Clarification and details of IHC and ISH assays used for determining HER2 status were made. Inclusion of patients who had received dose-dense chemotherapy regimens, provided at least 8 weeks of taxane-based therapy and at least 8 weeks of trastuzumab had been given. Revision of language to differentiate radiotherapy for T3 disease with and without lymph node involvement. Recommendations for hormonal therapy were revised to allow 5 to 10 years, rather than only 5 years, of tamoxifen therapy as a result of changing practice guidelines. Guidelines for managing the specific adverse events of nodular regenerative hyperplasia and interstitial lung disease were added. For nodular regenerative hyperplasia, a new appendix for guidelines for liver biopsy was added. Radiotherapy-related toxicity was split into interstitial lung disease and skin toxicity, in order to differentiate between radiation-induced and drug-induced toxicities. Text on use of strong/potent CYP3A4/5 inhibitors was revised to provide further instruction to investigators, and remove erythromycin from the list of examples as it is only a moderate CYP3A4/5 inhibitor, not a potent inhibitor. Suspected transmission of an infection agent by the study drug was added as an adverse event of special interest.

The duration of patient monitoring following first dose of trastuzumab emtansine was changed from 60 minutes to 90 minutes. Assessment of total protein at baseline was added to the list of assessments because it was inadvertently omitted. Requirements for long-term reporting of concomitant medication, adverse events and serious adverse events were clarified. Detail on severe/fatal hemorrhage was added under the identified risk of hematologic toxicity.

Addition of language to allow shorter duration of an escalated dose-dense administration of paclitaxel. Inclusion criteria were revised to clarify that if pre-chemotherapy LVEF assessments were not conducted, the screening LVEF assessment must be at least 55% in order for the patient to be eligible. Dose modifications related to increases in AST and for thrombocytopenia were revised. Guidelines for Grade 1-2 pneumonitis were updated such that to require diagnosis of drug-related ILD/pneumonitis should lead to permanent discontinuation of trastuzumab emtansine treatment.

The reporting of LVSD events as SAEs was clarified. Pregnancy reporting requirements were updated, in line with the Global Enhancement Pharmacovigilance Pregnancy Program.

Updated to correct a small but significant error in language in the general inclusion critieria, and indicate that left ventricular ejection fraction (LVEF) should be ≥50% prior to receiving neoadjuvant chemotherapy instead of after receiving neoadjuvant chemotherapy.