Protocol version 2.0 dd 14MAY2007. The main reason for this amendment is to extend the patient population to a subpopulation of large operable tumor with a worse prognosis than the global population of patients with large operable breast cancer (this worse prognosis is mainly due to the HER2 overexpression of these tumours). This subpopulation will consist of cT3cN0,1 any ER or cT2cN1 any ER or cT2cN0 ER negative. The dose levels have been amended by increasing alternatively the dose of Lapatinib and Docetaxel in order to properly document the relationship dose - safety profile and to understand whether we will obtain more anti-HER1/2 activity from a daily dose of 1250 mg than 1000 mg of Lapatinib. Please note that the content of Patient Information Sheet/Informed Consent and the summary of the protocol have not been modified by this substantial amendment, only the version has been updated according to the last version of the protocol.

Protocol version 3.0 , 20 February 2008 • The addition of a third treatment arm in order to assess the pathological complete response rate after the combination of trastuzumab + Lapatinib which implies the increase of patient population to 180 patients (30 patients for the phase I and 150 patients for the phase II) • The continuation of the adjuvant setting with the same anti-HER2 treatment used in the neo-adjuvant setting in combination with Docetaxel. • The Update of toxicity profile of Lapatinib due to the edition of a new Investigator’s Brochure

Protocol version 4.0, 9 July 2008 • The Update of the Investigator's Brochure, Protocol and the PIS/IC according to new data provided by GSK provided on the risk of hepatotoxicity of Lapatinib and it's management. • New Phase II secondary endpoints defined: In the context of the comparison between different neoadjuvant treatment regimens the possibility of the breast conservation measured by the rate of breast conserving surgery was added as secondary endpoint. • The recommendations regarding the Locoregional therapy after the chemotherapy had to be added in a tentative to make it uniform, improving the possibility to analyse the rate of breast conserving surgery as a secondary endpoint. • The removal of bridge step.

Protocol Version 5, March 09, 2009 • The escalation of dose to dose level 6: the addition of a test of the original dose level 6 (Docetaxel 100 mg/m2 and Lapatinib 1250 mg/day) with primary prophylactic GCSF. • The implementation of the Trastuzumab (Q3 Weeks) for one year as adjuvant treatment after surgery for all patients in the 3 arms.

Protocol version 6.0 , 26 may 2010 The main reasons for this substantial amendment to the protocol are the following: • The protocol and the patient information sheet have been updated according to new data gathered during the phase I part of the trial. For information, the intermediate Phase I report is already available and is appended • The Eligibility criteria have been reviewed. • New data emerging from two other published large trials using the same investigational medicinal products have identified diarrhea as a major safety issue. As a consequence, it has been decided to de-escalate the recommended dose of lapatinib from 1250mg to 1000mg daily and to modify the sequence of administration starting first by the combination with anti-HER-2 treatment followed by FEC. • To implement also guidelines for management of cardiac toxicity, diarrhea and interstitial lung disease.

Protocol version 7.0 dated 14OCT2010 • The protocol chapter (5.7) for concomitant medications has been updated regarding the drug interactions with lapatinib and the use with caution of the following medications: telithromycin, posaconazole, quinidine, cisapride, pimozide, repaglinide, digoxin. • A new protocol chapter (5.7.2.3) on overdose management has been added • The patient information sheet has been updated regarding the risk of acute renal failure in case of severe dehydration and the risk of hypersensitivity reactions.

Protocol version 8.0 dated 19DEC2011

Protocol version 9.0 dated 30OCT2012 Rationale for the amendment and its classification: Initial plan Phase I: depending on the toxicity profile, the phase I part of the study would enroll 12 to 30 patients Phase II: 150 patients randomized Arm 1:50 on docetaxel+lapatinib, Arm 2:50 on docetaxel+trastuzumab Arm 3:50 on docetaxel+lapatinib+trastuzumab Data conducted in different settings are all pointing in the same direction: that lapatinib monotherapy plus chemotherapy is either less effective, or not inferior to but more toxic, than chemotherapy plus Trastuzumab. As a consequence the following was decided in June 2012: - To close arm 1 for futility based on new information external to the trial. - To pursue the randomized Phase II study with 2 arms (arm 2 with docetaxel plus weekly trastuzumab and arm 3 with docetaxel plus weekly trastuzumab and lapatinib All centers have been informed accordingly in June 2012. Patients were allowed to be randomized only in the two remaining arms since then and until the enrollment of the last patient which took place on 29 January 2013. Therefore we declare the end of recruitment date to be the 29th of January 2013. Patients enrolled into the original first randomized arm that was discontinued, will be analyzed as a separate group in the final analysis. This arm will be too small for conclusions. So this can be called an exploratory analysis. Also, the preliminary analysis of the Phase I PharmacoKinetics samples have led to the conclusion that new PK analysis during the phase II will not give any new information. As a consequence, it has been decided to stop collecting PK samples in February 2012. The centers have been informed accordingly at that time.