Breast Cancer
Study Code:BC
Sample:Pending
Start Date:Apr.2004
Status:In progress
Contact:Margie Wright
More Info:QIMR only


1. Overview of Proposed Study

2. Aims and Objectives

3. Experimental Design

4. Patient Selection

5. Key Eligibility Criteria

6. Key Exclusion Criteria

7. Treatment Details

8. Proposed Study Measures - Introduction

9. Statistical Considerations

This study will examine the following hypotheses in patients with early stage breast cancer who are treated with adjuvant cytotoxic drugs as part of their standard care.

  1. The genotype of individuals will play a significant role in predicting change in cognitive function after treatment with cytotoxic drugs.
  2. Cognitive function will change during administration of cytotoxic drugs for some patients.
  3. Long term changes of cognitive function will be identified in a minority of patients.

Further details are below:

1. Overview of Proposed Study

The proposed study will be divided into two phases.  The first phase, for which applications for funding from the Cancer Council Australia (see Attachment QCF Grant Application Form) and Wesley Research Institute have been submitted, will document the cognitive profiles of patients with early stage breast cancer who are candidates for adjuvant cytotoxic drug treatment.  Objective neuropsychologic testing will be undertaken on these patients prior to, and at the completion of adjuvant cytotoxic drug treatment, and at six months and one year after completion of treatment.  Self report measures of quality of life, fatigue, anxiety and depression will be administered at the time of neuropsychologic testing.  This initial phase of the study will identify endophenotypes of cognitive function.  The second phase will seek additional funding for the longer term follow-up necessary to identify the presence of persistent cognitive dysfunction, as well as genotyping.  Blood samples will be taken at baseline.  Genotyping will build on our published experience of Apo E allele expression and novel genotypes identified in the QIMR twin study. 

2. Aims and Objectives

First Phase (Hypotheses 2, 3)

To identify profiles of cognitive function before and at completion of adjuvant cytotoxic drug treatment, and in follow-up at six months and one year. To evaluate the impact of self report measures of quality of life, distress, anxiety and depression on cognitive measures.

Second Phase (Hypotheses 1, 2, 3)

To assess whether common genetic factors, including Apo E allele expression and novel alleles identified in the QIMR twin cognition study, influence loss of cognitive function during and after treatment with cytotoxic drugs. To evaluate cognitive function and self report measures of quality of life, distress, anxiety and depression at a follow-up interval of two years. 

3. Experimental Design

Approximately 120 will be recruited for the study. 

Eligible candidates will be treated with conventional doses of standard cytotoxic drug regimens. 

4. Patient Selection

Participants will be recruited from clinics of the investigators (EW, NM, HJ, GB, DG).  The sources of recruitment will be the Royal Brisbane Hospital, Division of Medical Oncology (NM), South Brisbane Oncology Research Unit, Princess Alexandra Hospital (EW, HJ) and Wesley Medical Centre (private practice, GB DG).  All eligible participants will be under the direct care of these investigators.   

5. Key Eligibility Criteria

Histologically proven breast cancer treated initially by definitive surgery that includes axillary lymph node assessment.

18 years and less than 70 years.

No past history of cancer, except for non-melanoma skin cancer, carcinoma in-situ of cervix, lobular carcinoma in-situ.

No previous cytotoxic drug treatment.

Written informed consent provided according to participating institutional requirements.

Proficiency in English language since childhood.

Patients must be accessible for treatment and follow-up.

Adequate haematological and biochemical function.

Karnofsky performance status index 80%

Plan to receive adjuvant cytotoxic chemotherapy

6. Key Exclusion Criteria

The presence of metastatic disease.

A history of neurologic/psychiatric symptoms or signs that may lead to deviant neuropsychologic test results.

Medications that might lead to deviant neuropsychological test results.

Alcohol and/or drug addiction.

Concurrent treatment with other experimental drugs.

Male patients, as no data base exists for cognitive function testing in breast cancer.

7. Treatment Details

Participants who meet the eligibility criteria will be treated initially with definitive surgery, including sentinel lymph node biopsy and/or axillary dissection.  Cytotoxic drug regimens will be documented and can include the following drugs: Adriamycin, Epirubicin, Cyclophosphamide, Methotrexate, 5-Fluorouracil, Paclitaxel, Docetaxel.  Patients will be eligible if they are treated with endocrine treatments and Herceptin.  Radiation treatment, if indicated, will be administered after completion of cytotoxic drug treatment. 

8. Proposed Study Measures - Introduction

Demographic data will be collected on patients invited to participate in this study.  These data will include the following: - age, menopausal status, use of hormone replacement therapy, medications, and plan of cytotoxic drug, endocrine and radiation treatments.  These variables will be treated as covariates and will be documented at baseline and at each follow-up interval.  Demographic data will be collected prior to the study by hospital based data managers or research nurses.  Cognitive testing will take place in a quiet room either at one of the hospitals or at the participantís homes.  Self-report questionnaires for anxiety, depression, fatigue and quality of life will be administered immediately following the cognitive testing.  All tests and questionnaires will be administered to each participant in the same order and will take approximately 2 hours to complete.  Assessments will be made at baseline, at the end of adjuvant cytotoxic drug treatment, and at 6 and 12 months after cessation of therapy. Neuropsychologic tests will be administered by a registered psychologist in accordance with standard practice procedures.

9. Statistical Considerations

Clinical data, cognitive measures, self report scales and genetic results will be stored in a purpose designed relational database.  The database will be held at the Queensland Institute of Medical Research.  Mean changes in cognitive profiles, fatigue, anxiety and depression scores from baseline to post-treatment and for each follow-up will be presented as percentage changes, and tested using paired Student t-tests and repeated measures analysis of variance (ANOVA). Differences in the degree of cognitive decline between genetic groups of women will also be assessed using independent sample t-tests on mean differences, and repeated measures ANOVA by including a time by genotype interaction term. Multivariate linear regression will be used to assess the independent predictors of cognitive decline, including terms for age, treatment schedule (eg doses), disease characteristics (such as stage), menopausal status, fatigue, anxiety, depression and, after genotyping, genetic polymorphisms.

Power and sample size calculations have been conducted using means and standard deviations of changes in cognitive profiles, anxiety and depression derived from patients undergoing cardiac surgery55 and population Apo E allele frequencies as reported by Gelernter et al. To allow for patient withdrawal, 120 subjects will be invited to participate in the study.  For phase 1, 100 subjects will provide 90% power to detect a significant (at the 5% level) 10% decrease in Rey Auditory Verbal Learning scores (sd diff=2.00); 9% change in Trail Making Tests (sd diff=12.23); 5% change in WAIS III Digit Symbols (sd diff=6.36); 13% change in anxiety (sd diff=3.2); and a 15% change in depression (sd diff=2.5). The sizes of these changes are consistent with those reported in previous studies of cognitive function after treatment with cytotoxic drugs. For phase 2, 100 subjects will provide 90% power to detect a significantly greater decline in women who carry the Apo E allele (prevalence=20%) than those who do not carry this allele, with fold-difference in the order of: 2.0 for Rey Auditory Verbal Learning scores; 2.5 for Trail Making Tests.