window was added to Protocol Section 4.4.7. The option of paper questionnaires was added to Protocol Section 7.3. MRI was deleted as a method for left ventricular ejection fraction (LVEF) measurement because this is only done by echocardiography (ECHO) or multiple gated acquisition (MUGA). Time points for cardiac safety assessments were added to Protocol Section 5.1.2 following addition of an extra schedule of assessments (see below). A schedule of assessment for patients that received 6 cycles of trastuzumab prior to the study was added and time of assessments were corrected throughout the protocol. Further revisions to the schedule of assessments were made to clarify which assessments needed to be done at which time point, and a time window for PK sampling "within 1 day before administration" and a note [t] concerning hematology and chemistry were added.

The time point for completion of the questionnaires was clarified and a time window was added in Protocol Section 3.9.4. In inclusion criterion 6, the text 'except for patients in the neo-adjuvant setting' was deleted because this study only included patients in the adjuvant setting, and the text ‘in combination with chemotherapy’ was added to be compliant with the guidelines for breast cancer therapy. In inclusion criterion 7, LVEF was adjusted from ≥55% to ≥50% in line with the Dutch guidelines for mamma care "mammacarcinoom richtlijn, 2.0", which states that LVEF needs to be 50%-55% shortly before start of trastuzumab. In inclusion 7 criterion, the text ‘Except in case patient received anthracycline treatment previously then documented results within an acceptable limit from a cardiac assessment within 14 days prior to enrolment.’ was added. A section on Adverse Events of Special Interest (AESI) was added. In the schedule of assessment, LVEF at Cycle 1 Day 1 was deleted due to the change in inclusion criterion 7; the LVEF occurred at screening within 14 days prior to enrolment for all patients that received anthracycline treatment previously and did not need to be repeated at Cycle 1 Day 1.

The Multiplex Ligation-dependent Probe Amplification (MLPA) method was added as an additional test to determine HER2 status. The use of hormonal auterine devices (IUDs) was clarified in exclusion criterion 6. The time window for completion of the SF-36 en MASQ questionnaires was clarified (within one week after dosing at Cycles 3 and 9).