A Study of Pertuzumab in Combination With Herceptin in Patients With HER2 Positive Breast Cancer.

• ClinicalTrials.gov Identifier: NCT00545688
• Recruitment Status: Completed
• First Posted: October 17, 2007
• Results First Posted: January 26, 2016
• Last Update Posted: August 15, 2017
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Breast Cancer
• Interventions: Drug: Herceptin; Drug: Docetaxel; Drug: Pertuzumab
• Enrollment: 417

Participant Flow

Recruitment Details	A total of 107, 107, 107, and 96 participants (total 417) were randomized to Arms Trastuzumab plus (+) Docetaxel (T+ D) , Trastuzumab+Pertuzumab+Docetaxel (T+Ptz+D), Trastuzumab+Pertuzumab (T+Ptz), and Pertuzumab+Docetaxel (Ptz+D), respectively and were included in intent-to-treat population (as randomized).
Pre-assignment Details	3 participants did not receive correct treatment, as randomized, and 1 (in Arm Trastuzumab + Docetaxel) did not receive any treatment. Safety population (as treated) included 107, 107, 108, and 94 participants in Arms 'T+D', 'T+Ptz+D', 'T+Ptz', and 'Ptz+D', respectively. Participant flow was available for "As Treated" participants.

Arm/Group Title	Trastuzumab + Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Arm/Group Description	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab intravenous (IV) infusion at a loading dose of 8 milligrams per kilogram (mg/kg) on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 milligrams per square meter (mg/m^2) on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by 5-fluorouracil 600 mg/m^2 IV, epirubicin 90 mg/m^2 IV, and cyclophosphamide 600 mg/m^2 IV (FEC) on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21.
Period Title: Neo-Adjuvant Treatment Period
Started	107	107	108	94
Completed	103	102	94	88
Not Completed	4	5	14	6
Reason Not Completed
Protocol Violation	1	2	1	1
Refused Treatment	1	1	4	1
Lost to Follow-up	1	0	0	0
Death	0	1	0	0
Disease Progression	0	1	7	2
Unknown Reason	1	0	0	0
Adverse Event	0	0	2	2
Period Title: Adjuvant Treatment Period
Started	103	102	94	88
Completed	98	94	90	74
Not Completed	5	8	4	14
Reason Not Completed
Disease Progression	3	3	0	7
Refused Treatment	1	1	1	5
Lost to Follow-up	1	0	1	0
Adverse Event	0	3	2	2
Unknown Reason	0	1	0	0
Period Title: Follow-Up Period
Started	98	102	98	87
Completed	77	83	78	60
Not Completed	21	19	20	27
Reason Not Completed
Death	4	2	2	6
Disease Progression	6	5	9	9
Refused Treatment	6	2	0	2
Lost to Follow-up	3	3	3	1
Unspecified Reason	2	5	6	8
Violation of Selection Criteria at Entry	0	2	0	1

Baseline Characteristics

Arm/Group Title		Trastuzumab+Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel	Total
Arm/Group Description		Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21.	Total of all reporting groups
Overall Number of Baseline Participants		107	107	107	96	417
Baseline Analysis Population Description		Intent-To-Treat (ITT) Population included all randomized participants who received any amount of study medication. Analysis was performed according to initial randomization.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	107 participants	107 participants	107 participants	96 participants	417 participants
		50.9 (8.94)	49.6 (10.05)	49.7 (10.67)	48.9 (10.50)	49.8 (10.04)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	107 participants	107 participants	107 participants	96 participants	417 participants
	Female	107 100.0%	107 100.0%	107 100.0%	96 100.0%	417 100.0%
	Male	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Achieving Pathological Complete Response (pCR)
Description	pCR was defined as an absence of invasive neoplastic cells at microscopic examination of the tumor remnants after surgery following primary systemic therapy. Participants with invalid/missing pCR assessments were defined as non-responders
Time Frame	Approximately 4 months from randomization following surgery or early withdrawal, whichever occurred first (Surgery was performed within 2 weeks after Cycle 4)

Outcome Measure Data

Analysis Population Description

ITT Population; Analysis was performed according to initial randomization.

Arm/Group Title	Trastuzumab+Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Arm/Group Description:	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21.
Overall Number of Participants Analyzed	107	107	107	96
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	29.0; (20.6 to 38.5)	45.8; (36.1 to 55.7)	16.8; (10.3 to 25.3)	24.0; (15.8 to 33.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab+Docetaxel, Trastuzumab+Pertuzumab+Docetaxel
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0094
	Comments	Cochran-Mantel-Haenszel test stratified by breast cancer type (operable, locally advanced, or inflammatory) and estrogen and or progesterone positivity (either positive versus both negative).
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in Response rates
	Estimated Value	16.82
	Confidence Interval	(2-Sided) 95%; 3.5 to 30.1
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab+Docetaxel, Trastuzumab+Pertuzumab+Docetaxel
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0141
	Comments	P-value from Cochran-Mantel-Haenszel test, with Simes multiplicity adjustment.
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab+Docetaxel, Trastuzumab+Pertuzumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0198
	Comments	Cochran-Mantel-Haenszel test stratified by breast cancer type (operable, locally advanced, or inflammatory) and estrogen and or progesterone positivity (either positive versus both negative).
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in Response rates
	Estimated Value	-12.15
	Confidence Interval	(2-Sided) 95%; -23.8 to -0.5
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab+Docetaxel, Trastuzumab+Pertuzumab
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0198
	Comments	P-value from Cochran-Mantel-Haenszel test, with Simes multiplicity adjustment.
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab+Pertuzumab+Docetaxel, Pertuzumab+Docetaxel
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0010
	Comments	Cochran-Mantel-Haenszel test stratified by breast cancer type (operable, locally advanced, or inflammatory) and estrogen and or progesterone positivity (either positive versus both negative).
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in Response rates
	Estimated Value	-21.84
	Confidence Interval	(2-Sided) 95%; -35.1 to -8.5
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab+Pertuzumab+Docetaxel, Pertuzumab+Docetaxel
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0030
	Comments	P-value from Cochran-Mantel-Haenszel test, with Simes multiplicity adjustment.
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]

2. Primary Outcome

Title	Percentage of Participants Achieving pCR by Breast Cancer Type
Description	pCR was defined as an absence of invasive neoplastic cells at microscopic examination of the tumor remnants after surgery following primary systemic therapy. Based on the type of breast cancer participants were categorized as those with 1. Operable breast cancer, 2. Inflammatory breast cancer and 3. Locally advanced breast cancer. Participants with invalid/missing pCR assessments were defined as non-responders.
Time Frame	Approximately 4 months from randomization following surgery or early withdrawal, whichever occurred first (Surgery was performed within 2 weeks after Cycle 4)

Outcome Measure Data

Analysis Population Description

ITT Population; Analysis was performed according to initial randomization. Number (n) equal (=) number of participants included in the specified type of breast cancer.

Arm/Group Title	Trastuzumab+Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Arm/Group Description:	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21.
Overall Number of Participants Analyzed	107	107	107	96
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
Operable Breast Cancer (n=64,65,65,60)	23.4; (13.8 to 35.7)	47.7; (35.1 to 60.5)	16.9; (8.8 to 28.3)	26.7; (16.1 to 39.7)
Inflammatory Breast Cancer (n=7,10,7,5)	14.3; (0.4 to 57.9)	40.0; (12.2 to 73.8)	28.6; (3.7 to 71.0)	40.0; (5.3 to 85.3)
Locally Advance Breast Cancer (36,32,35,31)	41.7; (25.5 to 59.2)	43.8; (26.4 to 62.3)	14.3; (4.8 to 30.3)	16.1; (5.5 to 33.7)

3. Primary Outcome

Title	Percentage of Participants Achieving pCR by Hormone Receptor Status
Description	pCR was defined as an absence of invasive neoplastic cells at microscopic examination of the tumor remnants after surgery following primary systemic therapy. Participants were classified as Estrogen and/or Progesterone positive (+ve), Estrogen and/or Progesterone negative (-ve) or receptor status unknown. Participants with invalid/missing pCR assessments were defined as non-responders.
Time Frame	Approximately 4 months from randomization following surgery or early withdrawal, whichever occurred first (Surgery was performed within 2 weeks after Cycle 4)

Outcome Measure Data

Analysis Population Description

ITT Population; Analysis was performed according to initial randomization. n = number of participants included in the specified hormone receptor status.

Arm/Group Title	Trastuzumab+Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Arm/Group Description:	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21.
Overall Number of Participants Analyzed	107	107	107	96
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
Estrogen and/or Progesterone +ve (n=50,50,51,46)	20.0; (10.0 to 33.7)	26.0; (14.6 to 40.3)	5.9; (1.2 to 16.2)	17.4; (7.8 to 31.4)
Estrogen and/or Progesterone -ve (n=57,57,55,50)	36.8; (24.4 to 50.7)	63.2; (49.3 to 75.6)	27.3; (16.1 to 41.0)	30.0; (17.9 to 44.6)
Receptor Status Unknown (0,0,1,0)	NA [1]; (NA to NA)	NA [1]; (NA to NA)	0.0; (0.0 to 97.5)	NA [1]; (NA to NA)

[1]

There were no participants in this category.

4. Primary Outcome

Title	Percentage of Participants Achieving pCR by Lymph Node Status
Description	pCR was defined as an absence of invasive neoplastic cells at microscopic examination of the tumor remnants after surgery following primary systemic therapy. Lymph node status was defined as either negative lymph node at surgery or positive lymph node at surgery. Participants with invalid/missing pCR assessments were defined as non-responders.
Time Frame	Approximately 4 months from randomization following surgery or early withdrawal, whichever occurred first (Surgery was performed within 2 weeks after Cycle 4)

Outcome Measure Data

Analysis Population Description

ITT Population; Analysis was performed according to initial randomization.

Arm/Group Title	Trastuzumab+Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Arm/Group Description:	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21.
Overall Number of Participants Analyzed	107	107	107	96
Measure Type: Number; Unit of Measure: percentage of participants
pCR achieved and Negative Lymph Nodes at Surgery	21.5	39.3	11.2	17.7
pCR achieved and Positive Lymph Nodes at Surgery	7.5	6.5	5.6	6.3

5. Primary Outcome

Title	Percentage of Participants Achieving pCR by Presence or Absence of Residual Intraductal Carcinoma (DCIS) / Intalobular Carcinoma (LCIS)
Description	pCR was defined as an absence of invasive neoplastic cells at microscopic examination of the tumor remnants after surgery following primary systemic therapy. Participants with invalid/missing pCR assessments were defined as non-responders.
Time Frame	Approximately 4 months from randomization following surgery or early withdrawal, whichever occurred first (Surgery was performed within 2 weeks after Cycle 4)

Outcome Measure Data

Analysis Population Description

ITT Population; Analysis was performed according to initial randomization.

Arm/Group Title	Trastuzumab+Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Arm/Group Description:	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21.
Overall Number of Participants Analyzed	107	107	107	96
Measure Type: Number; Unit of Measure: percentage of participants
pCR Achieved and No residual DCIS/LCIS at Surgery	16.8	36.4	9.3	17.7
pCR Achieved and Residual DCIS/LCIS at Surgery	12.1	9.3	7.5	6.3

6. Secondary Outcome

Title	Percentage of Participants Achieving Best Primary Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD] or Disease Progression [PD]) During Neo-Adjuvant Treatment by X-Ray/Mammography
Description	Tumor assessments were made based upon the Response Evaluation Criteria in Solid Tumors (RECIST) criteria - version 1.0. The clinical response at each cycle up to the last assessment prior to surgery was derived for primary breast tumor using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is greater than (>)0 at screening or cycle 1 Day 1; PR: if measurement is at least a 30 percent (%) decreased compared to baseline levels . (Reference= baseline size or sum of sizes); SD: if measurement at a given cycle is not sufficient shrinkage to qualify for neither PR nor sufficient increase to qualify for PD compared to baseline levels. PD: if lesion is at least a 20 % increase from measurements at baseline.
Time Frame	Baseline up to Cycle 4 (assessed at, Baseline and Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months

Outcome Measure Data

Analysis Population Description

ITT Population; Analysis was performed according to initial randomization. Number of participants analyzed = participants evaluable for this outcome.

Arm/Group Title	Trastuzumab+Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Arm/Group Description:	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21.
Overall Number of Participants Analyzed	71	58	61	47
Measure Type: Number; Unit of Measure: percentage of participants
CR	18.3	19.0	13.1	19.1
PR	49.3	46.6	36.1	46.8
SD	31.0	32.8	44.3	34.0
PD	1.4	1.7	6.6	0.0

7. Secondary Outcome

Title	Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During Neo-Adjuvant Period by X-Ray/Mammography
Description	Tumor assessments were made based on the RECIST criteria - version 1.0 The overall response at each cycle up to the last assessment prior to surgery was derived for: i) the primary breast lesion; (ii) across secondary breast lesions, (iii) across all breast lesions (iv) across axillary nodes (v) across supraclavicular nodes and (vi) across all nodes (vii) across all lesions (overall) using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is >0 at screening or cycle 1 day 1; PR: if measurement is at least a 30% decreased compared to baseline levels . (Reference= baseline size or sum of sizes); SD: if measurement at a given cycle is not sufficient shrinkage to qualify for neither PR nor sufficient increase to qualify for PD compared to baseline levels. PD: if lesion is at least a 20 % increase from measurements at baseline. Overall response is derived based on the sum total of breast tumors and all nodes examined.
Time Frame	Baseline up to Cycle 4 (assessed at Baseline, Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months

Outcome Measure Data

Analysis Population Description

ITT Population; Analysis was performed according to initial randomization. Number of participants analyzed = participants evaluable for this outcome.

Arm/Group Title	Trastuzumab+Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Arm/Group Description:	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21.
Overall Number of Participants Analyzed	71	53	55	43
Measure Type: Number; Unit of Measure: percentage of participants
CR	18.3	18.9	12.7	18.6
PR	49.3	49.1	34.5	46.5
SD	31.0	30.2	45.5	34.9
PD	1.4	1.9	7.3	0.0

8. Secondary Outcome

Title	Percentage of Participants Achieving Best Primary Breast Tumor Response (CR, PR, SD or PD) During Neo-Adjuvant Period by Clinical Examination
Description	Tumor assessments were made based on the RECIST criteria - version 1.0 The clinical response at each cycle up to the last assessment prior to surgery was derived for primary breast tumor using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is >0 at screening or cycle 1 day 1; PR: if measurement is at least a 30% decreased compared to baseline levels . (Reference= baseline size or sum of sizes); SD: if measurement at a given cycle is not sufficient shrinkage to qualify for neither PR nor sufficient increase to qualify for PD compared to baseline levels. PD: if lesion is at least a 20 % increase from measurements at baseline. Overall response is derived based on the sum total of breast tumors and all nodes examined.
Time Frame	Baseline up to Cycle 4 (assessed at Baseline, Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months

Outcome Measure Data

Analysis Population Description

ITT Population; Analysis was performed according to initial randomization. Number of participants analyzed = participants evaluable for this outcome.

Arm/Group Title	Trastuzumab+Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Arm/Group Description:	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21.
Overall Number of Participants Analyzed	99	101	102	91
Measure Type: Number; Unit of Measure: percentage of participants
CR	23.2	30.7	16.7	20.9
PR	56.6	57.4	51.0	50.5
SD	20.2	11.9	30.4	28.6
PD	0.0	0.0	2.0	0.0

9. Secondary Outcome

Title	Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During the Neo-Adjuvant Period by Clinical Examination
Description	Tumor assessments were made based on the RECIST criteria - version 1.0 The clinical response at each cycle up to the last assessment prior to surgery was derived for: i) the primary breast lesion; (ii) across secondary breast lesions, (iii) across all breast lesions (iv) across axillary nodes (v) across supraclavicular nodes and (vi) across all nodes (vii) across all lesions (overall) using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is >0 at screening or cycle 1 day 1; PR: if measurement is at least a 30% decreased compared to baseline levels . (Reference= baseline size or sum of sizes); SD: if measurement at a given cycle is not sufficient shrinkage to qualify for neither PR nor sufficient increase to qualify for PD compared to baseline levels. PD: if lesion is at least a 20 % increase from measurements at baseline. Overall response is derived based on the sum total of breast tumors and all nodes examined.
Time Frame	Baseline up to Cycle 4 (assessed at Baseline, Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months

Outcome Measure Data

Analysis Population Description

ITT Population; Analysis was performed according to initial randomization. Number of participants analyzed = participants evaluable for this outcome.

Arm/Group Title	Trastuzumab+Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Arm/Group Description:	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21.
Overall Number of Participants Analyzed	97	100	98	88
Measure Type: Number; Unit of Measure: percentage of participants
CR	21.6	25.0	11.2	15.9
PR	59.8	63.0	55.1	58.0
SD	17.5	12.0	31.6	26.1
PD	1.0	0.0	2.0	0.0

10. Secondary Outcome

Title	Percentage of Participants Achieving Clinical Response During Neo-Adjuvant Period by X-Ray/Mammography
Description	Clinical response was determined based on tumor measurements by sponsor in combination with tumor response assessment by investigator. Tumor assessments were made based on the RECIST criteria - version 1.0 The clinical response at each cycle up to the last assessment prior to surgery was derived for: i) the primary breast lesion; (ii) across secondary breast lesions, (iii) across all breast lesions (iv) across axillary nodes (v) across supraclavicular nodes and (vi) across all nodes (vii) across all lesions (overall) using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is >0 at screening or cycle 1 day 1; PR: if measurement is at least a 30% decreased compared to baseline levels . (Reference= baseline size or sum of sizes). Clinical Responders are participants who have achieved CR or PR during the Neo-adjuvant treatment. Overall response is derived based on the sum total of breast tumors and all nodes examined.
Time Frame	Baseline up to Cycle 4 (assessed at Baseline, Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months

Outcome Measure Data

Analysis Population Description

ITT Population; Analysis was performed according to initial randomization. Number of participants analyzed = participants evaluable for this outcome and n = number participants analyzed in the specified category.

Arm/Group Title	Trastuzumab+Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Arm/Group Description:	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21.
Overall Number of Participants Analyzed	71	58	61	47
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
Primary Breast Tumor (n=71,58,61,47)	67.6; (55.5 to 78.2)	65.5; (51.9 to 77.5)	49.2; (36.1 to 62.3)	66.0; (50.7 to 79.1)
Overall Response (n=71,53,55,43)	67.6; (55.5 to 78.2)	67.9; (53.7 to 80.1)	47.3; (33.7 to 61.2)	65.1; (49.1 to 79.0)

11. Secondary Outcome

Title	Percentage of Participants Achieving Clinical Response During Neo-Adjuvant Period by Clinical Examination
Description	Tumor assessments were made based on the RECIST criteria - version 1.0 The clinical response at each cycle up to the last assessment prior to surgery was derived for: i) the primary breast lesion; (ii) across secondary breast lesions, (iii) across all breast lesions (iv) across axillary nodes (v) across supraclavicular nodes and (vi) across all nodes (vii) across all lesions (overall) using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is >0 at screening or cycle 1 day 1; PR: if measurement is at least a 30% decreased compared to baseline levels . (Reference= baseline size or sum of sizes). Clinical Responders are participants who have achieved CR or PR during the Neo-adjuvant treatment. Primary breast tumor clinical response is based on primary breast tumor assessment. Overall response is derived based on the sum total of breast tumors and all nodes examined.
Time Frame	Baseline up to Cycle 4 (assessed at Baseline, Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months

Outcome Measure Data

Analysis Population Description

ITT Population; Analysis was performed according to initial randomization. Number of participants analyzed = participants evaluable for this outcome and n = number participants analyzed in the specified category.

Arm/Group Title	Trastuzumab+Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Arm/Group Description:	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21.
Overall Number of Participants Analyzed	99	101	102	91
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
Primary Breast Tumor (n=99,101,102,91)	79.8; (70.5 to 87.2)	88.1; (80.2 to 93.7)	67.6; (57.7 to 76.6)	71.4; (61.0 to 80.4)
Overall Response (n=97,100,98,88)	81.4; (72.3 to 88.6)	88.0; (80.0 to 93.6)	66.3; (56.1 to 75.6)	73.9; (63.4 to 82.7)

12. Secondary Outcome

Title	Time to Clinical Response During Neo-Adjuvant Treatment Period
Description	Time to clinical response was defined as the time from the date of first dose received to the date of assessment of clinical response. Time to Clinical response was determined by Kaplan-Meier estimates. Tumor assessments were made based on the RECIST criteria - version 1.0. The clinical response at each cycle up to the last assessment prior to surgery was derived for: i) the primary breast lesion; (ii) across secondary breast lesions, (iii) across all breast lesions (iv) across axillary nodes (v) across supraclavicular nodes and (vi) across all nodes (vii) across all lesions (overall) using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is >0 at screening or cycle 1 day 1; PR: if measurement is at least a 30% decreased compared to baseline levels . (Reference= baseline size or sum of sizes). Clinical Responders are participants who have achieved CR or PR during the Neo-adjuvant treatment.
Time Frame	Baseline up to Cycle 4 (assessed at Baseline, Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months

Outcome Measure Data

Analysis Population Description

ITT Population; Analysis was performed according to initial randomization. Number of participants analyzed = participants evaluable for this outcome.

Arm/Group Title	Trastuzumab+Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Arm/Group Description:	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21.
Overall Number of Participants Analyzed	99	101	102	91
Median (80% Confidence Interval); Unit of Measure: months
	6.3; (6.0 to 7.0)	6.3; (4.0 to 7.0)	6.9; (6.0 to 9.0)	7.3; (6.0 to 9.0)

13. Secondary Outcome

Title	Percentage of Participants With Progressive Disease During Neo-Adjuvant Treatment Period
Description	Tumor assessments were made based upon the Response Evaluation Criteria in Solid Tumors (RECIST) criteria - version 1.0. The clinical response at each cycle up to the last assessment prior to surgery was derived for: i) the primary breast lesion; (ii) across secondary breast lesions, (iii) across all breast lesions (iv) across axillary nodes (v) across supraclavicular nodes and (vi) across all nodes (vii) across all lesions (overall) using the following algorithm: PD: if lesion is at least a 20 % increased from measurements at baseline. Percentage of participants along with 95% Confidence Interval (CI) for one sample binomial using Pearson-Clopper method were reported. Missing investigator assessments were considered as no progressive disease.
Time Frame	Baseline up to Cycle 4 (assessed at Baseline, Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months

Outcome Measure Data

Analysis Population Description

ITT Population; Analysis was performed according to initial randomization.

Arm/Group Title	Trastuzumab+Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Arm/Group Description:	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a loading dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a loading dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a loading dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21.
Overall Number of Participants Analyzed	107	107	107	96
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	0.0; (0.0 to 3.4)	0.9; (0.0 to 5.1)	7.5; (3.3 to 14.2)	2.1; (0.3 to 7.3)

14. Secondary Outcome

Title	Percentage of Participants Achieving Breast Conserving Surgery For Whom Mastectomy Was Planned
Description	Breast Conserving Surgery (BCS) was defined as quadrantectomy, lumpectomy, no surgery, sentinel node biopsy, axillary surgical resection or other method of avoiding mastectomy.
Time Frame	Surgery (Within 2 weeks after Cycle 4) Up to approximately 24 months

Outcome Measure Data

Analysis Population Description

ITT Population; Analysis was performed according to initial randomization. Number of participants analyzed = participants evaluable for this outcome.

Arm/Group Title	Trastuzumab+Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Arm/Group Description:	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21.
Overall Number of Participants Analyzed	62	56	61	60
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	22.6; (12.9 to 35.0)	23.2; (13.0 to 36.4)	18.0; (9.4 to 30.0)	31.7; (20.3 to 45.0)

15. Secondary Outcome

Title	Percentage of Participants Who Were Progression Free and Disease Free
Description	Disease-free survival (DFS) was defined as the time from first date of no disease to first documentation of PD or death. Participants without progression after surgery were considered Disease Free. Any evidence of contralateral disease in-situ was not considered as PD. Participants who were withdrawn from the study without documented progression and for whom evaluations were made, were censored at date of last assessment when participant was known to be disease-free. Progression-free survival (PFS) was defined as time from date of randomization to first documentation of PD or death. Any evidence of contralateral disease in-situ was not considered as PD. Participants who were withdrawn from study without documented progression and for whom evaluations were made, were censored at date of last assessment when the participant was known to be free from progressive disease. Participants without post baseline assessments but known to be alive were censored at the time of randomization.
Time Frame	Randomization up to a maximum of 329 weeks

Outcome Measure Data

Analysis Population Description

ITT Population; Analysis was performed according to initial randomization.

Arm/Group Title	Trastuzumab+Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Arm/Group Description:	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21.
Overall Number of Participants Analyzed	107	107	107	96
Measure Type: Number; Unit of Measure: percentage of participants
Progression Free	82.2	84.1	74.8	75.0
Disease Free	82.5	85.1	80.2	76.1

16. Secondary Outcome

Title	Progression Free and Disease Free Survival
Description	DFS was defined as the time from the first date of no disease (date of surgery) to the first documentation of PD or death. Participants without progression after surgery were considered Disease Free. Any evidence of contralateral disease in-situ was not considered as PD. PFS was defined as the time from the date of randomization to the first documentation of PD or death. Any evidence of contralateral disease in-situ was not considered as PD. DFS and PFS were determined using Kaplan-Meier estimates.
Time Frame	Randomization up to a maximum of 329 weeks

Outcome Measure Data

Analysis Population Description

ITT Population; Analysis was performed according to initial randomization.

Arm/Group Title	Trastuzumab+Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Arm/Group Description:	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21.
Overall Number of Participants Analyzed	107	107	107	96
Median (80% Confidence Interval); Unit of Measure: percentage of participants
PFS	NA [1]; (NA to NA)	71.0; (71.0 to 76.0)	NA [1]; (NA to NA)	NA [1]; (NA to NA)
DFS	NA [1]; (NA to NA)	67.2; (67.0 to 72.0)	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

Median and corresponding 80% confidence interval were not achieved due to o the low number of events in this participant population, as expected.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab+Docetaxel, Trastuzumab+Pertuzumab+Docetaxel
	Comments	PFS
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2983
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.69
	Confidence Interval	(2-Sided) 95%; 0.34 to 1.40
	Estimation Comments	HR is based on Cox proportional hazard regression stratified by breast cancer type and hormone positivity.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab+Docetaxel, Trastuzumab+Pertuzumab
	Comments	PFS
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4722
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.25
	Confidence Interval	(2-Sided) 95%; 0.68 to 2.30
	Estimation Comments	HR is based on Cox proportional hazard regression stratified by breast cancer type and hormone positivity.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab+Pertuzumab+Docetaxel, Pertuzumab+Docetaxel
	Comments	PFS
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0268
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	2.05
	Confidence Interval	(2-Sided) 95%; 1.07 to 3.93
	Estimation Comments	HR is based on Cox proportional hazard regression stratified by breast cancer type and hormone positivity.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab+Docetaxel, Trastuzumab+Pertuzumab+Docetaxel
	Comments	DFS
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1805
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.60
	Confidence Interval	(2-Sided) 95%; 0.28 to 1.27
	Estimation Comments	HR is based on Cox proportional hazard regression stratified by breast cancer type and hormone positivity.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab+Docetaxel, Trastuzumab+Pertuzumab
	Comments	DFS
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5901
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.83
	Confidence Interval	(2-Sided) 95%; 0.42 to 1.64
	Estimation Comments	HR is based on Cox proportional hazard regression stratified by breast cancer type and hormone positivity.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Trastuzumab+Pertuzumab+Docetaxel, Pertuzumab+Docetaxel
	Comments	DFS
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0250
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	2.16
	Confidence Interval	(2-Sided) 95%; 1.08 to 4.32
	Estimation Comments	HR is based on Cox proportional hazard regression stratified by breast cancer type and hormone positivity.

Adverse Events

Time Frame	Adverse events were recorded from the date of Screening until the clinical cut off date 20th October 2014 up to 7 years.
Adverse Event Reporting Description	The safety population included all participants who received at least one dose of study medication and at least one safety assessment performed at baseline. Participants were assigned to treatment groups according to treatment actually received.
Arm/Group Title	Trastuzumab+Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
Arm/Group Description	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17.	Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m^2 on Day 1 of Cycle 1 followed by 100 mg/m^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred. Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21.
All-Cause Mortality
	Trastuzumab+Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--	--/--	--/--
Serious Adverse Events
	Trastuzumab+Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	21/107 (19.63%)	22/107 (20.56%)	19/108 (17.59%)	21/94 (22.34%)
Blood and lymphatic system disorders
Febrile neutropenia * 1	10/107 (9.35%)	8/107 (7.48%)	4/108 (3.70%)	12/94 (12.77%)
Neutropenia * 1	1/107 (0.93%)	6/107 (5.61%)	3/108 (2.78%)	6/94 (6.38%)
Cardiac disorders
Left ventricular dysfunction * 1	0/107 (0.00%)	3/107 (2.80%)	0/108 (0.00%)	0/94 (0.00%)
Angina pectoris * 1	0/107 (0.00%)	1/107 (0.93%)	0/108 (0.00%)	0/94 (0.00%)
Cardiac failure congestive * 1	0/107 (0.00%)	0/107 (0.00%)	1/108 (0.93%)	0/94 (0.00%)
Gastrointestinal disorders
Diarrhoea * 1	2/107 (1.87%)	0/107 (0.00%)	0/108 (0.00%)	1/94 (1.06%)
Abdominal strangulated hernia * 1	0/107 (0.00%)	1/107 (0.93%)	0/108 (0.00%)	0/94 (0.00%)
Duodenal ulcer haemorrhage * 1	0/107 (0.00%)	0/107 (0.00%)	1/108 (0.93%)	0/94 (0.00%)
General disorders
Pyrexia * 1	1/107 (0.93%)	1/107 (0.93%)	2/108 (1.85%)	1/94 (1.06%)
Imparied healing * 1	0/107 (0.00%)	0/107 (0.00%)	1/108 (0.93%)	0/94 (0.00%)
Hepatobiliary disorders
Cholecystitis acute * 1	0/107 (0.00%)	1/107 (0.93%)	0/108 (0.00%)	0/94 (0.00%)
Hepatitis fulminant * 1	0/107 (0.00%)	1/107 (0.93%)	0/108 (0.00%)	0/94 (0.00%)
Immune system disorders
Drug hypersensitivity * 1	0/107 (0.00%)	1/107 (0.93%)	1/108 (0.93%)	0/94 (0.00%)
Infections and infestations
Neutropenic infection * 1	1/107 (0.93%)	1/107 (0.93%)	1/108 (0.93%)	0/94 (0.00%)
Appendicitis * 1	1/107 (0.93%)	0/107 (0.00%)	1/108 (0.93%)	0/94 (0.00%)
Pyelonephritis acute * 1	0/107 (0.00%)	2/107 (1.87%)	0/108 (0.00%)	0/94 (0.00%)
Urinary tract infection * 1	1/107 (0.93%)	0/107 (0.00%)	0/108 (0.00%)	0/94 (0.00%)
Wound infection * 1	2/107 (1.87%)	0/107 (0.00%)	0/108 (0.00%)	0/94 (0.00%)
Breast abscess * 1	1/107 (0.93%)	0/107 (0.00%)	0/108 (0.00%)	0/94 (0.00%)
Cellulitis * 1	0/107 (0.00%)	0/107 (0.00%)	0/108 (0.00%)	1/94 (1.06%)
Device related infection * 1	0/107 (0.00%)	1/107 (0.93%)	0/108 (0.00%)	0/94 (0.00%)
H1N1 influenza * 1	0/107 (0.00%)	1/107 (0.93%)	0/108 (0.00%)	0/94 (0.00%)
Infection * 1	0/107 (0.00%)	0/107 (0.00%)	1/108 (0.93%)	0/94 (0.00%)
Neutropenic sepsis * 1	1/107 (0.93%)	0/107 (0.00%)	0/108 (0.00%)	0/94 (0.00%)
Pneumonia * 1	0/107 (0.00%)	0/107 (0.00%)	1/108 (0.93%)	0/94 (0.00%)
Sepsis * 1	0/107 (0.00%)	0/107 (0.00%)	0/108 (0.00%)	1/94 (1.06%)
Septic shock * 1	0/107 (0.00%)	0/107 (0.00%)	1/108 (0.93%)	0/94 (0.00%)
Staphylococcal sepsis * 1	0/107 (0.00%)	0/107 (0.00%)	0/108 (0.00%)	1/94 (1.06%)
Injury, poisoning and procedural complications
Femur fracture * 1	0/107 (0.00%)	0/107 (0.00%)	1/108 (0.93%)	0/94 (0.00%)
Upper limb fracture * 1	0/107 (0.00%)	1/107 (0.93%)	0/108 (0.00%)	0/94 (0.00%)
Wound dehiscence * 1	0/107 (0.00%)	0/107 (0.00%)	1/108 (0.93%)	0/94 (0.00%)
Musculoskeletal and connective tissue disorders
Back pain * 1	0/107 (0.00%)	0/107 (0.00%)	1/108 (0.93%)	0/94 (0.00%)
Spinal pain * 1	0/107 (0.00%)	1/107 (0.93%)	0/108 (0.00%)	0/94 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour haemorrhage * 1	1/107 (0.93%)	0/107 (0.00%)	0/108 (0.00%)	0/94 (0.00%)
Nervous system disorders
Dural arteriovenous fistula * 1	0/107 (0.00%)	0/107 (0.00%)	0/108 (0.00%)	1/94 (1.06%)
Reproductive system and breast disorders
Metrorrhagia * 1	1/107 (0.93%)	0/107 (0.00%)	1/108 (0.93%)	0/94 (0.00%)
Ovarian cyst ruptured * 1	0/107 (0.00%)	0/107 (0.00%)	0/108 (0.00%)	1/94 (1.06%)
Ovarian disorder * 1	1/107 (0.93%)	0/107 (0.00%)	0/108 (0.00%)	0/94 (0.00%)
Uterine haemorrhage * 1	0/107 (0.00%)	0/107 (0.00%)	0/108 (0.00%)	1/94 (1.06%)
Respiratory, thoracic and mediastinal disorders
Epistaxis * 1	1/107 (0.93%)	0/107 (0.00%)	0/108 (0.00%)	0/94 (0.00%)
Skin and subcutaneous tissue disorders
Rash papular * 1	0/107 (0.00%)	0/107 (0.00%)	1/108 (0.93%)	0/94 (0.00%)
Skin mass * 1	0/107 (0.00%)	0/107 (0.00%)	1/108 (0.93%)	0/94 (0.00%)
Vascular disorders
Venous insufficiency * 1	0/107 (0.00%)	1/107 (0.93%)	0/108 (0.00%)	0/94 (0.00%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA (17.0)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Trastuzumab+Docetaxel	Trastuzumab+Pertuzumab+Docetaxel	Trastuzumab+Pertuzumab	Pertuzumab+Docetaxel
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	107/107 (100.00%)	105/107 (98.13%)	101/108 (93.52%)	94/94 (100.00%)
Blood and lymphatic system disorders
Neutropenia * 1	80/107 (74.77%)	64/107 (59.81%)	46/108 (42.59%)	67/94 (71.28%)
Leukopenia * 1	24/107 (22.43%)	13/107 (12.15%)	13/108 (12.04%)	15/94 (15.96%)
Anaemia * 1	9/107 (8.41%)	6/107 (5.61%)	11/108 (10.19%)	12/94 (12.77%)
Cardiac disorders
Palpitations * 1	2/107 (1.87%)	5/107 (4.67%)	7/108 (6.48%)	5/94 (5.32%)
Left ventricular dysfunction * 1	2/107 (1.87%)	6/107 (5.61%)	2/108 (1.85%)	5/94 (5.32%)
Eye disorders
Lacrimation increased * 1	3/107 (2.80%)	8/107 (7.48%)	6/108 (5.56%)	6/94 (6.38%)
Gastrointestinal disorders
Nausea * 1	70/107 (65.42%)	71/107 (66.36%)	52/108 (48.15%)	61/94 (64.89%)
Diarrhoea * 1	40/107 (37.38%)	55/107 (51.40%)	46/108 (42.59%)	52/94 (55.32%)
Vomiting * 1	31/107 (28.97%)	39/107 (36.45%)	31/108 (28.70%)	37/94 (39.36%)
Stomatitis * 1	12/107 (11.21%)	22/107 (20.56%)	21/108 (19.44%)	11/94 (11.70%)
Abdominal pain upper * 1	8/107 (7.48%)	9/107 (8.41%)	12/108 (11.11%)	12/94 (12.77%)
Constipation * 1	12/107 (11.21%)	14/107 (13.08%)	9/108 (8.33%)	6/94 (6.38%)
Abdominal pain * 1	9/107 (8.41%)	11/107 (10.28%)	8/108 (7.41%)	10/94 (10.64%)
Haemorrhoids * 1	5/107 (4.67%)	8/107 (7.48%)	8/108 (7.41%)	4/94 (4.26%)
Dyspepsia * 1	6/107 (5.61%)	6/107 (5.61%)	6/108 (5.56%)	5/94 (5.32%)
Abdominal distension * 1	1/107 (0.93%)	1/107 (0.93%)	2/108 (1.85%)	5/94 (5.32%)
General disorders
Fatigue * 1	35/107 (32.71%)	35/107 (32.71%)	34/108 (31.48%)	37/94 (39.36%)
Mucosal inflammation * 1	28/107 (26.17%)	33/107 (30.84%)	18/108 (16.67%)	28/94 (29.79%)
Asthenia * 1	22/107 (20.56%)	29/107 (27.10%)	19/108 (17.59%)	23/94 (24.47%)
Pyrexia * 1	16/107 (14.95%)	25/107 (23.36%)	21/108 (19.44%)	14/94 (14.89%)
Oedema peripheral * 1	12/107 (11.21%)	7/107 (6.54%)	18/108 (16.67%)	9/94 (9.57%)
Chills * 1	8/107 (7.48%)	4/107 (3.74%)	10/108 (9.26%)	2/94 (2.13%)
Chest pain * 1	4/107 (3.74%)	2/107 (1.87%)	4/108 (3.70%)	6/94 (6.38%)
Pain * 1	2/107 (1.87%)	3/107 (2.80%)	3/108 (2.78%)	7/94 (7.45%)
Oedema * 1	1/107 (0.93%)	0/107 (0.00%)	6/108 (5.56%)	4/94 (4.26%)
General Disorder * 1	17/107 (15.89%)	16/107 (14.95%)	15/108 (13.89%)	26/94 (27.66%)
Immune system disorders
Drug hypersensitivity * 1	2/107 (1.87%)	6/107 (5.61%)	12/108 (11.11%)	6/94 (6.38%)
Infections and infestations
Upper respiratory tract infection * 1	12/107 (11.21%)	9/107 (8.41%)	11/108 (10.19%)	13/94 (13.83%)
Nasopharyngitis * 1	12/107 (11.21%)	8/107 (7.48%)	7/108 (6.48%)	5/94 (5.32%)
Pharyngitis * 1	8/107 (7.48%)	4/107 (3.74%)	4/108 (3.70%)	5/94 (5.32%)
Urinary tract infection * 1	7/107 (6.54%)	4/107 (3.74%)	3/108 (2.78%)	6/94 (6.38%)
Injury, poisoning and procedural complications
Radiation skin injury * 1	21/107 (19.63%)	19/107 (17.76%)	22/108 (20.37%)	24/94 (25.53%)
Infusion related reaction * 1	6/107 (5.61%)	7/107 (6.54%)	8/108 (7.41%)	8/94 (8.51%)
Seroma * 1	6/107 (5.61%)	7/107 (6.54%)	4/108 (3.70%)	5/94 (5.32%)
Procedural pain * 1	2/107 (1.87%)	3/107 (2.80%)	6/108 (5.56%)	2/94 (2.13%)
Incision site pain * 1	1/107 (0.93%)	2/107 (1.87%)	3/108 (2.78%)	5/94 (5.32%)
Investigations
Alanine aminotransferase increased * 1	9/107 (8.41%)	2/107 (1.87%)	2/108 (1.85%)	5/94 (5.32%)
Weight increased * 1	4/107 (3.74%)	2/107 (1.87%)	9/108 (8.33%)	1/94 (1.06%)
Aspartate aminotransferase increased * 1	9/107 (8.41%)	0/107 (0.00%)	2/108 (1.85%)	2/94 (2.13%)
Metabolism and nutrition disorders
Decreased appetite * 1	19/107 (17.76%)	18/107 (16.82%)	15/108 (13.89%)	23/94 (24.47%)
Musculoskeletal and connective tissue disorders
Myalgia * 1	24/107 (22.43%)	25/107 (23.36%)	29/108 (26.85%)	22/94 (23.40%)
Arthralgia * 1	16/107 (14.95%)	18/107 (16.82%)	13/108 (12.04%)	19/94 (20.21%)
Musculoskeletal pain * 1	13/107 (12.15%)	13/107 (12.15%)	5/108 (4.63%)	11/94 (11.70%)
Bone pain * 1	13/107 (12.15%)	11/107 (10.28%)	7/108 (6.48%)	8/94 (8.51%)
Back pain * 1	7/107 (6.54%)	7/107 (6.54%)	8/108 (7.41%)	11/94 (11.70%)
Pain in extremity * 1	9/107 (8.41%)	7/107 (6.54%)	7/108 (6.48%)	6/94 (6.38%)
Nervous system disorders
Headache * 1	17/107 (15.89%)	14/107 (13.08%)	25/108 (23.15%)	22/94 (23.40%)
Dysgeusia * 1	16/107 (14.95%)	16/107 (14.95%)	14/108 (12.96%)	10/94 (10.64%)
Peripheral sensory neuropathy * 1	14/107 (13.08%)	10/107 (9.35%)	15/108 (13.89%)	14/94 (14.89%)
Dizziness * 1	8/107 (7.48%)	6/107 (5.61%)	14/108 (12.96%)	8/94 (8.51%)
Neuropathy peripheral * 1	10/107 (9.35%)	6/107 (5.61%)	4/108 (3.70%)	5/94 (5.32%)
Paraesthesia * 1	7/107 (6.54%)	2/107 (1.87%)	3/108 (2.78%)	5/94 (5.32%)
Psychiatric disorders
Insomnia * 1	14/107 (13.08%)	13/107 (12.15%)	8/108 (7.41%)	14/94 (14.89%)
Anxiety * 1	2/107 (1.87%)	3/107 (2.80%)	6/108 (5.56%)	0/94 (0.00%)
Reproductive system and breast disorders
Menstruation irregular * 1	7/107 (6.54%)	4/107 (3.74%)	10/108 (9.26%)	9/94 (9.57%)
Respiratory, thoracic and mediastinal disorders
Cough * 1	11/107 (10.28%)	9/107 (8.41%)	19/108 (17.59%)	12/94 (12.77%)
Epistaxis * 1	6/107 (5.61%)	11/107 (10.28%)	6/108 (5.56%)	6/94 (6.38%)
Oropharyngeal pain * 1	7/107 (6.54%)	9/107 (8.41%)	2/108 (1.85%)	10/94 (10.64%)
Dyspnoea * 1	5/107 (4.67%)	7/107 (6.54%)	7/108 (6.48%)	4/94 (4.26%)
Skin and subcutaneous tissue disorders
Alopecia * 1	75/107 (70.09%)	73/107 (68.22%)	59/108 (54.63%)	65/94 (69.15%)
Rash * 1	26/107 (24.30%)	30/107 (28.04%)	22/108 (20.37%)	30/94 (31.91%)
Nail disorder * 1	17/107 (15.89%)	13/107 (12.15%)	16/108 (14.81%)	13/94 (13.83%)
Pruritus * 1	8/107 (7.48%)	5/107 (4.67%)	10/108 (9.26%)	8/94 (8.51%)
Erythema * 1	5/107 (4.67%)	6/107 (5.61%)	7/108 (6.48%)	11/94 (11.70%)
Skin hyperpigmentation * 1	5/107 (4.67%)	7/107 (6.54%)	2/108 (1.85%)	6/94 (6.38%)
Urticaria * 1	1/107 (0.93%)	6/107 (5.61%)	4/108 (3.70%)	7/94 (7.45%)
Acne * 1	3/107 (2.80%)	7/107 (6.54%)	2/108 (1.85%)	4/94 (4.26%)
Dry skin * 1	7/107 (6.54%)	2/107 (1.87%)	3/108 (2.78%)	2/94 (2.13%)
Vascular disorders
Hot flush * 1	11/107 (10.28%)	12/107 (11.21%)	8/108 (7.41%)	7/94 (7.45%)
Lymphoedema * 1	4/107 (3.74%)	6/107 (5.61%)	12/108 (11.11%)	5/94 (5.32%)
Flushing * 1	6/107 (5.61%)	5/107 (4.67%)	5/108 (4.63%)	5/94 (5.32%)
Hypertension * 1	5/107 (4.67%)	6/107 (5.61%)	4/108 (3.70%)	3/94 (3.19%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA (17.0)

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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 after the first publication or presentation that involves the overall study. Sponsor may request that confidential information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.

Results Point of Contact

• Name/Title: Medical Communications
• Organization: Hoffmannb-LaRoche
• Phone: 1-800-821-8590
• EMail: genentech@druginfo.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Bianchini G, Kiermaier A, Bianchi GV, Im YH, Pienkowski T, Liu MC, Tseng LM, Dowsett M, Zabaglo L, Kirk S, Szado T, Eng-Wong J, Amler LC, Valagussa P, Gianni L. Biomarker analysis of the NeoSphere study: pertuzumab, trastuzumab, and docetaxel versus trastuzumab plus docetaxel, pertuzumab plus trastuzumab, or pertuzumab plus docetaxel for the neoadjuvant treatment of HER2-positive breast cancer. Breast Cancer Res. 2017 Feb 9;19(1):16. doi: 10.1186/s13058-017-0806-9.

Swain SM, Schneeweiss A, Gianni L, Gao JJ, Stein A, Waldron-Lynch M, Heeson S, Beattie MS, Yoo B, Cortes J, Baselga J. Incidence and management of diarrhea in patients with HER2-positive breast cancer treated with pertuzumab. Ann Oncol. 2017 Apr 1;28(4):761-768. doi: 10.1093/annonc/mdw695. Erratum In: Ann Oncol. 2018 Apr 1;29(4):1075. Ann Oncol. 2018 Jul 1;29(7):1607. Ann Oncol. 2019 Aug 1;30(8):1404.

Gianni L, Pienkowski T, Im YH, Tseng LM, Liu MC, Lluch A, Staroslawska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi GV, Magazzu D, McNally V, Douthwaite H, Ross G, Valagussa P. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol. 2016 Jun;17(6):791-800. doi: 10.1016/S1470-2045(16)00163-7. Epub 2016 May 11.

Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, Lluch A, Staroslawska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi G, Szado T, Ratnayake J, Ross G, Valagussa P. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012 Jan;13(1):25-32. doi: 10.1016/S1470-2045(11)70336-9. Epub 2011 Dec 6.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT00545688
• Other Study ID Numbers: WO20697
• First Submitted: October 16, 2007
• First Posted: October 17, 2007
• Results First Submitted: December 16, 2015
• Results First Posted: January 26, 2016
• Last Update Posted: August 15, 2017