ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) study. A randomised, multi-centre, open-label, phase III study of adjuvant lapatinib, trastuzumab, their sequence and their combination in patients with HER2/ErbB2 positive primary breast cancer.

INTERVENTION: Trade Name: Tyverb Product Name: Lapatinib Product Code: GW572016 Pharmaceutical Form: Film‐coated tablet INN or Proposed INN: Lapatinib ditosylate CAS Number: 388082‐78‐8 Current Sponsor code: GW572016 Other descriptive name: Lapatinib ditosylate monohydrate Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 250‐ Trade Name: Herceptin Product Name: Trastuzumab Pharmaceutical Form: Powder for solution for infusion INN or Proposed INN: Trastuzumab CAS Number: 18022‐69‐1 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 150‐ CONDITION: Operable primary breast cancer with over expression/ amplification of HER2. ; MedDRA version: 20.0 Level: PT Classification code 10006187 Term: Breast cancer System Organ Class: 10029104 ‐ Neoplasms benign, malignant and unspecified (incl cysts and polyps) PRIMARY OUTCOME: Main Objective: The primary objective for this study is to compare disease‐free survival (DFS) in patients with ErbB2 (HER2) overexpressing and/or amplified breast cancer randomised to trastuzumab for one year versus lapatinib for one year versus weekly trastuzumab (12 weeks) followed by a six‐week washout period followed by lapatinib (34 weeks) versus trastuzumab in combination with lapatinib for one year. Primary end point(s): The primary endpoint for analysis is disease‐free survival (DFS) which will be defined as the time from randomisation until the first occurrence of: ; 1. Breast cancer recurrence at any site;; 2. A second primary cancer (invasive contralateral breast or non‐breast malignancy);; 3. Death from any cause as first event. Secondary Objective: The secondary objectives of the study are to evaluate and compare the following criteria between treatment arms: Overall survival (OS), time to recurrence (TTR), time to distant recurrence (TTDR), cumulative incidence of brain metastases as the first site of breast cancer recurrance. In addition the safety and tolerability of all four treatment groups will be evaluated.; Exploratory Translational Research Objective: To evaluate the quantative HER2 protein and/or HER2 domain levels; (e.g. presence or absence of p95 HER2 domain or ratio of intracellular and extracellular HER2 expression; levels) and determine the relationship with response to HER2 targeted agents and clinical outcome. INCLUSION CRITERIA: 1. Age > or = 18 years; 2. Eastern Cooperative Oncology Group performance status < or = 1; 3. Non‐metastatic operable primary invasive adenocarcinoma of the breast fulfilling the following: a. Histologically confirmed; b. Adequately excised (exceptions: patients who have 'non‐resectable' deep margin invasion or histologically documented infiltration of the skin (pT4) are eligible provided they have had or will receive radiotherapy); c. Axilla dissected; sentinel node sampling is allowed provided that axillary dissection follows confirmation of a positive sentinel node (sentinel node sampling alone is not acceptable after neo‐adjuvant chemotherapy); d. Axillary node positive patient or node negative patient with a tumor of more than 1 cm in greatest diameter (> or = T1c); 4. Known hormone receptor status (ER/PgR or ER alone); 5. Must have received at least four cycles of an approved anthracycline‐based (neo‐) a