Trial Information

First Prospective Intergroup Translational Research Trial Assessing the Potential Predictive Value of p53 Using a Functional Assay in Yeast in Patients With Locally Advanced/Inflammatory or Large Operable Breast Cancer Prospectively Randomised to a Taxane Versus a Non Taxane Regimen

OBJECTIVES:

Primary

- Compare neoadjuvant fluorouracil, epirubicin, and cyclophosphamide vs docetaxel and
epirubicin followed by radiotherapy and surgery in women with locally advanced,
inflammatory, or large operable breast cancer.

- Assess overall differences between the two arms.

- Assess interaction between p53 status and outcomes in each arm.

- Compare the progression-free survival of patients treated with these regimens.

Secondary

- Compare the distant metastasis-free survival and survival of patients treated with
these regimens.

- Compare the clinical and pathological responses to these regimens in these patients.

- Compare the toxicity of these regimens in these patients.

Translational

- Determine the p53 status in order to study the treatment effect in each of the p53
subgroups and test the interaction between treatment and p53 status.

- Assess the level of agreement between p53 assessment by IHC method and functional test
in yeast.

- Evaluate the prognostic and predictive value of "high risk" p53 mutations.

- Perform a survival analysis according to gene clusters defined with the use of
microarrays.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to stage
of disease (large T2-3 vs locally advanced or inflammatory), p53 status (negative vs
positive vs unknown), and participating center. Patients are randomized to 1 of 2
chemotherapy treatment arms.

- Arm I (non-taxane arm): Patients receive 1 of 3 chemotherapy regimens comprising
fluorouracil, epirubicin, and cyclophosphamide (FEC) (according to participating
institution).

- FEC 100: Patients receive fluorouracil IV over 15 minutes, epirubicin IV over 1
hour, and cyclophosphamide IV over 1 hour on day 1. Treatment repeats every 3
weeks for 6 courses in the absence of disease progression or unacceptable
toxicity.

- Canadian FEC: Patients receive oral cyclophosphamide on days 1-14 and epirubicin
IV and fluorouracil IV on days 1 and 8. If oral medications are not tolerated,
patients may switch to cyclophosphamide IV on days 1 and 8. Treatment repeats
every 4 weeks for 6 courses in the absence of disease progression or unacceptable
toxicity.

- Tailored FEC: Patients receive fluorouracil IV over 15 minutes, epirubicin IV over
1 hour, and cyclophosphamide IV over 1-2 hours on day 1. Patients also receive
filgrastim (G-CSF) subcutaneously on days 2-15 or until blood counts recover.
Treatment repeats every 3 weeks for 6 courses in the absence of disease
progression or unacceptable toxicity.

- Arm II (taxane arm): Patients receive docetaxel IV over 1 hour on days 1, 22, and 43
followed by epirubicin IV over 15 minutes and docetaxel IV over 1 hour on days 64, 85,
and 106 in the absence of disease progression or unacceptable toxicity.

Following chemotherapy, patients may undergo loco-regional therapy comprising radiotherapy
with or without breast conservation surgery or mastectomy. Patients with estrogen- and/or
progesterone-receptor-positive disease also receive tamoxifen or an aromatase inhibitor for
5 years.

Two tumor samples (incisional or tricut biopsies) are taken before chemotherapy. Samples are
analyzed by IHC, a functional test in yeast, and microarray analysis.

Patients are followed every 3 months for 1 year, every 4 months for 1.5 years, and then
every 6 months thereafter.

PROJECTED ACCRUAL: A total of 1,850 patients will be accrued for this study within 5.5
years.