Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase III Study to Evaluate Letrozole as Adjuvant Endocrine Therapy for Postmenopausal Women With Receptor (ER and/or PgR) Positive Tumors
Brief Summary: RATIONALE: Estrogen can stimulate the growth of breast cancer cells. Hormone therapy using letrozole may fight breast cancer by reducing the production of estrogen. Hormone therapy using tamoxifen may fight breast cancer by blocking the uptake of estrogen by the tumor cells. If is not yet known which treatment regimen is most effective for breast cancer.

PURPOSE: Randomized double-blind phase III trial to compare the effectiveness of letrozole with that of tamoxifen in treating postmenopausal women who have breast cancer that has been surgically removed.


Options:
A: DISEASE CHARACTERISTICS:

* Histologically confirmed resectable adenocarcinoma of the breast

  * pT1, pT2, pT3, or minimal dermal involvement on pathology only
  * pN0, pN1, pN2, or M0

    * Negative nodal status

      * At least 8 nodes are negative
    * Unknown nodal status

      * Less than 8 nodes examined and no pathological finding
    * Positive nodal status

      * Any positive finding independent of the number of nodes examined
  * Negative sentinel node or no prior nodal dissection allowed if all other criteria met
* Must have had total mastectomy, lumpectomy, or quadrantectomy

  * Should have prior chest wall radiotherapy after segmental mastectomy or histopathologic T4 dermal involvement
* Stage I, II, or IIIa allowed if the tumor is completely removed macroscopically and margins of the resected tumor are microscopically free of tumor
* Must undergo chest wall radiotherapy or second resection if microscopic disease at the mastectomy margins
* No bilateral disease except in situ disease, either ductal or lobular of the contralateral breast
* Postmenopausal

  * Regardless of prior hormonal replacement therapy (HRT) or hysterectomy:

    * Bilateral oophorectomy and any age
    * Radiologic castration and amenorrheic for at least 3 months and any age
    * Not postmenopausal at the start of adjuvant chemotherapy AND and completed at least 6 courses of prior cyclophosphamide, methotrexate, and fluorouracil (CMF) or at least 4 courses of prior anthracycline-cyclophosphamide continuation therapy and at least age 45 with follicle stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2) postmenopausal levels
  * No prior HRT:

    * Prior hysterectomy and less than age 55 with FSH/LH/E2 postmenopausal levels
    * Prior hysterectomy and at least age 55
  * No prior HRT or hysterectomy:

    * Amenorrhea more than 1 year and less than age 50
    * Amenorrhea more than 6 months and at least age 50
  * Prior HRT regardless of hysterectomy:

    * At least 1 month since prior HRT and less than age 55 with FSH/LH/E2 postmenopausal levels
    * At least 1 month since prior HRT and at least age 55
  * FSH/LH/E2 postmenopausal levels and uncategorized
* No distant metastases, including bone scans showing hot spots unconfirmed as benign disease or skeletal pain of unknown cause
* At least 10% hormone receptor-positive tumor cells
* Hormone receptor status:

  * Estrogen receptor positive AND/OR
  * Progesterone receptor positive

PATIENT CHARACTERISTICS:

Age:

* 30 and over

Sex:

* Female

Menopausal status:

* Postmenopausal

Performance status:

* Not specified

Life expectancy:

* Not specified

Hematopoietic:

* WBC greater than 3,000/mm\^3
* Platelet count at least 100,000/mm\^3
* Hemoglobin greater than 10 g/dL

Hepatic:

* Bilirubin less than 3.0 mg/dL
* SGOT or SGPT less than 1.5 times upper limit of normal
* No hepatic disease that would preclude study

Renal:

* Creatinine less than 1.8 mg/dL
* No renal disease that would preclude study

Cardiovascular:

* No cardiovascular disease that would preclude study
* Prior deep vein thrombosis allowed if medically stable

Pulmonary:

* No lung embolism

Other:

* No other prior or concurrent malignancy within the past 5 years except adequately treated basal or squamous cell skin cancer or carcinoma in situ of the cervix
* No prior noncompliance to medical regimens
* No other nonmalignant systemic diseases that would preclude follow-up
* HIV negative

PRIOR CONCURRENT THERAPY:

Biologic therapy:

* Prior immunotherapy or biological response modifiers (e.g., interferon) allowed

Chemotherapy:

* See Disease Characteristics
* Prior adjuvant or neoadjuvant chemotherapy allowed
* Concurrent adjuvant chemotherapy allowed

Endocrine therapy:

* See Disease Characteristics
* Prior neoadjuvant hormonal therapy allowed (e.g., antiestrogens, progestins, or aromatase inhibitors) if no more than 4 months duration and no disease progression
* Prior corticosteroids allowed
* At least 4 weeks since prior HRT
* Prior adjuvant antiestrogen therapy allowed if less than 1 month duration and immediately after surgery, radiotherapy, and/or chemotherapy
* Prior antiestrogens for chemoprevention allowed if at least 18 months between completion of chemoprevention and diagnosis
* No other concurrent antiestrogens or aromatase inhibitors
* No concurrent raloxifene
* No concurrent systemic HRT with or without progestins of more than 3 months duration

Radiotherapy:

* See Disease Characteristics
* Concurrent radiotherapy allowed

Surgery:

* See Disease Characteristics

Other:

* At least 30 days since prior systemic investigational drugs
* At least 7 days since prior topical investigational drugs
* Concurrent bisphosphonates allowed
B: Inclusion Criteria:

1. Age ≥ 18 years
2. Receiving anastrozole (1mg) or letrozole (2.5 mg) orally once a day, for ≥ 21 days prior to registration and plan to continue it throughout the duration of study
3. Body Mass Index (BMI) between 18 and 35 kg/m\^2
4. Women who have undergone a total mastectomy or breast conserving surgery for primary breast cancer +/-chemo, +/-radiotherapy.
5. Must have BOTH ER and PR receptor-positive tumors and BOTH must be ≥26% positive. Alternatively, if ER and PR are determined by Allred score, the score needs to be 5 or higher
6. Women who are postmenopausal by surgery, radiotherapy or presence of natural amenorrhea ≥ 12 months
7. ≥ 5/10 arthralgia (in hands, wrist, knees, or hips) while being treated with anastrozole or letrozole which is felt by the patient to be caused by their aromatase inhibitor as defined in the protocol. Note: Patients may, or may not, be taking non-opioid analgesics
8. Ability to complete questionnaire(s) by themselves or with assistance
9. ECOG Performance Status (PS) 0, 1 or 2
10. Willing to provide informed written consent
11. Willing to return to an Alliance enrolling institution for follow-up
12. Willing to provide blood samples for correlative research purposes
13. Laboratory values prior to registration as defined in the protocol:

    1. Creatinine ≤1.5 x ULN
    2. Hemoglobin \> 11 g/dL
    3. WBC \> 3.0
    4. Platelet Count \> 100,000
    5. SGOT (AST) ≤ 1.5 x ULN

Exclusion Criteria:

1. Presence of residual or recurrent cancer (locally or metastatic)
2. Diabetes mellitus or glucose intolerance, defined as a fasting glucose \>125 mg/dL
3. History of coronary artery disease (angina or myocardial infarction)
4. Patients on hormone replacement therapy (HRT) ≤ 4 weeks prior to registration. This includes the use of vaginal estrogen therapy.
5. Known hypersensitivity to any component of testosterone.
6. Prolonged systemic corticosteroid treatment, except for topical applications (e.g. for rash), inhaled sprays (e.g. for obstructive airway diseases), eye drops or local insertion (e.g. intra-articular). Note: Short duration (\< 2 weeks) of systemic corticosteroids is allowed (e.g. for chronic obstructive pulmonary disease) but not within 30 days prior to registration.
7. Receiving any other investigational agent
8. History of a deep venous thrombosis or a thromboembolism
9. Concurrent use of the aromatase inhibitor exemestane, as it is structurally similar to an androgen
10. Concurrent radiation therapy or chemotherapy
11. Current or planned use of cyclosporine, anticoagulants, oxphenbutazone, insulin, oral or injectable vitamin D doses over 4,000IU/day, or tamoxifen
C: DISEASE CHARACTERISTICS:

* Diagnosis of cancer

  * CNS malignancy allowed with the exception of leptomeningeal carcinomatosis
* Must have painful sensory chemotherapy-induced peripheral neuropathy (CIPN) resulting from prior treatment with single-agent taxane or platinum agents (paclitaxel, docetaxel, nab-paclitaxel, oxaliplatin, cisplatin) (may not have received drugs from both classes)

  * CIPN \> grade 1 as measured by NCI-CTCAE v 4.0
  * Average neuropathic pain score ≥ 4
* Patients with the following illnesses known to cause peripheral neuropathy are eligible, provided they have no evidence of neuropathy from these illnesses:

  * Diabetes mellitus
  * Peripheral vascular disease
  * HIV infection
  * Significant degenerative or familial neurologic disorder known to cause peripheral neuropathy
* No clinical or subclinical neuropathy from nerve compression injuries (i.e., carpal tunnel syndrome, brachial plexopathy, spinal stenosis, or spinal nerve root compression)

PATIENT CHARACTERISTICS:

* AST ≤ 3 times upper limit of normal
* Total bilirubin ≤ normal
* Creatinine clearance \> 30 mL/min
* Not pregnant or nursing
* Able to take oral or enteral medication
* No history of seizure disorder
* No diagnosis of ethanol addiction or dependence within the past 10 years
* No history of narrow-angle glaucoma
* None of the following:

  * History of suicidal thoughts
  * Symptoms of or history of schizophrenia, bipolar disease, or a major depression
  * Serious eating disorder such as bulimia or anorexia where electrolyte imbalance is likely

PRIOR CONCURRENT THERAPY:

* At least 3 months since prior and no concurrent taxane or platinum agent
* At least 14 days since prior and no concurrent monoamine oxidase inhibitors or other antidepressants
* No other prior or concurrent neurotoxic drugs (e.g., vincristine, vinblastine, cytarabine, thalidomide, bortezomib, carboplatin, or procarbazine)
* No concurrent anticonvulsants
* No concurrent B or E vitamin supplementation in doses greater than the recommended daily allowance (RDA)

  * Centrum (standard formula) and One-A-Day "essential" formula which contain 100% RDA for vitamins B6, E, and B12 allowed
  * Other multivitamins allowed provided they contain no more than 100% RDA of B vitamins and vitamin E
* No concurrent treatment (pharmacologic) for depression
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