Neoadjuvant Chemotherapy Using Doxorubicin and Paclitaxel in Treating Women With Large Breast Cancer
Neoadjuvant Chemotherapy Using Doxorubicin and Paclitaxel in Treating Women With Large Breast Cancer
RATIONALE: Drugs used in chemotherapy, such as doxorubicin and paclitaxel, work in different
 ways to stop tumor cells from dividing so they stop growing or die. Giving chemotherapy
 before and after surgery may shrink the tumor so it can be removed and may kill any tumor
 cells remaining after surgery.

 PURPOSE: This randomized phase II trial is comparing two different regimens of doxorubicin
 and paclitaxel to see how well they work in treating women who are undergoing surgery for
 breast cancer.
OBJECTIVES:

 Primary

 -  Determine whether tumors in women with palpable invasive breast cancer with wild type
 p53 are more sensitive to doxorubicin than to paclitaxel when given as sequential
 single-agent neoadjuvant chemotherapy.

 -  Determine whether tumors with inactivated p53 are more sensitive to paclitaxel than to
 doxorubicin when given as sequential single-agent neoadjuvant chemotherapy in these
 patients.

 Secondary

 -  Correlate other biological markers (physiological and molecular) with tumor response in
 patients treated with these regimens.

 -  Determine changes in these biological markers during and after neoadjuvant chemotherapy
 in these patients.

 -  Compare breast MRI, in terms of assessing tumor response, with physical exam, mammogram,
 and ultrasound in patients treated with these regimens.

 -  Determine whether there are MRI indicators (e.g., tumor morphology or lesion
 enhancement) that are predictive of response in patients treated with these regimens.

 OUTLINE: This is a randomized, multicenter study. Patients are stratified according to tumor
 size (> 5 cm vs ≤ 3-5 cm) and presence of palpable regional lymph nodes (yes vs no). Patients
 are randomized to 1 of 2 treatment arms.

 All patients undergo biopsy, bilateral mammogram, MRI, ultrasound, blood marker, molecular
 (gene microarrays and functional p53 status), and physiologic studies before initiation of
 neoadjuvant chemotherapy. Some of these studies are repeated after completion of treatment
 with the first chemotherapeutic agent and after completion of treatment with the second
 chemotherapeutic agent as outlined below.

 -  Arm I: Patients receive doxorubicin IV on days 1, 15, 29, and 43. Patients with no
 residual tumor (indicated by clinical evaluation and radiologic studies) after
 completion of doxorubicin undergo definitive surgery. After surgery, patients receive
 paclitaxel IV over 1 hour on days 1, 8, 15, 22, 29, 36, 43, 50, and 57.

 Patients with residual tumor > 2 cm after completion of doxorubicin undergo 8-12 core needle
 biopsies. Patients with residual tumor < 2 cm after completion of doxorubicin undergo 4-6
 core needle biopsies. After core needle biopsies, patients receive paclitaxel as above.

 -  Arm II: Patients receive paclitaxel IV over 1 hour on days 1, 8, 15, 22, 29, 36, 43, 50,
 and 57. Patients with no residual tumor (indicated by clinical evaluation and radiologic
 studies) after completion of paclitaxel undergo definitive surgery. After surgery,
 patients receive doxorubicin IV on days 1, 15, 29, and 43.

 Patients with residual tumor > 2 cm after completion of paclitaxel undergo 8-12 core needle
 biopsies. Patients with residual tumor < 2 cm after completion of paclitaxel undergo 4-6 core
 needle biopsies. After core needle biopsies, patients receive doxorubicin as above.

 In both arms, treatment continues in the absence of disease progression or unacceptable
 toxicity.

 Samples from core needle biopsies are analyzed by microarray analysis for gene expression
 profiles.

 Patients are followed every 6 months for 5 years.

 PROJECTED ACCRUAL: A total of 100 patients (50 per treatment arm) will be accrued for this
 study within 4-5 years.
DISEASE CHARACTERISTICS:

 -  Diagnosis of invasive breast cancer

 -  Tumor ≥ 3 cm and palpable

 -  Multiple masses are allowed provided at least 1 mass is ≥ 3 cm

 -  Clinically positive axillary or supraclavicular lymph nodes allowed

 -  Fine needle aspiration or core needle biopsy positive for invasive breast cancer
 AND/OR fine needle aspiration of lymph nodes positive

 -  HER2/neu-positive OR negative

 -  No inflammatory breast cancer

 -  No distant metastases

 -  Hormone receptor status:

 -  Estrogen receptor (ER)-positive OR ER-negative

 PATIENT CHARACTERISTICS:

 Age

 -  18 and over

 Sex

 -  Female

 Menopausal status

 -  Premenopausal or postmenopausal

 Performance status

 -  Karnofsky 60-100%

 Life expectancy

 -  Not specified

 Hematopoietic

 -  Granulocyte count ≥ 1,000/mm^3

 -  Platelet count ≥ 100,000/mm^3

 Hepatic

 -  Bilirubin ≤ 2 times upper limit of normal (ULN)

 -  SGOT ≤ 2 times ULN

 Renal

 -  Not specified

 Cardiovascular

 -  LVEF ≥ 50%

 -  No congestive heart failure

 -  No serious conduction system abnormality

 -  No other significant cardiovascular disease

 Other

 -  Not pregnant or nursing

 -  Negative pregnancy test

 -  Fertile patients must use effective contraception

 -  Patients with other prior or concurrent malignancies allowed provided they have
 received no prior chemotherapy AND they are likely to have been cured from a prior
 malignancy

 -  No severe medical or psychiatric condition that would preclude study compliance

 -  No known HIV positivity

 PRIOR CONCURRENT THERAPY:

 Biologic therapy

 -  Not specified

 Chemotherapy

 -  No prior chemotherapy

 Endocrine therapy

 -  No prior hormonal therapy for breast cancer

 Radiotherapy

 -  No prior radiotherapy for this malignancy

 Surgery

 -  Not specified