Genetic Testing or Clinical Assessment in Determining the Need for Chemotherapy in Women With Breast Cancer That Involves No More Than 3 Lymph Nodes

OBJECTIVES:

Primary

• Compare a molecular profiling approach (70-gene signature) vs usual clinical assessment in assigning adequate risk categories (and the need to receive adjuvant chemotherapy or not) to breast cancer patients with 0-3 positive lymph nodes.
• Compare the efficacy and long-term toxicities of docetaxel and capecitabine vs standard anthracycline-based chemotherapy regimens in these patients.
• Determine the best endocrine treatment strategy (i.e., letrozole for 7 years vs sequential tamoxifen for 2 years followed by letrozole for 5 years) in these patients.

Secondary

• Compare both relative (hazard ratio) and absolute (percentage at 5 years) efficacy of these regimens, in terms of disease-free survival (DFS), distant metastasis-free survival (DMFS), and overall survival (OS), in these patients.
• Determine overall estimates of efficacy (DFS, DMFS, OS) for each treatment strategy according to clinical-pathological prognosis and molecular prognosis in these patients.
• Estimate the percentage of patients receiving chemotherapy per each prognostic method.
• Identify predictive gene expression profiles of clinical response/resistance to anthracycline-based and docetaxel-capecitabine chemotherapy in these patients.
• Compare novel gene expression signatures predicting clinical response in patients treated with sequential tamoxifen-letrozole vs letrozole alone.
• Compare the OS distributions in patients treated with these regimens.
• Compare the early and late toxicities of these regimens in these patients.
• Evaluate adjuvant endocrine treatment success or failure in the subgroup of postmenopausal patients with endocrine-responsive disease.
• Compare the safety profile of these two endocrine therapy regimens in these patients.

OUTLINE: This is a partially randomized, open-label, prospective, multicenter study.

Patients with both clinical high-risk (CHR) and genomic high-risk (GHR) disease are assigned to receive chemotherapy. Patients with both clinical low-risk (CLR) and genomic low-risk (GLR) disease do not receive chemotherapy. Patients with discordant risk between the 2 decision-making tools (standard clinical-pathological criteria vs 70-gene signature criteria) are randomized to receive chemotherapy or not. Patients with HER-2 positive tumors which have both methods discordant and were randomized to no chemotherapy, can receive adjuvant trastuzumab alone or with adjuvant endocrine therapy (if hormonal receptor positive), if decided by the treating physician. Patients with HER-2 positive tumors that are classified low-risk by both methods can receive adjuvant trastuzumab alone or with adjuvant endocrine therapy (if hormonal receptor positive), if decided by the treating physician and if no issues for trastuzumab reimbursement exist in the investigator's country.

• Chemotherapy: Patients are stratified according to participating center, risk group (GHR/CLR vs GLR/CHR), hormone receptor status (estrogen receptor [ER] positive and/or progesterone receptor [PR] positive vs ER and PR negative), age (< 50 years vs at least 50 years), HER2/neu status (positive vs negative vs unknown), method of axillary evaluation (sentinel only vs dissection), and type of surgery (mastectomy vs quadrantectomy/tumorectomy). In case PR is unknown, the patient will be stratified to the hormone receptor (HR) negative group if ER is negative, and to the HR positive group if ER is positive.

Three randomizations took place:

• One randomization on the discordant groups (where clinical risk did not match genomic risk) in treatment decision (R-T).
• One randomization for patients who are candidates for chemotherapy (R-C): randomization between anthracycline based chemotherapy and taxane/capecitabine chemotherapy.
• One randomization for patients who are candidates for endocrine therapy (R-E): randomization between 2 years of tamoxifen followed by 5 years of letrozole and 7 years of letrozole.

For the treatment decision randomization, patients for whom both methods are discordant will be randomized (R-T) between chemotherapy-decision-making according to clinical criteria (using Adjuvant! Online) or chemotherapy-decision-making according to genomic prognosis using the 70-gene signature.

For the chemotherapy randomization, patients are randomized to 1 of 2 treatment arms.

• Arm I (anthracycline-based): Patients may receive 1 of the following regimens*:

• FEC 100: Patients receive fluorouracil IV, epirubicin hydrochloride IV, and cyclophosphamide IV on day 1. Treatment repeats every 3 weeks for 6 courses.
• Canadian CEF: Patients receive oral cyclophosphamide on days 1-14 (or IV on days 1 and 8) and epirubicin hydrochloride IV and fluorouracil IV on days 1 and 8. Treatment repeats every 4 weeks for 6 courses.
• CAF: Patients receive cyclophosphamide IV, doxorubicin hydrochloride IV, and fluorouracil IV on day 1. Treatment repeats every 4 weeks for 6 courses.
• FAC: Patients receive cyclophosphamide IV and doxorubicin hydrochloride IV on day 1 and fluorouracil IV on days 1 and 8. Treatment repeats every 3 weeks for 6 courses.
• E-CMF: Patients receive epirubicin hydrochloride IV on day 1. Treatment repeats every 3 weeks for 4 courses. Patients then receive cyclophosphamide IV, methotrexate IV, and fluorouracil IV on days 1 and 8. Treatment repeats every 4 weeks for 4 courses.

NOTE: *Patients who refuse randomization may be treated with another chemotherapy regimen and still be included in the study.

• Arm II (docetaxel and capecitabine): Patients receive docetaxel IV over 1 hour on day 1 and oral capecitabine twice daily on days 1-14. Treatment repeats every 3 weeks for 6 courses.

For the endocrine therapy randomization (all postmenopausal and some premenopausal** patients who have endocrine-responsive tumors***): Patients are stratified according to participating center, risk group (GHR/CHR vs GHR/CLR vs GLR/CHR vs GLR/CLR), adjuvant chemotherapy (no vs nonrandomized vs arm I vs arm II), endocrine sensitivity (both ER and PR positive vs either ER or PR positive), age (< 50 years vs at least 50 years), HER2/neu status (positive vs negative vs unknown), method of axillary evaluation (sentinel only vs dissection), and type of surgery (mastectomy vs quadrantectomy/tumorectomy). In case PR is unknown, the patient will be stratified to the HR negative group if ER is negative, and to the HR positive group if ER is positive.

Therapy begins after prior surgery in patients who did not receive chemotherapy and after chemotherapy in those who did. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral tamoxifen citrate once daily for 2 years. Patients then receive oral letrozole once daily for 5 years.
• Arm II: Patients receive oral letrozole once daily for 7 years. NOTE: *The first dose of endocrine therapy should be administered within 4 weeks following the randomization (R-E) date. If treatment has not started within 300 days after definitive surgery, the patient becomes ineligible for randomized endocrine therapy.

NOTE: **Premenopausal women (< 50 years) must undergo adequate ovarian suppression (gonadotropin releasing hormone, bilateral oophorectomy, or bilateral ovarian radiation).

NOTE: ***Patients who have endocrine-responsive tumors but refuse randomization should receive standard endocrine therapy and may remain on study.

After completion of study treatment, patients are followed annually for at least 15 years.

FINAL ACCRUAL: A total of 6,694 patients have been accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically confirmed invasive breast cancer meeting the following criteria:

• T1, T2, or operable T3 disease
• Zero to three positive lymph nodes and no distant metastases
• Unilateral tumor

• Multifocal tumors are allowed provided that they have identical histology
• Ductal carcinoma in situ or lobular carcinoma in situ allowed
• Operable disease

• Must have undergone breast-conserving surgery or mastectomy with either a sentinel node procedure or full axillary clearance

• Radiotherapy is mandatory in the case of breast-conserving surgery
• Unresectable positive deep margins and will receive adjuvant radiotherapy provided that all other margins negative allowed
• Patients eligible for inclusion in the chemotherapy randomization must meet one of the following criteria:

• High-risk of recurrence according to both the clinical-pathological criteria and the 70-gene signature
• High risk of recurrence according to the clinical-pathological criteria and low-risk of recurrence according to the 70-gene signature and are randomized to use the clinical-pathological criteria for chemotherapy decision
• Low-risk of recurrence according to the clinical-pathological criteria and high-risk of recurrence according to the 70-gene signature and are randomized to use the 70-gene signature for chemotherapy decision
• Patients eligible for inclusion in the endocrine therapy randomization must meet all of the following criteria:

• Endocrine-responsive disease
• Hormone receptor-positive disease (estrogen receptor-positive, progesterone receptor-positive, or both)

PATIENT CHARACTERISTICS:

• Female
• WHO performance status 0-1
• Neutrophil count > 1,500/mm^3
• Platelet count > 100,000/mm^3
• Creatinine clearance at least 50 mL/min OR creatinine up to 1.5 times upper limit of normal (ULN)
• ALT and AST up to 2.5 times ULN
• Alkaline phosphatase up to 2.5 times ULN
• Bilirubin up to 2.0 times ULN
• Normal echocardiogram (ECHO) compatible with chemotherapy treatment
• No serious cardiac illness or medical condition including, but not limited to, any of the following:

• History of documented congestive heart failure
• High-risk uncontrolled arrhythmias
• Angina pectoris requiring antianginal medication
• Clinically significant valvular heart disease
• Evidence of transmural infarction on ECG
• Poorly controlled hypertension (e.g., systolic blood pressure [BP] > 180 mm Hg or diastolic BP > 100 mm Hg)
• Symptomatic coronary artery disease or a myocardial infarction within the past 12 months
• Other risk factors that contraindicate the use of anthracycline-based chemotherapy
• No serious uncontrolled infection or other serious uncontrolled disease
• No other cancer within the past 5 years except for adequately treated carcinoma in situ of the cervix, nonmelanoma skin cancer, lobular or ductal carcinoma in situ of the breast, or any invasive cancer (other than breast cancer)
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective barrier contraception
• No psychological, familial, sociological, or geographical condition that would preclude study treatment
• No psychiatric disability
• No history of uncontrolled seizures or CNS disorders
• Patients eligible for inclusion in the chemotherapy randomization must meet all of the following additional criteria:

• LVEF normal by ECHO or MUGA
• No prior severe hypersensitivity reaction to drugs formulated with polysorbate 80
• Must have physical integrity of the upper gastrointestinal tract
• Able to swallow tablets
• No malabsorption syndrome
• No prior thromboembolic disorder, deep vein thrombosis, or pulmonary emboli (for patients eligible for inclusion in the endocrine therapy randomization)

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No prior neoadjuvant chemotherapy, neoadjuvant endocrine therapy, or radiotherapy for primary breast cancer
• No participation in another investigational drug study within the past 4 weeks
• No systemic hormone replacement therapy (with or without progestins) for more than 3 months in duration
• Patients eligible for inclusion in the chemotherapy randomization must meet all of the following additional criteria:

• Interval between definitive surgery and start of chemotherapy 8-18 weeks
• No prior organ allografts requiring immunosuppressive therapy
• No concurrent sorivudine or chemically related analogues, such as brivudine
• Patients eligible for inclusion in the endocrine therapy randomization must meet all of the following additional criteria:

• No prior high-dose systemic corticosteroids (except as antiemetic treatment), immunotherapy, or biological response modifiers (e.g., interferon)
• No prior adjuvant antiestrogen therapy for > 1 month immediately after surgery, radiotherapy, and/or chemotherapy
• No hormone replacement therapy within the past 4 weeks
• No antiestrogens (e.g., tamoxifen or raloxifen) as chemoprevention or osteoporosis treatment for breast cancer within the past 18 months
• No concurrent primary prophylaxis with filgrastim (G-CSF), sargramostim (GM-CSF), or pegfilgrastim
• No other concurrent treatment during endocrine therapy, including the following:

• Anticancer therapy (anti-estrogens, aromatase inhibitors, chemotherapy)
• Investigational agents
• Raloxifene or other selective estrogen-receptor modulators
• Hormonal contraceptives (including depot injections and implants)

• Intrauterine devices, including progesterone-coated, allowed
• Oral or transdermal hormonal treatments, including estrogen, progesterone, androgen, or aromatase inhibitor

• Local vaginal (topical) estrogens with minimal systemic absorption allowed for severe vaginal dryness/dyspareunia
• Concurrent bisphosphonates allowed