Doxorubicin Hydrochloride, Cyclophosphamide, and Pacltaxel With or Without Trastuzumab in Treating Women With HER2-Positive Node-Positive or High-Risk Node-Negative Breast Cancer

• Status: Completed
• Trial end date: 2010-01-27
• Target enrollment: 0
• Participant gender: Female

Summary

This randomized phase III trial studies doxorubicin hydrochloride, cyclophosphamide, paclitaxel, and trastuzumab to see how well they work compared to combination chemotherapy alone in treating women with breast cancer that is human epidermal growth factor receptor 2 (HER2)-positive and has spread to the lymph nodes or high-risk and has not spread to the lymph nodes. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies such as trastuzumab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. It is not yet known whether combination chemotherapy is more effective with or without trastuzumab in treating breast cancer.

• Phase: Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: National Cancer Institute (NCI)
• Collaborators: Canadian Cancer Trials Group; Cancer and Leukemia Group B; Eastern Cooperative Oncology Group; Southwest Oncology Group
• Treatments: Albumin-Bound Paclitaxel; Antibodies; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Aromatase Inhibitors; Cyclophosphamide; Doxorubicin; Immunoglobulins; Liposomal doxorubicin; Paclitaxel; Tamoxifen; Trastuzumab; Trastuzumab biosimilar HLX02

Criteria

Inclusion Criteria:

• Required tumor parameters for node positive disease: NOTE: This study will continue to use the American Joint Committee on Cancer (AJCC) 5th edition for TNM classification and staging

• Operable, histologically confirmed adenocarcinoma of the female breast and positive lymph nodes

• Node positivity may be determined by either an axillary node dissection or a positive sentinel node finding by hematoxylin and eosin (H&E)

• NOTE: Positive nodes refers to H&E visible nodal metastases; immunohistochemistry (IHC) positive only cells in lymph nodes will not be considered positive nodes

• One or more positive lymph nodes whose tumors are T1-3, pN1-2, M0 are eligible

• cN2 disease is not eligible

• pN2 disease is eligible

• One positive lymph node by sentinel node biopsy or at least 6 axillary nodes must be examined on axillary node dissection with at least one positive lymph node

• Metaplastic carcinoma is eligible

• ER/PgR determination

• HER-2 positive (pre-entry requirement for registration)

• FISH must show gene amplification OR

• IHC assay must show a strong positive (3+) staining score

• NOTE: ductal carcinoma in situ (DCIS) components should not be counted in the determination of degree of IHC staining or FISH amplification

• Required tumor parameters for high-risk node-negative disease; NOTE: This study will continue to use the AJCC 5th edition for TNM classification and staging

• Operable, histologically confirmed adenocarcinoma of the female breast and negative lymph nodes

• Node status may be determined by either axillary node dissection or sentinel node biopsy with H&E staining; to be considered node negative, either of the following must be true: 1) negative sentinel node biopsy or 2) no positive lymph nodes found among at least 6 axillary nodes examined on axillary node dissection

• NOTE: IHC positive only cells in lymph nodes will not be considered positive nodes

• Tumors > 2.0 cm (irrespective of hormonal receptor status) or > 1.0 cm if ER-negative and PR-negative disease

• ER/PgR determination

• HER-2 positive (pre-entry requirement for registration)

• FISH must show gene amplification OR

• IHC assay must show a strong positive (3+) staining score

• NOTE: DCIS components should not be counted in the determination of degree of IHC staining or FISH amplification

• =< 84 days from mastectomy or =< 84 days from axillary dissection or sentinel node detection if the patient's most extensive breast surgery was a breast sparing procedure; (This timing is per a decision by the Breast Intergroup)

• Surgical resection margins. All tumor should be removed by either a modified radical mastectomy or a segmental mastectomy with axillary node dissection

• Mastectomy: There will be no evidence of gross or microscopic tumor (invasive or DCIS) at the surgical resection margins noted in the final surgery or pathology reports; patients with close margins are eligible

• Segmental mastectomy (lumpectomy): Margins must be clear of invasive cancer and DCIS

• Axillary dissection or sentinel node dissection: There will be no gross residual adenopathy

• TAM therapy

• May have received up to four weeks of TAM therapy, or any other hormonal agent, for this malignancy

• May have received TAM or raloxifene for purposes of chemoprevention (e.g., Breast Cancer Prevention Trial) or for other indications (including previous breast cancer if lobular carcinoma in situ [LCIS]) but must be discontinued before registration on this study

• May never have received TAM, raloxifene, or any other hormonal agent

• Absolute neutrophil count (ANC) >= 1500/mm^3

• Platelets (PLT) >= 100,000/mm^3

• Total bilirubin =< 1.5 x upper normal limit (UNL)

• Aspartate aminotransferase (AST) =< 2.0 x UNL

• Left ventricular ejection fraction (LVEF) within institutional normal range; if LVEF is > 75%, the investigator should consider performing a second review of the multigated acquisition (MUGA)/echocardiogram or performing a repeat MUGA/echocardiogram prior to registration; such re-reviews or repeat MUGA/echocardiogram are not permitted after registration

• Willingness to discontinue sex hormonal therapy, e.g., birth control pills, ovarian hormonal replacement therapy, etc., prior to registration and while on study

• Willingness to discontinue any hormonal agent such as raloxifene (Evista) prior to registration and while on study

• Non-breast malignancies that have not recurred within the last 5 years and are deemed to be at low risk for recurrence

EXCEPTIONS: These non-breast malignancies are eligible even if diagnosed =< 5 years prior to registration:

• Squamous or basal cell carcinoma of the skin that has been effectively treated

• Carcinoma in situ of the cervix that has been treated by surgery only

• Lobular carcinoma in situ (LCIS) of the ipsilateral or contralateral breast treated by surgery and/or tamoxifen only

• Patients undergoing breast conservation therapy (i.e., lumpectomy and axillary dissection) must have plans to receive radiation therapy to the breast +/- regional lymphatics following completion of the chemotherapy; for patients treated with mastectomy, the use of radiation therapy is required for 4 or more positive lymph nodes and must be started after completion of chemotherapy; the use of radiation therapy is at the discretion of the investigator for 0-3 positive lymph nodes but, if used, must be started after the completion of chemotherapy

• Prior to registration, the physician must designate if it is planned for the patient to receive radiation therapy (for adjuvant radiation therapy post-mastectomy or, less commonly, post-conservative therapy but not primary breast radiation as part of breast conserving treatment)

• Willing and able to sign an informed consent

• Gene amplified by FISH or strong positivity (3+) by HercepTest on central review; Note: The patient registers based on community HER-2 testing using FISH or IHC, AC chemotherapy is initiated; the tumor block or slides must be received =< 2 weeks from time of registration to the North Central Cancer Treatment Group (NCCTG) Operations Office for central HER-2 testing

Exclusion Criteria:

• Any of the following:

• Pregnant women

• Nursing women

• Women of childbearing potential or their sexual partners who are unwilling to employ adequate contraception (condoms, diaphragm, intrauterine device [IUD], surgical sterilization, or abstinence, etc.); hormonal birth control methods are not permitted

• Locally advanced tumors (classification T4) at diagnosis including tumors fixed to chest wall, peau d'orange, skin ulcerations/nodules, or clinical inflammatory changes (diffuse brawny cutaneous induration with an erysipeloid edge)

• Prior history of breast cancer, except LCIS

• Bilateral invasive carcinoma, either metachronous or synchronous (EXCEPTION: Patients diagnosed with unilateral invasive carcinoma and metachronous or synchronous DCIS of the contralateral breast treated with mastectomy are eligible)

• Prior chemotherapy, radiation therapy, immunotherapy, or biotherapy for breast cancer

• Active, unresolved infection

• Active cardiac disease

• Any prior myocardial infarction

• History of documented congestive heart failure (CHF)

• Current use of digitalis or beta-blockers for CHF

• Any prior history of arrhythmia or cardiac valvular disease requiring medications or clinically significant

• Current use of medications for treatment of arrhythmias or angina pectoris

• Current uncontrolled hypertension (diastolic > 100 mmHg or systolic > 200 mmHg)

• Clinically significant pericardial effusion

• Prior anthracycline or taxane therapy for any malignancy

• Sensitivity to benzyl alcohol

• Neurology/Neuropathy-Sensory >= grade 2 per the National Cancer Institute's (NCI's) Common Toxicity Criteria Version 2.0; EXCEPTION: Any chronic neurologic disorder will be looked at on a case-by-case basis by the study chair