Trial Outcomes & Findings for Study in Participants With Early-Stage or Locally Advanced Human Epidermal Growth Factor Receptor (HER) 2-Positive Breast Cancer to Evaluate Treatment With Trastuzumab Plus (+) Pertuzumab + Docetaxel Compared With Trastuzumab + Placebo + Docetaxel (NCT NCT02586025)

NCT ID: NCT02586025

Last Updated: 2023-05-22

Results Overview

This tpCR was assessed by the IRC. tpCR was defined as the absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes after completion of neoadjuvant therapy and surgery (that is, ypT0/is, ypN0, in accordance with the current American Joint Committee on Cancer \[AJCC\] staging system). The analysis was based on the ITT population with participants grouped by the treatment assigned at the time of randomization. Participants whose tpCR assessment was missing or invalid were counted as not achieving tpCR. The duration of one treatment cycle was 21 days; the administration of therapy in Cycle 5 did not occur until 2 weeks after surgery. The percentages have been rounded off to first decimal point.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 329 participants
• Primary outcome timeframe: At surgery (Cycle 4 Days 22-35)
• Results posted on: 2023-05-22

Participant Flow

A total of 329 participants with early-stage or locally advanced human epidermal growth factor receptor (HER) 2-positive breast cancer were enrolled in this study at 23 investigative sites in China, Republic of Korea, Taiwan, and Thailand from 14 March 2016 to 14 March 2022.

Participant milestones

Measure	Pertuzumab, Trastuzumab, and Chemotherapy Prior to surgery: Participants received trastuzumab, 8 milligrams per kilograms (mg/kg) loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, pertuzumab, 840 milligrams (mg) loading dose in Cycle 1, followed by 420 mg from Cycles 2-4, and docetaxel, 75 milligrams per square meter (mg/m\^2) from Cycles 1-4 (1 cycle = 21 days) by intravenous (IV) infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and pertuzumab, 840 mg loading dose in Cycle 8, followed by 420 mg from Cycles 9-20 (1 cycle = 21 days).	Placebo, Trastuzumab, and Chemotherapy Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, docetaxel, 75 mg/m\^2 and placebo from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and placebo from Cycles 8-20 (1 cycle =21 days).
Neoadjuvant Treatment STARTED	219	110
Neoadjuvant Treatment Received at Least One Dose of Study Treatment	218	110
Neoadjuvant Treatment Completed Neoadjuvant Treatment	214	108
Neoadjuvant Treatment Underwent Surgery	210	105
Neoadjuvant Treatment COMPLETED	208	103
Neoadjuvant Treatment NOT COMPLETED	11	7
Adjuvant Treatment STARTED	208	103
Adjuvant Treatment Started Adjuvant FEC Treatment	208	103
Adjuvant Treatment Started Adjuvant Anti-HER2 Treatment	204	99
Adjuvant Treatment COMPLETED	198	94
Adjuvant Treatment NOT COMPLETED	10	9
Treatment-Free Follow-Up STARTED	208	104
Treatment-Free Follow-Up COMPLETED	175	82
Treatment-Free Follow-Up NOT COMPLETED	33	22

Reasons for withdrawal

Measure	Pertuzumab, Trastuzumab, and Chemotherapy Prior to surgery: Participants received trastuzumab, 8 milligrams per kilograms (mg/kg) loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, pertuzumab, 840 milligrams (mg) loading dose in Cycle 1, followed by 420 mg from Cycles 2-4, and docetaxel, 75 milligrams per square meter (mg/m\^2) from Cycles 1-4 (1 cycle = 21 days) by intravenous (IV) infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and pertuzumab, 840 mg loading dose in Cycle 8, followed by 420 mg from Cycles 9-20 (1 cycle = 21 days).	Placebo, Trastuzumab, and Chemotherapy Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, docetaxel, 75 mg/m\^2 and placebo from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and placebo from Cycles 8-20 (1 cycle =21 days).
Neoadjuvant Treatment Withdrawal by Subject	4	3
Neoadjuvant Treatment Progression of Disease	2	3
Neoadjuvant Treatment Did Not Receive Study Drug	1	0
Neoadjuvant Treatment Death	1	0
Neoadjuvant Treatment Adverse Event	1	0
Neoadjuvant Treatment Physician Decision	2	1
Adjuvant Treatment Withdrawal by Subject	5	3
Adjuvant Treatment Recurrent Disease	4	5
Adjuvant Treatment Physician Decision	0	1
Adjuvant Treatment Pregnancy	1	0
Treatment-Free Follow-Up Death	11	11
Treatment-Free Follow-Up Lost to Follow-up	9	4
Treatment-Free Follow-Up Withdrawal by Subject	13	3
Treatment-Free Follow-Up Non-compliance	0	1
Treatment-Free Follow-Up Reason Not Specified	0	3

Baseline Characteristics

ITT Population

Baseline characteristics by cohort

Measure	Pertuzumab, Trastuzumab, and Chemotherapy n=219 Participants Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, pertuzumab, 840 mg loading dose in Cycle 1, followed by 420 mg from Cycles 2-4, and docetaxel, 75 mg/m\^2 from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and pertuzumab, 840 mg loading dose in Cycle 8, followed by 420 mg from Cycles 9-20 (1 cycle = 21 days).	Placebo, Trastuzumab, and Chemotherapy n=110 Participants Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, docetaxel, 75 mg/m\^2 and placebo from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and placebo from Cycles 8-20 (1 cycle =21 days).	Total n=329 Participants Total of all reporting groups
Age, Continuous	48.4 years STANDARD_DEVIATION 9.7 • n=219 Participants	49.5 years STANDARD_DEVIATION 9.1 • n=110 Participants	48.8 years STANDARD_DEVIATION 9.5 • n=329 Participants
Age, Customized <40 years old	40 Participants n=219 Participants	18 Participants n=110 Participants	58 Participants n=329 Participants
Age, Customized 40-49 years old	75 Participants n=219 Participants	40 Participants n=110 Participants	115 Participants n=329 Participants
Age, Customized 50-64 years old	96 Participants n=219 Participants	44 Participants n=110 Participants	140 Participants n=329 Participants
Age, Customized ≥65 years old	8 Participants n=219 Participants	8 Participants n=110 Participants	16 Participants n=329 Participants
Sex: Female, Male Female	219 Participants n=219 Participants	110 Participants n=110 Participants	329 Participants n=329 Participants
Sex: Female, Male Male	0 Participants n=219 Participants	0 Participants n=110 Participants	0 Participants n=329 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=219 Participants	0 Participants n=110 Participants	0 Participants n=329 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	219 Participants n=219 Participants	110 Participants n=110 Participants	329 Participants n=329 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=219 Participants	0 Participants n=110 Participants	0 Participants n=329 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=219 Participants	0 Participants n=110 Participants	0 Participants n=329 Participants
Race (NIH/OMB) Asian	219 Participants n=219 Participants	110 Participants n=110 Participants	329 Participants n=329 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=219 Participants	0 Participants n=110 Participants	0 Participants n=329 Participants
Race (NIH/OMB) Black or African American	0 Participants n=219 Participants	0 Participants n=110 Participants	0 Participants n=329 Participants
Race (NIH/OMB) White	0 Participants n=219 Participants	0 Participants n=110 Participants	0 Participants n=329 Participants
Race (NIH/OMB) More than one race	0 Participants n=219 Participants	0 Participants n=110 Participants	0 Participants n=329 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=219 Participants	0 Participants n=110 Participants	0 Participants n=329 Participants
Disease Category Early Stage	152 Participants n=219 Participants • ITT Population	77 Participants n=110 Participants • ITT Population	229 Participants n=329 Participants • ITT Population
Disease Category Locally Advanced	67 Participants n=219 Participants • ITT Population	33 Participants n=110 Participants • ITT Population	100 Participants n=329 Participants • ITT Population
Hormone Receptor Status Estrogen Receptor (ER) and Progesterone Receptor (PgR) Negative	105 Participants n=219 Participants	54 Participants n=110 Participants	159 Participants n=329 Participants
Hormone Receptor Status Estrogen Receptor (ER) and/or Progesterone Receptor (PgR) Positive	114 Participants n=219 Participants	56 Participants n=110 Participants	170 Participants n=329 Participants
Baseline LVEF value	66.41 percentage points of LVEF STANDARD_DEVIATION 4.93 • n=218 Participants • Safety Evaluable Population; only participants who received at least one dose of study drug are included.	66.03 percentage points of LVEF STANDARD_DEVIATION 5.19 • n=110 Participants • Safety Evaluable Population; only participants who received at least one dose of study drug are included.	66.28 percentage points of LVEF STANDARD_DEVIATION 5.01 • n=328 Participants • Safety Evaluable Population; only participants who received at least one dose of study drug are included.

PRIMARY outcome

Timeframe: At surgery (Cycle 4 Days 22-35)

Population: ITT population included all participants who were enrolled regardless of whether they received any study treatment.

This tpCR was assessed by the IRC. tpCR was defined as the absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes after completion of neoadjuvant therapy and surgery (that is, ypT0/is, ypN0, in accordance with the current American Joint Committee on Cancer [AJCC] staging system). The analysis was based on the ITT population with participants grouped by the treatment assigned at the time of randomization. Participants whose tpCR assessment was missing or invalid were counted as not achieving tpCR. The duration of one treatment cycle was 21 days; the administration of therapy in Cycle 5 did not occur until 2 weeks after surgery. The percentages have been rounded off to first decimal point.

Outcome measures

Measure	Pertuzumab, Trastuzumab, and Chemotherapy n=219 Participants Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, pertuzumab, 840 mg loading dose in Cycle 1, followed by 420 mg from Cycles 2-4, and docetaxel, 75 mg/m\^2 from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and pertuzumab, 840 mg loading dose in Cycle 8, followed by 420 mg from Cycles 9-20 (1 cycle = 21 days).	Placebo, Trastuzumab, and Chemotherapy n=110 Participants Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, docetaxel, 75 mg/m\^2 and placebo from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and placebo from Cycles 8-20 (1 cycle =21 days).
Percentage of Participants With Total Pathologic Complete Response (tpCR) as Assessed by the Independent Review Committee (IRC)	39.3 percentage of participants Interval 32.76 to 46.08	21.8 percentage of participants Interval 14.51 to 30.7

SECONDARY outcome

Timeframe: At surgery (Cycle 4 Days 22-35)

Population: ITT population included all participants who were enrolled regardless of whether they received any study treatment.

This tpCR was assessed by the local pathologist. tpCR was defined as the absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes after completion of neoadjuvant therapy and surgery (that is, ypT0/is, ypN0, in accordance with the current AJCC staging system). The analysis was based on the ITT population with participants grouped by the treatment assigned at the time of randomization. Participants whose tpCR assessment was missing or invalid were counted as not achieving tpCR. The duration of one treatment cycle was 21 days; the administration of therapy in Cycle 5 did not occur until 2 weeks after surgery. The percentages have been rounded off to first decimal point.

Outcome measures

Measure	Pertuzumab, Trastuzumab, and Chemotherapy n=219 Participants Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, pertuzumab, 840 mg loading dose in Cycle 1, followed by 420 mg from Cycles 2-4, and docetaxel, 75 mg/m\^2 from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and pertuzumab, 840 mg loading dose in Cycle 8, followed by 420 mg from Cycles 9-20 (1 cycle = 21 days).	Placebo, Trastuzumab, and Chemotherapy n=110 Participants Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, docetaxel, 75 mg/m\^2 and placebo from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and placebo from Cycles 8-20 (1 cycle =21 days).
Percentage of Participants With tpCR as Assessed by the Local Pathologist	39.3 percentage of participants Interval 32.76 to 46.08	20.9 percentage of participants Interval 13.74 to 29.7

SECONDARY outcome

Timeframe: At surgery (Cycle 4 Days 22-35)

Population: ITT population included all participants who were enrolled regardless of whether they received any study treatment.

This bpCR was assessed by the IRC. bpCR was defined as the absence of any residual invasive cancer on the hematoxylin and eosin evaluation of the resected breast specimen after completion of neoadjuvant therapy and surgery (that is, ypT0/is, in accordance with current AJCC staging system). The analysis was based on the ITT population with participants grouped by the treatment assigned at the time of randomization. Participants whose bpCR assessment was missing or invalid were counted as not achieving bpCR. The duration of one treatment cycle was 21 days; the administration of therapy in Cycle 5 did not occur until 2 weeks after surgery. The percentages have been rounded off to first decimal point.

Outcome measures

Measure	Pertuzumab, Trastuzumab, and Chemotherapy n=219 Participants Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, pertuzumab, 840 mg loading dose in Cycle 1, followed by 420 mg from Cycles 2-4, and docetaxel, 75 mg/m\^2 from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and pertuzumab, 840 mg loading dose in Cycle 8, followed by 420 mg from Cycles 9-20 (1 cycle = 21 days).	Placebo, Trastuzumab, and Chemotherapy n=110 Participants Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, docetaxel, 75 mg/m\^2 and placebo from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and placebo from Cycles 8-20 (1 cycle =21 days).
Percentage of Participants With Breast Pathologic Complete Response (bpCR), Defined as ypT0/is According to the AJCC Staging System as Assessed by the IRC	42.0 percentage of participants Interval 35.39 to 48.85	23.6 percentage of participants Interval 16.06 to 32.68

SECONDARY outcome

Timeframe: At surgery (Cycle 4 Days 22-35)

Population: ITT population included all participants who were enrolled regardless of whether they received any study treatment.

This bpCR was assessed by the local pathologist. bpCR was defined as the absence of any residual invasive cancer on the hematoxylin and eosin evaluation of the resected breast specimen after completion of neoadjuvant therapy and surgery (that is, ypT0/is in accordance with current AJCC staging system). The analysis was based on the ITT population with participants grouped by the treatment assigned at the time of randomization. Participants whose bpCR assessment was missing or invalid were counted as not achieving bpCR. The duration of one treatment cycle was 21 days; the administration of therapy in Cycle 5 did not occur until 2 weeks after surgery. The percentages have been rounded off to first decimal point.

Outcome measures

Measure	Pertuzumab, Trastuzumab, and Chemotherapy n=219 Participants Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, pertuzumab, 840 mg loading dose in Cycle 1, followed by 420 mg from Cycles 2-4, and docetaxel, 75 mg/m\^2 from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and pertuzumab, 840 mg loading dose in Cycle 8, followed by 420 mg from Cycles 9-20 (1 cycle = 21 days).	Placebo, Trastuzumab, and Chemotherapy n=110 Participants Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, docetaxel, 75 mg/m\^2 and placebo from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and placebo from Cycles 8-20 (1 cycle =21 days).
Percentage of Participants With bpCR as Assessed by the Local Pathologist	41.6 percentage of participants Interval 34.95 to 48.39	22.7 percentage of participants Interval 15.28 to 31.7

SECONDARY outcome

Timeframe: At surgery (Cycle 4 Days 22-35)

Population: ITT population included all participants who were enrolled regardless of whether they received any study treatment.

Clinical responses that include percentage of participants with a CR, PR, SD, or PD were determined by investigator during Cycles 1-4 (prior to surgery) on basis of RECIST version 1.1. CR=disappearance of all target lesions i.e., any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 millimeters (mm). PR=at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. SD=neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum during the study. PD=at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum during the study (nadir) with inclusion of baseline. Only participants with measurable disease at baseline were included in the analysis. 1 Cycle=21 days. The percentages have been rounded off to first decimal point.

Outcome measures

Measure	Pertuzumab, Trastuzumab, and Chemotherapy n=219 Participants Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, pertuzumab, 840 mg loading dose in Cycle 1, followed by 420 mg from Cycles 2-4, and docetaxel, 75 mg/m\^2 from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and pertuzumab, 840 mg loading dose in Cycle 8, followed by 420 mg from Cycles 9-20 (1 cycle = 21 days).	Placebo, Trastuzumab, and Chemotherapy n=110 Participants Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, docetaxel, 75 mg/m\^2 and placebo from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and placebo from Cycles 8-20 (1 cycle =21 days).
Percentage of Participants With Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD) During Cycles 1-4, According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Complete Response	11.0 percentage of participants Interval 7.15 to 15.87	10.0 percentage of participants Interval 5.1 to 17.19
Percentage of Participants With Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD) During Cycles 1-4, According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Partial Response	77.6 percentage of participants Interval 71.52 to 82.97	68.2 percentage of participants Interval 58.62 to 76.74
Percentage of Participants With Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD) During Cycles 1-4, According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Stable Disease	8.2 percentage of participants Interval 4.94 to 12.68	19.1 percentage of participants Interval 12.22 to 27.69
Percentage of Participants With Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD) During Cycles 1-4, According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Progressive Disease	0.5 percentage of participants Interval 0.01 to 2.52	1.8 percentage of participants Interval 0.22 to 6.41
Percentage of Participants With Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD) During Cycles 1-4, According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Missing or Unevaluable	2.7 percentage of participants 95% confidence intervals were only calculated for clinical responses.	0.9 percentage of participants 95% confidence intervals were only calculated for clinical responses.

SECONDARY outcome

Timeframe: At surgery (Cycle 4 Days 22-35)

Population: ITT population included all participants who were enrolled regardless of whether they received any study treatment.

An objective response was defined as the percentage of participants who achieved a CR or PR as the best tumor response during the neoadjuvant period (that is, during Cycles 1-4 prior to surgery), as determined by the investigator on the basis of RECIST version 1.1. CR=disappearance of all target lesions i.e., any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR=at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. No confirmation was required for objective response. Only participants with measurable disease at baseline were included in the analysis. The duration of one treatment cycle was 21 days; the administration of therapy in Cycle 5 did not occur until 2 weeks after surgery. The percentages have been rounded off to first decimal point.

Outcome measures

Measure	Pertuzumab, Trastuzumab, and Chemotherapy n=219 Participants Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, pertuzumab, 840 mg loading dose in Cycle 1, followed by 420 mg from Cycles 2-4, and docetaxel, 75 mg/m\^2 from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and pertuzumab, 840 mg loading dose in Cycle 8, followed by 420 mg from Cycles 9-20 (1 cycle = 21 days).	Placebo, Trastuzumab, and Chemotherapy n=110 Participants Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, docetaxel, 75 mg/m\^2 and placebo from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and placebo from Cycles 8-20 (1 cycle =21 days).
Percentage of Participants With an Objective Response (CR or PR) During Cycles 1-4, According to RECIST Version 1.1	88.6 percentage of participants Interval 83.61 to 92.47	78.2 percentage of participants Interval 69.3 to 85.49

SECONDARY outcome

Timeframe: From Baseline to EFS event or date last known to be alive and event-free at 1, 3, and 5 years

Population: ITT population included all participants who were enrolled regardless of whether they received any study treatment. Number analyzed per timepoint are unique number of participants out of all the assessed participants who remain at risk for an EFS event at that timepoint. Different participants may have contributed data for each timepoint.

Kaplan-Meier approach was used to estimate percentage of participants who were event-free for EFS at 1, 3 & 5 years. EFS=time from randomization to first documentation of one of the following events: PD (before surgery) as determined by investigator with RECIST v1.1. PD=at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum during the study (nadir) with inclusion of baseline. Any evidence of contralateral disease in situ was not identified as PD; Disease recurrence (local, regional, distant, or contralateral) after surgery; Death from any cause. After treatment completion/discontinuation, follow-up data was collected every 3 months for 1 year & then every 6 months thereafter, until disease progression/recurrence or until 5 years after randomization of last participant, whichever occurred first. Participants without an EFS event at time of analysis were censored as of the date they were last known to be alive & event-free.

Outcome measures

Measure	Pertuzumab, Trastuzumab, and Chemotherapy n=219 Participants Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, pertuzumab, 840 mg loading dose in Cycle 1, followed by 420 mg from Cycles 2-4, and docetaxel, 75 mg/m\^2 from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and pertuzumab, 840 mg loading dose in Cycle 8, followed by 420 mg from Cycles 9-20 (1 cycle = 21 days).	Placebo, Trastuzumab, and Chemotherapy n=110 Participants Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, docetaxel, 75 mg/m\^2 and placebo from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and placebo from Cycles 8-20 (1 cycle =21 days).
Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Event-Free Survival (EFS) at 1, 3, and 5 Years 1 Year	98.62 estimate of percentage of participants Interval 97.06 to 100.0	90.46 estimate of percentage of participants Interval 84.82 to 96.09
Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Event-Free Survival (EFS) at 1, 3, and 5 Years 3 Years	88.85 estimate of percentage of participants Interval 84.55 to 93.15	79.68 estimate of percentage of participants Interval 71.91 to 87.45
Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Event-Free Survival (EFS) at 1, 3, and 5 Years 5 Years	84.80 estimate of percentage of participants Interval 79.86 to 89.73	73.70 estimate of percentage of participants Interval 65.17 to 82.23

SECONDARY outcome

Timeframe: From surgery (Cycle 4: Days 22-35) to DFS event or date last known to be alive and event-free at 1, 3, and 5 years

Population: ITT population included all participants who were enrolled regardless of whether they received any study treatment. Overall number of participants analyzed are unique number of participants who underwent surgery. Number analyzed per timepoint are unique number of participants out of all the assessed participants who remain at risk for a DFS event at that timepoint. Different participants may have contributed data for each timepoint.

Kaplan-Meier approach was used to estimate the percentage of participants who were event-free for DFS at 1, 3 and 5 years. DFS = time from first date of no disease (i.e., date of surgery) to first documentation of one of the following events: Disease recurrence (local, regional, distant, or contralateral) after surgery or death from any cause. After treatment completion/discontinuation, follow-up data was collected every 3 months for 1 year and then every 6 months thereafter, until disease progression or recurrence or until 5 years after randomization of the last participant, whichever occurred first. Participants were considered to be disease-free if they underwent surgery and no recurrence of disease was reported thereafter. Data from participants who did not have an event at analysis were censored as of the date they were last known to be alive and event-free.

Outcome measures

Measure	Pertuzumab, Trastuzumab, and Chemotherapy n=210 Participants Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, pertuzumab, 840 mg loading dose in Cycle 1, followed by 420 mg from Cycles 2-4, and docetaxel, 75 mg/m\^2 from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and pertuzumab, 840 mg loading dose in Cycle 8, followed by 420 mg from Cycles 9-20 (1 cycle = 21 days).	Placebo, Trastuzumab, and Chemotherapy n=105 Participants Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, docetaxel, 75 mg/m\^2 and placebo from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and placebo from Cycles 8-20 (1 cycle =21 days).
Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Disease-Free Survival (DFS) at 1, 3, and 5 Years 1 Year	97.55 estimate of percentage of participants Interval 95.42 to 99.67	92.08 estimate of percentage of participants Interval 86.81 to 97.35
Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Disease-Free Survival (DFS) at 1, 3, and 5 Years 3 Years	90.09 estimate of percentage of participants Interval 85.97 to 94.22	81.10 estimate of percentage of participants Interval 73.44 to 88.75
Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Disease-Free Survival (DFS) at 1, 3, and 5 Years 5 Years	85.99 estimate of percentage of participants Interval 81.17 to 90.8	75.02 estimate of percentage of participants Interval 66.53 to 83.51

SECONDARY outcome

Timeframe: From Baseline to OS event or date last known to be alive at 1, 3, and 5 years

Population: ITT population included all participants who were enrolled regardless of whether they received any study treatment. Number analyzed per timepoint are unique number of participants out of all the assessed participants who remain at risk for an OS event at that timepoint. Different participants may have contributed data for each timepoint.

Kaplan-Meier approach was used to estimate the percentage of participants who were event-free for OS at 1, 3 and 5 years. OS was defined as the time from randomization to death from any cause. After treatment completion/discontinuation, follow-up data was collected every 3 months for 1 year and then every 6 months thereafter, until disease progression or recurrence or until 5 years after randomization of the last participant, whichever occurred first. Data from participants who were alive at the time of the analysis was censored as of the last date they were known to be alive.

Outcome measures

Measure	Pertuzumab, Trastuzumab, and Chemotherapy n=219 Participants Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, pertuzumab, 840 mg loading dose in Cycle 1, followed by 420 mg from Cycles 2-4, and docetaxel, 75 mg/m\^2 from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and pertuzumab, 840 mg loading dose in Cycle 8, followed by 420 mg from Cycles 9-20 (1 cycle = 21 days).	Placebo, Trastuzumab, and Chemotherapy n=110 Participants Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, docetaxel, 75 mg/m\^2 and placebo from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and placebo from Cycles 8-20 (1 cycle =21 days).
Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Overall Survival (OS) at 1, 3, and 5 Years 1 Year	99.54 estimate of percentage of participants Interval 98.64 to 100.0	100.00 estimate of percentage of participants Interval 100.0 to 100.0
Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Overall Survival (OS) at 1, 3, and 5 Years 3 Years	97.01 estimate of percentage of participants Interval 94.64 to 99.37	90.99 estimate of percentage of participants Interval 85.37 to 96.6
Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Overall Survival (OS) at 1, 3, and 5 Years 5 Years	93.86 estimate of percentage of participants Interval 90.49 to 97.23	89.97 estimate of percentage of participants Interval 84.06 to 95.87

SECONDARY outcome

Timeframe: Baseline up to end of Cycle 4 (1 cycle = 21 days)

Population: Safety evaluable population included all participants who received at least one dose of neoadjuvant study treatment and participants were grouped by the treatment they actually received.

The percentage of participants who experienced at least one AE during the neoadjuvant period is reported here. An AE is any untoward medical occurrence in a clinical investigation participant who is administered a pharmaceutical product regardless of the causal attribution. An adverse event was therefore any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Pre-existing conditions which worsened during the study were also considered as adverse events. The neoadjuvant treatment period began after randomization upon receiving the first dose of any of the neoadjuvant study medications and ended before receiving the first dose of adjuvant study treatment. The duration of one treatment cycle is 21 days. The percentages have been rounded off to first decimal point.

Outcome measures

Measure	Pertuzumab, Trastuzumab, and Chemotherapy n=218 Participants Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, pertuzumab, 840 mg loading dose in Cycle 1, followed by 420 mg from Cycles 2-4, and docetaxel, 75 mg/m\^2 from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and pertuzumab, 840 mg loading dose in Cycle 8, followed by 420 mg from Cycles 9-20 (1 cycle = 21 days).	Placebo, Trastuzumab, and Chemotherapy n=110 Participants Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, docetaxel, 75 mg/m\^2 and placebo from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and placebo from Cycles 8-20 (1 cycle =21 days).
Percentage of Participants With at Least One Adverse Event (AE) During the Neoadjuvant Treatment Period	97.7 percentage of participants	96.4 percentage of participants

SECONDARY outcome

Timeframe: From Cycle 5 (1 cycle = 21 days) up to 42 days after the last dose in Cycle 20 Day 1 (approximately 1 year)

Population: Safety evaluable population included all participants who received at least one dose of adjuvant study treatment and participants were grouped by the treatment they actually received. Overall number analyzed is the number of participants with data available for analysis.

Percentage of participants who experienced at least one adverse event during the adjuvant period is reported here. An AE is any untoward medical occurrence in a clinical investigation participant who is administered a pharmaceutical product regardless of the causal attribution. An adverse event was therefore any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Pre-existing conditions which worsened during the study were also considered as adverse events. Adjuvant treatment period began after primary surgery, upon receiving the first dose of any of the adjuvant study medications. It ended 42 days after last dose of adjuvant study treatment upon treatment completion or discontinuation. 1 Cycle=21 days. The percentages have been rounded off to first decimal point.

Outcome measures

Measure	Pertuzumab, Trastuzumab, and Chemotherapy n=208 Participants Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, pertuzumab, 840 mg loading dose in Cycle 1, followed by 420 mg from Cycles 2-4, and docetaxel, 75 mg/m\^2 from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and pertuzumab, 840 mg loading dose in Cycle 8, followed by 420 mg from Cycles 9-20 (1 cycle = 21 days).	Placebo, Trastuzumab, and Chemotherapy n=103 Participants Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, docetaxel, 75 mg/m\^2 and placebo from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and placebo from Cycles 8-20 (1 cycle =21 days).
Percentage of Participants With at Least One AE During the Adjuvant Treatment Period	98.1 percentage of participants	98.1 percentage of participants

SECONDARY outcome

Timeframe: From end of overall study treatment until disease progression or until 5 years after randomization of the last patient, whichever occurred first (up to 6 years)

Population: Safety evaluable population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received.

The percentage of participants who experienced at least one adverse event during the treatment-free follow-up period is reported here. An AE is any untoward medical occurrence in a clinical investigation participant who is administered a pharmaceutical product regardless of the causal attribution. An adverse event was therefore any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. The percentages have been rounded off to first decimal point.

Outcome measures

Measure	Pertuzumab, Trastuzumab, and Chemotherapy n=218 Participants Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, pertuzumab, 840 mg loading dose in Cycle 1, followed by 420 mg from Cycles 2-4, and docetaxel, 75 mg/m\^2 from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and pertuzumab, 840 mg loading dose in Cycle 8, followed by 420 mg from Cycles 9-20 (1 cycle = 21 days).	Placebo, Trastuzumab, and Chemotherapy n=110 Participants Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, docetaxel, 75 mg/m\^2 and placebo from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and placebo from Cycles 8-20 (1 cycle =21 days).
Percentage of Participants With at Least One Adverse Event During the Treatment-Free Follow-Up Period	6.0 percentage of participants	7.3 percentage of participants

SECONDARY outcome

Timeframe: From Baseline until end of study (up to 6 years)

Population: Safety evaluable population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received.

A primary cardiac event is defined as heart failure (New York Heart Association [NYHA] Class III or NYHA Class IV) and a drop in left ventricular ejection fraction (LVEF) of at least 10 ejection fraction points from baseline and to below 50%.

Outcome measures

Measure	Pertuzumab, Trastuzumab, and Chemotherapy n=218 Participants Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, pertuzumab, 840 mg loading dose in Cycle 1, followed by 420 mg from Cycles 2-4, and docetaxel, 75 mg/m\^2 from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and pertuzumab, 840 mg loading dose in Cycle 8, followed by 420 mg from Cycles 9-20 (1 cycle = 21 days).	Placebo, Trastuzumab, and Chemotherapy n=110 Participants Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, docetaxel, 75 mg/m\^2 and placebo from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and placebo from Cycles 8-20 (1 cycle =21 days).
Percentage of Participants Who Experienced a Primary Cardiac Event	0 percentage of participants	0 percentage of participants

SECONDARY outcome

Timeframe: From Baseline until end of study (up to 6 years)

Population: Safety evaluable population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received.

A secondary cardiac event is defined as an asymptomatic or mildly symptomatic (NYHA Class II) drop in LVEF by multiple-gated acquisition (MUGA) scan or echocardiogram confirmed by a second LVEF assessment within approximately 3 weeks showing also a documented drop. A significant LVEF drop is defined as an absolute decrease of at least 10 points below the baseline measurement and to below 50%.

Outcome measures

Measure	Pertuzumab, Trastuzumab, and Chemotherapy n=218 Participants Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, pertuzumab, 840 mg loading dose in Cycle 1, followed by 420 mg from Cycles 2-4, and docetaxel, 75 mg/m\^2 from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and pertuzumab, 840 mg loading dose in Cycle 8, followed by 420 mg from Cycles 9-20 (1 cycle = 21 days).	Placebo, Trastuzumab, and Chemotherapy n=110 Participants Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, docetaxel, 75 mg/m\^2 and placebo from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and placebo from Cycles 8-20 (1 cycle =21 days).
Percentage of Participants Who Experienced a Secondary Cardiac Event	0 percentage of participants	0 percentage of participants

SECONDARY outcome

Timeframe: Baseline; Day 1 of Cycles 2, 4, 5, 8, 11, and 20 (1 cycle = 21 days)

Population: Safety evaluable population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. Overall number analyzed is the number of participants with data available for analysis.

LVEF is the measurement of how much blood is being pumped out of the left ventricle of the heart (the main pumping chamber) with each contraction. A normal LVEF ranges from 55% to 70%, as measured by echocardiogram (preferred) or MUGA scan. The same method was used throughout the study for each participant and preferably performed and evaluated by the same assessor. Here, we report the maximum change from baseline in LVEF at any point during the study.

Outcome measures

Measure	Pertuzumab, Trastuzumab, and Chemotherapy n=215 Participants Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, pertuzumab, 840 mg loading dose in Cycle 1, followed by 420 mg from Cycles 2-4, and docetaxel, 75 mg/m\^2 from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and pertuzumab, 840 mg loading dose in Cycle 8, followed by 420 mg from Cycles 9-20 (1 cycle = 21 days).	Placebo, Trastuzumab, and Chemotherapy n=109 Participants Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, docetaxel, 75 mg/m\^2 and placebo from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and placebo from Cycles 8-20 (1 cycle =21 days).
Maximum Change From Baseline in LVEF	-6.55 percentage points of LVEF Standard Deviation 5.22	-6.20 percentage points of LVEF Standard Deviation 6.08

SECONDARY outcome

Timeframe: Baseline; Day 1 of Cycles 2, 4, 5, 8, 11, and 20 (1 cycle = 21 days)

Population: Safety evaluable population included all participants who received at least one dose of study drugs. Overall number analyzed is the number of participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at specified timepoints.

LVEF is the measurement of how much blood is being pumped out of the left ventricle of the heart (the main pumping chamber) with each contraction. A normal LVEF ranges from 55% to 70%, as measured by echocardiogram (preferred) or MUGA scan. The same method was used throughout the study for each participant and preferably performed and evaluated by the same assessor. Here, we report the change from baseline in LVEF over time.

Outcome measures

Measure	Pertuzumab, Trastuzumab, and Chemotherapy n=213 Participants Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, pertuzumab, 840 mg loading dose in Cycle 1, followed by 420 mg from Cycles 2-4, and docetaxel, 75 mg/m\^2 from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and pertuzumab, 840 mg loading dose in Cycle 8, followed by 420 mg from Cycles 9-20 (1 cycle = 21 days).	Placebo, Trastuzumab, and Chemotherapy n=108 Participants Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, docetaxel, 75 mg/m\^2 and placebo from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and placebo from Cycles 8-20 (1 cycle =21 days).
Change From Baseline in LVEF Over Time Cycle 2 Day 1	-0.62 percentage points of LVEF Interval -1.35 to 0.11	0.29 percentage points of LVEF Interval -0.89 to 1.46
Change From Baseline in LVEF Over Time Cycle 4 Day 1	-1.02 percentage points of LVEF Interval -1.72 to -0.32	0.09 percentage points of LVEF Interval -1.03 to 1.22
Change From Baseline in LVEF Over Time Cycle 5 Day 1	-0.96 percentage points of LVEF Interval -1.7 to -0.22	0.07 percentage points of LVEF Interval -1.12 to 1.26
Change From Baseline in LVEF Over Time Cycle 8 Day 1	-1.63 percentage points of LVEF Interval -2.44 to -0.81	-1.18 percentage points of LVEF Interval -2.3 to -0.05
Change From Baseline in LVEF Over Time Cycle 11 Day 1	-1.38 percentage points of LVEF Interval -2.16 to -0.61	-0.65 percentage points of LVEF Interval -1.91 to 0.62
Change From Baseline in LVEF Over Time Cycle 20 Day 1	-1.22 percentage points of LVEF Interval -2.05 to -0.38	-1.18 percentage points of LVEF Interval -2.56 to 0.2

Adverse Events

Pertuzumab, Trastuzumab, and Chemotherapy

Serious events: 37 serious events

Other events: 218 other events

Deaths: 12 deaths

Placebo, Trastuzumab, and Chemotherapy

Serious events: 15 serious events

Other events: 108 other events

Deaths: 11 deaths

Serious adverse events

Measure	Pertuzumab, Trastuzumab, and Chemotherapy n=218 participants at risk Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, pertuzumab, 840 mg loading dose in Cycle 1, followed by 420 mg from Cycles 2-4, and docetaxel, 75 mg/m\^2 from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and pertuzumab, 840 mg loading dose in Cycle 8, followed by 420 mg from Cycles 9-20 (1 cycle = 21 days).	Placebo, Trastuzumab, and Chemotherapy n=110 participants at risk Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, docetaxel, 75 mg/m\^2 and placebo from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and placebo from Cycles 8-20 (1 cycle =21 days).
Blood and lymphatic system disorders Anaemia	0.46% 1/218 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.91% 1/110 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Blood and lymphatic system disorders Blood Loss Anaemia	0.00% 0/218 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.91% 1/110 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Blood and lymphatic system disorders Febrile Neutropenia	4.1% 9/218 • Number of events 9 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	2.7% 3/110 • Number of events 3 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Blood and lymphatic system disorders Lymphadenitis	0.00% 0/218 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.91% 1/110 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Blood and lymphatic system disorders Myelosuppression	1.4% 3/218 • Number of events 3 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.00% 0/110 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Blood and lymphatic system disorders Neutropenia	0.46% 1/218 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.00% 0/110 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Blood and lymphatic system disorders Thrombocytopenia	0.46% 1/218 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.00% 0/110 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Cardiac disorders Palpitations	0.46% 1/218 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.00% 0/110 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Cardiac disorders Ventricular Arrhythmia	0.46% 1/218 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.91% 1/110 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Cardiac disorders Ventricular Fibrillation	0.00% 0/218 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.91% 1/110 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Gastrointestinal disorders Diarrhoea	0.92% 2/218 • Number of events 3 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.00% 0/110 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Gastrointestinal disorders Haemorrhoids	0.46% 1/218 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.00% 0/110 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Gastrointestinal disorders Pancreatitis Acute	0.46% 1/218 • Number of events 2 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.00% 0/110 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Gastrointestinal disorders Upper Gastrointestinal Haemorrhage	0.46% 1/218 • Number of events 2 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.00% 0/110 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Gastrointestinal disorders Vomiting	0.92% 2/218 • Number of events 2 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.00% 0/110 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
General disorders Chest Discomfort	0.00% 0/218 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.91% 1/110 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
General disorders Fatigue	0.46% 1/218 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.00% 0/110 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Hepatobiliary disorders Cholelithiasis	0.46% 1/218 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.00% 0/110 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Hepatobiliary disorders Liver Disorder	0.92% 2/218 • Number of events 2 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.00% 0/110 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Hepatobiliary disorders Liver Injury	0.00% 0/218 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.91% 1/110 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Immune system disorders Anaphylactic Shock	0.00% 0/218 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.91% 1/110 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Infections and infestations Bacteraemia	0.92% 2/218 • Number of events 2 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.00% 0/110 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Infections and infestations Device Related Infection	0.00% 0/218 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.91% 1/110 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Infections and infestations Herpes Zoster	0.00% 0/218 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.91% 1/110 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Infections and infestations Lung Abscess	0.46% 1/218 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.00% 0/110 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Infections and infestations Pneumonia	1.8% 4/218 • Number of events 4 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.91% 1/110 • Number of events 3 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Infections and infestations Pneumonia Influenzal	0.00% 0/218 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.91% 1/110 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Infections and infestations Postoperative Wound Infection	0.46% 1/218 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.00% 0/110 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Infections and infestations Sepsis	0.46% 1/218 • Number of events 2 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.00% 0/110 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Infections and infestations Skin Infection	0.00% 0/218 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.91% 1/110 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Infections and infestations Urinary Tract Infection	0.92% 2/218 • Number of events 2 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.91% 1/110 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Infections and infestations Wound Infection	0.46% 1/218 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.00% 0/110 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Injury, poisoning and procedural complications Flap Necrosis	0.46% 1/218 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.00% 0/110 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Injury, poisoning and procedural complications Vascular Access Complication	0.46% 1/218 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.00% 0/110 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Hepatic Neoplasm	0.00% 0/218 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.91% 1/110 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Papillary Thyroid Cancer	0.00% 0/218 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.91% 1/110 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Nervous system disorders Dizziness	0.46% 1/218 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.00% 0/110 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Nervous system disorders Syncope	0.46% 1/218 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.00% 0/110 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Nervous system disorders Transient Ischaemic Attack	0.46% 1/218 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.00% 0/110 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Pregnancy, puerperium and perinatal conditions Abortion	0.46% 1/218 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.00% 0/110 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Psychiatric disorders Completed Suicide	0.46% 1/218 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.00% 0/110 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Reproductive system and breast disorders Adnexa Uteri Cyst	0.00% 0/218 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.91% 1/110 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Respiratory, thoracic and mediastinal disorders Lung Cyst	0.00% 0/218 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.91% 1/110 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Respiratory, thoracic and mediastinal disorders Pulmonary Embolism	0.46% 1/218 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.00% 0/110 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Skin and subcutaneous tissue disorders Drug Eruption	0.46% 1/218 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.00% 0/110 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Skin and subcutaneous tissue disorders Urticaria	0.46% 1/218 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.00% 0/110 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Surgical and medical procedures Abortion Induced	0.00% 0/218 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.91% 1/110 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Vascular disorders Lymphorrhoea	0.46% 1/218 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.00% 0/110 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.

Other adverse events

Measure	Pertuzumab, Trastuzumab, and Chemotherapy n=218 participants at risk Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, pertuzumab, 840 mg loading dose in Cycle 1, followed by 420 mg from Cycles 2-4, and docetaxel, 75 mg/m\^2 from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and pertuzumab, 840 mg loading dose in Cycle 8, followed by 420 mg from Cycles 9-20 (1 cycle = 21 days).	Placebo, Trastuzumab, and Chemotherapy n=110 participants at risk Prior to surgery: Participants received trastuzumab, 8 mg/kg loading dose in Cycle 1, followed by 6 mg/kg from Cycles 2-4, docetaxel, 75 mg/m\^2 and placebo from Cycles 1-4 (1 cycle = 21 days) by IV infusion. Post surgery: Participants received chemotherapy with fluorouracil 500-600 mg/m\^2, epirubicin 90-120 mg/m\^2, and cyclophosphamide 500-600 mg/m\^2 by IV infusion every 3 weeks from Cycles 5-7 (1 cycle = 21 days) followed by trastuzumab, 8 mg/kg loading dose in Cycle 8, followed by 6 mg/kg from Cycles 9-20 and placebo from Cycles 8-20 (1 cycle =21 days).
Investigations Aspartate Aminotransferase Increased	24.8% 54/218 • Number of events 104 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	30.9% 34/110 • Number of events 48 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Blood and lymphatic system disorders Anaemia	34.4% 75/218 • Number of events 124 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	32.7% 36/110 • Number of events 66 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Blood and lymphatic system disorders Leukopenia	61.9% 135/218 • Number of events 379 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	60.9% 67/110 • Number of events 160 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Blood and lymphatic system disorders Neutropenia	70.2% 153/218 • Number of events 365 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	66.4% 73/110 • Number of events 161 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Blood and lymphatic system disorders Thrombocytopenia	13.3% 29/218 • Number of events 50 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	15.5% 17/110 • Number of events 29 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Gastrointestinal disorders Abdominal Discomfort	5.0% 11/218 • Number of events 11 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	2.7% 3/110 • Number of events 3 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Gastrointestinal disorders Abdominal Pain Upper	5.0% 11/218 • Number of events 11 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	7.3% 8/110 • Number of events 8 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Gastrointestinal disorders Constipation	11.5% 25/218 • Number of events 26 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	13.6% 15/110 • Number of events 21 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Gastrointestinal disorders Diarrhoea	39.9% 87/218 • Number of events 124 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	17.3% 19/110 • Number of events 20 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Gastrointestinal disorders Mouth Ulceration	13.8% 30/218 • Number of events 38 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	9.1% 10/110 • Number of events 10 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Gastrointestinal disorders Nausea	38.5% 84/218 • Number of events 147 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	36.4% 40/110 • Number of events 69 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Gastrointestinal disorders Stomatitis	3.2% 7/218 • Number of events 10 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	6.4% 7/110 • Number of events 8 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Gastrointestinal disorders Vomiting	16.5% 36/218 • Number of events 47 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	11.8% 13/110 • Number of events 17 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
General disorders Asthenia	8.7% 19/218 • Number of events 22 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	7.3% 8/110 • Number of events 9 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
General disorders Chills	5.5% 12/218 • Number of events 13 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	2.7% 3/110 • Number of events 4 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
General disorders Fatigue	11.9% 26/218 • Number of events 42 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	14.5% 16/110 • Number of events 26 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
General disorders Malaise	6.0% 13/218 • Number of events 14 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	4.5% 5/110 • Number of events 7 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
General disorders Oedema Peripheral	5.0% 11/218 • Number of events 14 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	7.3% 8/110 • Number of events 8 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
General disorders Pyrexia	17.0% 37/218 • Number of events 47 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	14.5% 16/110 • Number of events 17 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Hepatobiliary disorders Hepatic Function Abnormal	8.3% 18/218 • Number of events 22 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	6.4% 7/110 • Number of events 9 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Infections and infestations Nasopharyngitis	8.3% 18/218 • Number of events 26 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	4.5% 5/110 • Number of events 6 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Infections and infestations Upper Respiratory Tract Infection	26.6% 58/218 • Number of events 85 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	12.7% 14/110 • Number of events 23 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Injury, poisoning and procedural complications Infusion Related Reaction	5.0% 11/218 • Number of events 12 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	2.7% 3/110 • Number of events 3 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Injury, poisoning and procedural complications Procedural Pain	5.5% 12/218 • Number of events 14 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	4.5% 5/110 • Number of events 6 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Injury, poisoning and procedural complications Radiation Skin Injury	10.6% 23/218 • Number of events 23 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	5.5% 6/110 • Number of events 6 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Investigations Alanine Aminotransferase Increased	29.4% 64/218 • Number of events 126 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	37.3% 41/110 • Number of events 62 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Investigations Blood Cholesterol Increased	1.4% 3/218 • Number of events 4 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	5.5% 6/110 • Number of events 6 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Investigations Blood Triglycerides Increased	1.4% 3/218 • Number of events 5 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	6.4% 7/110 • Number of events 17 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Investigations Blood Uric Acid Increased	1.4% 3/218 • Number of events 5 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	7.3% 8/110 • Number of events 13 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Investigations Gamma-Glutamyltransferase Increased	4.1% 9/218 • Number of events 10 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	8.2% 9/110 • Number of events 14 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Investigations Low Density Lipoprotein Increased	2.3% 5/218 • Number of events 5 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	8.2% 9/110 • Number of events 15 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Metabolism and nutrition disorders Decreased Appetite	18.3% 40/218 • Number of events 49 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	11.8% 13/110 • Number of events 19 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Musculoskeletal and connective tissue disorders Arthralgia	7.3% 16/218 • Number of events 19 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	7.3% 8/110 • Number of events 8 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Musculoskeletal and connective tissue disorders Bone Pain	7.3% 16/218 • Number of events 17 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	7.3% 8/110 • Number of events 8 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Musculoskeletal and connective tissue disorders Myalgia	6.9% 15/218 • Number of events 16 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	8.2% 9/110 • Number of events 10 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Musculoskeletal and connective tissue disorders Pain in Extremity	6.0% 13/218 • Number of events 15 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	3.6% 4/110 • Number of events 4 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Nervous system disorders Dizziness	8.7% 19/218 • Number of events 25 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	8.2% 9/110 • Number of events 10 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Nervous system disorders Headache	6.9% 15/218 • Number of events 18 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	5.5% 6/110 • Number of events 6 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Nervous system disorders Hypoaesthesia	6.4% 14/218 • Number of events 15 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	6.4% 7/110 • Number of events 11 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Nervous system disorders Neuropathy Peripheral	5.5% 12/218 • Number of events 12 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	5.5% 6/110 • Number of events 6 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Psychiatric disorders Insomnia	11.0% 24/218 • Number of events 29 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	15.5% 17/110 • Number of events 21 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Respiratory, thoracic and mediastinal disorders Cough	10.6% 23/218 • Number of events 26 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	8.2% 9/110 • Number of events 12 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Respiratory, thoracic and mediastinal disorders Epistaxis	5.0% 11/218 • Number of events 16 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.00% 0/110 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Respiratory, thoracic and mediastinal disorders Oropharyngeal Pain	9.2% 20/218 • Number of events 24 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	8.2% 9/110 • Number of events 10 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Skin and subcutaneous tissue disorders Alopecia	52.8% 115/218 • Number of events 162 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	50.9% 56/110 • Number of events 77 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Skin and subcutaneous tissue disorders Pruritus	6.4% 14/218 • Number of events 18 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	5.5% 6/110 • Number of events 6 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Skin and subcutaneous tissue disorders Rash	12.8% 28/218 • Number of events 29 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	20.0% 22/110 • Number of events 26 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Skin and subcutaneous tissue disorders Rash Maculo-Papular	5.5% 12/218 • Number of events 16 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	0.91% 1/110 • Number of events 1 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Skin and subcutaneous tissue disorders Skin Hyperpigmentation	1.8% 4/218 • Number of events 4 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	6.4% 7/110 • Number of events 7 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.
Vascular disorders Hypertension	3.2% 7/218 • Number of events 7 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.	8.2% 9/110 • Number of events 11 • From first dose of any study drug through end of study (up to 6 years) Safety Evaluable Population included all participants who received at least one dose of study drugs and participants were grouped by the treatment they actually received. One participant in the pertuzumab arm discontinued from the study before receiving study treatment due to not meeting eligibility criteria. Therefore, there are only 218 participants in the pertuzumab arm in the safety population.

Additional Information

Medical Communications

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• Principal investigator is a sponsor employee The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
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Restriction type: OTHER