Suppression of Ovarian Function Plus Either Tamoxifen or Exemestane Compared With Tamoxifen Alone in Treating Premenopausal Women With Hormone-Responsive Breast Cancer

Inclusion Criteria:

• Premenopausal women (estradiol [E2] in the premenopausal range [according toinstitution parameters]) who meet the following criteria:

• Patients who did not receive chemotherapy should be randomized within 12 weeksafter definitive surgery; such patients should have estradiol (E2) in thepremenopausal range following surgery; the only patients who do not requiretesting of estradiol (E2) to confirm premenopausal status are those who havebeen menstruating regularly during the 6 months prior to randomization and havenot used any form of hormonal contraception or any other hormonal treatmentsduring the 6 months prior to randomization

• Patients who received prior adjuvant and/or neoadjuvant chemotherapy should berandomized after completing chemotherapy and within 8 months of the final doseof chemotherapy as soon as premenopausal status is confirmed; all such patientsshould have premenopausal status confirmed by an estradiol (E2) in thepremenopausal range between 2 weeks and 8 months after completing chemotherapy

• Adjuvant trastuzumab (Herceptin ®) is allowable, and is not considered to bechemotherapy for eligibility timing determination

• Patients with temporary chemotherapy-induced amenorrhea who regain premenopausalstatus within eight months of the final dose of chemotherapy are eligible; (please note that some patients taking tamoxifen or aromatase inhibitors, evenwithout evidence of menses, may have ovarian function recovery followingchemotherapy and resume estradiol secretion); in patients wishing to participatein the study, with postmenopausal hormone levels shortly after chemotherapy, itis recommended to recheck their estradiol level at a later timepoint within 8months of completing chemotherapy, even in the absence of return of menses

• Histologically proven, resected breast cancer; pathology material should be availablefor submission for central review as part of the quality control measures for thisprotocol

• Patients must have hormone receptor positive tumors; if there is more than one breasttumor, each tumor must be hormone receptor positive; hormone receptors must bedetermined using immunohistochemistry; estrogen receptor (ER) and/or progesteronereceptor (PgR) must be greater than or equal to 10% of the tumor cells positive byimmunohistochemical evaluation; biochemical determination alone is not acceptable

• The tumor must be confined to the breast and axillary nodes without detectedmetastases elsewhere, with the exception of tumor detected in internal mammary chainnodes by sentinel node procedure; patients who received neoadjuvant therapy must havehad operable disease prior to neoadjuvant treatment to be eligible; patients who hada pathological evaluation with tru cut or core biopsy of invasive breast cancer priorto neoadjuvant therapy and were found to have no invasive tumor in the pathologicalspecimen from definitive surgery are eligible; for these patients, pre-neoadjuvanttumor characteristics will be used for defining eligibility; in case of persistentdisease, pathology findings from the definitive surgery should be used

• Patients must have had proper surgery for primary breast cancer with no knownclinical residual loco-regional disease:

• A total mastectomy; radiotherapy is optional after mastectomy OR

• A breast-conserving procedure (lumpectomy, quadrantectomy or partial mastectomywith margins clear of invasive cancer and ductal breast carcinoma in situ [DCIS]); the local pathologist must document negative margins of resection inthe pathology report; if all other margins are clear, a positive posterior (deep) margin is permitted, provided the surgeon documents that the excision wasperformed down to the pectoral fascia and all tumor has been removed; likewise,if all other margins are clear, a positive anterior (superficial; abutting skin)margin is permitted provided the surgeon documents that all tumor has beenremoved; radiation therapy to the conserved breast is required; patients may berandomized before, during or after completion of radiation therapy to the breast

• Either axillary lymph node dissection (pathological examination of at least 6 nodesrecommended) or a negative axillary sentinel node biopsy (pN0[sn]) is required;patients with negative or microscopically axillary positive sentinel nodes (pN1mi:micrometastasis none > 2.0 mm) do not require further axillary therapy; those withpositive sentinel nodes must have either an axillary dissection or radiation ofaxillary nodes

• For International Breast Cancer Study Groups (IBCSG) centers, patients must havecompleted baseline Quality of Life (QL) Forms prior to randomization; the onlyexceptions are cognitive or physical impairment that interferes with QL assessment orinability to read any of the languages available on IBCSG QL forms; for non-IBCSGcenters, extent of participation in the QL study is to be determined at theactivation of the trial for each cooperative group

• Written informed consent must be signed and dated by the patient and the investigatorprior to randomization

• Patients must be accessible for follow-up

• Patients must be informed of and agree to data and tissue material transfer andhandling, in accordance with national data protection guidelines

Exclusion Criteria:

• Patients who are postmenopausal (i.e., do not have an estradiol [E2] level in thepremenopausal range) after surgery or after chemotherapy, whichever is later

• Patients with distant metastatic disease

• Patients with locally advanced inoperable breast cancer including inflammatory breastcancer or supraclavicular node involvement or with enlarged internal mammary nodes (unless pathologically negative) are not eligible; patients with involved internalmammary nodes detected by sentinel node biopsy that are not enlarged are eligible

• Patients with positive final margins (referring to only DCIS and invasive cancer, notlobular breast carcinoma in situ [LCIS]), except as noted; DCIS at a margin ispermitted if a complete mastectomy has been performed

• Patients with clinically detectable residual axillary disease

• Patients with a history of prior ipsilateral or contralateral invasive breast cancer;patients with synchronous bilateral invasive breast cancer (diagnosed histologicallywithin 2 months) are eligible if the bilateral disease meets all other eligibilitycriteria

• Patients with previous or concomitant invasive malignancy are not eligible; theexceptions are patients with the following (and only the following) malignancies (previous or concomitant) who are eligible if adequately treated:

• Basal or squamous cell carcinoma of the skin

• In situ non-breast carcinoma without invasion

• Contra- or ipsilateral in situ breast carcinoma

• Non-breast invasive malignancy diagnosed at least 5 years ago and withoutrecurrence:

• Stage I papillary thyroid cancer

• Stage Ia carcinoma of the cervix

• Stage Ia or b endometrioid endometrial cancer

• Borderline or stage I ovarian cancer

• Patients with other non-malignant systemic diseases (cardiovascular, renal, hepatic,lung, etc.) that would prevent prolonged follow-up; patients with previous thrombosis (e.g., deep vein thrombosis [DVT]) and/or embolism can be included only if medicallysuitable

• Patients who have had a bilateral oophorectomy or ovarian irradiation; patients whowill be recommended to undergo oophorectomy within 5 years (e.g., breast cancersusceptibility gene [BRCA]1/2 gene carriers) and therefore for whom randomization toa treatment arm without OFS is inappropriate

• Patients with a history of noncompliance to medical regimens and patients who areconsidered potentially unreliable

• Patients who are pregnant or lactating at the time of randomization or who desire apregnancy within 5 years; patients planning to use additional hormonal therapy apartfrom the randomized treatment during the next five years including all types ofhormonal contraception; a pregnancy test is recommended for women of child-bearingpotential who are sexually active and not using reliable contraceptive methods

• Patients who received endocrine therapy (including neoadjuvant and adjuvant) for morethan 8 months after their breast cancer diagnosis; patients who are receivingendocrine therapy at randomization (and have received it for less than 8 months) maycontinue such therapy until protocol-specified tamoxifen/exemestane is initiated

• Patients who were taking tamoxifen or other selective estrogen receptor modulator (SERM) (e.g. Raloxifene) or hormone replacement therapy (HRT) within one year priorto their breast cancer diagnosis; prior oral contraceptives are allowed

• Patients who have received GnRH analogues as part of their breast cancer treatmentprior to randomization

• Patients with psychiatric, addictive, or any disorder that would prevent compliancewith protocol requirements