Tamoxifen in Treating Women With High-Risk Breast Cancer
Tamoxifen in Treating Women With High-Risk Breast Cancer
RATIONALE: Estrogen can stimulate the growth of breast cancer cells. Hormone therapy using
 tamoxifen may fight breast cancer by blocking the uptake of estrogen. Chemotherapy uses
 different ways to stop tumor cells from dividing so they stop growing or die.

 PURPOSE: Phase III trial to study the effectiveness of tamoxifen following surgery and
 chemotherapy in treating women who have stage I breast cancer at high risk of recurrence or
 stage II or stage III breast cancer.
OBJECTIVES: I. Compare the duration of overall survival and disease-free survival in
 premenopausal women with operable, high risk node negative or axillary node-positive breast
 cancer who have undergone complete surgical resection of all known disease by means of total
 or partial mastectomy, and have received standard adjuvant chemotherapy with
 cyclophosphamide, methotrexate, and fluorouracil (CMF), cyclophosphamide, epirubicin, and
 fluorouracil (CEF), or doxorubicin and cyclophosphamide (AC) followed by either daily
 tamoxifen for 5 years or placebo. II. Compare the short- and long-term toxicity in patients
 receiving tamoxifen versus placebo. III. Monitor follicle-stimulating hormone, luteinizing
 hormone, and estradiol levels, and determine whether overall survival and disease-free
 survival are affected by hormonal or menopausal status during or at completion of adjuvant
 chemotherapy or during or after tamoxifen or placebo treatment in these patients.

 OUTLINE: This is a randomized, double blind study. Patients are stratified by adjuvant
 chemotherapy regimen (cyclophosphamide, epirubicin, and fluorouracil vs cyclophosphamide,
 methotrexate, and fluorouracil vs cyclophosphamide and doxorubicin), hormone receptor status
 (ER and/or PR positive vs ER and PR negative), number of positive nodes (1-3 vs 4-9 vs 10 or
 more), and participating institution. Patients receive one of three regimens of adjuvant
 chemotherapy at the discretion of the investigator. Regimen A: Patients receive oral
 cyclophosphamide on days 1-14 and epirubicin IV and fluorouracil IV on days 1 and 8. Courses
 repeat every 28 days for a total of 6 courses. Following chemotherapy, lumpectomy patients
 receive local radiotherapy daily for 5 weeks. Regimen B: Patients receive oral
 cyclophosphamide on days 1-14 or cyclophosphamide IV on day 1 and 8, methotrexate on days 1
 and 8, and fluorouracil IV on days 1 and 8. Courses repeat every 28 days for a total of 6
 courses. Concurrent with or following chemotherapy, lumpectomy patients receive local
 radiotherapy daily for 5 weeks. Regimen C: Patients receive doxorubicin IV and
 cyclophosphamide IV every 21 days for a total of 4 courses. Following chemotherapy,
 lumpectomy patients receive local radiotherapy daily for 5 weeks. Patients are then
 randomized to receive either oral tamoxifen or a placebo once daily for 5 years, beginning
 within 6 weeks of completion of chemotherapy. Treatment continues in the absence of disease
 progression or unacceptable toxicity. Patients are followed for survival.

 PROJECTED ACCRUAL: A total of 800 patients will be accrued for this study over 4 years.
DISEASE CHARACTERISTICS: Adenocarcinoma of the breast with 1 or more histologically proven
 positive axillary nodes OR Adenocarcinoma of the breast with negative axillary nodes or
 adverse prognostic factors such that the patient is at high risk for recurrence and node
 negative lesion is characterized by the following features: Tumor at least 1 cm Poorly
 differentiated, SBR grade III, or MSBR grade V and/or lymphatic/vascular invasion
 Pathologic review by experienced breast pathologist recommended if grade is unspecified and
 lymphatic/vascular invasion is absent Disease considered potentially curable and treated by
 1 of the following: Complete surgical removal of the breast plus axillary node dissection
 Partial surgical removal of the breast plus axillary node dissection, with the intention of
 giving breast irradiation following completion of an adjuvant chemotherapy regimen Regional
 nodal or chest wall irradiation not prohibited but strongly discouraged No evidence of
 residual tumor in the axilla following dissection No microscopic evidence of residual tumor
 at the resection margins following total mastectomy Further excision highly recommended if
 there is microscopic residual disease present at partial mastectomy margins If further
 excision is not undertaken, a radiotherapy boost to the tumor bed is required in addition
 to breast irradiation given following protocol chemotherapy Disease clinically staged prior
 to surgery as T1-T3a, N0-2, M0 No clinical T4 disease, i.e.: No extension to the chest wall
 No edema (including peau d'orange) No skin ulceration No satellite skin nodules confined to
 the same breast No inflammatory carcinoma Disease pathologically staged following surgery
 as TNM stage I, II, or III (T0-4; N0-2; M0) T4 allowed only with dermal involvement on
 pathology assessment No evidence of metastatic disease beyond the homolateral axillary
 nodes on pre-chemotherapy chest x-ray, bone scan (with radiographs of suspicious areas),
 and abdominal ultrasound (required only if bilirubin, alkaline phosphatase, or AST/ALT are
 elevated) Simultaneous bilateral breast carcinoma allowed Complete tumor resection on both
 breasts required Axillary dissection on both sides must meet criteria as above if both
 sides are clinically node-positive Axillary dissection on the second side optional if the
 axilla is clinically negative at the time of surgery and the other side is node-positive
 Adjuvant chemotherapy must begin within 14 weeks of initial pathologic diagnosis Hormone
 receptor status: Any receptor level allowed (values must be available if biochemical method
 used; immunocytochemical assay permitted)

 PATIENT CHARACTERISTICS: Age: Not specified Sex: Female Menopausal status: Pre- or
 perimenopausal, i.e., meeting at least 1 of the following criteria: Normal menstruation
 Amenorrhea for less than 1 year (up to 3 years in patients under age 52) Biochemical
 evidence of ovarian function Hysterectomy without bilateral oophorectomy in patients under
 age 56 Premenopausal women no greater than age 50 who were started on replacement hormone
 therapy before amenorrhea are eligible Performance status: ECOG 0-2 prior to chemotherapy
 Hematopoietic: WBC at least 3,000/mm3 Polymorphs and bands at least 1,500/mm3 Platelet
 count at least 100,000/mm3 Hepatic: (unless abdominal ultrasound indicates liver
 metastasis) Alkaline phosphatase no greater than 2 times normal AST and/or ALT no greater
 than 2 times normal Renal: Not specified Other: No history of serious underlying medical
 illness or psychiatric or addictive disorder No second malignancy within 5 years except:
 Curatively treated nonmelanomatous skin cancer Curatively treated endometrium, colon, or
 thyroid cancer or carcinoma in situ of the cervix No plan for pregnancy during the 5-year
 study period Fertile women must use effective contraception (other than oral contraception)
 Accessible for treatment and follow-up

 PRIOR CONCURRENT THERAPY: Biologic therapy: Colony-stimulating factors allowed (use must be
 documented) Chemotherapy: No prior chemotherapy No concurrent other cytotoxic therapy
 Endocrine therapy: Adjuvant tamoxifen (20 mg po daily) allowed up to 2 weeks before or
 during adjuvant chemotherapy provided drug is discontinued at randomization No long-term
 prednisone or other hormones Radiotherapy: See Disease Characteristics Surgery: See Disease
 Characteristics