A Study to Evaluate Patient Preference and Satisfaction of Subcutaneous Administration of the Fixed-Dose Combination of Pertuzumab and Trastuzumab in Participants With HER2-Positive Early Breast Cancer

Study Overview
=================
Brief Summary
-----------------
This is a Phase II, randomized, multicentre, multinational, open-label, cross-over study in adult patients who have completed neoadjuvant chemotherapy with neoadjuvant pertuzumab and trastuzumab and have undergone surgical treatment of human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. The study will consist of two adjuvant treatment periods: a treatment cross-over period and a treatment continuation period. It will evaluate participant-reported preference for a subcutaneously administered fixed-dose combination formulation (FDC SC) of pertuzumab and trastuzumab compared with intravenously (IV) administered pertuzumab and trastuzumab formulations. The study will also evaluate participant-reported satisfaction with pertuzumab and trastuzumab FDC SC and health-related quality of life outcomes; healthcare professionals' perceptions of time/resource use and convenience of pertuzumab and trastuzumab FDC SC compared with pertuzumab and trastuzumab IV formulations; as well as the safety and efficacy of each study regimen.

Official Title
-----------------
A Randomized, Multicenter, Open-Label Cross-Over Study to Evaluate Patient Preference and Satisfaction of Subcutaneous Administration of the Fixed-Dose Combination of Pertuzumab and Trastuzumab in Patients With HER2-Positive Early Breast Cancer

Conditions
-----------------
HER2-Positive Early Breast Cancer

Intervention / Treatment
-----------------
* Drug: Pertuzumab and Trastuzumab Fixed-Dose Combination for Subcutaneous Administration (PH FDC SC)
* Drug: Pertuzumab IV
* Drug: Trastuzumab IV


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Disease-specific criteria: Female or male with histologically confirmed, HER2-positive (HER2+) inflammatory, locally advanced or early-stage breast cancer who have received neoadjuvant pertuzumab and trastuzumab and have completed neoadjuvant chemotherapy and subsequently undergone surgery for their breast cancer. HER2+ breast cancer assessed at the local laboratory prior to initiation of neoadjuvant therapy. HER2+ status must be determined based on breast biopsy material obtained prior to neoadjuvant treatment and is defined as 3+ by immunohistochemistry (IHC) and/or positive by HER2 amplification by in situ hybridization (ISH) with a ratio of ≥2 for the number of HER2 gene copies to the number of chromosome 17 copies. Hormone receptor status of the primary tumour determined by local assessment. Hormone receptor status may be either positive or negative. Completed all neoadjuvant chemotherapy and surgery. Adjuvant radiotherapy may be planned or ongoing at study entry and adjuvant hormone therapy is allowed during the study. Note that study treatment cannot be initiated within <2 weeks of surgery but must be initiated ≤9 weeks from the last administration of systemic neoadjuvant therapy. No evidence of residual, locally recurrent or metastatic disease after completion of surgery. Patients with clinical suspicion of metastases must undergo radiological assessments per institutional practice to rule out distant disease. Wound healing after breast cancer surgery adequate per investigator's assessment to allow initiation of study treatment within ≤9 weeks of last systemic neoadjuvant therapy No adjuvant chemotherapy planned. Note that adjuvant hormonal treatment is allowed during the study. General criteria: Ability to comply with the study protocol, in the investigator's judgment Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Intact skin at planned site of subcutaneous injections (thigh) Left ventricular ejection fraction (LVEF) ≥55% measured by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan within 28 days of study randomization No major surgical procedure unrelated to breast cancer within 28 days prior to randomization or anticipation of the need for major surgery during the course of study treatment For women of childbearing potential: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating eggs, Women must remain abstinent or use non-hormonal contraceptive methods with a failure rate of <1% per year, or two effective non-hormonal contraceptive methods during the study treatment periods and for 7 months after the last dose of study treatment For men: agreement to remain abstinent or use a condom, and agreement to refrain from donating sperm, men must remain abstinent or use a condom during the study treatment periods and for seven months after the last dose of study treatment to avoid exposing the embryo. Men must refrain from donating sperm during this same period A negative serum pregnancy test must be available prior to randomization for women of childbearing potential Exclusion Criteria: Cancer-specific criteria: Stage IV (metastatic) breast cancer Current or prior history of active malignancy within the last five years. Appropriately treated non-melanoma skin cancer; in situ carcinomas, including cervix, colon, or skin; or Stage I uterine cancer within the last five years are allowed Previous systemic therapy for treatment or prevention of breast cancer, except neoadjuvant Perjeta, Herceptin and chemotherapy for current breast cancer General criteria: Investigational treatment within four weeks of enrolment Serious cardiac illness or medical conditions History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such as structural heart disease, coronary heart disease, clinically significant electrolyte abnormalities, or family history of sudden unexplained death or long QT syndrome Inadequate bone marrow, renal and impaired liver function Current severe, uncontrolled systemic disease that may interfere with planned treatment Pregnant or breastfeeding, or intending to become pregnant during the study or within seven months after the last dose of study treatment. Women of childbearing potential must have a negative serum pregnancy test result within seven days prior to initiation of study treatment Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in, and completion of, the study Known active liver disease, for example, active viral hepatitis infection, autoimmune hepatic disorders, or sclerosing cholangitis Concurrent, serious, uncontrolled infections, or known infection with human immunodeficiency virus (HIV) Known hypersensitivity to any of the study drugs, excipients, and/or murine proteins Current chronic daily treatment with corticosteroids

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A: P+H IV Followed by PH FDC SC<br>In the Treatment Cross-Over Period of the study, participants randomized to Arm A first received pertuzumab IV and trastuzumab IV (P+H IV) administration for 3 treatment cycles followed by the pertuzumab and trastuzumab fixed-dose combination for subcutaneous administration (PH FDC SC) for 3 treatment cycles (1 cycle = 21 days). Following completion of this study period, participants chose one of the two study treatments to receive in the Treatment Continuation Period for the remaining anti-HER2 treatment cycles (18 planned cycles in total, including pre-study neoadjuvant treatment). After completing study treatment, participants entered the Follow-up Period wherein they were to be followed for 3 years from the date the last participant was randomized. | Drug: Pertuzumab and Trastuzumab Fixed-Dose Combination for Subcutaneous Administration (PH FDC SC)<br>* PH FDC SC will be administered subcutaneously (SC) at a fixed non-weight-based dose. A loading dose of 1200 mg pertuzumab and 600 mg trastuzumab is then followed by a maintenance dose of 600 mg pertuzumab and 600 mg trastuzumab once every 3 weeks (Q3W).<br>* Other names: RG6264;Drug: Pertuzumab IV<br>* Pertuzumab will be administered intravenously (IV) as a fixed non-weight-based dose of 840-mg IV loading dose and then 420-mg IV maintenance dose Q3W.<br>* Other names: Perjeta®;Drug: Trastuzumab IV<br>* Trastuzumab will be administered intravenously (IV) as an 8-mg/kg IV loading dose and then 6 mg/kg IV maintenance dose Q3W.<br>* Other names: Herceptin®;|
| Experimental: B: PH FDC SC Followed by P+H IV<br>In the Treatment Cross-Over Period of the study, participants randomized to Arm B first received the pertuzumab and trastuzumab fixed-dose combination for subcutaneous administration (PH FDC SC) for 3 treatment cycles followed by pertuzumab intravenous (IV) and trastuzumab IV (P+H IV) administration for 3 treatment cycles (1 cycle = 21 days). Following completion of this study period, participants chose one of the two study treatments to receive in the Treatment Continuation Period for the remaining anti-HER2 treatment cycles (18 planned cycles in total, including pre-study neoadjuvant treatment). After completing study treatment, participants entered the Follow-up Period wherein they were to be followed for 3 years from the date the last participant was randomized. | Drug: Pertuzumab and Trastuzumab Fixed-Dose Combination for Subcutaneous Administration (PH FDC SC)<br>* PH FDC SC will be administered subcutaneously (SC) at a fixed non-weight-based dose. A loading dose of 1200 mg pertuzumab and 600 mg trastuzumab is then followed by a maintenance dose of 600 mg pertuzumab and 600 mg trastuzumab once every 3 weeks (Q3W).<br>* Other names: RG6264;Drug: Pertuzumab IV<br>* Pertuzumab will be administered intravenously (IV) as a fixed non-weight-based dose of 840-mg IV loading dose and then 420-mg IV maintenance dose Q3W.<br>* Other names: Perjeta®;Drug: Trastuzumab IV<br>* Trastuzumab will be administered intravenously (IV) as an 8-mg/kg IV loading dose and then 6 mg/kg IV maintenance dose Q3W.<br>* Other names: Herceptin®;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants by Their Preferred Method of Pertuzumab and Trastuzumab Administration, as Assessed in Question 1 of the Patient Preference Questionnaire (PPQ) | Question 1 of the Patient Preference Questionnaire (PPQ) asked participants the following question: All things considered, which method of administration did you prefer? The three available options for a participant's response were: IV, SC, or No preference. A point estimate with associated exact Clopper-Pearson binomial 95% confidence interval was calculated only for the percentage of participants who preferred PH FDC SC. | Cycle 6 Day 1 (each cycle is 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants by Responses to the Strength of Their Preferred Method of Pertuzumab and Trastuzumab Administration, as Assessed in Question 2 of the Patient Preference Questionnaire (PPQ) | Question 1 of the Patient Preference Questionnaire (PPQ) was as follows: All things considered, which method of administration did you prefer? The available options for a participant's response were IV, SC, or No preference. In Question 2 of the PPQ, participants who reported a preference for one of the two administration routes in Question 1 of the PPQ were asked to rate the strength of their preference (very strong, fairly strong, not very strong). | Cycle 6 Day 1 (each cycle is 21 days) | 
| Percentage of Responses From Participants to the Two Main Reasons for Their Preferred Method of Pertuzumab and Trastuzumab Administration, as Assessed in Question 3 of the Patient Preference Questionnaire (PPQ) | In Question 3 of the PPQ, participants who reported a preference for one of the two administration routes in Question 1 of the PPQ were asked to provide the two main reasons for their preference. The five available options for a participant's response were: Feels less emotionally distressing; Requires less time in the clinic; Lower level of injection-site pain; Feels more comfortable during administration; and Other reason. | Cycle 6 Day 1 (each cycle is 21 days) | 
| Percentage of Participants by Their Level of Satisfaction With the Respective Methods of Administration (IV and SC), Question 1 of the Therapy Administration Satisfaction Questionnaire -Intravenous (TASQ-IV) and -Subcutaneous (TASQ-SC) | The Therapy Administration Satisfaction Questionnaire (TASQ) is a 12-item, patient-reported questionnaire measuring the impact of each mode of treatment administration (TASQ-IV for IV treatment and TASQ-SC for SC treatment) on five domains: Physical Impact, Psychological Impact, Impact on Activities of Daily Living, Convenience, and Satisfaction. The TASQ-IV/-SC was administered at treatment Cycles 3 and 6 according to the order of treatment received per arm during the Cross-Over Period. Question 1 of the TASQ-IV/TASQ-SC is one of two items in the Satisfaction domain, with participants providing their answers to the following question: How satisfied or dissatisfied were you with the IV infusion/SC injection? The five available options for a participant's response were: very satisfied, satisfied, neither satisfied nor dissatisfied, dissatisfied, and very dissatisfied. | Cycle 3 Day 1, Cycle 6 Day 1 (each cycle is 21 days) | 
| Mean Scores of the Five Domains of the TASQ-IV and TASQ-SC (Satisfaction, Physical Impact, Psychological Impact, Impact on Activities of Daily Living, and Convenience) to Assess the Impact of IV and SC Routes of Administration | The TASQ is a 12-item, patient-reported questionnaire measuring the impact of the mode of treatment administration (TASQ-IV for IV treatment and TASQ-SC for SC treatment) on 5 domains: Physical Impact (3 items: Question [Q]2. Pain, Q3. Swelling, Q4. Redness), Psychological Impact (1 item: Q5. Feeling restricted), Impact on Activities of Daily Living (1 item: Q8. Lost/gained time), Convenience (2 items: Q6. Is it convenient?, Q7. Bothered by the amount of time?), and Satisfaction (2 items: Q1. How satisfied or dissatisfied are you with treatment?, Q12: Would you recommend the way you received the treatment?). In addition, 3 questions in the TASQ (Q9, Q10, Q11) are not part of the domains. Responses for the 3 domains that contain more than 1 item were scored from 0 to 100, with a higher score indicating a better outcome. Responses for the 2 domains with 1 item were scored from 1 to 5, with a higher score indicating a better outcome. | Cycle 3 Day 1, Cycle 6 Day 1 (each cycle is 21 days) | 
| Percentage of Participants by Their Responses to Question 9 of the TASQ-IV and TASQ-SC, Assessing Whether Participants Receiving IV and SC Administration Have as Much Time as They Would Like to Talk to Their Nurse and/or Doctor About Their Illness | The TASQ is a 12-item, patient-reported questionnaire measuring the impact of the mode of treatment administration (TASQ-IV for IV treatment and TASQ-SC for SC treatment) on 5 domains. In addition, 3 questions (Q.9-11) are not part of the domains. The TASQ-IV/-SC was administered at treatment Cycles 3 and 6 according to the order of treatment received per arm during the Cross-Over Period. Question 9 asked the participant, When you receive the IV infusion/SC injection treatment, are you able to talk to your nurse and/or doctor as much as you would like about your illness? There were five available response options: a) Yes, I had more than enough time to talk to my nurse and/or doctor; b) Yes, but I would have liked more time to talk to my nurse and/or doctor; c) It does not matter to me if I have time to talk to my nurse and/or doctor during my treatment; d) No, I did not have enough time to talk to my nurse and/or doctor; and e) No, I did not talk to my nurse and/or doctor at all. | Cycle 3 Day 1 and Cycle 6 Day 1 (each cycle is 21 days) | 
| Percentage of Participants by Their Responses to Question 10 of the TASQ-IV and TASQ-SC, Assessing Whether IV and SC Administration Have an Impact on the Amount of Time Participants Have to Talk to Their Nurse and/or Doctor About Their Illness | The Therapy Administration Satisfaction Questionnaire (TASQ) is a 12-item, patient-reported questionnaire measuring the impact of the mode of treatment administration (TASQ-IV for IV treatment and TASQ-SC for SC treatment) on 5 domains (questions [Q] 1 to 8 and Q12): Physical Impact, Psychological Impact, Impact on Activities of Daily Living, Convenience, and Satisfaction. In addition, 3 questions in the TASQ-IV/-SC (Q 9-11) are not part of the domains. The TASQ-IV/-SC were administered at treatment Cycles 3 and 6 according to the order of treatment received in each study arm during the Cross-Over Period. Question 10 of the TASQ-IV/-SC asked the participant Does the IV infusion/SC injection impact the amount of time you have to talk to your nurse and/or doctor about your illness and other concerns? There were two available options for the participant's response: Yes or No. | Cycle 3 Day 1 and Cycle 6 Day 1 (each cycle is 21 days) | 
| Percentage of Participants by Their Responses to Question 11 of the TASQ-IV and TASQ-SC, Assessing the Participants' Preferred Method for Receiving Cancer Treatment | The Therapy Administration Satisfaction Questionnaire (TASQ) is a 12-item, patient-reported questionnaire measuring the impact of the mode of treatment administration (TASQ-IV for IV treatment and TASQ-SC for SC treatment) on 5 domains (questions [Q] 1 to 8 and Q12): Physical Impact, Psychological Impact, Impact on Activities of Daily Living, Convenience, and Satisfaction. In addition, 3 questions in the TASQ-IV/-SC (Q 9-11) are not part of the domains. The TASQ-IV/-SC was administered at treatment Cycles 3 and 6 according to the order of treatment received during the Cross-Over Period. Question 11 of the TASQ-IV/-SC asked the participant, There are two ways to get cancer treatment: a) IV infusion given through a port or small tube; b) SC (subcutaneous) injection in your thigh. Which would you prefer? There were three available options for the participant's response: IV, SC, or No Preference. | Cycle 3 Day 1 and Cycle 6 Day 1 (each cycle is 21 days) | 
| Percentage of Participants by Their Choice of Treatment in the Treatment Continuation Period (PH FDC SC or P+H IV) and by Consistency of This Choice With Their Preferred Method of Administration Reported in Question 1 of the PPQ | At treatment Cycle 6, Day 1, participants were expected to select the study treatment formulation (PH FDC SC or P+H IV) they would receive during the Treatment Continuation Period (starting at Cycle 7) to complete their 18 cycles of neo/adjuvant HER2-targeted treatment. Additionally, for each participant's preference category (SC, IV, and No preference) as per the question 1 of the patient preference questionnaire (PPQ), the percentage of participants who selected each treatment administration route for the Treatment Continuation Period (PH FDC SC or P+H IV) was summarized. | Cycle 6 Day 1 (each cycle is 21 days) | 
| Duration of Treatment Administration Activities According to Healthcare Professionals' Responses on Perception of Time by Treatment Cycle, Question 1 of the Healthcare Professional Questionnaire (HCPQ) - Treatment Room | The Healthcare Professional Questionnaire (HCPQ)-Treatment Room Question 1 was completed at each treatment cycle of the Treatment Cross-Over Period by the healthcare professionals (HCPs) who administered treatment to the study's participants. HCPs responded to the following parts of Question 1 that sought to evaluate the amount of time it took to complete activities related to treatment administration: If new IV access was needed for this cycle of treatment, please indicate what type of IV access was provided (central venous catheter, peripherally inserted central catheter, or peripheral vein cannulation) and how long (in minutes) this took to set up (only for participants receiving IV treatment)? How long (in minutes) did it take to administer the treatment, i.e. total infusion duration? How long (in minutes) was the patient in the Treatment Room for in total? | Day 1 of Cycles 1-6 (each cycle is 21 days) | 
| Percentage of Healthcare Professionals (HCPs) by Their Responses on Perception of Impact of PH FDC SC on Clinical Management and Clinical Efficiency, Question 2 of the HCPQ - Treatment Room | HCPs who administered study treatment responded at Cycle 6 of the Treatment Cross-Over Period to the following HCPQ-Treatment Room Question 2: If all P+H IV infusions are switched to FDC SC injections, please indicate how strongly you agree or disagree with each of the following statements: a) Patients will be moved outside of infusion unit to receive FDC SC; b) FDC SC route will allow more flexible scheduling; c) More patients will be treated in the infusion unit; d) Waiting list for any P+H IV treatment at the infusion unit will be reduced; e) Staff resources will be redistributed to other departments of the hospital; f) There will still be sufficient interaction time between HCPs and patients; g) Staff will spend more time for further education/development; h) Staff will dedicate more time attending to administrative tasks for Perjeta-Herceptin patients; i) Patients will spend less time in the care unit; j) Administration by FDC SC injection is preferred by patients. | Day 1 of Cycle 6 (each cycle is 21 days) | 
| Percentage of Healthcare Professionals (HCPs) by Their Responses on Perception of Time/Resource Use and Convenience of Each Study Regimen, Questions 3 to 7 of the HCPQ - Treatment Room | Healthcare professionals (HCPs) who administered study treatment responded at Cycle 6 of the Treatment Cross-Over Period to the following HCPQ-Treatment Room Questions 3 to 7: Looking back over the Perjeta-Herceptin treatment sessions, please indicate based on your opinion which administration method: Q3. Which Method Was Most Convenient for the Patient? Q4. Which Method Was Best for Optimizing Patient Care in Your Centre? Q5. Which Method Took the Least Time from Start to Finish of Administration? Q6. Which Method Required the Least Resource Use for Administration? Q7. Which Method Was Preferred by Patients? The four available response options were: P+H IV, FDC SC, No Difference, and Unsure. | Day 1 of Cycle 6 (each cycle is 21 days) | 
| Percentage of Healthcare Professionals (HCPs) by Their Responses to Question 8 of the HCPQ - Treatment Room | Healthcare professionals (HCPs) who administered study treatment responded at Cycle 6 of the Treatment Cross-Over Period to the following HCPQ-Treatment Room Question 8: How frequently would you offer or recommend FDC SC administration to your patients in the future? The three available response options were: Always, Sometimes, and Never. | Day 1 of Cycle 6 (each cycle is 21 days) | 
| Duration of Treatment Preparation According to Healthcare Professionals' Responses on Perception of Time by Treatment Cycle, Question 1 of the HCPQ - Drug Preparation Room | The Healthcare Professional Questionnaire (HCPQ)-Drug Preparation Room Question 1 was completed at each treatment cycle of the Treatment Cross-Over Period by the healthcare professionals (HCPs) within the pharmacy/drug preparation area where pertuzumab IV and trastuzumab IV and pertuzumab and trastuzumab FDC SC were prepared and dispensed for treating the study's participants. HCPs responded to the following question: How long (in minutes) did it take to prepare the treatment for use? | Day 1 of Cycles 1-6 (each cycle is 21 days) | 
| Percentage of Healthcare Professionals (HCPs) by Their Responses on Perception of Impact of PH FDC SC on Clinical Management and Clinical Efficiency, Question 2 of the HCPQ - Drug Preparation Room | Healthcare professionals (HCPs) who prepared study treatment within the pharmacy/drug preparation area responded at Cycle 6 of the Treatment Cross-Over Period to the following HCPQ-Drug Preparation Room Question 2: If all P+H IV infusions are switched to FDC SC injections, please indicate how strongly you agree or disagree with each of the following statements: a) Staff will have increased availability for other tasks in the pharmacy; b) Administrative procedures around FDC SC will require less time; c) FDC SC formulations will provide more flexibility for staff in managing their workload; d) Due to ready-to-use FDC SC formulations, potential dosing errors will be avoided; e) Due to ready-to-use FDC SC formulations, there will be less drug wastage; f) Without having to reconstitute the drug, less storage space for FDC SC related supplies will be required in the pharmacy; g) Preparation procedures and associated time staff time commitment will be reduced. | Day 1 of Cycle 6 (each cycle is 21 days) | 
| Percentage of Healthcare Professionals (HCPs) by Their Responses on Perception of Time/Resource Use of Each Study Regimen, Questions 3 and 4 of the HCPQ - Drug Preparation Room | Healthcare professionals (HCPs) who prepared study treatment within the pharmacy/drug preparation area responded at Cycle 6 of the Treatment Cross-Over Period to the following HCPQ-Drug Preparation Room Questions 3 and 4: Looking back over the Perjeta-Herceptin treatment sessions, please indicate based on your opinion which administration method: Q3. Was quickest from start to end of preparation to finish of administration (excluding observation period)?; Q4. Required less resource use for preparation and administration, for example nursing time, facility costs, equipment etc? The three available response options were: P+H IV, FDC SC, and No Difference. | Day 1 of Cycle 6 (each cycle is 21 days) | 
| Change From Baseline Over Time in Health-Related Quality of Life (HRQoL) as Assessed by the Global Health Status (GHS)/HRQoL Scale Score of the the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30 (EORTC QLQ-C30) | The EORTC QLQ-C30 questionnaire consisted of 30 questions covering treatment-related symptoms, functioning, and GHS/HRQoL. Questions were answered by participants on a scale from 1 to 4 or 1 to 7. Raw scores were transformed to scale scores that ranged from 0 to 100 where a higher scale score indicating a higher response (i.e., on the functioning and GHS/QoL scales a higher score meant better functioning/QoL, whereas on the symptom scales a higher score meant greater [worse] symptoms). The EORTC QLQ-C30 data was scored according to the EORTC scoring manual (Fayers 2001). In the event of incomplete data, for all questionnaire subscales, if more than 50% of the constituent items are completed, a pro-rated score was to be computed consistent with the scoring manuals and published validation reports. For subscales with less than 50% of the items completed, the subscale was to be considered as missing. | Baseline (Day 1 of Cycle 1); Day 1 of Cycles 3, 6, and 15 (or last treatment cycle; each cycle is 21 days); 1.5, 2, and 3 years (up to 3 years) | 
| Change From Baseline Over Time in the Physical Functioning Scale Score of the EORTC QLQ-C30 | The EORTC QLQ-C30 questionnaire consisted of 30 questions covering treatment-related symptoms, functioning, and GHS/HRQoL. Questions were answered by participants on a scale from 1 to 4 or 1 to 7. Raw scores were transformed to scale scores that ranged from 0 to 100 where a higher scale score indicating a higher response (i.e., on the functioning and GHS/QoL scales a higher score meant better functioning/QoL, whereas on the symptom scales a higher score meant greater [worse] symptoms). The EORTC QLQ-C30 data was scored according to the EORTC scoring manual (Fayers 2001). In the event of incomplete data, for all questionnaire subscales, if more than 50% of the constituent items are completed, a pro-rated score was to be computed consistent with the scoring manuals and published validation reports. For subscales with less than 50% of the items completed, the subscale was to be considered as missing. | Baseline (Day 1 of Cycle 1); Day 1 of Cycles 3, 6, and 15 (or last treatment cycle; each cycle is 21 days); 1.5, 2, and 3 years (up to 3 years) | 
| Change From Baseline Over Time in the Role Functioning Scale Score of the EORTC QLQ-C30 | The EORTC QLQ-C30 questionnaire consisted of 30 questions covering treatment-related symptoms, functioning, and GHS/HRQoL. Questions were answered by participants on a scale from 1 to 4 or 1 to 7. Raw scores were transformed to scale scores that ranged from 0 to 100 where a higher scale score indicating a higher response (i.e., on the functioning and GHS/QoL scales a higher score meant better functioning/QoL, whereas on the symptom scales a higher score meant greater [worse] symptoms). The EORTC QLQ-C30 data was scored according to the EORTC scoring manual (Fayers 2001). In the event of incomplete data, for all questionnaire subscales, if more than 50% of the constituent items are completed, a pro-rated score was to be computed consistent with the scoring manuals and published validation reports. For subscales with less than 50% of the items completed, the subscale was to be considered as missing. | Baseline (Day 1 of Cycle 1); Day 1 of Cycles 3, 6, and 15 (or last treatment cycle; each cycle is 21 days); 1.5, 2, and 3 years (up to 3 years) | 
| Change From Baseline Over Time in the Emotional Functioning Scale Score of the EORTC QLQ-C30 | The EORTC QLQ-C30 questionnaire consisted of 30 questions covering treatment-related symptoms, functioning, and GHS/HRQoL. Questions were answered by participants on a scale from 1 to 4 or 1 to 7. Raw scores were transformed to scale scores that ranged from 0 to 100 where a higher scale score indicating a higher response (i.e., on the functioning and GHS/QoL scales a higher score meant better functioning/QoL, whereas on the symptom scales a higher score meant greater [worse] symptoms). The EORTC QLQ-C30 data was scored according to the EORTC scoring manual (Fayers 2001). In the event of incomplete data, for all questionnaire subscales, if more than 50% of the constituent items are completed, a pro-rated score was to be computed consistent with the scoring manuals and published validation reports. For subscales with less than 50% of the items completed, the subscale was to be considered as missing. | Baseline (Day 1 of Cycle 1); Day 1 of Cycles 3, 6, and 15 (or last treatment cycle; each cycle is 21 days); 1.5, 2, and 3 years (up to 3 years) | 
| Change From Baseline Over Time in the Cognitive Functioning Scale Score of the EORTC QLQ-C30 | The EORTC QLQ-C30 questionnaire consisted of 30 questions covering treatment-related symptoms, functioning, and GHS/HRQoL. Questions were answered by participants on a scale from 1 to 4 or 1 to 7. Raw scores were transformed to scale scores that ranged from 0 to 100 where a higher scale score indicating a higher response (i.e., on the functioning and GHS/QoL scales a higher score meant better functioning/QoL, whereas on the symptom scales a higher score meant greater [worse] symptoms). The EORTC QLQ-C30 data was scored according to the EORTC scoring manual (Fayers 2001). In the event of incomplete data, for all questionnaire subscales, if more than 50% of the constituent items are completed, a pro-rated score was to be computed consistent with the scoring manuals and published validation reports. For subscales with less than 50% of the items completed, the subscale was to be considered as missing. | Baseline (Day 1 of Cycle 1); Day 1 of Cycles 3, 6, and 15 (or last treatment cycle; each cycle is 21 days); 1.5, 2, and 3 years (up to 3 years) | 
| Change From Baseline Over Time in the Social Functioning Scale Score of the EORTC QLQ-C30 | The EORTC QLQ-C30 questionnaire consisted of 30 questions covering treatment-related symptoms, functioning, and GHS/HRQoL. Questions were answered by participants on a scale from 1 to 4 or 1 to 7. Raw scores were transformed to scale scores that ranged from 0 to 100 where a higher scale score indicating a higher response (i.e., on the functioning and GHS/QoL scales a higher score meant better functioning/QoL, whereas on the symptom scales a higher score meant greater [worse] symptoms). The EORTC QLQ-C30 data was scored according to the EORTC scoring manual (Fayers 2001). In the event of incomplete data, for all questionnaire subscales, if more than 50% of the constituent items are completed, a pro-rated score was to be computed consistent with the scoring manuals and published validation reports. For subscales with less than 50% of the items completed, the subscale was to be considered as missing. | Baseline (Day 1 of Cycle 1); Day 1 of Cycles 3, 6, and 15 (or last treatment cycle; each cycle is 21 days); 1.5, 2, and 3 years (up to 3 years) | 
| Change From Baseline Over Time in the Fatigue Scale Score of the EORTC QLQ-C30 | The EORTC QLQ-C30 questionnaire consisted of 30 questions covering treatment-related symptoms, functioning, and GHS/HRQoL. Questions were answered by participants on a scale from 1 to 4 or 1 to 7. Raw scores were transformed to scale scores that ranged from 0 to 100 where a higher scale score indicating a higher response (i.e., on the functioning and GHS/QoL scales a higher score meant better functioning/QoL, whereas on the symptom scales a higher score meant greater [worse] symptoms). The EORTC QLQ-C30 data was scored according to the EORTC scoring manual (Fayers 2001). In the event of incomplete data, for all questionnaire subscales, if more than 50% of the constituent items are completed, a pro-rated score was to be computed consistent with the scoring manuals and published validation reports. For subscales with less than 50% of the items completed, the subscale was to be considered as missing. | Baseline (Day 1 of Cycle 1); Day 1 of Cycles 3, 6, and 15 (or last treatment cycle; each cycle is 21 days); 1.5, 2, and 3 years (up to 3 years) | 
| Change From Baseline Over Time in the Nausea and Vomiting Scale Score of the EORTC QLQ-C30 | The EORTC QLQ-C30 questionnaire consisted of 30 questions covering treatment-related symptoms, functioning, and GHS/HRQoL. Questions were answered by participants on a scale from 1 to 4 or 1 to 7. Raw scores were transformed to scale scores that ranged from 0 to 100 where a higher scale score indicating a higher response (i.e., on the functioning and GHS/QoL scales a higher score meant better functioning/QoL, whereas on the symptom scales a higher score meant greater [worse] symptoms). The EORTC QLQ-C30 data was scored according to the EORTC scoring manual (Fayers 2001). In the event of incomplete data, for all questionnaire subscales, if more than 50% of the constituent items are completed, a pro-rated score was to be computed consistent with the scoring manuals and published validation reports. For subscales with less than 50% of the items completed, the subscale was to be considered as missing. | Baseline (Day 1 of Cycle 1); Day 1 of Cycles 3, 6, and 15 (or last treatment cycle; each cycle is 21 days); 1.5, 2, and 3 years (up to 3 years) | 
| Change From Baseline Over Time in the Pain Scale Score of the EORTC QLQ-C30 | The EORTC QLQ-C30 questionnaire consisted of 30 questions covering treatment-related symptoms, functioning, and GHS/HRQoL. Questions were answered by participants on a scale from 1 to 4 or 1 to 7. Raw scores were transformed to scale scores that ranged from 0 to 100 where a higher scale score indicating a higher response (i.e., on the functioning and GHS/QoL scales a higher score meant better functioning/QoL, whereas on the symptom scales a higher score meant greater [worse] symptoms). The EORTC QLQ-C30 data was scored according to the EORTC scoring manual (Fayers 2001). In the event of incomplete data, for all questionnaire subscales, if more than 50% of the constituent items are completed, a pro-rated score was to be computed consistent with the scoring manuals and published validation reports. For subscales with less than 50% of the items completed, the subscale was to be considered as missing. | Baseline (Day 1 of Cycle 1); Day 1 of Cycles 3, 6, and 15 (or last treatment cycle; each cycle is 21 days); 1.5, 2, and 3 years (up to 3 years) | 
| Change From Baseline Over Time in the Dyspnoea Scale Score of the EORTC QLQ-C30 | The EORTC QLQ-C30 questionnaire consisted of 30 questions covering treatment-related symptoms, functioning, and GHS/HRQoL. Questions were answered by participants on a scale from 1 to 4 or 1 to 7. Raw scores were transformed to scale scores that ranged from 0 to 100 where a higher scale score indicating a higher response (i.e., on the functioning and GHS/QoL scales a higher score meant better functioning/QoL, whereas on the symptom scales a higher score meant greater [worse] symptoms). The EORTC QLQ-C30 data was scored according to the EORTC scoring manual (Fayers 2001). In the event of incomplete data, for all questionnaire subscales, if more than 50% of the constituent items are completed, a pro-rated score was to be computed consistent with the scoring manuals and published validation reports. For subscales with less than 50% of the items completed, the subscale was to be considered as missing. | Baseline (Day 1 of Cycle 1); Day 1 of Cycles 3, 6, and 15 (or last treatment cycle; each cycle is 21 days); 1.5, 2, and 3 years (up to 3 years) | 
| Change From Baseline Over Time in the Insomnia Scale Score of the EORTC QLQ-C30 | The EORTC QLQ-C30 questionnaire consisted of 30 questions covering treatment-related symptoms, functioning, and GHS/HRQoL. Questions were answered by participants on a scale from 1 to 4 or 1 to 7. Raw scores were transformed to scale scores that ranged from 0 to 100 where a higher scale score indicating a higher response (i.e., on the functioning and GHS/QoL scales a higher score meant better functioning/QoL, whereas on the symptom scales a higher score meant greater [worse] symptoms). The EORTC QLQ-C30 data was scored according to the EORTC scoring manual (Fayers 2001). In the event of incomplete data, for all questionnaire subscales, if more than 50% of the constituent items are completed, a pro-rated score was to be computed consistent with the scoring manuals and published validation reports. For subscales with less than 50% of the items completed, the subscale was to be considered as missing. | Baseline (Day 1 of Cycle 1); Day 1 of Cycles 3, 6, and 15 (or last treatment cycle; each cycle is 21 days); 1.5, 2, and 3 years (up to 3 years) | 
| Change From Baseline Over Time in the Appetite Loss Scale Score of the EORTC QLQ-C30 | The EORTC QLQ-C30 questionnaire consisted of 30 questions covering treatment-related symptoms, functioning, and GHS/HRQoL. Questions were answered by participants on a scale from 1 to 4 or 1 to 7. Raw scores were transformed to scale scores that ranged from 0 to 100 where a higher scale score indicating a higher response (i.e., on the functioning and GHS/QoL scales a higher score meant better functioning/QoL, whereas on the symptom scales a higher score meant greater [worse] symptoms). The EORTC QLQ-C30 data was scored according to the EORTC scoring manual (Fayers 2001). In the event of incomplete data, for all questionnaire subscales, if more than 50% of the constituent items are completed, a pro-rated score was to be computed consistent with the scoring manuals and published validation reports. For subscales with less than 50% of the items completed, the subscale was to be considered as missing. | Baseline (Day 1 of Cycle 1); Day 1 of Cycles 3, 6, and 15 (or last treatment cycle; each cycle is 21 days); 1.5, 2, and 3 years (up to 3 years) | 
| Change From Baseline Over Time in the Constipation Scale Score of the EORTC QLQ-C30 | The EORTC QLQ-C30 questionnaire consisted of 30 questions covering treatment-related symptoms, functioning, and GHS/HRQoL. Questions were answered by participants on a scale from 1 to 4 or 1 to 7. Raw scores were transformed to scale scores that ranged from 0 to 100 where a higher scale score indicating a higher response (i.e., on the functioning and GHS/QoL scales a higher score meant better functioning/QoL, whereas on the symptom scales a higher score meant greater [worse] symptoms). The EORTC QLQ-C30 data was scored according to the EORTC scoring manual (Fayers 2001). In the event of incomplete data, for all questionnaire subscales, if more than 50% of the constituent items are completed, a pro-rated score was to be computed consistent with the scoring manuals and published validation reports. For subscales with less than 50% of the items completed, the subscale was to be considered as missing. | Baseline (Day 1 of Cycle 1); Day 1 of Cycles 3, 6, and 15 (or last treatment cycle; each cycle is 21 days); 1.5, 2, and 3 years (up to 3 years) | 
| Change From Baseline Over Time in the Diarrhoea Scale Score of the EORTC QLQ-C30 | The EORTC QLQ-C30 questionnaire consisted of 30 questions covering treatment-related symptoms, functioning, and GHS/HRQoL. Questions were answered by participants on a scale from 1 to 4 or 1 to 7. Raw scores were transformed to scale scores that ranged from 0 to 100 where a higher scale score indicating a higher response (i.e., on the functioning and GHS/QoL scales a higher score meant better functioning/QoL, whereas on the symptom scales a higher score meant greater [worse] symptoms). The EORTC QLQ-C30 data was scored according to the EORTC scoring manual (Fayers 2001). In the event of incomplete data, for all questionnaire subscales, if more than 50% of the constituent items are completed, a pro-rated score was to be computed consistent with the scoring manuals and published validation reports. For subscales with less than 50% of the items completed, the subscale was to be considered as missing. | Baseline (Day 1 of Cycle 1); Day 1 of Cycles 3, 6, and 15 (or last treatment cycle; each cycle is 21 days); 1.5, 2, and 3 years (up to 3 years) | 
| Change From Baseline Over Time in the Financial Difficulties Scale Score of the EORTC QLQ-C30 | The EORTC QLQ-C30 questionnaire consisted of 30 questions covering treatment-related symptoms, functioning, and GHS/HRQoL. Questions were answered by participants on a scale from 1 to 4 or 1 to 7. Raw scores were transformed to scale scores that ranged from 0 to 100 where a higher scale score indicating a higher response (i.e., on the functioning and GHS/QoL scales a higher score meant better functioning/QoL, whereas on the symptom scales a higher score meant greater [worse] symptoms). The EORTC QLQ-C30 data was scored according to the EORTC scoring manual (Fayers 2001). In the event of incomplete data, for all questionnaire subscales, if more than 50% of the constituent items are completed, a pro-rated score was to be computed consistent with the scoring manuals and published validation reports. For subscales with less than 50% of the items completed, the subscale was to be considered as missing. | Baseline (Day 1 of Cycle 1); Day 1 of Cycles 3, 6, and 15 (or last treatment cycle; each cycle is 21 days); 1.5, 2, and 3 years (up to 3 years) | 
| Safety Summary for Assessment of Switching Between the FDC SC and IV Formulations: Number of Participants With at Least One Adverse Event During the Treatment Cross-Over Period by Study Arm and Treatment Received | Investigators used the NCI CTCAE v4.0 grading scale for assessing adverse event (AE) severity; if not listed, AE severity was graded as follows: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe or medically significant; Grade 4 = life-threatening; Grade 5 = death related to AE. Severity and seriousness are not synonymous and investigators independently assessed these criteria for each AE. Investigators also determined whether an AE was considered to be related to the study drug. Adverse events to monitor were defined based on known risks associated with the study drugs and included: hypersensitivity reactions, administration-related reactions (ARRs), cardiac dysfunction, diarrhea grade ≥3, rash/skin reactions, mucositis, interstitial lung disease (ILD), (febrile) neutropenia, pulmonary events that may occur as a result of an ARR, and pregnancy/neonatal related. Multiple occurrences of AEs were counted only once per participant. LVEF = left ventricular ejection fraction | From Day 1 of Cycle 1 to the end of Cycle 3 of Cross-Over Period; from Day 1 of Cycle 4 to the end of Cycle 6 of Cross-Over Period (1 cycle is 21 days) | 
| Safety Summary of the FDC SC and IV Formulations: Number of Participants With at Least One Adverse Event During the Treatment Cross-Over and Treatment Continuation Periods | Investigators used the NCI CTCAE v4.0 grading scale for assessing adverse event (AE) severity; if not listed, AE severity was graded as follows: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe or medically significant; Grade 4 = life-threatening; Grade 5 = death related to AE. Severity and seriousness are not synonymous and investigators independently assessed these criteria for each AE. Investigators also determined whether an AE was considered to be related to the study drug. Adverse events to monitor were defined based on known risks associated with the study drugs and included: hypersensitivity reactions, administration-related reactions (ARRs), cardiac dysfunction, diarrhea grade ≥3, rash/skin reactions, mucositis, interstitial lung disease (ILD), (febrile) neutropenia, pulmonary events that may occur as a result of an ARR, and pregnancy/neonatal related. Multiple occurrences of AEs were counted only once per participant. LVEF = left ventricular ejection fraction | From Day 1 of Cycle 1 to end of Cycle 6 of the Treatment Cross-Over Period; from Day 1 of Cycle 7 up to the completion of 18 cycles of neo/adjuvant anti-HER2 treatment in the Treatment Continuation Period (1 cycle is 21 days) | 
| Number of Participants With at Least One Event of Heart Failure With the FDC SC and IV Formulations During the Treatment Cross-Over and Treatment Continuation Periods | Heart failure is defined as a disorder characterized by the inability of the heart to pump blood at an adequate volume to meet tissue metabolic requirements, or, the ability to do only at an elevation in the filling pressure. Any adverse event of symptomatic left ventricular systolic dysfunction (LVSD; also referred to as heart failure) occurring during the study was to be reported as a serious adverse event. | From Day 1 of Cycle 1 to end of Cycle 6 of the Treatment Cross-Over Period; from Day 1 of Cycle 7 up to the completion of 18 cycles of neo/adjuvant anti-HER2 treatment in the Treatment Continuation Period (1 cycle is 21 days) | 
| Number of Participants With at Least One Event of Ejection Fraction Decreased With the FDC SC and IV Formulations During the Treatment Cross-Over and Treatment Continuation Periods | Left ventricular ejection fraction (LVEF) is the measurement of how much blood is being pumped out of the left ventricle of the heart (the main pumping chamber) with each contraction. All participants who enrolled in this study must have had a baseline LVEF ≥55%. Verbatim description of adverse events was mapped to Medical Dictionary for Regulatory Activities (MedDRA) version 25.1. The MedDRA preferred term of 'ejection fraction decreased' is defined as an LVEF decrease of at least 10 percentage points from baseline and to below 50%. | Baseline; Day 1 of Cycles 4, 7, and 11 (each cycle is 21 days); End of Treatment Visit (up to 1 year) | 
| Number of Participants With Targeted Vital Signs Outside the Normal Limits Among Those Without an Abnormality at Baseline During the Treatment Cross-Over and Treatment Continuation Periods | The number of participants at any post-baseline timepoint with abnormal readings outside the normal range for vital signs of diastolic and systolic blood pressure, pulse rate, respiratory rate, and body temperature were summarized according the specified direction of the abnormal reading (high or low). The number analyzed (denominator) in the results table represents participants without the specified abnormal vital sign at baseline. Not every vital sign abnormality qualified as an adverse event (AE). A vital sign result must have been reported as an AE if it met any of the following criteria: was accompanied by clinical symptoms; resulted in a change in study treatment (e.g., dosage modification, treatment interruption, or treatment discontinuation); resulted in a medical intervention or a change in concomitant therapy; or, was clinically significant in the investigator's judgment. | Pre-dose at Day 1 of Cycles 1 (baseline), 4, and 7, and end of treatment (up to 18 cycles; 1 cycle is 21 days) | 
| Number of Participants With Chemistry and Hematology Laboratory Test Result Shifts From NCI-CTCAE Grade 0-2 at Baseline to Grade 3-4 Post-Baseline During the Treatment Cross-Over and Treatment Continuation Periods | Laboratory data for targeted chemistry and hematology parameters were classified according to the NCI CTCAE v4.0; Grade 0 is normal and Grades 1 to 4 represent worsening levels of the parameter outside of the normal range in the specified direction of the abnormality (high and low are above and below the range, respectively). The results show the shifts in the number of participants with Grade 0-2 at baseline to Grade 3-4 post-baseline; those with missing baseline values were counted as Grade 0-2 at baseline. Not every laboratory abnormality qualified as an adverse event, only if it met any of the following criteria: was accompanied by clinical symptoms; resulted in a change in study treatment (e.g., dosage modification, treatment interruption, or treatment discontinuation); resulted in a medical intervention or a change in concomitant therapy; or, was clinically significant in the investigator's judgment. SGOT/AST = aspartate aminotransferase; SGPT/ALT = alanine aminotransferase | Pre-dose at Day 1 of Cycles 1 (baseline), 4, 7, 11, 15, and end of treatment (up to 18 cycles; 1 cycle is 21 days) | 
| Number of Participants With an Event for Overall Survival, Overall and by Treatment Sequence | Overall survival (OS) is defined as the time from randomization to death due to any cause. The number of participants who had an OS event (i.e., died) while on study is reported. | Up to 3 years, 10 months | 
| Kaplan-Meier Estimate of the Percentage of Participants Who Were Event-Free for Overall Survival, Overall and by Treatment Sequence | Overall survival is defined as the time from randomization to death due to any cause. Participants who were not reported as having died at the time of analysis were censored at the date when they were last known to be alive. Participants who did not have post-baseline information were censored at the date of randomization +1 day. Kaplan-Meier methodology was used to estimate the percentage of participants who were alive (event-free) at 12, 24, and 36 months. | At 12, 24, and 36 months | 
| Number of Participants With an Event for Invasive Disease-Free Survival Including Second Primary Non-Breast Cancer, Overall and by Treatment Sequence | Invasive Disease-Free Survival is defined as the time from randomization to the first occurrence of one of the following events: ipsilateral invasive breast tumour recurrence, ipsilateral local-regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, and death from any cause. Second primary non-breast invasive cancer (with the exception of non-melanoma skin cancers and in situ carcinoma of any site) was included as an event. | Up to 3 years, 10 months | 
| Kaplan-Meier Estimate of the Percentage of Participants Who Were Event-Free for Invasive Disease-Free Survival Including Second Primary Non-Breast Cancer, Overall and by Treatment Sequence | Invasive Disease-Free Survival is defined as the time from randomization to the first occurrence of one of the following events: ipsilateral invasive breast tumour recurrence, ipsilateral local-regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, and death from any cause. Second primary non-breast invasive cancer (with the exception of non-melanoma skin cancers and in situ carcinoma of any site) was included as an event. Participants who had not experienced invasive disease at the time of analysis were censored: i) at the time of the last clinical breast examination if they had post-baseline clinical breast examination; ii) on the date of randomization +1 day if no post-baseline clinical breast examination. Kaplan-Meier methodology was used to estimate the percentage of participants who were event-free at 12, 24, and 36 months. | At 12, 24, and 36 months | 
| Number of Participants With an Event for Invasive Disease-Free Survival, Overall and by Treatment Sequence | Invasive Disease-Free Survival is defined as the time from randomization to the first occurrence of one of the following events: ipsilateral invasive breast tumour recurrence, ipsilateral local-regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, and death from any cause. Ipsilateral or contralateral in situ disease and second primary non-breast cancers (including in situ carcinomas and non-melanoma skin cancers) were not counted as recurrence. | Up to 3 years, 10 months | 
| Kaplan-Meier Estimate of the Percentage of Participants Who Were Event-Free for Invasive Disease-Free Survival, Overall and by Treatment Sequence | Invasive Disease-Free Survival is defined as the time from randomization to the first occurrence of one of the following events: ipsilateral invasive breast tumour recurrence, ipsilateral local-regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, and death from any cause. Ipsilateral or contralateral in situ disease and second primary non-breast cancers (including in situ carcinomas and non-melanoma skin cancers) were not counted as recurrence. Participants who had not experienced invasive disease at the time of analysis were censored: i) at the time of the last clinical breast examination if they had post-baseline clinical breast examination; ii) on the date of randomization +1 day if no post-baseline clinical breast examination. Kaplan-Meier methodology was used to estimate the percentage of participants who were event-free at 12, 24, and 36 months. | At 12, 24, and 36 months | 
| Number of Participants With an Event for Distant Disease-Free Survival, Overall and by Treatment Sequence | Distant disease-free survival (DDFS) is defined as the time from randomization to the date of distant breast cancer recurrence (i.e., evidence of breast cancer in any anatomic site other than for ipsilateral [loco-regional] invasive breast cancer recurrence that has either been histologically confirmed or clinically diagnosed as recurrent invasive breast cancer). | Up to 3 years, 10 months | 
| Kaplan-Meier Estimate of the Percentage of Participants Who Were Event-Free for Distant Disease-Free Survival, Overall and by Treatment Sequence | Distant disease-free survival (DDFS) is defined as the time from randomization to the date of distant breast cancer recurrence (i.e., evidence of breast cancer in any anatomic site other than for ipsilateral [loco-regional] invasive breast cancer recurrence that has either been histologically confirmed or clinically diagnosed as recurrent invasive breast cancer). Participants who had not experienced invasive disease at the time of analysis were censored: i) at the time of the last clinical breast examination if they had post-baseline clinical breast examination; ii) on the date of randomization +1 day if no post-baseline clinical breast examination. Kaplan-Meier methodology was used to estimate the percentage of participants who were event-free at 12, 24, and 36 months. | At 12, 24, and 36 months |