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.