Protocol version B included the following amendments: -To clarify and simplify the guidance regarding capecitabine dose modifications for toxicity; -To clarify that left ventricular ejection fraction (LVEF) assessments performed locally will also be read centrally by an Independent Review Facility (IRF). All patient management decisions will be made by the Investigator based on the local LVEF assessments. The Independent Data Monitoring Committee (IDMC) will review both local and central LVEF results as part of their interim safety data review.; -To clarify that MRI or PET scans are allowed as an alternative to isotope bone scans at Investigator sites where there is a lack of radioisotope. Skeletal X-rays can now be used instead of bone scans for tumour assessments if there is no suitable alternative.; -Information on concomitant medication within 90 days prior to randomization is collected.; -Clarification regarding patient contact following premature withdrawal.; -To clarify that death due solely to progression of the underlying malignancy is not reported as an SAE.; -To clarify recording of deaths and provides information on SUSAR reporting.; -Clarification regarding the time interval allowed following the previous dose of pertuzumab/trastuzumab before the patient is required to be withdrawn from all study treatment.

Protocol version C included the following amendments: -The IDMC, at its kick-off meeting, recommended additional cardiac safety monitoring as a precautionary measure to provide added reassurance to what was already in the protocol. Their recommendation is not as a result of any emergent safety signal observed in the study. The protocol has been amended to incorporate the IDMC recommendations regarding additional cardiac monitoring. As recommended by the IDMC, all additional cardiac safety assessments are to be performed on new patients randomized into the study. For those patients already in the study, any remaining additional cardiac assessments are to be performed. The additional cardiac assessments on all patients in the study are to continue until the IDMC recommends that they are no longer required.; -Exclusion criteria amended to clarify that patients with known infection with HIV, HBV or HCV, either active infection or carriers, are not eligible for the study.

Protocol version D included the following amendments: -Statistical analysis plan (SAP): Revision to the final OS analysis timepoint from death or withdrawals in 90% of enrolled patients to death in 67% of enrolled patients (approximately 300 deaths), Incorporation of an interim OS analysis at the time of the primary PFS endpoint analysis of 337 IRF−assessed PFS events, Addition of a 2-year truncated OS analysis as a secondary endpoint; -Now referred to as a Phase III rather than a Phase II study; -If any analysis of OS meets the predefined criteria for statistical significance and is considered clinically meaningful, pertuzumab (in addition to current study drugs) will be offered to those patients who are still on treatment in the comparator arm (Arm A).; -After the cutoff for the primary PFS analysis, tumor assessments are to continue per protocol until investigator−assessed progressive disease. However, no additional IRF reviews will be performed. -After the cutoff for the final OS analysis, tumor assessments are to continue according to routine clinical practice until investigator-assessed progressive disease.; The IDMC met on 17 April 2013 to review the safety data in patients in the MO22324 study. No safety concerns were identified. The Sponsor and the IDMC have agreed that the additional assessments that had been previously implemented in Protocol Amendment C as a precautionary measure at the request of the IDMC are now no longer required. Patients will continue to have cardiac monitoring, and all other cardiac assessments will be performed.; -All patients will enter a 2 year safety follow-up.; -Potential Hy’s law cases are to be reported to the Sponsor within 24 hours as non-serious AE of special interest.

Protocol version E included the following amendments: -To clarify that all patients should be followed for survival until the planned final OS analysis after 300 deaths.; -A change to the duration of required contraceptive use and the prohibition of breastfeeding from 6 to 7 months after receipt of the final dose of all study drugs for consistency with the updated pharmacokinetic (PK) findings for trastuzumab. This change was not based on any new safety findings, and the benefit−risk assessment for patients treated with trastuzumab remains positive.; -The mandatory baseline serum samples that have been collected in Study MO22324 will not be immediately used to measure HER2-ECD (human epidermal growth factor receptor-2, extracellular domain) and HER ligands. However, the mandatory blood samples will be retained in case improved technology becomes available in the future for HER ligands and/or if a strong scientific rationale evolves to measure HER2-ECD.; -Those patients who are still on capecitabine study drug treatment will be informed about additional possible side effects, in line with the recent update to the Xeloda® IB, version 16.