Trial Outcomes & Findings for A Study to Compare Subcutaneous (SC) Versus Intravenous (IV) Administration of Herceptin (Trastuzumab) in Women With Human Epidermal Growth Factor Receptor (HER) 2-Positive Early Breast Cancer (NCT NCT00950300)

Last Updated: 2018-01-23

Results Overview

Pre-dose samples were obtained prior to surgery (Cycle 8). The observed Ctrough was recorded, averaged among all participants, and expressed in micrograms per milliliter (μg/mL).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

596 participants

Primary outcome timeframe

Pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days)

Results posted on

2018-01-23

Participant Flow

A total of 833 participants were screened, out of which, 596 participants were enrolled into the study.

Participant milestones

Participant milestones
Measure	Herceptin IV + Chemotherapy Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 milligrams per meter-squared (mg/m\^2) every 21 days for four cycles followed by 5-fluorouracil 500 mg/m\^2, epirubicin 75 mg/m\^2, and cyclophosphamide 500 mg/m\^2 (FEC) every 21 days for four cycles. Herceptin was administered as 8 milligrams per kilogram (mg/kg) on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the Treatment-Free Follow-Up (TFFU) Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the Survival Follow-Up (SFU) Period.	Herceptin SC + Chemotherapy Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-milligram (mg) fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Neoadjuvant/Adjuvant Treatment Periods STARTED	299	297
Neoadjuvant/Adjuvant Treatment Periods Received Neoadjuvant Treatment	298	297
Neoadjuvant/Adjuvant Treatment Periods Underwent Surgery	277	273
Neoadjuvant/Adjuvant Treatment Periods Entered Adjuvant Treatment	277	274
Neoadjuvant/Adjuvant Treatment Periods COMPLETED	257	255
Neoadjuvant/Adjuvant Treatment Periods NOT COMPLETED	42	42
TFFU Period STARTED	265	268
TFFU Period COMPLETED	165	161
TFFU Period NOT COMPLETED	100	107
SFU Period STARTED	118	123
SFU Period COMPLETED	40	45
SFU Period NOT COMPLETED	78	78

Reasons for withdrawal

Reasons for withdrawal
Measure	Herceptin IV + Chemotherapy Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 milligrams per meter-squared (mg/m\^2) every 21 days for four cycles followed by 5-fluorouracil 500 mg/m\^2, epirubicin 75 mg/m\^2, and cyclophosphamide 500 mg/m\^2 (FEC) every 21 days for four cycles. Herceptin was administered as 8 milligrams per kilogram (mg/kg) on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the Treatment-Free Follow-Up (TFFU) Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the Survival Follow-Up (SFU) Period.	Herceptin SC + Chemotherapy Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-milligram (mg) fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Neoadjuvant/Adjuvant Treatment Periods Adverse Event or Intercurrent Illness	6	15
Neoadjuvant/Adjuvant Treatment Periods Death	1	3
Neoadjuvant/Adjuvant Treatment Periods Insufficient Therapeutic Response	3	0
Neoadjuvant/Adjuvant Treatment Periods Violation of Selection Criteria	2	1
Neoadjuvant/Adjuvant Treatment Periods Protocol Violation	1	0
Neoadjuvant/Adjuvant Treatment Periods Participant Refusal/Withdrawal	4	5
Neoadjuvant/Adjuvant Treatment Periods Lost to Follow-up	2	1
Neoadjuvant/Adjuvant Treatment Periods Progression of Disease	12	11
Neoadjuvant/Adjuvant Treatment Periods Recurrence of Disease	10	5
Neoadjuvant/Adjuvant Treatment Periods Other	1	1
TFFU Period Adverse Event or Intercurrent Illness	3	4
TFFU Period Death	4	1
TFFU Period Refused Treatment	10	11
TFFU Period Failure to Return	16	16
TFFU Period Recurrence of Disease	63	72
TFFU Period Other	4	3
SFU Period Death	44	42
SFU Period Lost to Follow-up	30	28
SFU Period Withdrawal by Subject	4	8

Baseline Characteristics

A Study to Compare Subcutaneous (SC) Versus Intravenous (IV) Administration of Herceptin (Trastuzumab) in Women With Human Epidermal Growth Factor Receptor (HER) 2-Positive Early Breast Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Herceptin IV + Chemotherapy n=297 Participants Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Herceptin SC + Chemotherapy n=294 Participants Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Total n=591 Participants Total of all reporting groups
Age, Continuous	49.5 years STANDARD_DEVIATION 10.83 • n=5 Participants	50.3 years STANDARD_DEVIATION 11.08 • n=7 Participants	49.9 years STANDARD_DEVIATION 10.95 • n=5 Participants
Sex: Female, Male Female	297 Participants n=5 Participants	294 Participants n=7 Participants	591 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: Pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days)

Population: Primary Pharmacokinetic (PK) Per Protocol (PP) Population: All participants with at least one measurable trastuzumab serum concentration and who did not have any major protocol violations related to PK sampling for the primary endpoint.

Pre-dose samples were obtained prior to surgery (Cycle 8). The observed Ctrough was recorded, averaged among all participants, and expressed in micrograms per milliliter (μg/mL).

Outcome measures

Outcome measures
Measure	Herceptin IV + Chemotherapy n=235 Participants Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Herceptin SC + Chemotherapy n=234 Participants Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Observed Serum Trough Concentration (Ctrough) of Trastuzumab Prior to Surgery	57.8 μg/mL Standard Deviation 30.3	78.7 μg/mL Standard Deviation 43.9

PRIMARY outcome

Timeframe: After surgery following eight cycles of Herceptin + chemotherapy (approximately 6 months from Baseline)

Population: Efficacy (E) PP Population: All participants with at least one on-treatment efficacy assessment who received a full eight cycles of study treatment according to randomization and who met additional protocol-specified criteria.

Participants were evaluated following eight cycles of treatment and after surgery to assess for pCR, defined as absence of neoplastic invasive cells in the breast according to pathologist examination. The percentage of participants with pCR was reported, and the 95% CI for one-sample binomial was constructed using the Pearson-Clopper method.

Outcome measures

Outcome measures
Measure	Herceptin IV + Chemotherapy n=263 Participants Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Herceptin SC + Chemotherapy n=260 Participants Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Percentage of Participants With Pathological Complete Response (pCR)	40.7 percentage of participants Interval 34.7 to 46.9	45.4 percentage of participants Interval 39.2 to 51.7

SECONDARY outcome

Timeframe: Pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days)

Population: Secondary PKPP Population: All participants with at least one measurable trastuzumab serum concentration and who did not have any major protocol violations related to PK sampling for the secondary endpoint.

Pre-dose samples were obtained after surgery (Cycle 13). The observed Ctrough was recorded, averaged among all participants, and expressed in μg/mL.

Outcome measures

Outcome measures
Measure	Herceptin IV + Chemotherapy n=223 Participants Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Herceptin SC + Chemotherapy n=227 Participants Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Observed Ctrough of Trastuzumab After Surgery	62.1 μg/mL Standard Deviation 37.1	90.4 μg/mL Standard Deviation 41.9

SECONDARY outcome

Timeframe: Pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days)

Population: PKPP Population: All participants with at least one measurable trastuzumab serum concentration.

Predicted Ctrough at pre-dose prior to surgery (Cycle 8) was determined on the basis of a population PK model from Study BP22023 (NCT00800436). The mean predicted Ctrough was expressed in μg/mL.

Outcome measures

Outcome measures
Measure	Herceptin IV + Chemotherapy n=276 Participants Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Herceptin SC + Chemotherapy n=278 Participants Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Predicted Ctrough of Trastuzumab Prior to Surgery	51.4 μg/mL Standard Deviation 19.4	80.3 μg/mL Standard Deviation 33.2

SECONDARY outcome

Timeframe: Pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days)

Population: PKPP Population; only participants with a Cycle 13 pre-dose PK measurement were included in the analysis.

Predicted Ctrough at pre-dose after surgery (Cycle 13) was determined on the basis of a population PK model from Study BP22023 (NCT00800436). The mean predicted Ctrough was expressed in μg/mL.

Outcome measures

Outcome measures
Measure	Herceptin IV + Chemotherapy n=236 Participants Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Herceptin SC + Chemotherapy n=236 Participants Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Predicted Ctrough of Trastuzumab After Surgery	51.7 μg/mL Standard Deviation 20.0	80.6 μg/mL Standard Deviation 33.4

SECONDARY outcome

Timeframe: Pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days)

Population: Primary PKPP Population

Pre-dose samples were obtained prior to surgery (Cycle 8). The number of participants who had an observed Ctrough \>20 μg/mL was reported.

Outcome measures

Outcome measures
Measure	Herceptin IV + Chemotherapy n=235 Participants Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Herceptin SC + Chemotherapy n=234 Participants Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Number of Participants With Ctrough of Trastuzumab >20 μg/mL Prior to Surgery	232 participants	227 participants

SECONDARY outcome

Timeframe: Pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days)

Population: Secondary PKPP Population

Pre-dose samples were obtained after surgery (Cycle 13). The number of participants who had an observed Ctrough \>20 μg/mL was reported.

Outcome measures

Outcome measures
Measure	Herceptin IV + Chemotherapy n=223 Participants Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Herceptin SC + Chemotherapy n=227 Participants Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Number of Participants With Ctrough of Trastuzumab >20 μg/mL After Surgery	216 participants	227 participants

SECONDARY outcome

Timeframe: Pre-dose (0 hours) and at end of 30-minute infusion (Herceptin IV only) on Day 1 of Cycle 7; on Days 2, 4, 8, 15 of Cycle 7; pre-dose (0 hours) on Day 1 of Cycle 8 (cycle length of 21 days)

Population: Primary PKPP Population; only those participants who provided evaluable data were included.

PK samples were obtained prior to surgery (Cycle 7). The Cmax during Cycle 7 was recorded, averaged among all participants, and expressed in μg/mL.

Outcome measures

Outcome measures
Measure	Herceptin IV + Chemotherapy n=235 Participants Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Herceptin SC + Chemotherapy n=233 Participants Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Maximum Serum Concentration (Cmax) of Trastuzumab Prior to Surgery	221 μg/mL Standard Deviation 118	149 μg/mL Standard Deviation 64.8

SECONDARY outcome

Population: Primary PKPP Population; only those participants who provided evaluable data were included.

PK samples were obtained prior to surgery (Cycle 7). The Tmax during Cycle 7 was recorded, averaged among all participants, and expressed in days.

Outcome measures

Outcome measures
Measure	Herceptin IV + Chemotherapy n=235 Participants Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Herceptin SC + Chemotherapy n=233 Participants Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Time of Maximum Serum Concentration (Tmax) of Trastuzumab Prior to Surgery	0.05 days Standard Deviation 0.04	4.12 days Standard Deviation 2.91

SECONDARY outcome

Population: Primary PKPP Population; only those participants who provided evaluable data were included.

PK samples were obtained prior to surgery (Cycle 7). Values were extrapolated beyond Day 15 to produce the area over the full 21-day cycle. The AUC21d value at Cycle 7 was calculated from trastuzumab concentration-time profiles using standard non-compartmental PK methods, averaged among all participants, and expressed in days multiplied by micrograms per milliliters (d\*μg/mL).

Outcome measures

Outcome measures
Measure	Herceptin IV + Chemotherapy n=235 Participants Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Herceptin SC + Chemotherapy n=233 Participants Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Area Under the Concentration-Time Curve From 0 to 21 Days (AUC21d) of Trastuzumab Prior to Surgery	2056 d*μg/mL Standard Deviation 598	2268 d*μg/mL Standard Deviation 875

SECONDARY outcome

Timeframe: Pre-dose (0 hours) and at end of 30-minute infusion (Herceptin IV only) on Day 1 of Cycle 12; on Days 2, 4, 8, 15 of Cycle 12; pre-dose (0 hours) on Day 1 of Cycle 13 (cycle length of 21 days)

Population: Secondary PKPP Population; only those participants who provided evaluable data were included.

PK samples were obtained after surgery (Cycle 12). The Cmax during Cycle 12 was recorded, averaged among all participants, and expressed in μg/mL.

Outcome measures

Outcome measures
Measure	Herceptin IV + Chemotherapy n=223 Participants Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Herceptin SC + Chemotherapy n=223 Participants Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Cmax of Trastuzumab After Surgery	230 μg/mL Standard Deviation 118	166 μg/mL Standard Deviation 58.8

SECONDARY outcome

Population: Secondary PKPP Population; only those participants who provided evaluable data were included.

PK samples were obtained after surgery (Cycle 12). The Tmax during Cycle 12 was recorded, averaged among all participants, and expressed in days.

Outcome measures

Outcome measures
Measure	Herceptin IV + Chemotherapy n=223 Participants Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Herceptin SC + Chemotherapy n=222 Participants Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Tmax of Trastuzumab After Surgery	0.06 days Standard Deviation 0.13	4.08 days Standard Deviation 2.87

SECONDARY outcome

Population: Secondary PKPP Population; only those participants who provided evaluable data were included.

PK samples were obtained after surgery (Cycle 12). Values were extrapolated beyond Day 15 to produce the area over the full 21-day cycle. The AUC21d value at Cycle 12 was calculated from trastuzumab concentration-time profiles using standard non-compartmental PK methods, averaged among all participants, and expressed in d\*μg/mL.

Outcome measures

Outcome measures
Measure	Herceptin IV + Chemotherapy n=223 Participants Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Herceptin SC + Chemotherapy n=223 Participants Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
AUC21d of Trastuzumab After Surgery	2179 d*μg/mL Standard Deviation 725	2610 d*μg/mL Standard Deviation 945

SECONDARY outcome

Timeframe: After surgery following eight cycles of Herceptin + chemotherapy (approximately 6 months from Baseline)

Population: EPP Population

Participants were evaluated following eight cycles of treatment and after surgery to assess for tpCR, defined as absence of neoplastic invasive cells in the breast and axillary lymph nodes according to pathologist examination. The percentage of participants with tpCR was reported, and the 95% CI for one-sample binomial was constructed using the Pearson-Clopper method.

Outcome measures

Outcome measures
Measure	Herceptin IV + Chemotherapy n=263 Participants Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Herceptin SC + Chemotherapy n=260 Participants Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Percentage of Participants With Total Pathological Complete Response (tpCR)	34.2 percentage of participants Interval 28.5 to 40.3	39.2 percentage of participants Interval 33.3 to 45.5

SECONDARY outcome

Timeframe: Tumor assessments at Baseline; on Day 1 of Cycles 3, 5, 7 (cycle length of 21 days); and at time of surgery following eight cycles of Herceptin + chemotherapy (approximately 6 months overall)

Population: EPP Population; only participants with measurable disease at Baseline were included.

Tumor response was assessed using RECIST version 1.0. CR was defined as disappearance of all target lesions and short-axis reduction of any pathological lymph nodes to less than (\<) 10 millimeters (mm) with no prior assessment of progressive disease (PD). PR was defined as greater than or equal to (≥) 30% decrease from Baseline in sum diameter (SD) of target lesions with no prior assessment of PD. PD was defined as ≥20% relative increase and ≥5 mm of absolute increase in the SD of target lesions, taking as reference the smallest SD recorded since treatment started; or appearance of 1 or more new lesions. The percentage of participants with overall response of CR or PR at the end of neoadjuvant treatment was reported, and the 95% CI for one-sample binomial was constructed using the Pearson-Clopper method.

Outcome measures

Outcome measures
Measure	Herceptin IV + Chemotherapy n=260 Participants Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Herceptin SC + Chemotherapy n=258 Participants Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Percentage of Participants With Complete Response (CR) or Partial Response (PR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0, Among Those With Measurable Disease at Baseline	88.8 percentage of participants Interval 84.4 to 92.4	87.2 percentage of participants Interval 82.5 to 91.0

SECONDARY outcome

Timeframe: Tumor assessments at Baseline; on Day 1 Cycles 3, 5, 7 (cycle length of 21 days); and at time of surgery following eight cycles of chemotherapy (approximately 6 months overall)

Population: EPP Population; only participants with measurable disease at Baseline and a response of CR or PR were included.

Tumor response was assessed using RECIST version 1.0. CR was defined as disappearance of all target lesions and short-axis reduction of any pathological lymph nodes to \<10 mm with no prior assessment of PD. PR was defined as ≥30% decrease from Baseline in SD of target lesions with no prior assessment of PD. PD was defined as ≥20% relative increase and ≥5 mm of absolute increase in the SD of target lesions, taking as reference the smallest SD recorded since treatment started; or appearance of 1 or more new lesions. Time to response was defined as the time from first dose of study medication to the first assessment of CR or PR, which was the date the response was first documented by objective evidence, among participants with an overall response of CR or PR.

Outcome measures

Outcome measures
Measure	Herceptin IV + Chemotherapy n=231 Participants Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Herceptin SC + Chemotherapy n=225 Participants Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Time to Response According to RECIST Version 1.0, Among Those With Measurable Disease at Baseline	6.14 weeks Interval 3.0 to 25.0	6.14 weeks Interval 3.0 to 28.0

SECONDARY outcome

Timeframe: Screening; Day 1 of Cycle 18 (cycle length of 21 days); and Months 6, 12, 24, 36, 48, 60 from last dose of Cycle 18; then every 6 months until withdrawal for any reason (up to approximately 87 months overall)

Population: ITT Population

Protocol-defined events included disease recurrence/progression (local, regional, distant, contralateral) or death from any cause. Imaging was performed at specified visits for up to 5 years after last dose. Thereafter, participants were followed for survival only. The percentage of participants who experienced a protocol-defined event at any time during the study was reported.

Outcome measures

Outcome measures
Measure	Herceptin IV + Chemotherapy n=297 Participants Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Herceptin SC + Chemotherapy n=294 Participants Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Percentage of Participants Who Experienced a Protocol-Defined Event	33.3 percentage of participants	32.7 percentage of participants

SECONDARY outcome

Population: ITT Population

Protocol-defined events included disease recurrence or progression (local, regional, distant, contralateral) or death from any cause. Imaging was performed at specified visits for up to 5 years after last dose. Thereafter, participants were followed for survival only. EFS was estimated by Kaplan-Meier analysis and defined as the time from randomization to the first protocol-defined event.

Outcome measures

Outcome measures
Measure	Herceptin IV + Chemotherapy n=297 Participants Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Herceptin SC + Chemotherapy n=294 Participants Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Event-Free Survival (EFS)	NA months Interval 1.0 to 82.0 The median time to event could not be determined because of a high number (\>50%) of censored observations. Full range includes censored observations.	NA months Interval 1.0 to 76.0 The median time to event could not be determined because of a high number (\>50%) of censored observations. Full range includes censored observations.

SECONDARY outcome

Timeframe: Continuously during treatment (up to 12 months); at Months 1, 3, 6 from last dose of Cycle 18 (cycle length of 21 days); then every 6 months until withdrawal for any reason (up to approximately 87 months overall)

Population: ITT Population

The percentage of participants who died at any time during the study was reported.

Outcome measures

Outcome measures
Measure	Herceptin IV + Chemotherapy n=297 Participants Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Herceptin SC + Chemotherapy n=294 Participants Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Percentage of Participants Who Died	14.5 percentage of participants	13.6 percentage of participants

SECONDARY outcome

Population: ITT Population

OS was estimated by Kaplan-Meier analysis and defined as the time from randomization to death from any cause.

Outcome measures

Outcome measures
Measure	Herceptin IV + Chemotherapy n=297 Participants Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Herceptin SC + Chemotherapy n=294 Participants Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Overall Survival (OS)	NA months Interval 2.0 to 82.0 The median time to event could not be determined because of a high number (\>50%) of censored observations. Full range includes censored observations.	NA months Interval 3.0 to 79.0 The median time to event could not be determined because of a high number (\>50%) of censored observations. Full range includes censored observations.

SECONDARY outcome

Timeframe: Baseline; pre-dose (0 hours) on Day 1 of Cycles 2, 5, 13, 18 (cycle length of 21 days); and Months 3, 6, 12, 18, 24, 30, 36, 42, 48, 54, 60 from last dose of Cycle 18

Population: Safety Population: All participants who received at least one dose of study medication. Here, Overall Number of Participants Analyzed = participants who were evaluable for this outcome measure.

Participants provided PK samples for evaluation of anti-trastuzumab antibodies. The number of participants with "Treatment-induced ADAs" and "Treatment-enhanced ADA" against trastuzumab at any time during or after treatment was reported. Treatment-induced ADA = a participant with negative or missing Baseline ADA result(s) and at least one positive post-Baseline ADA result. Treatment-enhanced ADA = a participant with positive ADA result at Baseline who has one or more post Baseline titer results that are at least 0.60 titer unit greater than the Baseline titer result (four-fold increase of titer).

Outcome measures

Outcome measures
Measure	Herceptin IV + Chemotherapy n=296 Participants Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Herceptin SC + Chemotherapy n=295 Participants Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Number of Participants With Anti-Drug Antibodies (ADAs) Against Trastuzumab Treatment-induced ADAs	28 participants	46 participants
Number of Participants With Anti-Drug Antibodies (ADAs) Against Trastuzumab Treatment-enhanced ADA	2 participants	1 participants

SECONDARY outcome

Timeframe: Baseline; pre-dose (0 hours) on Day 1 of Cycles 2, 5, 13, 18 (cycle length of 21 days); and Months 3, 6, 12, 18, 24, 30, 36, 42, 48, 54, 60 from last dose of Cycle 18

Population: Safety Population; as rHuPH20 is unique to SC formulation, this outcome measure was applicable for "Herceptin SC + Chemotherapy" arm only. Here, Overall Number of Participants Analyzed = participants who were evaluable for this outcome measure.

Participants in the Herceptin SC arm provided PK samples for evaluation of anti-rHuPH20 antibodies. The number of participants with "Treatment-induced ADAs" and "Treatment-enhanced ADA" against rHuPH20 (an excipient unique to the SC formulation) at any time during or after treatment was reported. Treatment-induced ADA = a participant with negative or missing Baseline ADA result(s) and at least one positive post-Baseline ADA result. Treatment-enhanced ADA = a participant with positive ADA result at Baseline who has one or more post Baseline titer results that are at least 0.60 titer unit greater than the Baseline titer result (four-fold increase of titer).

Outcome measures

Outcome measures
Measure	Herceptin IV + Chemotherapy n=295 Participants Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Herceptin SC + Chemotherapy Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Number of Participants With ADAs Against Recombinant Human Hyaluronidase (rHuPH20) Treatment-induced ADA	49 participants	—
Number of Participants With ADAs Against Recombinant Human Hyaluronidase (rHuPH20) Treatment-enhanced ADA	13 participants	—

Adverse Events

Herceptin IV + Chemotherapy

Serious events: 45 serious events

Other events: 277 other events

Deaths: 0 deaths

Herceptin SC + Chemotherapy

Serious events: 65 serious events

Other events: 283 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Communications

Hoffmann-La Roche

Phone: 800-821-8590

Email: [email protected]

Results disclosure agreements

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.
Publication restrictions are in place

Restriction type: OTHER

Measure	Herceptin IV + Chemotherapy n=298 participants at risk Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Herceptin SC + Chemotherapy n=297 participants at risk Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Infections and infestations Respiratory tract infection viral	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Vascular disorders Lymphorrhoea	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.34% 1/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.00% 0/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Endometrial cancer	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.67% 2/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Myeloid leukaemia	0.34% 1/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.00% 0/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Cardiac disorders Cardiac failure congestive	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.67% 2/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Endocrine disorders Goitre	0.34% 1/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.00% 0/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Respiratory, thoracic and mediastinal disorders Emphysema	0.34% 1/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.00% 0/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Blood and lymphatic system disorders Febrile neutropenia	3.4% 10/298 • Approximately 87 months overall Analysis was performed on Safety Population.	4.4% 13/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Blood and lymphatic system disorders Neutropenia	3.0% 9/298 • Approximately 87 months overall Analysis was performed on Safety Population.	2.4% 7/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Blood and lymphatic system disorders Leukopenia	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Blood and lymphatic system disorders Lymphadenopathy	0.34% 1/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.00% 0/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Infections and infestations Tonsillitis	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.67% 2/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Infections and infestations Pneumonia	1.3% 4/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.67% 2/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Infections and infestations Atypical pneumonia	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Infections and infestations Cellulitis	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.67% 2/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Infections and infestations Febrile infection	0.34% 1/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.00% 0/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Infections and infestations Gastroenteritis	0.34% 1/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.00% 0/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Infections and infestations H1N1 influenza	0.34% 1/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.00% 0/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Infections and infestations Hepatitis B	0.34% 1/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.00% 0/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Infections and infestations Lower respiratory tract infection	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.67% 2/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Infections and infestations Periorbital cellulitis	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Infections and infestations Postoperative wound infection	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.67% 2/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Infections and infestations Respiratory tract infection	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Infections and infestations Septic shock	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Infections and infestations Urinary tract infection	0.34% 1/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.00% 0/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Infections and infestations Cystitis	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Infections and infestations Abscess	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Infections and infestations Encephalitis viral	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Infections and infestations Herpes zoster	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Infections and infestations Infected lymphocele	0.34% 1/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.00% 0/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Infections and infestations Infection	0.34% 1/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.00% 0/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Infections and infestations Post procedural infection	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Infections and infestations Pyelonephritis acute	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Infections and infestations Sepsis	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Infections and infestations Wound infection	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Gastrointestinal disorders Haemorrhoids	0.34% 1/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Gastrointestinal disorders Nausea	0.34% 1/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Gastrointestinal disorders Diarrhoea	0.34% 1/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.00% 0/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Gastrointestinal disorders Vomiting	0.34% 1/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.00% 0/297 • Approximately 87 months overall Analysis was performed on Safety Population.
General disorders Pyrexia	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.67% 2/297 • Approximately 87 months overall Analysis was performed on Safety Population.
General disorders General physical health deterioration	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
General disorders Sudden death	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Cardiac disorders Arrhythmia	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Cardiac disorders Myocardial infarction	0.34% 1/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Cardiac disorders Angina pectoris	0.34% 1/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.00% 0/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Cardiac disorders Atrial fibrillation	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Cardiac disorders Coronary artery disease	0.34% 1/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.00% 0/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Cardiac disorders Myocardial ischaemia	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Psychiatric disorders Anxiety	0.34% 1/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.00% 0/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Psychiatric disorders Depression	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Psychiatric disorders Schizophrenia	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Vascular disorders Haematoma	0.34% 1/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Vascular disorders Thrombophlebitis	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Immune system disorders Hypersensitivity	0.67% 2/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.00% 0/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Injury, poisoning and procedural complications Post procedural haematoma	0.34% 1/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.00% 0/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Injury, poisoning and procedural complications Radius fracture	0.34% 1/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Injury, poisoning and procedural complications Humerus fracture	0.34% 1/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.00% 0/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Injury, poisoning and procedural complications Incision site haematoma	0.34% 1/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.00% 0/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Injury, poisoning and procedural complications Lumbar vertebral fracture	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Injury, poisoning and procedural complications Pulmonary radiation injury	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Injury, poisoning and procedural complications Radiation pneumonitis	0.34% 1/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.00% 0/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Pregnancy, puerperium and perinatal conditions Abortion spontaneous	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Pregnancy, puerperium and perinatal conditions Pregnancy	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.67% 2/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.67% 2/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Nervous system disorders Dizziness	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Nervous system disorders Cerebrovascular accident	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Renal and urinary disorders Renal colic	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Reproductive system and breast disorders Menorrhagia	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Reproductive system and breast disorders Ovarian haemorrhage	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Reproductive system and breast disorders Ovarian mass	0.34% 1/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.00% 0/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Reproductive system and breast disorders Vaginal prolapse	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Thyroid cancer	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Investigations Tumour marker increased	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Skin and subcutaneous tissue disorders Erythema multiforme	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Infections and infestations Mastitis	0.34% 1/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Infections and infestations Tonsillitis bacterial	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
General disorders Death	0.34% 1/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.00% 0/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Investigations Ejection fraction	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Musculoskeletal and connective tissue disorders Spinal pain	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Infections and infestations Breast abscess	0.34% 1/298 • Approximately 87 months overall Analysis was performed on Safety Population.	0.34% 1/297 • Approximately 87 months overall Analysis was performed on Safety Population.

Measure	Herceptin IV + Chemotherapy n=298 participants at risk Participants received eight cycles of Herceptin IV plus chemotherapy prior to surgery and ten cycles of Herceptin IV after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as 8 mg/kg on Day 1 and then as 6 mg/kg on Day 22 and every 21 days thereafter. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.	Herceptin SC + Chemotherapy n=297 participants at risk Participants received eight cycles of Herceptin SC plus chemotherapy prior to surgery and ten cycles of Herceptin SC after surgery. Chemotherapy consisted of docetaxel 75 mg/m\^2 every 21 days for four cycles followed by FEC every 21 days for four cycles. Herceptin was administered as a 600-mg fixed dose given every 21 days. The first eight cycles prior to surgery comprised the Neoadjuvant Treatment Period, and the ten cycles of Herceptin IV after surgery comprised the Adjuvant Treatment Period. Thereafter, participants entered the TFFU Period. Participants who were withdrawn from the Neoadjuvant Treatment Period for any reason, or who experienced disease recurrence during either the Adjuvant Treatment Period or TFFU Period, could be entered into the SFU Period.
Skin and subcutaneous tissue disorders Alopecia	63.1% 188/298 • Approximately 87 months overall Analysis was performed on Safety Population.	63.0% 187/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Skin and subcutaneous tissue disorders Rash	14.8% 44/298 • Approximately 87 months overall Analysis was performed on Safety Population.	16.2% 48/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Skin and subcutaneous tissue disorders Nail disorder	10.4% 31/298 • Approximately 87 months overall Analysis was performed on Safety Population.	9.8% 29/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	6.0% 18/298 • Approximately 87 months overall Analysis was performed on Safety Population.	6.7% 20/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Skin and subcutaneous tissue disorders Pruritus	9.1% 27/298 • Approximately 87 months overall Analysis was performed on Safety Population.	8.8% 26/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Skin and subcutaneous tissue disorders Erythema	2.7% 8/298 • Approximately 87 months overall Analysis was performed on Safety Population.	7.1% 21/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Gastrointestinal disorders Nausea	49.3% 147/298 • Approximately 87 months overall Analysis was performed on Safety Population.	48.8% 145/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Gastrointestinal disorders Diarrhoea	36.6% 109/298 • Approximately 87 months overall Analysis was performed on Safety Population.	34.0% 101/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Gastrointestinal disorders Vomiting	23.2% 69/298 • Approximately 87 months overall Analysis was performed on Safety Population.	23.2% 69/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Gastrointestinal disorders Stomatitis	17.1% 51/298 • Approximately 87 months overall Analysis was performed on Safety Population.	19.2% 57/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Gastrointestinal disorders Constipation	15.1% 45/298 • Approximately 87 months overall Analysis was performed on Safety Population.	14.5% 43/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Gastrointestinal disorders Dyspepsia	10.1% 30/298 • Approximately 87 months overall Analysis was performed on Safety Population.	11.1% 33/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Gastrointestinal disorders Abdominal pain upper	9.1% 27/298 • Approximately 87 months overall Analysis was performed on Safety Population.	7.1% 21/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Gastrointestinal disorders Abdominal pain	5.4% 16/298 • Approximately 87 months overall Analysis was performed on Safety Population.	7.4% 22/297 • Approximately 87 months overall Analysis was performed on Safety Population.
General disorders Asthenia	25.2% 75/298 • Approximately 87 months overall Analysis was performed on Safety Population.	25.3% 75/297 • Approximately 87 months overall Analysis was performed on Safety Population.
General disorders Fatigue	26.8% 80/298 • Approximately 87 months overall Analysis was performed on Safety Population.	23.6% 70/297 • Approximately 87 months overall Analysis was performed on Safety Population.
General disorders Mucosal inflammation	13.1% 39/298 • Approximately 87 months overall Analysis was performed on Safety Population.	10.4% 31/297 • Approximately 87 months overall Analysis was performed on Safety Population.
General disorders Pyrexia	11.7% 35/298 • Approximately 87 months overall Analysis was performed on Safety Population.	11.8% 35/297 • Approximately 87 months overall Analysis was performed on Safety Population.
General disorders Oedema peripheral	10.1% 30/298 • Approximately 87 months overall Analysis was performed on Safety Population.	7.7% 23/297 • Approximately 87 months overall Analysis was performed on Safety Population.
General disorders Injection site pain	0.00% 0/298 • Approximately 87 months overall Analysis was performed on Safety Population.	6.1% 18/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Blood and lymphatic system disorders Neutropenia	45.3% 135/298 • Approximately 87 months overall Analysis was performed on Safety Population.	43.1% 128/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Blood and lymphatic system disorders Leukopenia	15.4% 46/298 • Approximately 87 months overall Analysis was performed on Safety Population.	10.1% 30/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Blood and lymphatic system disorders Anaemia	13.8% 41/298 • Approximately 87 months overall Analysis was performed on Safety Population.	11.4% 34/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Musculoskeletal and connective tissue disorders Myalgia	18.1% 54/298 • Approximately 87 months overall Analysis was performed on Safety Population.	20.5% 61/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Musculoskeletal and connective tissue disorders Arthralgia	20.1% 60/298 • Approximately 87 months overall Analysis was performed on Safety Population.	17.8% 53/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	7.4% 22/298 • Approximately 87 months overall Analysis was performed on Safety Population.	6.1% 18/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Musculoskeletal and connective tissue disorders Back pain	8.4% 25/298 • Approximately 87 months overall Analysis was performed on Safety Population.	8.8% 26/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Musculoskeletal and connective tissue disorders Pain in extremity	8.7% 26/298 • Approximately 87 months overall Analysis was performed on Safety Population.	9.8% 29/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Musculoskeletal and connective tissue disorders Bone pain	3.4% 10/298 • Approximately 87 months overall Analysis was performed on Safety Population.	6.4% 19/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Nervous system disorders Headache	14.8% 44/298 • Approximately 87 months overall Analysis was performed on Safety Population.	16.8% 50/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Nervous system disorders Peripheral sensory neuropathy	9.1% 27/298 • Approximately 87 months overall Analysis was performed on Safety Population.	11.1% 33/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Nervous system disorders Dysgeusia	7.4% 22/298 • Approximately 87 months overall Analysis was performed on Safety Population.	8.1% 24/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Nervous system disorders Dizziness	9.4% 28/298 • Approximately 87 months overall Analysis was performed on Safety Population.	9.8% 29/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Nervous system disorders Neuropathy peripheral	6.0% 18/298 • Approximately 87 months overall Analysis was performed on Safety Population.	8.1% 24/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Metabolism and nutrition disorders Decreased appetite	19.8% 59/298 • Approximately 87 months overall Analysis was performed on Safety Population.	19.5% 58/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Infections and infestations Nasopharyngitis	13.4% 40/298 • Approximately 87 months overall Analysis was performed on Safety Population.	8.1% 24/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Infections and infestations Upper respiratory tract infection	10.1% 30/298 • Approximately 87 months overall Analysis was performed on Safety Population.	10.1% 30/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Infections and infestations Urinary tract infection	7.4% 22/298 • Approximately 87 months overall Analysis was performed on Safety Population.	3.4% 10/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Respiratory, thoracic and mediastinal disorders Cough	8.1% 24/298 • Approximately 87 months overall Analysis was performed on Safety Population.	11.8% 35/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Respiratory, thoracic and mediastinal disorders Epistaxis	6.0% 18/298 • Approximately 87 months overall Analysis was performed on Safety Population.	6.4% 19/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Respiratory, thoracic and mediastinal disorders Dyspnoea	7.4% 22/298 • Approximately 87 months overall Analysis was performed on Safety Population.	7.1% 21/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Injury, poisoning and procedural complications Incision site pain	8.1% 24/298 • Approximately 87 months overall Analysis was performed on Safety Population.	11.1% 33/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Injury, poisoning and procedural complications Procedural pain	5.4% 16/298 • Approximately 87 months overall Analysis was performed on Safety Population.	6.1% 18/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Injury, poisoning and procedural complications Radiation skin injury	11.4% 34/298 • Approximately 87 months overall Analysis was performed on Safety Population.	13.8% 41/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Vascular disorders Hot flush	10.4% 31/298 • Approximately 87 months overall Analysis was performed on Safety Population.	10.1% 30/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Vascular disorders Hypertension	4.7% 14/298 • Approximately 87 months overall Analysis was performed on Safety Population.	8.1% 24/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Psychiatric disorders Insomnia	10.4% 31/298 • Approximately 87 months overall Analysis was performed on Safety Population.	8.8% 26/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Investigations Alanine aminotransferase increased	6.4% 19/298 • Approximately 87 months overall Analysis was performed on Safety Population.	5.4% 16/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Skin and subcutaneous tissue disorders Skin hyperpigmentation	8.1% 24/298 • Approximately 87 months overall Analysis was performed on Safety Population.	6.7% 20/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Skin and subcutaneous tissue disorders Dermatitis	5.0% 15/298 • Approximately 87 months overall Analysis was performed on Safety Population.	4.7% 14/297 • Approximately 87 months overall Analysis was performed on Safety Population.
General disorders Oedema	5.0% 15/298 • Approximately 87 months overall Analysis was performed on Safety Population.	3.4% 10/297 • Approximately 87 months overall Analysis was performed on Safety Population.
General disorders Pain	5.0% 15/298 • Approximately 87 months overall Analysis was performed on Safety Population.	4.0% 12/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Infections and infestations Pharyngitis	3.7% 11/298 • Approximately 87 months overall Analysis was performed on Safety Population.	5.1% 15/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	6.4% 19/298 • Approximately 87 months overall Analysis was performed on Safety Population.	6.4% 19/297 • Approximately 87 months overall Analysis was performed on Safety Population.
Reproductive system and breast disorders Amenorrhoea	3.4% 10/298 • Approximately 87 months overall Analysis was performed on Safety Population.	5.1% 15/297 • Approximately 87 months overall Analysis was performed on Safety Population.