Taxotere and Adriamycin/Cytoxan (AC) Validation in Breast Cancer Patients

Large clinical trials have confirmed the value of systemic adjuvant therapy in decreasing the
risk of recurrence and death in patients with early breast cancer. However, the need to
identify breast cancer patients who will benefit from adjuvant therapy, while sparing others
from the side effects of futile treatment, is spurring research into predictive markers of
chemotherapy sensitivity and resistance. In the adjuvant setting, extremely large trials and
long follow-up would be required to prospectively validate the predictive value of biomarkers
of chemotherapy sensitivity or resistance. In part this is because response is not directly
observable. Preoperative chemotherapy for large tumors (>3cm) or inoperable breast cancer is
well established and is the standard of care for locally advanced breast cancer. Data from
large series of patients have demonstrated that preoperative (neoadjuvant) chemotherapy leads
to significant reduction of tumor size (downstaging) and improves both the rate and the
cosmetic results of breast- conserving surgery. The degree of response to neoadjuvant therapy
has been shown to predict improved overall survival. This is therefore an attractive setting
to study predictors of response because tissue is accessible from pre- therapeutic biopsies
and tumor response is directly observable.

In an early proof-of-principle pilot study of single agent neoadjuvant docetaxol, we
identified a predictive gene expression pattern, and, using leave-one-cross validation, a
method of internal validation, we demonstrated that the pattern was likely to accurately
discriminate between responders and non-responders (Chang, J.C., et al., Gene expression
profiling for the prediction of therapeutic response to docetaxel in patients with breast
cancer. Lancet, 2003. 362(9381): p. 362-9). A similar pilot study of neoadjuvant AC
undertaken by a collaborator in the UK suggests that different profiles will be predictive
for AC response.

In order to definitively determine predictive patterns for both regimens (T and AC) using
improved technology for RNA preparation and a larger, more comprehensive gene expression
array, we undertook a randomized Phase II trial of these two widely used regimens (Protocol
H-11624 - A RANDOMIZED MULTICENTER TRIAL OF NEOADJUVANT TAXOTERE AND ADRIAMYCIN/CYTOXAN (AC):
A BIOLOGIC CORRELATIVE STUDY). The trial is nearing completion, having recruited more than 90
patients out of an expected 120 patients. To date, the risks associated with this study have
been modest, and there have been no unexpected adverse events. The laboratory work is well
underway and gives every indication that clinically useful classifiers to predict treatment
efficacy will result.

Inclusion Criteria:

1. All patients must be female.

2. Signed informed consent.

3. Primary breast cancers must be of clinical and/or radiologic size >3 cm, and deemed
surgically operable.

4. Negative serum pregnancy test (bHCG) within 7 days of starting study, if of
child-bearing potential.

5. Adequate bone marrow function:

- Hematocrit of greater than 30%,

- total neutrophil count must be >1.5 x 10^9/L and

- platelets of > 100 x 10^9/L prior to the start of any cycle.

6. Renal function tests:

- creatinine within 1.5 times of the institution's upper limit of normal (ULN).

7. Liver function tests:

- Total serum bilirubin within ULN, and

- liver transaminases within 2.5 times ULN, and

- alkaline phosphatase within 5 times ULN.

8. Electrocardiogram showing no acute ischemic changes.

9. Performance status (World Health Organization [WHO] scale) <2.

10. Age > 18 years.

11. Patients older than 70 years of age should have left ventricular ejection fraction
within ULN by multigated acquisition scan (MUGA) or 2D echocardiogram.

Exclusion Criteria:

1. Patients with metastatic breast cancer.

2. Pregnancy or unwillingness to use a reliable contraceptive method in women of
child-bearing potential.

3. Women who are lactating or breastfeeding.

4. Severe underlying chronic illness or disease.

5. Peripheral neuropathy - grade 2 or greater.

6. Patients on other investigational drugs while on study will be excluded.

7. Severe or uncontrolled hypertension, history of congestive heart failure, acute
myocardial infarction, or severe coronary arterial disease.

8. Prior taxane or anthracycline chemotherapy for malignancy.

9. Patients with a history of severe hypersensitivity reaction to Taxotere or other drugs
formulated with polysorbate 80.

10. No previous or current malignancies at other sites within the last 5 years, with
exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri
and basal or squamous cell carcinoma of the skin.