• Disease-free survival [ Designated as safety issue: No ]
• Distant recurrence-free interval [ Designated as safety issue: No ]
• Recurrence-free interval [ Designated as safety issue: No ]
• Overall survival [ Designated as safety issue: No ]

• Disease-free survival
• Distant recurrence-free interval
• Recurrence-free interval
• Overall survival

RATIONALE: Estrogen can cause the growth of breast cancer cells. Hormone therapy may fight breast cancer by blocking the use of estrogen by the tumor cells or by lowering the amount of estrogen the body makes. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving hormone therapy together with more than one chemotherapy drug (combination chemotherapy) has been shown to reduce the chance of breast cancer recurrence, but the benefit of adding chemotherapy to hormone therapy for women with node-negative, estrogen-receptor positive breast cancer is small. New tests may provide information about which patients are more likely to benefit from chemotherapy.

PURPOSE: This randomized phase III trial is trying to find out the best individual therapy for women who have node-negative, estrogen-receptor positive breast cancer by using a special test (Oncotype DX), and whether hormone therapy alone or hormone therapy together with combination chemotherapy is better for women who have an Oncotype DX recurrence score of 11-25.

OBJECTIVES:

Primary

• Compare the disease-free survival of women with previously resected axillary-node negative breast cancer with an Oncotype DX Recurrence Score (ODRS) of 11-25 treated with adjuvant combination chemotherapy and hormonal therapy vs adjuvant hormonal therapy alone.
• Compare the distant recurrence-free interval, recurrence-free interval, and overall survival of patients with an ODRS of 11-25 treated with these regimens.
• Create a tissue and specimen bank that includes formalin-fixed, paraffin-embedded tumor specimens, tissue microarrays, plasma, and DNA obtained from peripheral blood of patients enrolled in this trial.

Secondary

• Determine if adjuvant hormonal therapy alone is sufficient treatment (i.e., 10-year distant disease-free survival of at least 95%) for patients with an ODRS of ≤ 10.
• Determine the disease-free survival, distant recurrence-free interval, recurrence-free interval, and overall survival of patients with ODRS of ≤ 10.
• Compare the outcomes projected at 10 years using classical pathologic information, including tumor size, hormone receptor status, and histologic grade, with those made by the Genomic Health Oncotype DX test in patients treated with these regimens.
• Estimate failure rates as a function of ODRS separately in patients treated with combination chemotherapy (group 2/arm II and group 3) and in patients treated with no chemotherapy (group 1 and group 2/arm I).
• Determine the prognostic significance of the ODRS and of the individual recurrent score gene groups (proliferation gene group, HER2 gene group, estrogen receptor gene group, invasion gene group, and other genes) in patients treated with these regimens.

OUTLINE: This is a multicenter, partially randomized study. Patients are assigned to 1 of 3 treatment groups based on their risk of distant recurrence determined by Oncotype DX Breast Cancer Assay.

• Group 1 (Secondary study group 1; Oncotype DX recurrence score [ODRS] < 11): Patients receive standard hormonal therapy (e.g., oral tamoxifen alone, oral aromatase inhibitor [e.g., anastrozole, letrozole, or exemestane] alone, or oral tamoxifen followed by oral aromatase inhibitor) at the discretion of the treating physician for 5 or 10 years.

• Group 2 (Primary study group; ODRS 11-25): Patients are stratified according to tumor size (≤ 2.0 cm vs ≥ 2.1 cm), menopausal status (postmenopausal vs premenopausal vs perimenopausal), planned chemotherapy (taxane-containing [i.e., paclitaxel, docetaxel] vs nontaxane-containing), planned radiotherapy (whole breast with no boost planned vs whole breast with boost planned vs partial breast irradiation planned vs no planned radiation therapy [for patients who have had a mastectomy]) and Oncotype DX Recurrence Score (11-15 vs 16-20 vs 21-25). Patients are then randomized to receive either hormonal therapy alone or combination chemotherapy and hormonal therapy.

  • Arm I (experimental): Patients receive hormonal therapy as in group 1 at the discretion of the treating physician.
  • Arm II (standard): Patients receive standard combination chemotherapy at the discretion of the treating physician. Within 4 weeks after the last dose of chemotherapy, patients receive hormonal therapy as in group 1 at the discretion of the treating physician.
• Group 3 (Secondary study group 2; ODRS > 25): Patients receive combination chemotherapy as in group 2, arm II followed by hormonal therapy as in group 1.

Patients in all groups who have had breast-conservation surgery are also treated with radiotherapy. Radiotherapy should begin within 4 weeks of registration for patients receiving hormonal therapy alone or within 8 weeks after completion of chemotherapy. Patients participating in NSABP and/or RTOG partial irradiation trial(s) may receive partial breast radiation.

Tissue obtained at surgery (performed prior to study entry) is examined by the Oncotype DX Recurrence Score Assay and other assays to correlate response with various biomarkers.

After completion of study treatment, patients are followed periodically for up to 20 years.

PROJECTED ACCRUAL: A total of 11,248 patients will be accrued for this study.

• Drug: anastrozole
• Drug: chemotherapy
• Drug: exemestane
• Drug: letrozole
• Drug: tamoxifen citrate

• Experimental: Patients in this group will receive hormone therapy with tamoxifen, anastrozole, letrozole, or exemestane by mouth for up to 5 years. Some patients will then continue to receive hormone therapy for an additional 5 years.
• Experimental: Patients in this group will be randomly assigned to receive either hormone therapy alone or combination chemotherapy and hormone therapy.
• Experimental: Patients receive hormonal therapy as in group 1 at the discretion of the treating physician.
• Active Comparator: Patients receive standard combination chemotherapy at the discretion of the treating physician. Within 4 weeks after the last dose of chemotherapy, patients receive hormonal therapy as in group 1 at the discretion of the treating physician.
• Experimental: Patients in this group will receive combination chemotherapy followed by hormone therapy similar to the patients in group two who are assigned to receive both types of treatment.

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the breast
• Hormone receptor status: estrogen and/or progesterone receptor positive tumor
• Her2/neu negative tumor by either fluorescent in situ hybridization (FISH) or immunohistochemistry (e.g., 0 or 1+ by DAKO Herceptest)

• Must have undergone surgery to remove the primary tumor by either a mastectomy or local excision plus an acceptable axillary procedure (i.e., sentinel lymph node biopsy and/or axillary dissection) within the past 84 days

  • Must have adequate (i.e., ≥ 1 mm, if margin width specified) tumor-free margins of resection for invasive and ductal carcinoma in situ

    • Lobular carcinoma in situ involving the resection margins are allowed
  • Negative axillary nodes as determined by a sentinel lymph node biopsy and/or axillary dissection as defined by the American Joint Committee on Cancer sixth edition staging system

• Tumor size 1.1-5.0 cm

  • Tumors that measure 5 mm-1.0 cm are allowed provided there are unfavorable histological features, defined as intermediate or poor nuclear and/or histologic grade or lymphovascular invasion

  • Pathologic tumor size should be used

    • If microscopic measurement is used and tumor includes ductal carcinoma in situ, the measurement should include only the invasive component of the tumor

• Tissue specimen from the primary tumor available for diagnostic testing with Oncotype DX to determine Oncotype Recurrence Score

  • No prior Oncotype DX Assay unless patient has a recurrence score of 11-25
• Patients who develop breast cancer while receiving a selective estrogen-receptor modulator (SERM) (e.g., tamoxifen, toremifene, or raloxifene) or an aromatase inhibitor (e.g., anastrazole, letrozole, or exemestane) for breast cancer prevention or a SERM for other indications (e.g., raloxifene for osteoporosis) are ineligible
• No prior ipsilateral or contralateral invasive breast cancer, bilateral synchronous cancers, or prior ipsilateral or contralateral ductal carcinoma in situ

PATIENT CHARACTERISTICS:

• Female only
• Any menopausal status allowed
• WBC count ≥ 3,500/mm^3
• Platelet count ≥ 100,000/mm^3
• Creatinine ≤ 1.5 mg/dL
• AST ≤ 3 times upper limit of normal
• Life expectancy ≥ 10 years
• No chronic obstructive pulmonary disease requiring treatment
• No chronic liver disease (e.g., cirrhosis or chronic active hepatitis)
• No history of cerebrovascular accident
• No history of congestive heart failure or other cardiac disease that would contradict the use of an anthracycline (e.g., doxorubicin hydrochloride or epirubicin)
• No chronic psychiatric condition or other condition that would preclude study compliance
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective nonhormonal contraception (e.g., intrauterine device, condoms, diaphragm, abstinence)
• No other invasive malignancies within the past 5 years except curatively treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No prior chemotherapy or radiotherapy (including MammoSite^® brachytherapy radiotherapy) for this cancer
• Prior SERM or aromatase inhibitor therapy that was administered for up to 8 weeks for this cancer is allowed
• No concurrent radiotherapy with chemotherapy
• Concurrent enrollment on another CTSU study allowed provided patient is already enrolled on ECOG-PACCT-1 and the treatment options in the other study are consistent with PACCT-1-specified treatment assignment (i.e., chemohormonal therapy or hormonal therapy alone)

• National Cancer Institute (NCI)
• Southwest Oncology Group
• Cancer and Leukemia Group B
• American College of Surgeons
• North Central Cancer Treatment Group
• NCIC Clinical Trials Group
• National Surgical Adjuvant Breast and Bowel Project (NSABP)