Trastuzumab in Treating Older Women With Early-Stage Breast Cancer

Phase 2

Completed

Conditions: Breast Cancer

Interventions: Biological: trastuzumab
Other: laboratory biomarker analysis
Procedure: adjuvant therapy
Procedure: quality-of-life assessment

Registration Number: NCT00796978

Lead Sponsor: Cynthia Owusu, MD

Brief Summary: RATIONALE: 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.

PURPOSE: This phase II trial is studying the side effects of trastuzumab and to see how well it works in treating older women with early-stage breast cancer.

Detailed Description: OBJECTIVES:

Primary

* To evaluate the 3-year cumulative incidence of cardiac events in women 60 years and older with HER2-positive breast cancer who receive single agent trastuzumab (Herceptin®) in the adjuvant setting.

Secondary

* To evaluate the 1-year cumulative incidence of asymptomatic cardiac left ventricular dysfunction in women 60 years and older with Her2-positive breast cancer who receive single agent trastuzumab in the adjuvant setting.

* To evaluate long-term cardiac toxicity (5-year cumulative incidence of cardiac events) in women 60 years and older with Her2-positive breast cancer who receive single agent trastuzumab in the adjuvant setting.

* To assess the relation between physiologic markers of chronic heart failure and trastuzumab-related cardiac dysfunction in women 60 years and older with Her2-positive breast cancer who receive single agent trastuzumab.

* To assess the relation between pro-inflammatory cytokines and trastuzumab-related cardiac dysfunction in women 60 years and older with Her2-positive breast cancer.

* To determine the effect of this drug on the health-related quality of life and functional, cognitive, and mental status of women 60 years and older with Her2-positive breast cancer.

* To determine the 5-year disease-free survival and overall survival of women 60 years and older with Her2-positive breast cancer who receive single agent trastuzumab in the adjuvant setting.

OUTLINE: This is a multicenter study.

Patients receive trastuzumab (Herceptin®) IV over 30-90 minutes on day 1. Treatment repeats every 3 weeks for up to 52 weeks in the absence of disease progression or unacceptable toxicity.

Blood is collected every 6 weeks during treatment. Samples are assessed for plasma cardiac markers (N-terminal brain natriuretic protein and troponin-I) and pro-inflammatory cytokines (interleukin-6 and tumor necrosis factor-α). Patients complete Quality of Life and Quality of Health and Comprehensive Geriatric assessments of functional, cognitive, and mental status changes at baseline, weeks 26, and 52.

After completion of study therapy, patients are followed periodically for 4 years.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 56

Inclusion Criteria

Histologically confirmed adenocarcinoma of the breast
Immunohistochemical staining for Her2 protein of 3+ intensity or Her2 gene amplification of ≥ 2.0 by FISH testing.
Life expectancy > 6 months
ECOG performance status ≤ 2
Node positive disease irrespective of tumor size
Node negative disease:
- TNM Stage (AJCC Cancer Staging Manual 6th edition) T1b-T4, N0-3, M0, irrespective of hormonal status
Baseline LVEF ≥ lower limit of normal for a particular institution
Complete surgical removal of invasive cancer by mastectomy or lumpectomy
Complete staging work-up with CT of chest, abdomen, and pelvis plus bone scan or alternatively with PET scan for stage II and higher disease, or as determined by symptoms for all other stages. Additional staging work-up as per symptoms.
Adequate bone marrow function as indicated by the following:
- ANC >1000/µL
- Platelets ≥100,000/µL
- Hemoglobin >10 g/dL
Adequate liver function, as indicated by bilirubin ≤1.5 x upper limit of normal (ULN) Adequate renal function, as indicated by creatinine ≤1.5 x ULN
AST or ALT <2 x ULN unless related to primary disease.
Signed informed consent

Exclusion Criteria

Enrollment after more than 120 days from the last day of mastectomy or lumpectomy
Patients able to tolerate and willing to receive chemotherapy
Prior chemotherapy for current malignancy
Prior herceptin therapy
Active cardiac disease
- Myocardial infarction (asymptomatic changes on EKG suggestive of old MI is not an exclusion)
- Angina pectoris requiring anti-anginal treatment
- Documented congestive heart failure (CHF)
- Current use of any therapy specifically for CHF
- Cardiac arrhythmia requiring medication
- Current uncontrolled hypertension (diastolic >100 mmHg or systolic > 200 mmHg)
- Clinically significant valvular abnormality (associated with New York Heart Association (NYHA) class II, III, or IV symptoms)
- Clinically significant pericardial effusion (associated with New York Heart Association (NYHA) class II, III, or IV symptoms)
Past cardiac disease
- Prior myocardial infarction (asymptomatic changes on EKG suggestive of old MI is not an exclusion)
- Prior history of CHF
- History of cardiomyopathy
Other diseases and conditions
- Evidence of metastatic breast cancer (clinical or radiological evidence)
- Active infection
- Concomitant malignancies or previous malignancies within the last 3 years, with the exception of adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix.
- Hypersensitivity to trastuzumab

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
trastuzumab	adjuvant therapy	-
trastuzumab	laboratory biomarker analysis	-
trastuzumab	quality-of-life assessment	-
trastuzumab	trastuzumab	-

Primary Outcome Measures

Name	Time	Method
Percent of Participants Experiencing Cardiac Events at 1 Year	At 1 year	Number of participants that experience cardiac events that include cardiac death due to congestive heart failure (CHF), Myocardial infarction (MI) or documented arrhythmia, death without definitive cause, or signs and symptoms of CHF as defined by New York Heart Association (NYHA) class III or IV symptoms.

Secondary Outcome Measures

Name	Time	Method
Percent of Participants With Asymptomatic LV Cardiac Dysfunction at Five Years	At 5 years	Five-year cumulative incidence as measured by percent of participants that had asymptomatic LV cardiac dysfunction with/without permanent discontinuation
Mean Change in Nutritional Status	From baseline to end-of-treatment (52 weeks)	Mean Change in Mini Nutrition Assessment scores From Baseline to End of Treatment. The Mini Nutritional Screening is a scale comprised of six questions. The sum of the six questions is totaled to determine a score which is designed to assess if there is a risk of malnutrition. The highest score possible, 14, indicated no risk, and the minimum score of 0 indicates the highest risk possible. 12 points or greater is considered no risk or normal. Meanwhile, a score below 11 indicates possible malnutrition.
Overall Survival (OS) as Measured by Percent of Participants Alive at 2 Years	Up to 2 years	OS defined as percent of participants alive between time from initiation of treatment to the date of protocol-defined outcome from any cause and censored to the date of last follow-up for survivors.
Mean Change in Cognitive Status	From baseline to end-of-treatment (52 weeks)	Mean Change in Mini Mental Status Exam (MMSE scores) From Baseline to End of Treatment. The Mini-Mental Status Exam contains 11 items to gauge cognitive function. The minimum score is 0. The maximum score is 30. A score of 23 or lower is indicative of cognitive impairment. The higher the score, the better the participant's function (Scores 30-24 indicate uncertain cognitive impairment; scores 23-18 indicate mild to moderate cognitive impairment; scores 17-0 indicate severe cognitive impairment).
Mean Change in Plasma Cardiac Markers	From baseline to end-of-treatment (52 weeks)	Mean change in plasma cardiac markers from baseline end of treatment
Mean Change in Quality of Life From Baseline to End of Treatment	From baseline to end-of-treatment (52 weeks)	Quality of life was assessed by using the mean change in Functional Assessment of Cancer Therapy-Breast (FACTB) scoring instrument. The Functional Assessment of Cancer Therapy-Breast (FACT-B) is a 37-item instrument designed to measure five domains of HRQOL in breast cancer patients: Physical, social, emotional, and functional well-being, as well as a breast-cancer subscale (BCS). Each question response is based on a 5-point Likert-type scale. Scores range from 0-148. High scores indicate better QOL.
Mean Change in Psychosocial Status (Depression)	From baseline to end-of-treatment (52 weeks)	Mean Change in Geriatric Depression Scores from Baseline to End of Treatment. The Geriatric Depression Scale (GDS) is a validated tool with 15 items. The minimum score is 0, and the maximum is 15. Scores of 0-4 are considered normal, depending on age, education, and complaints; 5-8 indicate mild depression; 9-11 indicate moderate depression; and 12-15 indicate severe depression.
Percent of Participants Experiencing Cardiac Events at 3 Years	At 3 years	Number of participants that experience cardiac events that include cardiac death due to congestive heart failure (CHF), Myocardial infarction (MI) or documented arrhythmia, death without definitive cause, or signs and symptoms of CHF as defined by New York Heart Association (NYHA) class III or IV symptoms.
Percent of Participants Experiencing Cardiac Events at 5 Years	At 5 years	Number of participants that experience cardiac events that include cardiac death due to congestive heart failure (CHF), Myocardial infarction (MI) or documented arrhythmia, death without definitive cause, or signs and symptoms of CHF as defined by New York Heart Association (NYHA) class III or IV symptoms.
Percent of Participants of Asymptomatic Left Ventricular (LV) Cardiac Dysfunction at 1 Year	At 1 year	One-year cumulative incidence of LV cardiac dysfunction as measured by percent of participants that had asymptomatic LV cardiac dysfunction with/without permanent discontinuation
Percent of Participants With Asymptomatic LV Cardiac Dysfunction at Three Years	At 3 years	Three-year cumulative incidence of LV cardiac dysfunction as measured by percent of participants that had asymptomatic LV cardiac dysfunction with/without permanent discontinuation
Percent of Participants With DFS	At 2 years	Percent of participants with DFS measured between the time from initiation of treatment to the date of first loco-regional or distant treatment failure, ignoring any intervening contralateral breast cancers or other second primary cancers. Deaths without evidence of recurrence will be treated censoring events.
Overall Survival (OS) as Measured by Percent of Participants Alive at 1 Year	Up to 1 years	OS defined as percent of participants alive between time from initiation of treatment to the date of protocol-defined outcome from any cause and censored to the date of last follow-up for survivors.
Overall Survival (OS) as Measured by Percent of Participants Alive at 3 Years	Up to 3 years	OS defined as percent of participants alive between time from initiation of treatment to the date of protocol-defined outcome from any cause and censored to the date of last follow-up for survivors.
Overall Survival (OS) as Measured by Percent of Participants Alive at 5 Years	Up to 5 years	OS defined as percent of participants alive between time from initiation of treatment to the date of protocol-defined outcome from any cause and censored to the date of last follow-up for survivors.
Mean Change in Pro-inflammatory Cytokines	From baseline to end-of-treatment (52 weeks)	Mean change in pro-inflammatory cytokines from baseline to end of treatment
Percent of Participants With Disease-free Survival (DFS)	At 5 years	Percent of participants with DFS measured between the time from initiation of treatment to the date of first loco-regional or distant treatment failure, ignoring any intervening contralateral breast cancers or other second primary cancers. Deaths without evidence of recurrence will be treated censoring events.
Mean Change in Quality of Life From Baseline to Mid-treatment	From Baseline to mid-treatment (week 26)	Quality of life was assessed by using the mean change in Functional Assessment of Cancer Therapy-Breast (FACTB) scoring instrument. The Functional Assessment of Cancer Therapy-Breast (FACT-B) is a 37-item instrument designed to measure five domains of HRQOL in breast cancer patients: Physical, social, emotional, and functional well-being, as well as a breast-cancer subscale (BCS). Each question response is based on a 5-point Likert-type scale. Scores range from 0-148. High scores indicate better QOL.
Mean Change in Functional Status	baseline to end-of-treatment (52 weeks)	Mean Change in ADL/IADL scores From Baseline to End of Treatment. The functional status will be measured by a Comprehensive Geriatric Assessment comprised of two validated instruments: Katz's Activity of Daily Living (ADL) instrument and Lawton's Instrumental of Activities of Daily Living (IADL). The IADL scale contains eight items with a summary score from 0 (low function) to 8 (high function), with higher scores indicating higher function. The ADL scale contains six items with a summary score of 0 to 6, with higher scores indicating higher independence. A score of 6 indicates complete independence; a score of 4 indicates moderate impairment; 2 or less indicates severe functional impairment. The scores of both scales will be added together for a comprehensive geriatric assessment score.
Mean Change in Psychosocial Status (Social Support)	From baseline to end-of-treatment (52 weeks)	Mean Change in MOS social support scores From Baseline to End of Treatment. The Medical Outcomes Study (MOS) Social Support survey tool measures multiple domains. It is a 19-item tool comprised of four subscales in one overall summary index. The subscales are Emotional/Informational Support, Tangible Support, Affectionate support, and Positive Social Interaction. The overall index score is determined by calculating the mean of all 19 items. Scores range from 19 to 95, with higher scores indicating high support availability to participants.

Trial Locations

Locations (11): University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center
🇺🇸
Cleveland, Ohio, United States
UHHS Westlake Medical Center
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Cleveland, Ohio, United States
University Suburban Health Center
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Cleveland, Ohio, United States
UHHS Chagrin Highlands Medical Center
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Cleveland, Ohio, United States
University of Pittsburgh
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Pittsburgh, Pennsylvania, United States
University of Miami, Sylvester Comprehensive Cancer Center
🇺🇸
Miami, Florida, United States
Wake Forrest
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Winston-Salem, North Carolina, United States
Lake/University Seidman Cancer Center
🇺🇸
Cleveland, Ohio, United States
Southwest General Health Center
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Cleveland, Ohio, United States
Sharon Health Center
🇺🇸
Wadsworth, Ohio, United States
UH-Monarch
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Mayfield Heights, Ohio, United States