Suppression of Ovarian Function With 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 to
   institution parameters]) who meet the following criteria:

      - Patients who did not receive chemotherapy should be randomized within 12 weeks
      after definitive surgery; such patients should have estradiol (E2) in the
      premenopausal range following surgery; the only patients who do not require
      testing of estradiol (E2) to confirm premenopausal status are those who have been
      menstruating regularly during the 6 months prior to randomization and have not
      used any form of hormonal contraception or any other hormonal treatments during
      the 6 months prior to randomization

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

      - Adjuvant trastuzumab (Herceptin ®) is allowable, and is not considered to be
      chemotherapy for eligibility timing determination

      - Patients with temporary chemotherapy-induced amenorrhea who regain premenopausal
      status within eight months of the final dose of chemotherapy are eligible;
      (please note that some patients taking tamoxifen or aromatase inhibitors, even
      without evidence of menses, may have ovarian function recovery following
      chemotherapy and resume estradiol secretion); in patients wishing to participate
      in the study, with postmenopausal hormone levels shortly after chemotherapy, it
      is recommended to recheck their estradiol level at a later timepoint within 8
      months of completing chemotherapy, even in the absence of return of menses

   - Histologically proven, resected breast cancer; pathology material should be available
   for submission for central review as part of the quality control measures for this
   protocol

   - Patients must have hormone receptor positive tumors; if there is more than one breast
   tumor, each tumor must be hormone receptor positive; hormone receptors must be
   determined using immunohistochemistry; estrogen receptor (ER) and/or progesterone
   receptor (PgR) must be greater than or equal to 10% of the tumor cells positive by
   immunohistochemical evaluation; biochemical determination alone is not acceptable

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

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

      - A total mastectomy; radiotherapy is optional after mastectomy OR

      - A breast-conserving procedure (lumpectomy, quadrantectomy or partial mastectomy
      with margins clear of invasive cancer and ductal breast carcinoma in situ
      [DCIS]); the local pathologist must document negative margins of resection in the
      pathology report; if all other margins are clear, a positive posterior (deep)
      margin is permitted, provided the surgeon documents that the excision was
      performed 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 been
      removed; radiation therapy to the conserved breast is required; patients may be
      randomized before, during or after completion of radiation therapy to the breast

   - Either axillary lymph node dissection (pathological examination of at least 6 nodes
   recommended) 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 with
   positive sentinel nodes must have either an axillary dissection or radiation of
   axillary nodes

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

   - Written informed consent must be signed and dated by the patient and the investigator
   prior to randomization

   - Patients must be accessible for follow-up

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

Exclusion Criteria:

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

   - Patients with distant metastatic disease

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

   - Patients with positive final margins (referring to only DCIS and invasive cancer, not
   lobular breast carcinoma in situ [LCIS]), except as noted; DCIS at a margin is
   permitted 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 histologically
   within 2 months) are eligible if the bilateral disease meets all other eligibility
   criteria

   - Patients with previous or concomitant invasive malignancy are not eligible; the
   exceptions 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 without
      recurrence:

         - 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 medically
   suitable

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

   - Patients with a history of noncompliance to medical regimens and patients who are
   considered potentially unreliable

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

   - Patients who received endocrine therapy (including neoadjuvant and adjuvant) for more
   than 8 months after their breast cancer diagnosis; patients who are receiving
   endocrine therapy at randomization (and have received it for less than 8 months) may
   continue 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 prior to
   their breast cancer diagnosis; prior oral contraceptives are allowed

   - Patients who have received GnRH analogues as part of their breast cancer treatment
   prior to randomization

   - Patients with psychiatric, addictive, or any disorder that would prevent compliance
   with protocol requirements