This randomized phase III trial studies how well doxorubicin hydrochloride and cyclophosphamide followed by paclitaxel with or without carboplatin work in treating patients with triple-negative breast cancer. Drugs used in chemotherapy, such as doxorubicin hydrochloride, cyclophosphamide, paclitaxel, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether doxorubicin hydrochloride and cyclophosphamide is more effective when followed by paclitaxel alone or paclitaxel and carboplatin in treating triple-negative breast cancer.
PRIMARY OBJECTIVES: I. To determine whether the addition of carboplatin to an adjuvant chemotherapy regimen of doxorubicin (doxorubicin hydrochloride)/cyclophosphamide followed by paclitaxel will improve the invasive disease-free survival (IDFS) compared to doxorubicin/cyclophosphamide followed by paclitaxel when administered to patients with operable node-positive or high-risk node-negative triple-negative breast cancer. SECONDARY OBJECTIVES: I. To determine whether the addition of carboplatin to an adjuvant chemotherapy regimen of doxorubicin/cyclophosphamide followed by paclitaxel will improve the overall survival (OS) compared to doxorubicin/cyclophosphamide followed by paclitaxel when administered to patients with operable node-positive or high-risk node-negative triple-negative breast cancer. II. To determine whether the addition of carboplatin to an adjuvant chemotherapy regimen of doxorubicin/cyclophosphamide followed by paclitaxel will improve the breast cancer-free survival (BCFS) compared to doxorubicin/cyclophosphamide followed by paclitaxel when administered to patients with operable node-positive or high-risk node-negative triple-negative breast cancer. III. To determine whether the addition of carboplatin to an adjuvant chemotherapy regimen of doxorubicin/cyclophosphamide followed by paclitaxel will improve the recurrence-free interval (RFI) compared to doxorubicin/cyclophosphamide followed by paclitaxel when administered to patients with operable node-positive or high-risk node-negative triple-negative breast cancer. IV. To determine whether the addition of carboplatin to an adjuvant chemotherapy regimen of doxorubicin/cyclophosphamide followed by paclitaxel will improve the distant recurrence-free interval (DRFI) compared to doxorubicin/cyclophosphamide followed by paclitaxel when administered to patients with operable node-positive or high-risk node-negative triple-negative breast cancer. V. To determine the toxicity of doxorubicin/cyclophosphamide followed by paclitaxel administered concurrently with carboplatin compared to the toxicity of doxorubicin/cyclophosphamide followed by paclitaxel alone. VI. To determine if germline breast cancer (BRCA) status is associated with benefit in IDFS or OS from the addition of carboplatin to an adjuvant chemotherapy regimen of doxorubicin/cyclophosphamide followed by paclitaxel in patients with operable node-positive or high-risk node-negative triple-negative breast cancer. VII. To determine if the addition of carboplatin will improve the RFI among the homologous recombination (HR) deficient patients as determined by the homologous recombination deficiency (HRD) score. VIII. To determine whether the efficacy of carboplatin on RFI in HR-deficient patients differs from that in patients who are not HR-deficient. IX. To collect tissue and blood samples at several occasions for future biomarkers development in predicting risk of breast cancer recurrence in patients with operable node-positive or high-risk node-negative triple-negative breast cancer treated with doxorubicin/cyclophosphamide followed by paclitaxel with or without carboplatin and predicting benefit from the addition of carboplatin among these patients. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I (DOXORUBICIN HYDROCHLORIDE \[A\] CYCLOPHOSPHAMIDE \[C\]--\>WEEKLY PACLITAXEL \[WP\]): Patients receive doxorubicin hydrochloride intravenously (IV) over 15 minutes and cyclophosphamide IV over 30 minutes on day 1. Treatment repeats every 2 weeks for 4 courses in the absence of disease progression or unacceptable toxicity. Patients then receive paclitaxel IV over 60 minutes on day 1. Treatment repeats weekly for 12 courses in the absence of disease progression or unacceptable toxicity. ARM II (AC--\>WP + CARBOPLATIN): Patients receive doxorubicin hydrochloride and cyclophosphamide as in Arm I. Patients then receive paclitaxel IV over 60 minutes on days 1, 8, and 15 and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 6 months for 5 years and then every 12 months for 5 years.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
782
Given IV
Given IV
Given IV
Correlative studies
Given IV
Southern Cancer Center PC-Mobile
Mobile, Alabama, United States
Southern Cancer Center PC-Providence
Mobile, Alabama, United States
Southern Cancer Center PC-Springhill
Mobile, Alabama, United States
Anchorage Associates in Radiation Medicine
Anchorage, Alaska, United States
Anchorage Radiation Therapy Center
Anchorage, Alaska, United States
IDFS
IDFS events are local invasive recurrence after mastectomy, local invasive recurrence in the ipsilateral breast after lumpectomy, regional recurrence, distant recurrence, contralateral invasive breast cancer, second non-breast primary cancer (excluding squamous or basal cell carcinoma of the skin), or death from any cause before recurrence or second primary cancer. IDFS will be compared between the two treatment arms by the stratified log-rank test. The Kaplan-Meier estimates will be calculated separately for patients under the different treatment regimens.
Time frame: Up to 10 years
BCFS
The stratified log-rank tests will be 2-sided with significance level 0.05. Treatment efficacy in these secondary endpoints will be assessed by Cox models adjusting for clinical factors such as age, number of positive nodes, BRCA mutation status, tumor size, and tumor grade.
Time frame: From randomization until local recurrence (invasive or DCIS), regional recurrence, or distant recurrence, contralateral breast cancer (invasive or DCIS), or death from any causes, assessed up to 10 years
DRFI
The stratified log-rank tests will be 2-sided with significance level 0.05. Treatment efficacy in these secondary endpoints will be assessed by Cox models adjusting for clinical factors such as age, number of positive nodes, BRCA mutation status, tumor size, and tumor grade.
Time frame: From randomization until distant metastasis or death from breast cancer, regardless of occurrence of any intervening local or regional recurrences, contralateral breast cancers, or non-breast second primary cancers, assessed up to 10 years
Frequencies of adverse events categorized using the National Cancer Institute CTCAE v4.0
Frequencies of all adverse events during the treatment period will be tabulated by treatment, toxicity type, and grade. The Pearson Chi-squared test with continuity adjustment will be used to compare toxicity grades in each type between the two treatment regimens. The test will be 2-sided with significance level 0.05.
Time frame: Up to 10 years
OS
The stratified log-rank tests will be 2-sided with significance level 0.05. Treatment efficacy in these secondary endpoints will be assessed by Cox models adjusting for clinical factors such as age, number of positive nodes, BRCA mutation status, tumor size, and tumor grade.
Time frame: From randomization until death from any cause, assessed up to 10 years
RFI
The stratified log-rank tests will be 2-sided with significance level 0.05. Treatment efficacy in these secondary endpoints will be assessed by Cox models adjusting for clinical factors such as age, number of positive nodes, BRCA mutation status, tumor size, and tumor grade.
Time frame: From randomization until invasive local, regional, or distant recurrence, or death from breast cancer (censored for death from other causes), assessed up to 10 years
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