Suppression of Ovarian Function With Either Tamoxifen or Exemestane Compared With Tamoxifen Alone in Treating Premenopausal Women With Hormone-Responsive Breast Cancer
Suppression of Ovarian Function With Either Tamoxifen or Exemestane Compared With Tamoxifen Alone in Treating Premenopausal Women With Hormone-Responsive Breast Cancer
RATIONALE: Estrogen can stimulate the growth of breast tumor cells. Ovarian function
 suppression combined with hormone therapy using tamoxifen or exemestane may fight breast
 cancer by reducing the production of estrogen. It is not yet known whether suppression of
 ovarian function plus either tamoxifen or exemestane is more effective than tamoxifen alone
 in preventing the recurrence of hormone-responsive breast cancer.

 PURPOSE: This randomized phase III trial studies ovarian suppression with either tamoxifen or
 exemestane to see how well they work compared to tamoxifen alone in treating premenopausal
 women who have undergone surgery for hormone-responsive breast cancer.
OBJECTIVES:

 -  Compare the disease-free survival, breast cancer-free interval, distant recurrence-free
 interval and overall survival of premenopausal women with endocrine-responsive breast
 cancer when treated with tamoxifen + ovarian function suppression (by triptorelin,
 oophorectomy, or ovarian irradiation) or exemestane + ovarian function suppression vs.
 tamoxifen alone. The primary comparison is ovarian function suppression with either
 tamoxifen or exemestane vs. tamoxifen alone.

 -  Compare the quality of life, including late side effects of early menopause, of patients
 treated with these regimens.

 OUTLINE: This is a randomized, multicenter study. Patients are stratified according to
 participating center, prior adjuvant/neoadjuvant chemotherapy (yes vs no), and number of
 positive axillary and/or internal mammary lymph nodes (0 vs 1 or more) and intended initial
 method of ovarian function suppression (triptorelin vs oophorectomy vs ovarian irradiation).
 Treatment duration is 5 years. Patients are followed every 3 months for 1 year, every 6
 months for 5 years, and then annually thereafter. Quality of life is assessed at baseline,
 every 6 months for 2 years, and then annually for 4 years.
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