Summary

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.

Objectives

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 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 cycles 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 cycles 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 cycles 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.

Eligibility

1. The patient must have signed and dated an Institutional Review Board (IRB)-approved consent form that conforms to federal and institutional guidelines
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
3. The tumor must be unilateral invasive adenocarcinoma of the breast on histologic examination
4. All of the following staging criteria (according to the 7th edition of the American Joint Committee on Cancer [AJCC] Cancer Staging Manual) must be met: * By pathologic evaluation, primary tumor must be pT1-3 * By pathologic evaluation, ipsilateral nodes must be pN0, pN1 (pN1mi, pN1a, pN1b, pN1c), pN2a, pN2b, pN3a, or pN3b * If pN0, pathological tumor must be >= 3.0 cm
5. The tumor must have been determined to be human epidermal growth factor receptor 2 (HER2)-negative as follows: * Immunohistochemistry (IHC) 0-1+; or * IHC 2+ and in situ hybridization (ISH) non-amplified with a ratio of HER2 to centromere enumerator probe 17 (CEP17) < 2.0, and if reported, average HER2 gene copy number < 4 signals/cells; or * ISH non-amplified with a ratio of HER2 to CEP17 < 2.0, and if reported, average HER2 gene copy number < 4 signals/cells
6. The tumor must have estrogen receptor (ER)-and progesterone receptor (PgR)-status assessed using current American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines; patients are eligible if the tumor staining meets one of the following criteria: * ER-negative and PgR- negative by ASCO/CAP guidelines, OR * ER or PgR stains are positive in 1-9% of cells and neither is positive in >= 10% of cells
7. The patient must have undergone either a mastectomy (total, skin-sparing, or nipple-sparing) or lumpectomy
8. For patients who undergo lumpectomy, the margins of the resected specimen must be histologically free of invasive tumor and ductal carcinoma in situ (DCIS) as determined by the local pathologist; if pathologic examination demonstrates tumor at the line of resection, additional excisions may be performed to obtain clear margins; if tumor is still present at the resected margin after re-excision(s), the patient must undergo mastectomy to be eligible; (patients with margins positive for lobular carcinoma in situ [LCIS] are eligible without additional resection)
9. For patients who undergo mastectomy, the margins must be free of residual gross tumor; (patients with microscopic positive margins are eligible as long as post-mastectomy radiation therapy [RT] of the chest wall will be administered)
10. The patient must have completed one of the procedures for evaluation of pathologic nodal status listed below. * Sentinel lymphadenectomy alone: ** If pathologic nodal staging based on sentinel lymphadenectomy is pN0 or pN1b; ** If pathologic nodal staging based on sentinel lymphadenectomy is pN1mi or pN1a and the patient has undergone breast conserving surgery (with planned breast radiotherapy), the primary tumor must be T1 or T2 by pathologic evaluation and the nodal involvement must be limited to 1 or 2 positive nodes * Sentinel lymphadenectomy followed by removal of additional non-sentinel lymph nodes if the sentinel node (SN) is positive; or * Axillary lymphadenectomy with or without SN isolation procedure
11. The interval between the last surgery for breast cancer (including re-excision of margins) and randomization must be no more than 60 days
12. Absolute neutrophil count (ANC) must be >= 1200/mm^3 (within 6 weeks prior to randomization)
13. Platelet count must be >= 100,000/mm^3 (within 6 weeks prior to randomization)
14. Hemoglobin must be >= 10 g/dL (within 6 weeks prior to randomization)
15. Total bilirubin must be =< upper limit of normal (ULN) for the laboratory (lab) unless the patient has a bilirubin elevation > ULN to 1.5 x ULN due to Gilbert’s disease or similar syndrome involving slow conjugation of bilirubin (within 6 weeks prior to randomization)
16. Alkaline phosphatase must be =< 2.5 x ULN for the lab (within 6 weeks prior to randomization)
17. Aspartate aminotransferase (AST) must be =< 1.5 x ULN for the lab (within 6 weeks prior to randomization) * Note: If alanine aminotransferase (ALT) is performed instead of AST (per institution's standard practice), the ALT value must be =< 1.5 x ULN; if both were performed, the AST must be =< 1.5 x ULN
18. Patients with AST or alkaline phosphatase > ULN are eligible for inclusion in the study if liver imaging (computed tomography [CT], magnetic resonance imaging [MRI], positron emission tomography [PET]-CT, or PET scan) performed within 90 days prior to randomization does not demonstrate metastatic disease and the requirements above are met
19. Patients with alkaline phosphatase that is > ULN but =< 2.5 x ULN or unexplained bone pain are eligible for inclusion in the study if a bone scan, PET-CT scan, or PET scan performed within 90 days prior to randomization does not demonstrate metastatic disease
20. Adequate renal function determined within 6 weeks prior to randomization defined as the most recent serum creatinine =< ULN or measured or calculated creatinine clearance > 60 mL/min
21. Left ventricular ejection fraction (LVEF) assessment must be performed within 90 days prior to randomization; (LVEF assessment performed by 2-dimensional [D] echocardiogram is preferred; however, multi gated acquisition [MUGA] scan may be substituted based on institutional preferences;) the LVEF must be >= 50% regardless of the cardiac imaging facility's lower limit of normal

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