Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase III Trial Evaluating the Role of Ovarian Function Suppression and the Role of Exemestane as Adjuvant Therapies for Premenopausal Women With Endocrine Responsive Breast Cancer
Brief 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.


Options:
A: DISEASE CHARACTERISTICS:

* Histologically confirmed invasive breast cancer

  * Stage I-IIIA
  * Operable disease
* Bilateral synchronous invasive breast cancer allowed provided primary tumors were diagnosed no more than 1 month apart and both tumors are hormone receptor negative
* Must be planning to receive 3-8 months of a preoperative or postoperative chemotherapy regimen containing alkylating agents (anthracyclines or non-anthracyclines), meeting 1 of the following criteria:

  * 3-month/4-course anthracycline-based regimen
  * 6- to 8-month/course anthracycline-based regimen
  * 6- to 8-month/course non-anthracycline-based regimen
* Hormone receptor status:

  * Estrogen receptor negative
  * Progesterone receptor negative

PATIENT CHARACTERISTICS:

Age

* 18 to 49

Sex

* Female

Menopausal status

* Premenopausal

Performance status

* Zubrod 0-2

Life expectancy

* Not specified

Hematopoietic

* Not specified

Hepatic

* Not specified

Renal

* Not specified

Other

* Not pregnant or nursing
* Fertile patients must use effective barrier contraception
* No other prior malignancy except adequately treated basal cell or squamous cell skin cancer or any in situ cancer from which the patient has been disease-free for at least 5 years after treatment with curative intent

PRIOR CONCURRENT THERAPY:

Biologic therapy

* Not specified

Chemotherapy

* See Disease Characteristics
* No prior cytotoxic chemotherapy

Endocrine therapy

* No other concurrent hormonal therapy

Radiotherapy

* Concurrent radiotherapy to the breast, chest wall, or lymph nodes allowed

Surgery

* See Disease Characteristics

Other

* Concurrent participation in other therapeutic clinical trials, including SWOG-S0221, allowed
B: DISEASE CHARACTERISTICS:

* Histologically or cytologically confirmed breast cancer resected at time of original diagnosis

  * Stage I-III disease
* Candidate for 1 of the following adjuvant chemotherapy regimens:

  * FEC (fluorouracil, epirubicin hydrochloride, and cyclophosphamide) every 21 or 28 days
  * CMF (cyclophosphamide, methotrexate, and fluorouracil) every 28 days
  * A→CMF (doxorubicin hydrochloride followed by CMF)
  * EC→P (epirubicin hydrochloride and cyclophosphamide every 21 days followed by paclitaxel every 21 days)
  * FEC→P (FEC every 21 days followed by paclitaxel every 21 days)
  * EC→D (EC every 21 days followed by docetaxel every 21 days)
  * AC (doxorubicin hydrochloride and cyclophosphamide) every 21 days
  * AC→P (AC every 21 days followed by paclitaxel every 21 days)
  * E→CMF (epirubicin hydrochloride followed by CMF every 28 days)
* No evidence of metastases or localized or distant recurrence

  * Investigation to exclude metastases required for any suspicious manifestation
* Premenopausal, defined as the presence of active menstrual cycles or normal menses within six weeks before initiation of chemotherapy
* Hormone receptor status not specified

PATIENT CHARACTERISTICS:

* Female
* No other malignancy within the past 5 years except basal cell or squamous cell skin cancer or adequately treated in situ carcinoma of the cervix
* No history of noncompliance to medical regimens or patients who are considered potentially unreliable
* Not pregnant or nursing
* Negative pregnancy test

PRIOR CONCURRENT THERAPY:

* See Disease Characteristics
* No prior chemotherapy and/or radiotherapy for cancer or non-neoplastic disease
* No other concurrent hormonal therapy except for tamoxifen
C: DISEASE CHARACTERISTICS:

* Histologically confirmed breast cancer
* Completely resected disease

  * No clinically detectable residual loco-regional axillary disease
  * Prior surgery for primary breast cancer of 1 of the following types:

    * Total mastectomy with or without adjuvant radiotherapy
    * Breast-conserving procedure (e.g., lumpectomy, quadrantectomy, or partial mastectomy with margins negative\* for invasive disease and ductal carcinoma in situ) with planned radiotherapy NOTE: \*If all other margins are clear a positive posterior (deep) margin is permitted, provided the excision was performed down to the pectoral fascia and all tumor has been removed OR a positive anterior (superficial; abutting skin) margin is allowed provided all tumor was removed
* Tumor confined to the breast and axillary nodes

  * Tumor detected in internal mammary chain nodes by sentinel node procedure and is not enlarged is allowed
* Axillary lymph node dissection or a negative axillary sentinel node biopsy required

  * Patients with negative or microscopically positive axillary sentinel nodes are eligible
  * Positive sentinel nodes must have either axillary dissection or radiation of axillary nodes
* No distant metastases
* No locally advanced inoperable breast cancer, including any of the following:

  * Inflammatory breast cancer
  * Supraclavicular node involvement
  * Enlarged internal mammary nodes (unless pathologically negative)
* Bilateral synchronous invasive breast cancer allowed if disease meets all other eligibility criteria
* No prior ipsilateral or contralateral invasive breast cancer
* Hormone receptor status:

  * Estrogen and/or progesterone receptor positive

    * At least 10% of the tumor cells positive by immunohistochemistry
    * If \> 1 breast tumor, each tumor must be hormone receptor positive

PATIENT CHARACTERISTICS:

Age

* Premenopausal

Sex

* Female

Menopausal status

* Premenopausal

  * Estradiol in the premenopausal range after prior surgery OR meets the following criteria:

    * Menstruating regularly for the past 6 months
    * Has not used any form of hormonal treatment (including hormonal contraception) within the past 6 months

Performance status

* Not specified

Life expectancy

* Not specified

Hematopoietic

* Not specified

Hepatic

* No systemic hepatic disease that would preclude prolonged follow-up

Renal

* No systemic renal disease that would preclude prolonged follow-up

Cardiovascular

* No systemic cardiovascular disease that would preclude prolonged follow-up
* No prior thrombosis (e.g., deep vein thrombosis) and/or embolism unless patient is medically suitable

Pulmonary

* No systemic pulmonary disease that would preclude prolonged follow-up

Other

* Not pregnant or nursing
* Fertile patients must use effective nonhormonal contraception
* No history of noncompliance to medical regimens
* No other nonmalignant systemic disease that would preclude prolonged follow-up
* No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, nonbreast carcinoma in situ, contralateral or ipsilateral carcinoma in situ of the breast, or other nonrecurrent invasive nonbreast malignancy, including any of the following:

  * Stage I papillary thyroid cancer
  * Stage IA carcinoma of the cervix
  * Stage IA or B endometrioid endometrial cancer
  * Borderline or stage I ovarian cancer
* No psychiatric, addictive, or other disorder that would preclude study compliance

PRIOR CONCURRENT THERAPY:

Biologic therapy

* Prior or concurrent neoadjuvant or adjuvant trastuzumab allowed

Chemotherapy

* No prior neoadjuvant or adjuvant chemotherapy

Endocrine therapy

* No prior tamoxifen, other selective estrogen-receptor modulators (SERMs) (e.g., raloxifene), or hormone replacement therapy for more than 1 year before breast cancer diagnosis
* No prior neoadjuvant or adjuvant endocrine therapy since diagnosis of breast cancer
* No concurrent oral or transdermal hormonal therapy
* No other concurrent estrogen, progesterone, or androgens
* No other concurrent aromatase inhibitors
* No concurrent oral or other hormonal contraceptives (i.e., implants or depot injections)

Radiotherapy

* See Disease Characteristics
* No prior ovarian radiotherapy

Surgery

* See Disease Characteristics
* No prior bilateral oophorectomy

Other

* No concurrent bisphosphonates, except in the following cases:

  * Bone density is at least 1.5 standard deviations below the young adult normal mean
  * Participation in a randomized clinical study testing bisphosphonates in the adjuvant breast cancer setting
* No other concurrent investigational agents
D: 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

Answer: D