• Text was added to the section on administration of neoadjuvant chemotherapy to be in line with the French regulatory authority’s recommendation. • Administrative changes were made.

• Three exclusion criteria were clarified. • To avoid repetition of procedures at Screening, an update was made to allow results from previous assessments (even if they had occurred before the signing of informed consent) to be used as screening procedures as long as they were within 28 days of randomisation. • Text was clarified and editorial/administrative changes were implemented where appropriate.

• The period that women of childbearing potential had to agree to use contraception was increased from 6 to 7 months in line with updated SmPC for Herceptin®. • Results from a bilateral mammography performed within 6 weeks before randomisation was now acceptable as a screening procedure because significant changes in a few weeks were unlikely. • A definition of disease stage when tumour size was 2.0 cm (T1) was added to the stratification factors. • A paragraph on pooling data from centres for the efficacy analysis was deleted because subjects were randomised by country not centre. • The axillary staging procedures were updated in accordance with recent breast surgery guidelines. • Text was further clarified and editorial/administrative changes were implemented where appropriate.

• Determination of sample size and its rationale was updated as a result of newly found literature and references added to the bibliography [Chang, 2008]. The expected bpCR rate was changed from 40% to 37.5%, the number of evaluable subjects to meet an 80% power changed from 220 to 358 subjects per arm and the equivalence margin changed from within 15% to 0.785 to 1.546. The number of subjects to be randomised was therefore changed from 249 to 403 per arm and the expected dropout rate changed from 12% to 11%. • The number of subjects to be randomised was increased from 498 to 806 and the expected recruitment period increased from 12 to 15 months. • The criteria for declaring equivalence between the two treatments (primary efficacy endpoint) was modified: From: Equivalence between the two treatment groups will be declared if the two-sided 95% (CI) of the difference in the pCR rate between treatments is entirely contained within the equivalence margin of [-15%, 15%]. The two-sided 95% CI of the difference will be estimated for the PPS. To: To demonstrate equivalence in the pCR rate between the two treatment groups in accordance with both FDA and EMA recommendation, the ratio and the difference in pCR rate will be analysed for the primary analysis. Equivalence will be declared if the two-sided 95% (CI) of the ratio in the pCR rate between treatments is entirely contained within the equivalence margin of [0.785, 1.546] or, if the 95% CI of the difference in the pCR rate between treatments is entirely contained within the equivalence margin of [-13%, 13%]. The 95% CIs of the difference will be estimated for the PPS. The difference of pCR will be used for EMA submission and the relative ratio of pCR will be used for FDA submission.

• References (different versions of NCI-CTCAE) to be used to grade the severity of AEs of CHF, left ventricular dysfunction and febrile neutropenia were added. • Sample size for PK Population was amended from 270 (135 per arm) to 300 subjects (150 per arm). The expected non-evaluable rate was updated from 22% to 30%. • Clarifications were made to PK sample procedures. • More detail and clarification was added to the sections on dose modification and delays of IP and non-IP. • Premature withdrawal criteria were updated with regard to allowed treatment delays. • In Appendix 4 of the protocol, a section was added on quality control of pCR by central review. • In the case of high-risk subjects, G-CSF was allowed as a primary prophylaxis for neutropenic events. • Text was further clarified and editorial/administrative changes were implemented where appropriate.