Suppression of Ovarian Function With Either Tamoxifen or Exemestane Compared With Tamoxifen Alone in Treating Premenopausal Women With Hormone-Responsive Breast Cancer
Condition: Estrogen Receptor Positive Breast Cancer; Progesterone Receptor Positive Tumor; Recurrent Breast Carcinoma; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Exemestane; Laboratory Biomarker Analysis; Oophorectomy; Quality-of-Life Assessment; Radiation Therapy; Tamoxifen; Triptorelin
Intervention description: Exemestane 25mg orally daily for 5 years plus ovarian function suppression; Correlative studies; Undergo bilateral surgical oophorectomy; Ancillary studies; Undergo ovarian irradiation; Tamoxifen 20mg orally daily for 5 years; 3.75 mg by im injection q28 days for 5 years
Intervention MeSH terms: Tamoxifen; Triptorelin Pamoate; Exemestane; Tryptophan
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 3066.0
Sex: Female
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: tamoxifen; ovarian function suppression + tamoxifen; ovarian function suppression + exemestane

Summary:

      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.
    

Eligibility criteria:

        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