Trastuzumab in Treating Older Women With Early-Stage Breast Cancer

Safety and Efficacy of Single Agent Adjuvant Trastuzumab (Herceptin®) in Older Women With Early-Stage and Locally Advanced Breast Cancer: A Phase II Trial

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.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Biological: trastuzumab; Other: laboratory biomarker analysis; Procedure: adjuvant therapy; Procedure: quality-of-life assessment

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.

• Study Type: Interventional
• Enrollment (Actual): 56
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami, Sylvester Comprehensive Cancer Center
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forrest
  • Ohio
    • Cleveland, Ohio, United States, 44106-5065
      • University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center
    • Cleveland, Ohio, United States, 44121
      • University Suburban Health Center
    • Cleveland, Ohio, United States, 44122
      • UHHS Chagrin Highlands Medical Center
    • Cleveland, Ohio, United States, 44130
      • Southwest General Health Center
    • Cleveland, Ohio, United States, 44145
      • UHHS Westlake Medical Center
    • Cleveland, Ohio, United States, 44060
      • Lake/University Seidman Cancer Center
    • Mayfield Heights, Ohio, United States, 44124
      • UH-Monarch
    • Wadsworth, Ohio, United States, 44281
      • Sharon Health Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: trastuzumab

Biological: trastuzumab; 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.; Other Names: Herceptin; Other: laboratory biomarker analysis; 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).; Procedure: adjuvant therapy; 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.; Procedure: quality-of-life assessment; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent of Participants Experiencing Cardiac Events 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.	At 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent of Participants Experiencing Cardiac Events 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.	At 3 years
Percent of Participants Experiencing Cardiac Events 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.	At 5 years
Percent of Participants of Asymptomatic Left Ventricular (LV) Cardiac Dysfunction 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	At 1 year
Percent of Participants With Asymptomatic LV Cardiac Dysfunction at Three 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	At 3 years
Percent of Participants With Asymptomatic LV Cardiac Dysfunction at Five Years	Five-year cumulative incidence as measured by percent of participants that had asymptomatic LV cardiac dysfunction with/without permanent discontinuation	At 5 years
Percent of Participants With Disease-free Survival (DFS)	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.	At 1 year
Percent of Participants With DFS	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.	At 2 years
Percent of Participants With Disease-free Survival (DFS)	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.	At 3 years
Percent of Participants With Disease-free Survival (DFS)	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.	At 5 years
Overall Survival (OS) as Measured by Percent of Participants Alive at 1 Year	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.	Up to 1 years
Overall Survival (OS) as Measured by Percent of Participants Alive at 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.	Up to 2 years
Overall Survival (OS) as Measured by Percent of Participants Alive at 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.	Up to 3 years
Overall Survival (OS) as Measured by Percent of Participants Alive at 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.	Up to 5 years
Mean Change in Quality of Life From Baseline to Mid-treatment	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.	From Baseline to mid-treatment (week 26)
Mean Change in Quality of Life From Baseline to End of Treatment	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.	From baseline to end-of-treatment (52 weeks)
Mean Change in Functional Status	Mean Change in ADL/IADL scores From Baseline to Mid-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.	From Baseline to mid-treatment (week 26)
Mean Change in Functional Status	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.	baseline to end-of-treatment (52 weeks)
Mean Change in Cognitive Status	Mean Change in Mini Mental Status Exam (MMSE scores) From Baseline to Mid-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).	From Baseline to mid-treatment (week 26)
Mean Change in Cognitive Status	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).	From baseline to end-of-treatment (52 weeks)
Mean Change in Psychosocial Status (Depression)	Mean Change in Geriatric Depression Scores From Baseline to Mid-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.	From Baseline to mid-treatment (week 26)
Mean Change in Psychosocial Status (Depression)	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.	From baseline to end-of-treatment (52 weeks)
Mean Change in Psychosocial Status (Social Support)	Mean Change in MOS social support scores From Baseline to Mid-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.	From Baseline to mid-treatment (week 26)
Mean Change in Psychosocial Status (Social Support)	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.	From baseline to end-of-treatment (52 weeks)
Mean Change in Nutritional Status	Mean Change in Mini Nutrition Assessment scores From Baseline to Mid-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.	From Baseline to mid-treatment (week 26)
Mean Change in Nutritional Status	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.	From baseline to end-of-treatment (52 weeks)
Mean Change in Pro-inflammatory Cytokines	Mean change in pro-inflammatory cytokines from baseline to mid-treatment	From Baseline to mid-treatment (week 26)
Mean Change in Pro-inflammatory Cytokines	Mean change in pro-inflammatory cytokines from baseline to end of treatment	From baseline to end-of-treatment (52 weeks)
Mean Change in Plasma Cardiac Markers	Mean change in plasma cardiac markers from baseline to mid-treatment	From Baseline to mid-treatment (week 26)
Mean Change in Plasma Cardiac Markers	Mean change in plasma cardiac markers from baseline end of treatment	From baseline to end-of-treatment (52 weeks)

Other Outcome Measures

Outcome Measure	Time Frame
Mean Change in Pro-inflammatory Cytokines From Baseline to Mid-treatment and Baseline to End of Treatment	Every 6 weeks during treatment up to three years
Mean Change in Plasma Cardiac Markers From Baseline to Mid-treatment and Baseline to End of Treatment	Every 6 weeks during treatment up to three years

Collaborators and Investigators

• Sponsor: Cynthia Owusu, MD
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Cynthia Owusu, MD, MSc, University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): February 5, 2009
• Primary Completion (Actual): January 6, 2016
• Study Completion (Actual): February 26, 2020

Study Registration Dates

• First Submitted: November 21, 2008
• First Submitted That Met QC Criteria: November 21, 2008
• First Posted (Estimated): November 24, 2008

Study Record Updates

• Last Update Posted (Actual): May 1, 2024
• Last Update Submitted That Met QC Criteria: April 4, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: stage IIIA breast cancer; stage IIIB breast cancer; stage II breast cancer; stage IIIC breast cancer; HER2-positive breast cancer; stage I breast cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Antineoplastic Agents; Antineoplastic Agents, Immunological; Trastuzumab
• Other Study ID Numbers: CASE10107 (Case Comprehensive Cancer Center); P30CA043703 (U.S. NIH Grant/Contract); CASE-10107-CC443 (Other Identifier: Cancer Center IRB)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No