Trastuzumab in Treating Older Women With Early-Stage Breast Cancer

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.

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