Amendment 1 (20 Aug 2012): A window of opportunity sub-study (n = 60) was included, to compare the predictive value of several biomarkers for resistance to HER2 targeted therapy, in a cohort treated with either trastuzumab, pertuzumab, or a combination of both agents. In this substudy, HER2-positive subjects received 6 weeks of treatment with either trastuzumab, pertuzumab or combination of both. The clinical response after 6 weeks and biomarker profile was compared between groups and correlated to response after the addition of 4 cycles of taxane and at the end of the main study. Amendment 1 also changed the cut-off for definition of HER2-positive disease by in situ hybridization from ≥ 2.2 to ≥ 2.0 according to FDA as well American Society of Clinical Onocology (ASCO)/ College of American Pathologists (CAP) therapy recommendations.

An interim safety analysis of data was performed for the first 60 subjects to complete systemic treatment with nab-paclitaxel 150 mg/m2 (n = 30) or sb-paclitaxel (n = 30) which revealed that the nab-paclitaxel dose of 150 mg/m2 was observed to have a higher incidence of non hematological toxicities (Jackisch, 2013). In particular, there was a higher incidence in the nab-paclitaxel group compared with the sb-paclitaxel group for the following: - Peripheral sensory neuropathy (73.3% vs 43.3% for all grades, and 10% vs 0% for Grade 3-4). - Incidence of treatment discontinuation (26.7% vs 3.3%, respectively) and - Incidence of dose reductions (33.3% vs 13.3%, respectively). These observations led to an agreement with the IDMC to amend the study and reduce the nab-paclitaxel dose to 125 mg/m2 QW. The amendment also required that subjects with Grade 2 PSN did not receive further nab-paclitaxel dosing until resolution to Grade ≤ 1. In case of resolution to Grade ≤ 1 therapy of the subsequent applications was continued with reduced dose in a 3 of 4 schedule, i.e. 3 applications, the next was cancelled, etc. If symptoms were not resolved to Grade ≤ 1 within 3 weeks, taxane treatment had to be stopped definitively. In case of Grade 3/4 PSN taxane treatment had to be stopped. An additional interim analysis was conducted to include another 60 subjects who were already enrolled and treated, in which a continued imbalance of PSN was observed which was higher for subjects in the nab-paclitaxel group compared with the sb-paclitaxel group. Prior to the implementation of the amended dose level, 38% (464/1229) of subjects had already been recruited into the Trial.

Prior to Amendment 3, follow-up of subjects post-surgery was limited to the collection of health status based on yearly chart reviews or information from the GBG registry of previous study participants. Amendment 3 clarified that follow-up will continue until the analysis of invasive disease-free survival (IDFS) (and other time-to-event secondary endpoints) after 248 progression events have occurred. This is anticipated to occur at the end of 2017/early 2018, approximately 5 years after the first subject was enrolled. A secondary endpoint was added to assess quality of life, with a focus on PN (using the Functional Assessment of Cancer Therapy [FACT]-Taxane [version 4] questionnaire) and on cardiac toxicity. Secondary endpoints were also added to correlate pCR rate with circulating tumor DNA at the time of surgery, to identify early relapses based on circulating tumor deoxyribonucleic acid (DNA) during follow up, to collect information about BRCA status and other mutations, and to assess smoking habits and alcohol consumption in relation to efficacy and safety of treatment and genetic changes in the tumor. To support these objectives, the following information will be collected during follow up: - Clinical history (including smoking habits and alcohol consumption) and concomitant medication - Symptoms and toxicities (including cardiac toxicities) - FACT-Taxane (version 4) questionnaire to assess quality of life with a focus on PN - Treatment of (persisting) PN