7. Adjuvant Systemic Therapy

7.1 Study of Tamoxifen in the Prevention of Skeletal and Cardiovascular Morbidity of Adjuvant Chemotherapy in Premenopausal Women with Stage I or II Breast Cancer

Objectives

I. Compare the bone density in the femoral neck and lumbar spine and cholesterol levels in premenopausal women with stage I or II breast cancer treated with adjuvant chemotherapy with or without tamoxifen.

II. Collect information regarding breast cancer risk factors, treatment, pathology, diet, activity levels, weight, and smoking in these patients.

Participation Criteria

• Age: 35 to 50.
  
  
• Menopausal status: Premenopausal by follicle stimulating hormone and estradiol levels.
  
  
• Hormone receptor status: Not specified.
  
  
• Histologically proven stage I or II breast cancer.
  
  
• Must be scheduled to receive adjuvant chemotherapy with or without tamoxifen.

Protocol

Patients receive adjuvant chemotherapy with or without oral tamoxifen at the discretion of the treating physician.

Prior to starting chemotherapy, patients undergo blood draw to measure baseline levels of follicle stimulating hormone, estradiol, total cholesterol, high density lipoproteins, and low density lipoproteins. Patients undergo baseline bone scan of the femoral neck and lumbar spine to assess bone density prior to starting chemotherapy or within 30 days of the first drug treatment. Laboratory studies and bone scan are repeated at years 1 and 2. A comparison is made between the study findings at baseline and at years 1 and 2.

Monica Morrow, Chair Principal Investigator
Ph: 312-926-9039 Robert H. Lurie Comprehensive Cancer Center Northwestern University

7.2 Phase III Randomized Study of Wide Local Excision Alone Versus Wide Local Excision Followed by Radiotherapy with or without Tamoxifen Versus Wide Local Excision Plus Tamoxifen in Patients with Stage I Breast Cancer

Protocol

Objectives

I. Compare the effectiveness of wide local excision alone versus wide local excision followed by radiotherapy with or without tamoxifen versus wide local excision plus tamoxifen in patients with stage I breast cancer.

II. Assess local occurrence in the treated breast, regional recurrence, distant recurrence, death from breast cancer, and occurrence of cancer in the opposite breast in these patients when treated with one of these regimens.

Participation Criteria

• Age: Under 70
  
  
• Histologically confirmed unilateral stage I invasive breast cancer.
  
  
• No more than 1 tumor and no greater than 2 cm.
  
  
• Grade 1 tumor of any histological type OR No special type OR Mixed type allowed.
  
  
• No lymph node involvement.
  
  
• No in situ carcinoma only or ductal carcinoma in situ with microinvasion.
  
  
• No vascular invasion.
  
  
• No Paget's disease of the nipple.
  
  
• Well-differentiated special type of primary mammary carcinoma including: tubular, tubular/cribriform, cribriform, papillary, mucoid.
  
  
• No lobular, medullary, or other rarer types of mammary carcinomas including: adenoid cystic, carcinoid, secretory, spindle cell, apocrine.
  
  
• No other concurrent adjuvant systemic therapy.

Protocol

Outline All patients undergo wide local excision of the tumor and axillary node dissection.

R.W. Blamey, Chair Principal Investigator
Ph: 115 969 1169 British Association of Surgical Oncology: Breast Group Nottingham City Hospital NHS Trust Nottingham, England, United Kingdom

7.3 Phase III Randomized Study of Medroxyprogesterone Acetate and Observation for Prevention of Endometrial Pathology in Patients with Postmenopausal Breast Cancer Treated with Adjuvant Tamoxifen

Objectives

I. Compare endometrial pathologic diagnoses (in particular, proliferative changes, simple or cystic hyperplasia, complex adenomatous hyperplasia, hyperplasia with atypia and carcinoma) for postmenopausal, tamoxifen- treated breast carcinoma patients randomly assigned to observation or cyclical medroxyprogesterone acetate (MA).

II. Compare endometrial pathologic diagnoses resulting in tamoxifen discontinuation (persistent endometrial hyperplasia, atypia or carcinoma) and intermittent bleeding in breast cancer patients receiving tamoxifen and randomized to observation or cyclical MA.

III. Characterize the incidence of spontaneous regression and progression of simple or cystic hyperplasia in these patients.

IV. Characterize endometrial biopsy results using different endometrial stripe width cut-off points, for cases in which the width is at least 5 mm by endovaginal ultrasound for women receiving tamoxifen.

V. Compare changes over time in endometrial oncogene expression (e.g., c-fos, c-jun, p53, IGF1) and receptor status for postmenopausal tamoxifen-treated breast carcinoma patients with or without prior chemotherapy randomly assigned to MA vs observation.

VI. Describe associations among change in gene expression, receptor status, endometrial abnormality, length of tamoxifen exposure, and prior chemotherapy for these patients.

VII. Determine the feasibility of collecting centrally frozen tissue hysterectomy specimens from tamoxifen-treated breast carcinoma patients for the purpose of analyzing the regulation of 17 beta-hydroxysteroid dehydrogenase activity in endometrial tissue.

VIII. Establish a national repository of paraffin blocks and frozen endometrial tissue from tamoxifen- treated breast cancer patients.

Participation Criteria

• Postmenopausal defined as:
  
  
  • At least 1 year since menstrual period
    
    
  • At least 2 months since bilateral oophorectomy prior to breast cancer diagnosis
    
    
  • 4-12 months since menstrual period and FSH elevated to postmenopausal range
    
    
• Postmenopausal estrogen therapy and 55 years of age or older.
  
  
• Hormone receptor status: Candidate for adjuvant tamoxifen therapy.
  
  
• Histologically proven primary invasive adenocarcinoma of the breast.
  
  
• Stage I, IIA, or IIB (T1-3, N0-1, M0).
  
  
• No recurrent invasive breast cancer OR ductal carcinoma in situ OR lobular carcinoma in situ with microinvasion OR Paget's disease of the nipple.
  
  
• Prior definitive local treatment of primary lesion (mastectomy or breast-sparing procedure with radiotherapy) and either axillary node or sentinel node biopsy.
  
  
• Biopsy requirement waived for ductal or lobular carcinoma in situ with minimal microinvasion.
  
  
• Patients with breast-sparing procedure must have received or be planning to receive radiotherapy at start of tamoxifen treatment.
  
  
• No endometrial hyperplasia, proliferative changes, complex (adenomatous) or atypical hyperplasia, or carcinoma.
  
  
• Patients must be planning one of the following: Starting adjuvant tamoxifen for five years OR Started tamoxifen within 28 days prior to study and be planning to receive adjuvant tamoxifen for five years.
  
  
• Adjuvant chemotherapy allowed.
  
  
• No concurrent chemotherapy.
  
  
• No prior hormonal treatment (except tamoxifen).
  
  
• No concurrent postmenopausal estrogen therapy.
  
  
• No prior or concurrent hysterectomy.

Randomization

Ronald Keith Potkul, Chair
Ph: 708-327-3314 Southwest Oncology Group

7.4 Women's Intervention Nutrition Study (WINS): Randomized Study to Determine the Efficacy of Dietary Fat Reduction in Addition to Conventional Systemic Adjuvant Therapy in Postmenopausal Women Surgically Treated for Primary Invasive Breast Cancer

Objectives

I. Determine whether dietary fat reduction will effectively prolong disease-free and overall survival in women surgically treated for early stage breast cancer who are receiving adjuvant therapy with or without either tamoxifen, cyclophosphamide, methotrexate, fluorouracil (CMF), doxorubicin, cyclophosphamide (AC), fluorouracil, doxorubicin, cyclophosphamide (FAC, CAF), or AC followed by paclitaxel.

II. Evaluate whether differences in the lipid profile are associated with dietary group assignment and dietary fat.

Participation Criteria

• Age: 48 to 78.
  
  
• Menopausal status: Postmenopausal.
  
  
• Hormone receptor status: Any estrogen receptor (ER) or progesterone receptor (PR) status allowed. ER assessment required, PR assessment recommended.
  
  
• Histologically proven, invasive, localized carcinoma of the breast.
  
  
• Stage I/II/IIIA disease, i.e.: tumor confined to breast on clinical examination.
  
  
• Overlying skin movable with respect to tumor.
  
  
• Tumor movable in relation to underlying muscle and chest wall. Tumor size requirements: No greater than 5 cm if lymph nodes are positive. Greater than 1 cm if lymph nodes are negative.
  
  
• Tumor definitively treated by one of the following procedures:
  
  
  • Total mastectomy with axillary node dissection
    
    
  • Segmental mastectomy with or without axillary node dissection and/or sentinel node biopsy followed by breast irradiation, provided:
    ¥ Surgical margins are histologically free of invasive or noninvasive tumor with one additional resection allowed to obtain clear margins.
    
    
  • Total mastectomy required if clear margins are not obtained at second resection.
    
    
• The following conditions exclude:
  
  
  • Bilateral malignancy or any mass in the contralateral breast unless proven nonmalignant by biopsy.
    
    
  • Palpable lymph nodes in the contralateral axilla or probable supraclavicular or infraclavicular nodal involvement unless proven nonmalignant by biopsy.
    
    
  • 10 or more positive lymph nodes.
    
    
  • Inflammatory breast cancer. l Ulceration or erythema.
    
    
  • Infiltration of the skin or peau d'orange. Tethering or dimpling of the skin or nipple inversion should not be considered skin infiltration.
    
    
  • Satellite breast nodules.
    
    
  • Parasternal nodules.
    
    
  • Edema of the arm.
    
    
• Less than 365 days between definitive surgery and randomization.
  
  
• Concurrent adjuvant cyclophosphamide, methotrexate, fluorouracil (CMF), doxorubicin, cyclophosphamide (AC), AC followed by paclitaxel, or fluorouracil/doxorubicin/ cyclophosphamide (FAC, CAF) allowed.
  
  
• If ER-negative, approved chemotherapy regimen and/or tamoxifen required.
  
  
• No more than 120 days between definitive surgery and initiation of adjuvant systemic chemotherapy.
  
  
• Concurrent adjuvant tamoxifen required if ER- positive (if ER negative, tamoxifen and/or an approved chemotherapy regimen required).
  
  
• No more than 180 days between definitive surgery and initiation of tamoxifen (if receiving tamoxifen alone).
  
  
• If receiving adjuvant CMF, AC, or FAC, CAF, or AC, paclitaxel, tamoxifen begins after completion of adjuvant therapy.
  
  
• Radiotherapy required within 56 days following segmental mastectomy.
  
  
• Definitive surgery required.

Randomization

Daniel W. Nixon
Chair Principal Investigator Ph: 212-551-2502 American Health Foundation New York, New York 7.5

Phase III Randomized Study of Zoledronate as Adjuvant Therapy in Patients with Stage I, II, or IIIA Nonmetastatic Breast Cancer

Objectives

I. Compare disease-free and overall survival in patients with stage I, II, or IIIA nonmetastatic breast cancer treated with standard adjuvant therapy and zoledronate to those treated with standard adjuvant therapy alone (observation only).

II. Assess whether zoledronate added to standard adjuvant therapy influences the first site of recurrence in these patients.

III. Compare the first site of recurrence in PTHrP positive patients with the first site of recurrence in PTHrP negative patients in the group not receiving zoledronate.

IV. Explore whether treatment effects are different within the PTHrP positive and PTHrP negative subsets.

Participation Criteria

• Age: Not specified.
  
  
• Menopausal status: Not specified.
  
  
• Hormone Receptor Status: Not specified.
  
  
• Histologically confirmed stage I, II, or IIIA primary invasive adenocarcinoma of the breast.
  
  
• No evidence of metastatic disease.
  
  
• Must have undergone modified radical mastectomy or breast-sparing surgery plus either axillary node dissection or sentinel node biopsy.
  
  
• Prior or concurrent standard systemic adjuvant therapy required.
  
  
• Prior neoadjuvant chemotherapy allowed.
  
  
• Combined hormonal/chemotherapy allowed.
  
  
• Combined hormonal/chemotherapy or hormonal therapy alone allowed.
  
  
• Concurrent radiotherapy to breast/chest wall/lymph node groups allowed.

Randomization

Charles A. Coltman
Jr., Chair Ph: 210-616-5580 Southwest Oncology Group University of Colorado Cancer Center Denver, Colorado

7.6 NCI HIGH-PRIORITY CLINICAL TRIAL: Phase III Randomized Study of Intensive Sequential Doxorubicin, Paclitaxel, and Cyclophosphamide Versus Doxorubicin and Cyclophosphamide Followed By STAMP I or STAMP V Combination Chemotherapy with Autologous Stem Cell Rescue in Women with Primary Breast Cancer and At Least 4 Involved Axillary Lymph Nodes

Objectives

I. Compare disease-free survival and overall survival in women with operable breast cancer and at least 4 positive axillary lymph nodes treated with intensive sequential chemotherapy with doxorubicin, paclitaxel, and cyclophosphamide versus standard dose doxorubicin and cyclophosphamide followed by high dose STAMP I (cyclophosphamide, cisplatin, and carmustine) or STAMP V (cyclophosphamide, carboplatin, and thiotepa) and autologous stem cell rescue.

II. Compare the toxic effects of these regimens in this patient population.

III. Measure the breast cancer cell content of the peripheral blood progenitor cell (PBPC) fractions from patients randomized to the PBPC supported arm and correlate the results with the disease-free survival, survival, and pattern of relapse in these patients.

Participation Criteria

• Concurrent registration on S9719.
  
  
• Histologically proven adenocarcinoma of the breast with at least 4 involved axillary and/or intramammary lymph nodes.
  
  
• No known T4, N3, or M1 disease.
  
  
• Dermal lymphatic involvement without clinical inflammatory changes (edema, peau d'orange, erythema) allowed.
  
  
• Must have undergone breast-conserving surgery or modified radical mastectomy plus axillary lymph node dissection.
  
  
• Surgical margins negative for invasive or noninvasive ductal carcinoma.
  
  
• At least 10 nodes sampled.
  
  
• No more than 12 weeks since definitive surgery.
  
  
• Synchronous bilateral breast carcinoma allowed if:
  
  
  • Diagnosed within 4 weeks of initial histologic diagnosis.
    
    
  • One breast meets the eligibility criteria.
    
    
  • Other breast has fewer than 10 involved nodes and is not N3 or T4.
    
    
  • Both breasts treated by modified radical mastectomy or breast-conserving surgery with axillary node dissection.
    
    
  • No prior hormonal therapy for breast cancer.
    
    
  • No prior radiotherapy to the breast.

Randomization

Harvest:

Patients undergo harvest of autologous bone marrow and/or peripheral blood stem cells (PBSC). Patients who undergo harvest of PBSC alone do not receive mobilization chemotherapy but receive hematopoietic growth factors prior to harvest. High dose myeloablative chemotherapy:
Patients receive STAMP I OR STAMP V:

STAMP I:
Patients receive cyclophosphamide IV over 1 hour and cisplatin IV over 24 hours on days -6 to -4 and carmustine IV over 2 hour on day -3.
STAMP V:
Patients receive cyclophosphamide IV over 24 hours, carboplatin IV over 24 hours, and thiotepa IV over 24 hours on days -7 to -4.

Transplantation:
Autologous bone marrow and/or PBSC are reinfused on day 0.
Both arms:
Patients who are postmenopausal or who have hormone receptor-positive disease receive oral tamoxifen daily beginning 4 weeks after the completion of chemotherapy and continuing for 5 years. Patients who underwent breast-conserving surgery receive locoregional radiotherapy 5 days a week for 4.5-5.5 weeks beginning 4-6 weeks after the completion of chemotherapy. Patients who underwent modified radical mastectomy may receive locoregional radiotherapy 5 days a week for 5 weeks at the discretion of their physician.

Scott I. Bearman, Chair Principal Investigator
Ph: 303-372-9000 Southwest Oncology Group University of Colorado Cancer Center Denver, Colorado

7.7 Phase III Randomized Study of Adjuvant Doxorubicin and Cyclophosphamide Followed by Docetaxel Versus Doxorubicin and Docetaxel Versus Doxorubicin, Docetaxel, and Cyclophosphamide in Women with Breast Cancer and Positive Axillary Nodes

Objectives

I. Compare adjuvant doxorubicin, cyclophosphamide, and docetaxel given concurrently versus adjuvant doxorubicin and cyclophosphamide followed by docetaxel in prolonging overall survival and disease-free survival of breast cancer patients with positive axillary lymph nodes.

II. Compare adjuvant doxorubicin and docetaxel versus regimens containing cyclophosphamide in these patients.

III. Compare the toxicities of these three regimens in these patients.

IV. Compare the quality of life of these patients treated with one of these three regimens.

V. Compare the differences in amenorrhea in premenopausal women in each treatment arm and its relationship to symptoms, quality of life, disease-free survival, and overall survival. Participation Criteria

• Hormone receptor status: estrogen and progesterone status known.
  
  
• Invasive adenocarcinoma of the breast confined to the breast and ipsilateral axilla on clinical exam. Stage I, II, or IIIA (T1-3, N0-1, M0).
  
  
• Spread to at least one axillary lymph node. Sentinel node biopsy allowed if followed by axillary dissection. No suspicious palpable nodes in the contralateral axilla or palpable supraclavicular or infraclavicular nodes, unless proven on biopsy to not be involved with tumor.
  
  
• No bilateral malignancy or mass in the opposite breast, unless mass histologically proven to be benign.
  
  
• Must have undergone either a total mastectomy and axillary dissection (modified radical mastectomy) OR lumpectomy and axillary dissection.
  
  
• Patients must receive radiotherapy after randomization (not before).
  
  
• Clear margins.
  
  
• No ipsilateral lymph nodes fixed to one another or to other structures and/or any positive nonaxillary lymph nodes (intramammary nodes are considered axillary nodes).
  
  
• No histologically evident invasive tumor or ductal carcinoma in situ.
  
  
• No diffuse tumors by mammography that would not be amenable to lumpectomy.
  
  
• No other dominant mass in the ipsilateral breast remnant histologically benign OR surgically removed with clear margins if malignant.
  
  
• No ulceration, erythema, infiltration of the skin or underlying chest wall (complete fixation), peau d'orange, or skin edema of any magnitude. Tethering or dimpling of the skin or nipple inversion allowed.
  
  
• No metastatic disease by x-ray, MRI, or biopsy. Skeletal pain allowed if bone scan negative for metastases.
  
  
• No previous biological therapy, chemotherapy, hormone therapy, or radiation therapy for breast cancer.
  
  
• No more than 63 days since histological diagnosis and randomization.

Randomization

AC = Doxorubicin and Cyclophosphamide
AT = Doxorubicin and Docetaxel
ATC = Doxorubicin, Cyclophosphamide, and Docetaxel
T = Docetaxel

Estrogen receptor (ER)-positive and/or progesterone receptor (PR)-positive patients receive oral tamoxifen daily for 5 years beginning on day 1 of course 1 of chemotherapy in all arms. Patients who are 50 and over may also receive tamoxifen at the discretion of their physician if they are ER negative, PR negative, or ER/PR unknown.

Participating Organizations/Investigators Principal Investigator
Sandra M. Swain, Chair National Surgical Adjuvant Breast and Bowel Project Ph: 301-496-4916 Comprehensive Breast Center Washington, District of Columbia

7.8 Phase III Randomized Study of Doxorubicin and Cyclophosphamide Followed by Paclitaxel with or without Trastuzumab (Herceptin) in Women with Node Positive Breast Cancer That Overexpresses HER2

Objectives:

I. Compare the cardiotoxicity of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab (Herceptin) in patients with operable, node-positive breast cancer that overexpresses HER2.

II. Compare the effect of these regimens, with or without tamoxifen, on disease-free and overall survival of these patients.

Participation Criteria

• Invasive adenocarcinoma of the breast, stage IIA, IIB, or IIIA (T1-3, N0-1, M0).
  
  
• Confined to the breast and ipsilateral axilla on clinical examination.
  
  
• At least 1 axillary node histologically positive.
  
  
• No lymph nodes clinically fixed to each other or to other structures (N2 disease).
  
  
• HER2 strongly positive (3+ by immunostain OR gene amplification by FISH).
  
  
• One third or more invasive tumor cells must stain positive.
  
  
• Submission of tumor block required.
  
  
• Must have undergone axillary dissection and either total mastectomy OR lumpectomy.
  
  
• Sentinel node dissection allowed, if followed by axillary dissection.
  
  
• No diffuse tumors by mammography in patients treated with lumpectomy.
  
  
• No bilateral malignancy or contralateral mass or mammographic abnormality unless histologically proven as benign.
  
  
• No suspicious palpable nodes in the contralateral axilla or palpable supraclavicular or infraclavicular nodes unless histologically proven not to be involved with tumor.
  
  
• No ulceration, erythema, infiltration of the skin or underlying chest wall, peau d'orange, or skin edema of any magnitude. Tethering or dimpling of the skin or nipple inversion allowed.
  
  
• No concurrent hormonal therapy, selective estrogen receptor modulator therapy, or radiotherapy (except as specified in study).

Randomization

AC = Doxorubicin and cyclophosphamide
Taxol = Paclitaxel
Herceptin = Trastuzumab

All patients with estrogen or progesterone receptor- positive tumors receive oral tamoxifen daily for 5 years, beginning on the first day of chemotherapy. Patients over 50 years of age or with tumors that are estrogen or progesterone receptor-negative or indeterminable status may also receive tamoxifen at the discretion of the principal investigator.

Patients who have received prior tamoxifen for prevention may be treated with additional tamoxifen at the discretion of the investigator. All patients treated with lumpectomy undergo breast irradiation beginning after completion of chemotherapy and concurrently with trastuzumab (in arm II) administration. Patients treated with mastectomy may also receive radiotherapy. Radiotherapy is administered daily for 5-6 weeks.

Edward H. Romond, Chair
Ph: 859-323-8043 National Surgical Adjuvant Breast and Bowel Project

7.9 Phase III Randomized Study of Doxorubicin Plus Cyclophosphamide Followed by Paclitaxel with or without Trastuzumab (Herceptin) in Patients With HER-2 Overexpressing Breast Cancer

Objectives

I. Compare the disease-free survival of patients with HER-2 overexpressing breast cancer when treated with doxorubicin plus cyclophosphamide followed by paclitaxel with or without trastuzumab (Herceptin).

II. Compare the cardiotoxicities of these treatments in these patients.

III. Compare the overall survival of these patients when treated with one of these regimens.

IV. Determine whether higher levels of shed extracellular domain or autoantibodies to HER-2 and HER-1 measured in the serum prior to treatment are prognostic for disease-free and overall survival in these patients.

V. Determine the concordance of HER-2 overexpression with disease-free and overall survival in this patient population.

Participation Criteria

• Menopausal status: Any status.
  
  
• Histologically confirmed adenocarcinoma of the breast.
  
  
• One or more positive lymph nodes (T1-3, pN1-2, M0).
  
  
• No cN2 disease allowed.
  
  
• Metaplastic carcinoma and pN2 disease allowed.
  
  
• Overexpression of HER-2/neu 3+ (0-2+ allowed if positive FISH assay).
  
  
• No locally advanced (T4) tumors including: tumors fixed to chest wall, peau d'orange, skin ulcerations/nodules, clinical inflammatory changes (diffuse brawny cutaneous induration with an erysipeloid edge).
  
  
• No dermal lymphatic involvement without clinical inflammatory changes.
  
  
• No bilateral invasive carcinoma or ductal carcinoma in situ (metachronous or synchronous).
  
  
• No gross or microscopic disease at margins.
  
  
• No concurrent hormonal therapy (e.g., birth control pills, hormone replacement therapy).
  
  
• No concurrent raloxifene.
  
  
• No more than four weeks of prior tamoxifen therapy allowed.
  
  
• No prior radiotherapy for breast cancer.

Participation Criteria

Patients may undergo radiotherapy at the completion of chemotherapy. All estrogen or progesterone receptor-positive patients receive oral tamoxifen daily for five years beginning no later than 5 weeks after the last dose of paclitaxel.

Edith A. Perez, Chair Principal Investigator
Ph: 904-953-7283 North Central Cancer Treatment Group Mayo Clinic Cancer Center Rochester, Minnesota

7.10 Phase III Randomized Study of Adjuvant Clodronate with or without Systemic Chemotherapy and/or Tamoxifen in Women with Early-Stage Breast Cancer

Protocol IDs: NSABP-B-34 Projected Accrual: A total of 2,400 patients will be accrued for this study within 4 years.

Objectives

I. Determine whether clodronate administered alone or in addition to adjuvant chemotherapy and/or tamoxifen improves disease-free survival in patients with early-stage breast cancer.

II. Determine whether clodronate reduces the incidence of skeletal metastases and non-skeletal metastases in these patients.

III. Determine whether clodronate improves overall and relapse-free survival in these patients.

IV. Determine whether clodronate reduces the incidence of skeletal morbidity (e.g., skeletal fractures, hypercalcemia, skeletal pain, need for radiotherapy, spinal cord compression) in these patients.

V. Determine the relevance of serum markers of bone turnover as a prognostic factor for the development of bone metastasis in these patients.

Participation Criteria

• Histologically proven invasive adenocarcinoma of the breast Stage I or II (T1-3, N0-1, M0).
  
  
• No significant nonmalignant bone disease that is likely to interfere with interpretation of bone x-rays.
  
  
• Skeletal pain allowed only if bone scan and/or roentgenological examination fails to disclose metastatic disease. Suspicious findings must be confirmed as benign by x-ray, MRI, or biopsy.

Randomization

This is a randomized, double-blind, placebo-controlled study. Patients are stratified by age (under 50 vs 50 and over), number of positive lymph nodes (0 vs 1-3 vs 4 or more), and hormone receptor status (estrogen receptor (ER) and progesterone receptor (PR)-negative vs ER and/or PR-positive). Patients are randomized to one of two treatment arms.

Patients in both arms continue treatment for 3 years in the absence of bone metastasis or unacceptable toxicity. Study medication must be continued in the case of documented visceral or soft tissue metastasis or other event without skeletal metastasis.

Patients in both arms may also receive adjuvant chemotherapy and/or tamoxifen at the discretion of the protocol investigator. Patients receiving chemotherapy must begin study medication within 1 week of the first dose of chemotherapy.

Norman Wolmark, Chair
Ph: 412-359-3336 National Surgical Adjuvant Breast and Bowel Project