Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase III Trial Evaluating The Role Of Exemestane Plus GnRH Analogue As Adjuvant Therapy For Premenopausal Women With Endocrine Responsive Breast Cancer
Brief Summary: RATIONALE: Estrogen can stimulate the growth of breast cancer cells. Hormone therapy using triptorelin, exemestane, and tamoxifen may fight breast cancer by blocking the use of estrogen. It is not yet known whether giving triptorelin together with exemestane is more effective than triptorelin and tamoxifen in treating hormone-responsive breast cancer.

PURPOSE: This randomized phase III trial is studying triptorelin and exemestane to see how well they work compared to triptorelin and tamoxifen in treating premenopausal women with hormone-responsive breast cancer.


Options:
A: 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
B: Inclusion Criteria:

1. Patients must have undergone excision of the primary breast mass, proven histologically to be invasive breast adenocarcinoma.
2. Patients must be within 3 months after the last cycle of chemotherapy.
3. Patients must have the history of normal menstruation prior to the start of chemotherapy.
4. Stage I, II or III
5. Woman, less than or equal to 45 years of age
6. Hormone receptor status : ER+ve and/or PgR+ve
7. WHO performance status 0, 1 or 2.
8. Patients who were treated with cytotoxic chemotherapy in pre- or post- surgery.
9. Adequate haematological function defined by haemoglobin 10g/dL, neutrophil count 1.5x109/L and platelets 100x109/L.
10. Adequate hepatic function defined by AST and ALT 2.5xupper limit of normal. Alkaline phosphatase 5xupper limit of normal, unless bone metastases in the absence of liver disease. Renal function adequate defined by creatinine\<175mmol/L.

Exclusion Criteria:

1. Patients whose primary breast cancer was classified as:

   * ER(-),ER unknown
2. Patients with the history of hysterectomy or oophorectomy
3. Sarcomas or squamous cell carcinomas of the breast are not eligible.
4. Patients with malignancies (other than breast cancer) within the last 5 years, except for adequately treated in situ carcinoma of the cervix or basal cell / squamous cell carcinoma of the skin.
5. Investigational drugs given within the previous 4 weeks.
6. Patients known to be on any unlicensed non-cancer investigational agent.
7. Patients with thrombocytopaenia (platelets \<100 x 109/l or on anti- coagulant therapy (contra-indicated due to risk of bleeding with i.m. injection of Zoladex).
8. Patients treated with CMF(cyclophosphamide/methotrexate/5-fluorouracil) as prior chemotherapy
9. Patients who are pregnant or lactating are ineligible.
C: Inclusion Criteria:

1. All patients must have signed and dated an informed consent form
2. Patients must be female
3. Primary invasive breast cancer pathologically approved by core needle or open biopsy
4. Ipsilateral axillary or internal mammary nodes positive, or tumor size is equal to or larger than 4cm. Definition of nodes positive is according to the staging system of AJCC 6th edition (American Joint Cancer Commission) for breast carcinoma. The micrometastasis must be at least 0.2mm
5. Patients must have undergone standard surgery for primary breast cancer as shown in the following:

   * a standard radical mastectomy or modified mastectomy
   * standard breast conservation surgery (BCS), which is lumpectomy or qaudrantectomy accompany with axillary dissection, and the surgical margins of the resected specimen must be negative. BCS must be followed by standardized adjuvant radiotherapy to the partial conserved breast (delivered after adjuvant chemotherapy completed)
   * Treatment for confirmed breast cancer including the surgery modality listed above, loco-regional radiotherapy after lumpectomy, adjuvant radiotherapy to the chest wall and/or internal mammary nodes and/or supraclavicular lymph nodes, adjuvant chemotherapy
6. adjuvant endocrine therapy of TAM or Fareston must be started within 6 weeks when adjuvant chemotherapy or radiotherapy was finished
7. The date of randomization must be processed after taking TAM or Fareston for 2 or more than 2 years, but not more than 3 years of time
8. Patients taking neo-chemotherapy are eligible, and lymph node status could be identified during surgery before neo-adjuvant chemotherapy or after neo-adjuvant chemotherapy. The definition of lymph node positive is:

   * evaluation of lymph node status before neo-adjuvant chemotherapy must include pathological axillary nodes, internal mammary nodes (pN2b option) or supraclavicular nodes (pN3c option) involved. Micro-metastasis (i.e.≥0.2mm, pN1-pN3c) can be identified by the following method: fine needle aspiration (FNA) or sentinel node biopsy (SNB) or sampling/ total procedure of axillary dissection
   * patients with no nodes positive after neo-adjuvant chemotherapy, lymph node positive must be evaluated during surgery. Its definition was the either of following:

     * According the clinical practice guidelines of the local cancer center, it is acceptable when positive nodes was identified by SNB or axillary dissection
     * There is pathological evidence in lymph nodes positive (pN1-pN3c) during breast surgery after neo-adjuvant chemotherapy
9. Patients diagnosed as occult breast cancer clinically are found to pathologically have primary invasive carcinoma or DCIS with micro-invasive lesion in ipsilateral breast, and primary lesion or axillary node metastasis express ER and/or PR positive
10. Patients with synchronous bilateral cancers are eligible on the condition that If one side is IDC and the other side is DCIS, the IDC side should be of the ER and/or PR positive phenotype and IF two sides are both IDC, they must be ER and/or PR positive phenotype at the same time
11. Hormone receptor positive (≥＋) is defined as detecting ER or PR expression at any time is eligible. The situation of only PR positive and ER negative is eligible, too
12. According to the standard operation principles for clinical practice of local cancer center, patients must be randomized within 4 weeks after definitive physical examination, imaging examination and laboratory testing show no evidence of recurrence or metastasis
13. Based on the study objective, all patients are required to be premenopausal as defined by

    * menstruating actively
    * less than 6 months since last menstrual period (LMP), or patients younger than 40 years of age who became amenorrheic not more than 1 year if the serum free E2、FSH and LH level was premenopausal (according to the reference value of local center).
    * had previous hysterectomy with one or both ovaries left intact are eligible if the serum free E2、FSH and LH level are premenopausal (according to the reference value of local center).
14. patients must have an ECOG performance status of 0 or 1 (0-fully active, able to carry on all pre-disease performance without restriction, 1-restricted in physical strenuous actively but ambulatory)
15. leucocyte count must be ≥3.0\*10\^9/L and platelet count must be ≥100\*10\^9/L
16. AST/SGOT or ALT/AGPT must be \<3 times the ULN
17. serum creatinine must be \<2 times the ULN
18. patients can swallow pills
19. pregnancy testing is negative and are willing to do contraception during the treatment period

Exclusion Criteria:

1. patients with metastatic malignant tumor
2. previous history of asynchronous bilateral breast cancer
3. any previous malignancy in the past 5 years, except for those treated with curative intent, such as carcinoma in situ of the cervix, squamous carcinoma of the skin or basal cell carcinoma of the skin
4. any non-malignant systemic disease which interfere long time follow up
5. history of medical ovarian ablation therapy
6. history of AI therapy
7. severe live dysfunction, Child-Pugh is grade C
8. Occult breast cancer is found pathologically no IDC lesion or only DCIS without micro-invasive lesion in the ipsilateral breast
9. patients with Her-2 overexpression had used, or is using, or intending to use adjuvant trastuzumab
10. severe heart dysfunction, heart functional classification is above Class III Table 2 Child-Pugh score of hepatic cirrhosis
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: A