Doxorubicin and Cyclophosphamide Followed By Trastuzumab, Paclitaxel, and Lapatinib in Treating Patients With Early-Stage HER2-Positive Breast Cancer That Has Been Removed By Surgery

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT00436566
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 122
• Location: 1
• Actual Duration (Months): 148.2
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as doxorubicin, cyclophosphamide, and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Lapatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving combination chemotherapy together with trastuzumab and lapatinib after surgery may kill any tumor cells that remain after surgery.

PURPOSE: This randomized phase II trial is studying the side effects and how well giving doxorubicin together with cyclophosphamide followed by trastuzumab, paclitaxel, and lapatinib works in treating patients with early-stage HER2-positive breast cancer that has been removed by surgery.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer; Cardiac Toxicity	Biological: trastuzumab; Drug: cyclophosphamide; Drug: doxorubicin hydrochloride; Drug: lapatinib ditosylate; Drug: paclitaxel; Genetic: gene expression analysis; Genetic: reverse transcriptase-polymerase chain reaction; Other: fluorophotometry; Other: laboratory biomarker analysis; Other: mass spectrometry; Procedure: adjuvant therapy; Procedure: quality-of-life assessment	Phase 2

Detailed Description

OBJECTIVES:

Primary

• Determine the cardiac safety of adjuvant therapy comprising doxorubicin hydrochloride and cyclophosphamide followed by paclitaxel, trastuzumab (Herceptin®), and lapatinib ditosylate in patients with resected early-stage HER2-positive breast cancer.

Secondary

• Determine the adverse event profile of this regimen in these patients.

• Determine the cumulative incidence of cardiac events in patients treated with this regimen.

• Determine the LVEF in patients treated with this regimen.

• Determine the disease-free and overall survival of patients treated with this regimen.

• Compare selected quality-of-life (QOL) questionnaires in these patients.

• Evaluate QOL of patients treated with this regimen.

• Determine the cumulative incidence of pulmonary events in patients treated with this regimen.

Tertiary

• Compare Veridex CellSearch system vs quantitative reverse transcriptase polymerase chain reaction for detecting circulating tumor cells.

• Determine the relationship between serum levels of HER1 and HER2 and response to treatment.

• Evaluate cardiac markers (i.e., troponin-T, troponin-I, brain natriuretic peptide, and creatine kinase MB isoenzyme) at baseline.

• Determine the association between abnormal levels of cardiac markers and incidence of cardiac adverse events.

• Evaluate patterns of 500 metabolites in plasma in patients treated with this regimen and determine the association between metabolite patterns/molecular signatures and cardiotoxicity.

• Determine the time course of these molecular signatures and evaluate whether they are accurate predictors of cardiotoxicity that precede other evidence of cardiotoxicity (e.g., changes in left ventricular function seen by echocardiogram or MUGA scan).

• Compare metabolic signatures of cardiotoxicity with known laboratory evidence of cardiac damage (e.g., troponins or brain natriuretic peptide) in terms of sensitivity and specificity.

OUTLINE: This is a randomized, pilot, multicenter study. Patients are stratified according to educational level (less than high school vs high school or GED vs formal education beyond high school).

Patients receive doxorubicin hydrochloride IV and cyclophosphamide IV on day 1. Treatment repeats every 2-3 weeks for 4 courses. Patients then receive paclitaxel IV over 60 minutes and trastuzumab (Herceptin®) IV over 90 minutes on days 1, 8, and 15 and oral lapatinib ditosylate on days 1-21. Treatment with paclitaxel, trastuzumab, and lapatinib repeats every 3 weeks for up to 4 courses. Patients then receive trastuzumab IV over 30-90 minutes on day 1 and oral lapatinib ditosylate on days 1-21. Treatment with trastuzumab and lapatinib ditosylate repeats every 3 weeks for up to 12 courses.

Patients complete Linear Anologue Self Assessment (LASA) and Symptoms Distress Scale (SDS) questionnaires, including fatigue, diarrhea, and rash assessment, at baseline, after 2-3, 5-6, and 18 months of treatment, and 5 years after completion of treatment. Patients are also randomized to 1 of 2 arms to complete additional quality of life questionnaires at these same time points.

• Arm I: Patients complete EORTC QLQ-C30 and EORTC QLQ-BR23 questionnaires.

• Arm II: Patients complete FACT-B questionnaire. Blood samples are acquired periodically throughout and at the completion of study treatment. Samples are analyzed for circulating tumor cells by Veridex CellSearch system, quantitative reverse transcriptase polymerase chain reaction, and liquid chromatography with tandem mass spectrometry, soluble HER1- and HER2-receptor concentrations, circulating cardiac markers, and metabolic markers for possible correlation with cardiac events.

After completion of study treatment, patients are followed periodically for up to 10 years.

PROJECTED ACCRUAL: A total of 109 patients will be accrued for this study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 122 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Primary Purpose: Treatment
• Official Title: Phase II Study of Cardiac Safety and Tolerability of an Adjuvant Chemotherapy Plus Trastuzumab With Lapatinib in Patients With Resected HER2 + Breast Cancer
• Actual Study Start Date: Mar 16, 2007
• Actual Primary Completion Date: Apr 1, 2009
• Actual Study Completion Date: Jul 22, 2019

Outcome Measures

Primary Outcome Measures

1. Number of Patients With Congestive Heart Failure (CHF) While on Active Treatment [6 months]

Secondary Outcome Measures

1. Adverse Event Profile as Measured by NCI CTCAE v 3.0 [5 years]

   Measured by number of patients with at least one with grade 3+, Grade 4+, Hem, and Non-Hem AEs.

2. Cumulative Incidence (CI) of Cardiac Events [5 years]

   Evaluable patients included those completed the AC phase of their treatment regimen; with post AC cardiac evaluation indicates they are eligible to begin treatment with PTL; and those have begun their post-AC therapy. Cardiac events: symptomatic congestive heart failure (CHF), cardiac death and other cardiac events (NCI Common Terminology Criteria for Adverse Events (CTCAE) Grade >=3)

3. Number of Patients Who Experience >= 10 Percent Drop in Left Ventricular Ejection Fraction (LVEF) [5 years]

   Number of Patients Who Experience >= 10 Percent Drop in Left Ventricular Ejection Fraction (LVEF) from baseline to any post-baseline time point.

4. Percentage of Participants With Disease-Free Survival (DFS) [5 years]

   DFS was defined as the time from registration to the earliest date of documentation of any local, regional, or distant recurrence of breast cancer (BC); the development of a contralateral BC or second primary other than squamous or basal cell carcinoma of the skin, carcinoma in situ of the cervix, or lobular carcinoma in situ of the breast; or death from any cause without the documentation of one of these events. Participants were followed for a maximum of 5 years from randomization. The median OS with 95%CI was estimated using the Kaplan Meier method.

5. Percentage of Participants With Overall Survival (OS) [5 years]

   OS was defined as the time from registration to death of any cause. Participants were followed for a maximum of 5 years from randomization. The median OS with 95%CI was estimated using the Kaplan Meier method.

6. Change in Overall LINEAR ANALOGUE SELF ASSESSMENT (LASA) and Change in Symptom Distress Scale (SDS) Overall QOL [5 years]

   LASA score is from 0-90 with 0 being the worst and 90 being the best. SDS score is from 13-65 with 65 being the worst and 13 being the best.

7. Proportion of Patients Experienced a Significant Decline in LINEAR ANALOGUE SELF ASSESSMENT (LASA) and a Overall Symptom Distress Scale (SDS) QOL Measurements [5 years]

   Overall Symptom Distress Scale (SDS) QOL Measurement and Overall LINEAR ANALOGUE SELF ASSESSMENT (LASA) QOL Measurement

8. Incidence of Pulmonary Events [5 years]

   Pulmonary events to be included were grade 3 and higher pulmonary adverse events at least possibly related to study treatment, which occur at any time after post-AC treatment is begun, but prior to documentation of a breast cancer recurrence, contralateral breast cancer, secondary primary cancer, non-pulmonary death, or pulmonary death not related to study treatment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 120 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Histologically confirmed diagnosis of early-stage breast cancer

• HER2 positive by immunohistochemistry (IHC) (3+) or fluorescent in situ hybridization (FISH)

• Ductal carcinoma in situ (DCIS) components should not be counted in the determination of degree of IHC staining or FISH amplification

• No locally advanced tumors (i.e., T4) at diagnosis, including the following:

• Tumors fixed to chest wall

• Peau d'orange

• Skin ulcerations or nodules

• Clinical inflammatory changes (e.g., diffuse brawny cutaneous induration with an erysipeloid edge)

• Has undergone mastectomy or lumpectomy with axillary node or sentinel node dissection within the past 84 days

• Patients who have undergone a mastectomy must meet the following criteria:

• No evidence of gross or microscopic tumor (i.e., invasive DCIS) at the surgical resection margins noted in final surgery or pathology reports

• Patients with close margins are eligible

• Radiation therapy is required for 4 or more positive lymph nodes and must be started after completion of chemotherapy

• Patients who have undergone a lumpectomy with axillary node or sentinel node dissection must meet the following criteria:

• No evidence of invasive cancer or DCIS at the surgical resection margins

• No gross residual adenopathy

• Planning to undergo radiation therapy to the breast with or without regional lymphatics after completion of chemotherapy

• No active hepatic or biliary disease

• Patients with liver metastases, stable chronic liver disease, Gilbert's syndrome, or asymptomatic gallstones are eligible

• Hormone receptor status:

• Estrogen receptor and progesterone receptor status known

PATIENT CHARACTERISTICS:

• Male or female

• Menopausal status not specified

• ECOG performance status 0-2

• Absolute neutrophil count ≥ 1,500/mm³

• Platelet count ≥ 100,000/mm³

• Hemoglobin ≥ 10.0 g/dL

• Bilirubin ≤ 1.5 times upper limit of normal (ULN)

• AST and ALT ≤ 2.5 times ULN

• Alkaline phosphatase ≤ 2.5 times ULN

• Creatinine normal OR creatinine clearance ≥ 60 mL/min

• LVEF ≥ 50% by MUGA scan or echocardiogram

• Able to complete questionnaire(s) by themselves or with assistance

• Able and willing to provide blood and tissue samples

• No known sensitivity to benzyl alcohol

• No sensory neuropathy ≥ grade 2

• No active cardiac disease, including any of the following:

• Myocardial infarction within the past 6 months

• Prior or concurrent congestive heart failure

• Prior or concurrent arrhythmia or cardiac valvular disease requiring medications or that is clinically significant

• Uncontrolled hypertension, defined as diastolic blood pressure (BP) >100 mm Hg or systolic BP > 200 mm Hg on 2 separate occasions ≥ 14 days apart

• Clinically significant pericardial effusion

• Prior or concurrent uncontrolled or symptomatic angina

• Other cardiac condition that, in the opinion of the treating physician, would put the patient at hazardous risk

• No history of allergic reactions attributed to compounds of similar chemical or biologic composition as lapatinib ditosylate

• No uncontrolled intercurrent illness including, but not limited to, the following:

• Ongoing or active infection

• Psychiatric illness or social situations that would preclude study compliance

• Able to swallow and retain oral medication

• No history of gastrointestinal (GI) disease resulting in an inability to take oral medication, including any of the following:

• Malabsorption syndrome

• Requirement for IV alimentation

• Prior surgical procedures affecting absorption

• Uncontrolled inflammatory GI disease (e.g., Crohn's disease or ulcerative colitis)

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception during and for 6 months after completion of study treatment

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• No prior chemotherapy, radiation therapy, immunotherapy, or biotherapy for breast cancer

• No primary breast radiation therapy as part of breast-conserving treatment

• No prior anthracycline or taxane therapy for any malignancy

• No prior epidermal growth factor receptor-targeting therapies (e.g., gefitinib, cetuximab, erlotinib hydrochloride, rituximab, trastuzumab [Herceptin®], lapatinib ditosylate, panitumumab, or nimotuzumab)

• At least 14 days since prior and no concurrent CYP3A4 inducers, including the following:

• Rifamycin-class antibiotics (e.g., rifampin, rifabutin, or rifapentine)

• Anticonvulsants (e.g., phenytoin, carbamazepine, or barbiturates [e.g., phenobarbital])

• Antiretrovirals (e.g., efavirenz or nevirapine)

• Glucocorticoids (e.g., oral cortisone, hydrocortisone, prednisone, methylprednisolone, or dexamethasone)

• Daily oral dexamethasone ≤ 1.5 mg (or equivalent) allowed

• Modafinil

• Hypericum perforatum (St. John's wort)

• At least 7 days since prior and no concurrent CYP3A4 inhibitors, including the following:

• Antibiotics (e.g., clarithromycin, erythromycin, or troleandomycin)

• Antifungals (e.g., itraconazole, ketoconazole, fluconazole [> 150 mg daily], or voriconazole)

• Antiretrovirals and protease inhibitors (e.g., delaviridine, nelfinavir, amprenavir, ritonavir, indinavir, saquinavir, or lopinavir)

• Calcium channel blockers (e.g., verapamil or diltiazem)

• Antidepressants (e.g., nefazodone or fluvoxamine)

• Gastrointestinal agents (e.g., cimetidine or aprepitant)

• Grapefruit and grapefruit juice

• At least 6 months since prior and no concurrent amiodarone

• No herbal or alternative medicines or supplements ≥ 14 days before, during, and for 30 days after completion of study treatment

• No concurrent hormonal agents (e.g., birth control pills, ovarian hormonal replacement therapy, or raloxifene)

• Adjuvant hormonal agents (e.g., tamoxifen, aromatase inhibitors) allowed after completion of chemotherapy as part of treatment for breast cancer

• No concurrent antiretroviral therapy for HIV-positive patients

• No concurrent digitalis or beta-blockers for congestive heart failure

• No concurrent arrhythmia or angina pectoris medication

• No other concurrent investigational agents or anticancer therapies, including cytotoxic agents or immunotherapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic Cancer Research Consortium	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic
• National Cancer Institute (NCI)

Investigators

• Study Chair: Edith A. Perez, MD, Mayo Clinic
• Principal Investigator: Donald W. Northfeld, MD, Mayo Clinic
• Principal Investigator: James N. Ingle, MD, Mayo Clinic in Rochester

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mayo Clinic
• ClinicalTrials.gov Identifier: NCT00436566
• Other Study ID Numbers: CDR0000533793; P30CA015083; RC0639; 06-004049
• First Posted: Feb 19, 2007
• Last Update Posted: Aug 5, 2022
• Last Verified: Jan 1, 2019

• Keywords provided by Mayo Clinic: cardiac toxicity; male breast cancer; stage I breast cancer; stage II breast cancer; stage IIIA breast cancer
• Additional relevant MeSH terms: Breast Neoplasms; Cardiotoxicity; Paclitaxel; Cyclophosphamide; Doxorubicin; Liposomal doxorubicin; Trastuzumab; Lapatinib

Study Results

Participant Flow

Recruitment Details	One-hundred and twenty-two (122) participants were recruited between April 2007 and October 2008 at Mayo Clinic. Ten (10) participants were deemed ineligible due to HER-2+ not corroborated by the central laboratory evaluation. These 10 participants and 3 participants (those who did not completed the treatment) were excluded from all analysis.

Arm/Group Title	AC/PTL
Arm/Group Description	Standard doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel (80 mg/m^2) x 12 with concurrent standard dose trastuzumab (weekly x 12, then repeat 3 weeks for an additional 9 months) plus daily lapatinib (modified to 750 mg during Paclitaxel + Trastuzumab + Lapatinib (PTL) and 1000 mg during trastuzumab + lapatinib (TL)) for a total of 12 months.
Period Title: Overall Study
STARTED	112
COMPLETED	109
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	AC/PTL
Arm/Group Description	Standard doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel (80 mg/m^2) x 12 with concurrent standard dose trastuzumab (weekly x 12, then repeat 3 weeks for an additional 9 months) plus daily lapatinib (modified to 750 mg during Paclitaxel + Trastuzumab + Lapatinib (PTL) and 1000 mg during trastuzumab + lapatinib (TL)) for a total of 12 months.
Overall Participants	109
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	51
Sex: Female, Male (Count of Participants)
Female	109 100%
Male	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.9%
Asian	2 1.8%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	12 11%
White	94 86.2%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	109 100%
Eastern Cooperative Oncology Group (ECOG) performance status (participants) [Number]
0	91 83.5%
1	18 16.5%
T Stage (participants) [Number]
T1=Tumor <=2 cm (3/4 of an inch) across	43 39.4%
T2=2cm < Tumor <5 cm across	58 53.2%
T3=Tumor > 5 cm across	6 5.5%
Missing	2 1.8%
Nodal Status (participants) [Number]
N0	49 45%
N1	32 29.4%
N2	12 11%
N3	14 12.8%
SLN+ without full axillary dissection	2 1.8%
Hormonal Status (participants) [Number]
Estrogen and/or Progesterone Positive	54 49.5%
Estrogen and Progesterone Negative	55 50.5%
HER2 Status - Positive (participants) [Number]
FISH Amp/IHC Pos	93 85.3%
FISH Amp/IHC Neg	8 7.3%
FISH Not Amp/IHC Pos	6 5.5%
FISH Not Done/IHC Pos	2 1.8%
Left Ventricular Ejection Fraction (LVEF) Measurement (percentage) [Median (Full Range) ]
Median (Full Range) [percentage]	63.3
Smoking status (participants) [Number]
Never	60 55%
Former	24 22%
Current	25 22.9%
Current use of hypertensive medication (participants) [Number]
Yes	28 25.7%
No	81 74.3%
History of diabetes (participants) [Number]
Yes	10 9.2%
No	99 90.8%
Menopausal status (participants) [Number]
Premenopausal	43 39.4%
Perimenopausal	8 7.3%
Postmenopausal	58 53.2%
Education level (participants) [Number]
Less than high school	3 2.8%
High school	35 32.1%
Beyond high school	71 65.1%

Outcome Measures

1. Primary Outcome

Title	Number of Patients With Congestive Heart Failure (CHF) While on Active Treatment
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AC/PTL
Arm/Group Description	Standard doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel (80 mg/m^2) x 12 with concurrent standard dose trastuzumab (weekly x 12, then repeat 3 weeks for an additional 9 months) plus daily lapatinib (modified to 750 mg during Paclitaxel + Trastuzumab + Lapatinib (PTL) and 1000 mg during trastuzumab + lapatinib (TL)) for a total of 12 months.
Measure Participants	109
Number [participants]	0 0%

2. Secondary Outcome

Title	Adverse Event Profile as Measured by NCI CTCAE v 3.0
Description	Measured by number of patients with at least one with grade 3+, Grade 4+, Hem, and Non-Hem AEs.
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AC/PTL
Arm/Group Description	Standard doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel (80 mg/m^2) x 12 with concurrent standard dose trastuzumab (weekly x 12, then repeat 3 weeks for an additional 9 months) plus daily lapatinib (modified to 750 mg during Paclitaxel + Trastuzumab + Lapatinib (PTL) and 1000 mg during trastuzumab + lapatinib (TL)) for a total of 12 months.
Measure Participants	109
Grade 3+ Adverse Event	84 77.1%
Grade 4+ Adverse Event	27 24.8%
Grade 3+ Hem Adverse Event	33 30.3%
Grade 4+ Hem Adverse Event	23 21.1%
Grade 3+ Non-Hem Adverse Event	80 73.4%
Grade 4+ Non-Hem Adverse Event	12 11%

3. Secondary Outcome

Title	Cumulative Incidence (CI) of Cardiac Events
Description	Evaluable patients included those completed the AC phase of their treatment regimen; with post AC cardiac evaluation indicates they are eligible to begin treatment with PTL; and those have begun their post-AC therapy. Cardiac events: symptomatic congestive heart failure (CHF), cardiac death and other cardiac events (NCI Common Terminology Criteria for Adverse Events (CTCAE) Grade >=3)
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

102 patients began post-AC therapy

Arm/Group Title	AC/PTL
Arm/Group Description	Standard doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel (80 mg/m^2) x 12 with concurrent standard dose trastuzumab (weekly x 12, then repeat 3 weeks for an additional 9 months) plus daily lapatinib (modified to 750 mg during Paclitaxel + Trastuzumab + Lapatinib (PTL) and 1000 mg during trastuzumab + lapatinib (TL)) for a total of 12 months.
Measure Participants	102
Number [Post AC Cardiac Adverse Event]	5

4. Secondary Outcome

Title	Number of Patients Who Experience >= 10 Percent Drop in Left Ventricular Ejection Fraction (LVEF)
Description	Number of Patients Who Experience >= 10 Percent Drop in Left Ventricular Ejection Fraction (LVEF) from baseline to any post-baseline time point.
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AC/PTL
Arm/Group Description	Standard doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel (80 mg/m^2) x 12 with concurrent standard dose trastuzumab (weekly x 12, then repeat 3 weeks for an additional 9 months) plus daily lapatinib (modified to 750 mg during Paclitaxel + Trastuzumab + Lapatinib (PTL) and 1000 mg during trastuzumab + lapatinib (TL)) for a total of 12 months.
Measure Participants	104
Drop ≤ 10 between any 2 time points	41 37.6%
Drop ≥ 10 between any 2 time points	63 57.8%

5. Secondary Outcome

Title	Percentage of Participants With Disease-Free Survival (DFS)
Description	DFS was defined as the time from registration to the earliest date of documentation of any local, regional, or distant recurrence of breast cancer (BC); the development of a contralateral BC or second primary other than squamous or basal cell carcinoma of the skin, carcinoma in situ of the cervix, or lobular carcinoma in situ of the breast; or death from any cause without the documentation of one of these events. Participants were followed for a maximum of 5 years from randomization. The median OS with 95%CI was estimated using the Kaplan Meier method.
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AC/PTL
Arm/Group Description	Standard doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel (80 mg/m^2) x 12 with concurrent standard dose trastuzumab (weekly x 12, then repeat 3 weeks for an additional 9 months) plus daily lapatinib (modified to 750 mg during Paclitaxel + Trastuzumab + Lapatinib (PTL) and 1000 mg during trastuzumab + lapatinib (TL)) for a total of 12 months.
Measure Participants	109
Number (95% Confidence Interval) [percentage of participants]	91.9 84.3%

6. Secondary Outcome

Title	Percentage of Participants With Overall Survival (OS)
Description	OS was defined as the time from registration to death of any cause. Participants were followed for a maximum of 5 years from randomization. The median OS with 95%CI was estimated using the Kaplan Meier method.
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	AC/PTL
Arm/Group Description	Standard doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel (80 mg/m^2) x 12 with concurrent standard dose trastuzumab (weekly x 12, then repeat 3 weeks for an additional 9 months) plus daily lapatinib (modified to 750 mg during Paclitaxel + Trastuzumab + Lapatinib (PTL) and 1000 mg during trastuzumab + lapatinib (TL)) for a total of 12 months.
Measure Participants	109
Number (95% Confidence Interval) [percentage of participants]	95.0 87.2%

7. Secondary Outcome

Title	Change in Overall LINEAR ANALOGUE SELF ASSESSMENT (LASA) and Change in Symptom Distress Scale (SDS) Overall QOL
Description	LASA score is from 0-90 with 0 being the worst and 90 being the best. SDS score is from 13-65 with 65 being the worst and 13 being the best.
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

Number who completed the QOL questions for each Timeframe.

Arm/Group Title	AC/PTL
Arm/Group Description	Standard doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel (80 mg/m^2) x 12 with concurrent standard dose trastuzumab (weekly x 12, then repeat 3 weeks for an additional 9 months) plus daily lapatinib (modified to 750 mg during Paclitaxel + Trastuzumab + Lapatinib (PTL) and 1000 mg during trastuzumab + lapatinib (TL)) for a total of 12 months.
Measure Participants	109
LASA Time from Cycle 5 Baseline (Months 2-3)	-11.1
LASA Time from Cycle 5 Baseline (Months 5-6)	-13.2
LASA Time from Cycle 5 Baseline (Month 18-Year 3)	-3.6
LASA Time from Cycle 5 Baseline (Year 4-5)	-0.5
SDS Time from Cycle 5 Baseline (Months 2-3)	-6.7
SDS Time from Cycle 5 Baseline (Months 5-6)	-9.5
SDS Time from Cycle 5 Baseline (Month 18-Year 3)	-1.4
SDS Time from Cycle 5 Baseline (Year 4-5)	0.3

8. Secondary Outcome

Title	Proportion of Patients Experienced a Significant Decline in LINEAR ANALOGUE SELF ASSESSMENT (LASA) and a Overall Symptom Distress Scale (SDS) QOL Measurements
Description	Overall Symptom Distress Scale (SDS) QOL Measurement and Overall LINEAR ANALOGUE SELF ASSESSMENT (LASA) QOL Measurement
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

Number who completed the QOL questions for each Timeframe.

Arm/Group Title	AC/PTL
Arm/Group Description	Standard doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel (80 mg/m^2) x 12 with concurrent standard dose trastuzumab (weekly x 12, then repeat 3 weeks for an additional 9 months) plus daily lapatinib (modified to 750 mg during Paclitaxel + Trastuzumab + Lapatinib (PTL) and 1000 mg during trastuzumab + lapatinib (TL)) for a total of 12 months.
Measure Participants	109
SDS Time from Cycle 5 Baseline (Months 2-3)	32 29.4%
SDS Time from Cycle 5 Baseline (Months 5-6)	33 30.3%
SDS Time from Cycle 5 Baseline (Month 18-Year 3)	12 11%
SDS Time from Cycle 5 Baseline (Year 4-5)	7 6.4%
LASA Time from Cycle 5 Baseline (Months 2-3)	67 61.5%
LASA Time from Cycle 5 Baseline (Months 5-6)	45 41.3%
LASA Time from Cycle 5 Baseline (Month 18-3 Year)	40 36.7%
LASA Time from Cycle 5 Baseline (Year 4-5)	19 17.4%

9. Secondary Outcome

Title	Incidence of Pulmonary Events
Description	Pulmonary events to be included were grade 3 and higher pulmonary adverse events at least possibly related to study treatment, which occur at any time after post-AC treatment is begun, but prior to documentation of a breast cancer recurrence, contralateral breast cancer, secondary primary cancer, non-pulmonary death, or pulmonary death not related to study treatment.
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

No patients experienced grade 3 or higher pulmonary adverse events at least possibly related to study treatment after at any time after post-AC treatment began.

Arm/Group Title	AC/PTL
Arm/Group Description	Standard doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel (80 mg/m^2) x 12 with concurrent standard dose trastuzumab (weekly x 12, then repeat 3 weeks for an additional 9 months) plus daily lapatinib (modified to 750 mg during Paclitaxel + Trastuzumab + Lapatinib (PTL) and 1000 mg during trastuzumab + lapatinib (TL)) for a total of 12 months.
Measure Participants	109
Number [pulmonary adverse events]	0

Adverse Events

Adverse Event Reporting Description	Adverse event data is not available on one patient, thus, only 108 patients were included in adverse events table.
Arm/Group Title	AC/PTL
Arm/Group Description	Standard doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel (80 mg/m^2) x 12 with concurrent standard dose trastuzumab (weekly x 12, then repeat 3 weeks for an additional 9 months) plus daily lapatinib (modified to 750 mg during Paclitaxel + Trastuzumab + Lapatinib (PTL) and 1000 mg during trastuzumab + lapatinib (TL)) for a total of 12 months.
All Cause Mortality
	AC/PTL
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	AC/PTL
	Affected / at Risk (%)	# Events
Total	17/108 (15.7%)
Blood and lymphatic system disorders
Febrile neutropenia	1/108 (0.9%)	1
Cardiac disorders
Left ventricular failure	1/108 (0.9%)	1
Gastrointestinal disorders
Diarrhea	6/108 (5.6%)	9
General disorders
Fatigue	1/108 (0.9%)	1
Infections and infestations
Pneumonia	1/108 (0.9%)	1
Skin infection	1/108 (0.9%)	1
Urinary tract infection	1/108 (0.9%)	2
Investigations
Alanine aminotransferase increased	1/108 (0.9%)	1
Aspartate aminotransferase increased	1/108 (0.9%)	1
Leukopenia	2/108 (1.9%)	2
Neutrophil count decreased	4/108 (3.7%)	4
Metabolism and nutrition disorders
Hypokalemia	1/108 (0.9%)	1
Nervous system disorders
Peripheral sensory neuropathy	1/108 (0.9%)	1
Respiratory, thoracic and mediastinal disorders
Cough	1/108 (0.9%)	1
Pulmonary	1/108 (0.9%)	1
Vascular disorders
Thrombosis	1/108 (0.9%)	1
Other (Not Including Serious) Adverse Events
	AC/PTL
	Affected / at Risk (%)	# Events
Total	107/108 (99.1%)
Blood and lymphatic system disorders
Anemia	33/108 (30.6%)	80
Febrile neutropenia	4/108 (3.7%)	4
Hemolysis	1/108 (0.9%)	1
Lymph node pain	1/108 (0.9%)	1
Cardiac disorders
Diastolic dysfunction	9/108 (8.3%)	17
Left ventricular failure	45/108 (41.7%)	87
Ear and labyrinth disorders
Ear pain	1/108 (0.9%)	1
Middle ear inflammation	1/108 (0.9%)	1
Eye disorders
Dry eye	2/108 (1.9%)	4
Vision	1/108 (0.9%)	1
Vision-Blurred	3/108 (2.8%)	4
Watering eyes	1/108 (0.9%)	3
Gastrointestinal disorders
Abdominal pain	4/108 (3.7%)	4
Anal hemorrhage	1/108 (0.9%)	2
Constipation	1/108 (0.9%)	1
Diarrhea	93/108 (86.1%)	426
Dry mouth	2/108 (1.9%)	3
Dyspepsia	9/108 (8.3%)	16
Esophagitis	1/108 (0.9%)	1
Flatulence	1/108 (0.9%)	1
Gastritis	1/108 (0.9%)	1
Mucositis oral	11/108 (10.2%)	17
Nausea	31/108 (28.7%)	60
Oral cavity Mucositis/stomatitis (clinical exam)	8/108 (7.4%)	12
Oral pain	1/108 (0.9%)	1
Rectal pain	1/108 (0.9%)	2
Vomiting	16/108 (14.8%)	23
General disorders
Chills	2/108 (1.9%)	2
Constitutional Symptoms	1/108 (0.9%)	1
Edema limbs	5/108 (4.6%)	6
Fatigue	101/108 (93.5%)	624
Fever	2/108 (1.9%)	2
Influenza Symptoms	1/108 (0.9%)	1
Pain-Chest	2/108 (1.9%)	2
Immune system disorders
Hypersensitivity	1/108 (0.9%)	1
Infections and infestations
Bladder infection	1/108 (0.9%)	1
Bronchial infection	1/108 (0.9%)	1
Catheter related infection	1/108 (0.9%)	1
Clostridial infection	1/108 (0.9%)	1
Dental-tooth infection	1/108 (0.9%)	2
Infection without neutropenia	3/108 (2.8%)	5
Mucosa infection	1/108 (0.9%)	2
Opportunisitic infection	1/108 (0.9%)	1
Pneumonia	1/108 (0.9%)	1
Sinus infection	1/108 (0.9%)	1
Sinusitis	3/108 (2.8%)	4
Skin (cellulites) infection	3/108 (2.8%)	3
Stomach infection	1/108 (0.9%)	1
Upper airway infection	1/108 (0.9%)	1
Urinary tract infection	3/108 (2.8%)	3
Vaginal infection	1/108 (0.9%)	1
Wound infection	2/108 (1.9%)	3
Injury, poisoning and procedural complications
Appendix injury	1/108 (0.9%)	1
Dermatitis radiation	1/108 (0.9%)	1
Investigations
Alanine aminotransferase increased	20/108 (18.5%)	60
Alkaline phosphatase increased	1/108 (0.9%)	2
Aspartate aminotransferase increased	20/108 (18.5%)	49
Leukopenia	32/108 (29.6%)	96
Lymphopenia	12/108 (11.1%)	31
Neutrophil count decreased	35/108 (32.4%)	85
Platelet count decreased	6/108 (5.6%)	6
Weight loss	4/108 (3.7%)	15
Metabolism and nutrition disorders
Anorexia	7/108 (6.5%)	17
Dehydration	9/108 (8.3%)	14
Hyperglycemia	3/108 (2.8%)	5
Hyperuricemia	1/108 (0.9%)	3
Hypoalbuminemia	2/108 (1.9%)	2
Hypocalcemia	2/108 (1.9%)	2
Hypoglycemia	1/108 (0.9%)	2
Hypokalemia	5/108 (4.6%)	6
Hyponatremia	2/108 (1.9%)	5
Obesity	1/108 (0.9%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	55/108 (50.9%)	216
Bone pain	53/108 (49.1%)	136
Joint effusion	1/108 (0.9%)	1
Muscle Weakness	1/108 (0.9%)	1
Myalgia	58/108 (53.7%)	199
Nervous system disorders
Dizziness	7/108 (6.5%)	8
Headache	7/108 (6.5%)	12
Neuralgia	1/108 (0.9%)	1
Peripheral motor neuropathy	2/108 (1.9%)	2
Peripheral sensory neuropathy	64/108 (59.3%)	348
Sinus pain	1/108 (0.9%)	1
Syncope	2/108 (1.9%)	2
Taste	6/108 (5.6%)	16
Psychiatric disorders
Agitation	2/108 (1.9%)	3
Anxiety	5/108 (4.6%)	5
Confusion	1/108 (0.9%)	1
Depression	3/108 (2.8%)	6
Insomnia	6/108 (5.6%)	9
Renal and urinary disorders
Bladder spasm	1/108 (0.9%)	1
Cystitis	1/108 (0.9%)	1
Glomerular filtration rate	1/108 (0.9%)	1
Urethra Hemorrhage	1/108 (0.9%)	1
Reproductive system and breast disorders
Vaginal inflammation	2/108 (1.9%)	3
Respiratory, thoracic and mediastinal disorders
Cough	1/108 (0.9%)	1
Dyspnea	46/108 (42.6%)	133
Epistaxis	3/108 (2.8%)	3
Nasal congestion	1/108 (0.9%)	1
Pneumonitis	3/108 (2.8%)	11
Voice alteration	1/108 (0.9%)	1
Skin and subcutaneous tissue disorders
Acne	53/108 (49.1%)	177
Alopecia	34/108 (31.5%)	144
Dermatology	1/108 (0.9%)	1
Dry skin	5/108 (4.6%)	6
Hand-foot skin reaction	6/108 (5.6%)	11
Nail Changes	11/108 (10.2%)	21
Pruritus	1/108 (0.9%)	1
Rash	2/108 (1.9%)	2
Skin hyperpigmentation	2/108 (1.9%)	4
Sweating	1/108 (0.9%)	2
Urticaria	1/108 (0.9%)	1
Vascular disorders
Flushing	1/108 (0.9%)	1
Hot flashes	5/108 (4.6%)	8
Hypotension	1/108 (0.9%)	1

Limitations/Caveats

[Not Specified]

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Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT 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.