Neoadjuvant Chemotherapy Using Doxorubicin and Paclitaxel in Treating Women With Large Breast Cancer

April 7, 2017 updated by: Alphonse Taghian, MD, PhD, Massachusetts General Hospital

Neoadjuvant Chemotherapy in Palpable Breast Cancer: Evaluation of Physiologic, Radiologic, and Molecular Markers in Predicting Response

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.

Study Overview

Status

Completed

Conditions

Breast Cancer

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

Phase

Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

United States
- Massachusetts
  - Boston, Massachusetts, United States, 02115
    - Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
  - Boston, Massachusetts, United States, 02114-2617
    - Massachusetts General Hospital Cancer Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 120 years (Adult, Older Adult)

Accepts Healthy Volunteers

Genders Eligible for Study

Female

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Interventional Model: Parallel Assignment
Masking: None (Open Label)

Number of Arms

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Sequence Doxorubicin followed by Paclitaxel Patients will be randomized into 2 groups based on sequence of neoadjuvant chemotherapy: Doxorubicin followed by Paclitaxel versus Paclitaxel followed by Doxorubicin	Other: Doxorubicin followed by Paclitaxel Patients will be randomized into 2 groups based on sequence of neoadjuvant chemotherapy: Doxorubicin followed by Paclitaxel Paclitaxel followed by Doxorubicin Other: Paclitaxel followed by Doxorubicin Patients will be randomized into 2 groups based on sequence of neoadjuvant chemotherapy: Doxorubicin followed by Paclitaxel versus Paclitaxel followed by Doxorubicin
Other: Sequence of neoadjuvant CT: Paclitaxel followed by Doxorubicin Patients will be randomized into 2 groups based on sequence of neoadjuvant chemotherapy: Doxorubicin followed by Paclitaxel versus Paclitaxel followed by Doxorubicin	Other: Paclitaxel followed by Doxorubicin Patients will be randomized into 2 groups based on sequence of neoadjuvant chemotherapy: Doxorubicin followed by Paclitaxel versus Paclitaxel followed by Doxorubicin