S1207 Hormone Therapy With or Without Everolimus in Treating Patients With Breast Cancer
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: anastrozole; everolimus; exemestane; goserelin acetate; letrozole; leuprolide acetate; tamoxifen citrate; placebo
Intervention description: Given orally; Given PO; Given orally; Given subcutaneously or intramuscularly; Given orally; Given subcutaneously or intramuscularly; Given PO; Given PO
Intervention MeSH terms: Tamoxifen; Everolimus; Letrozole; Anastrozole; Exemestane; Leuprolide; Goserelin
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 1939.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: estrogen receptor-positive breast cancer; HER2-negative breast cancer; stage IA breast cancer; stage IB breast cancer; stage II breast cancer; stage IIIA breast cancer; stage IIIB breast cancer; stage IIIC breast cancer; progesterone receptor-positive breast cancer; male breast cancer

Summary:

      RATIONALE: Estrogen can cause the growth of breast cancer cells. Hormone therapy using
      tamoxifen citrate, goserelin acetate, leuprolide acetate, anastrozole, letrozole, or
      exemestane, may fight breast cancer by lowering the amount of estrogen the body makes.
      Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell
      growth. It is not yet know whether hormone therapy is more effective when given with or
      without everolimus in treating breast cancer.

      PURPOSE: This randomized phase III trial studies how well giving hormone therapy together
      with or without everolimus work in treating patients with breast cancer.
    

Eligibility criteria:

        DISEASE CHARACTERISTICS:

          -  Patients must have a histologically confirmed diagnosis of invasive breast carcinoma
             with positive estrogen (ER)- and/or progesterone-receptor (PR) status, and negative
             human epidermal growth factor receptor (HER)2, for whom standard adjuvant endocrine
             therapy is planned

               -  ER and PR positivity must be assessed according to American Society of Clinical
                  Oncology (ASCO)/College of American Pathologists (CAP) guidelines as either ER or
                  PR ≥ 1% positive nuclear staining

               -  HER2 test result negativity must be assessed as per ASCO/CAP 2013 guidelines
                  using IHC, ISH or both.

        HER2 is negative if a single test (or all tests) performed in a tumor specimen show:

          1. IHC negative (0 or 1+)

          2. ISH negative using single probe or dual probe. If IHC is 2+, evaluation for gene
             amplification (ISH) must be performed and the ISH must be negative; ISH is not
             required if IHC is 0 or 1+.

        HER2 equivocal is not eligible.

          -  Patients must not have metastatic breast cancer (stage IV disease); patients with
             multifocal, multicentric, and synchronous bilateral, and primary inflammatory breast
             cancers are allowed

               -  Multifocal disease is defined as more than one invasive cancer < 2 cm from the
                  largest lesion within the same breast quadrant

               -  Multicentric disease is defined as more than one invasive cancer ≥ 2 cm from the
                  largest lesion within the same breast quadrant or more than one lesion in
                  different quadrants

               -  Synchronous bilateral disease is defined as invasive breast cancer with positive
                  lymph nodes (axillary or intramammary) in at least one breast, diagnosed within
                  30 days of each other

          -  Patients must be high risk by belonging to one of the following risk groups:

               -  Completion of adjuvant chemotherapy and pathologically negative axillary nodes,
                  and a tumor measuring ≥ 2 cm in greatest diameter, and an Oncotype DX® recurrence
                  score (RS) > 25 (completed as standard of care). Patients with micrometastases as
                  the only nodal involvement (pN1mi) are eligible, and will be categorized as
                  node-negative.

               -  Completion of adjuvant chemotherapy, and pathologically 1-3 positive lymph nodes,
                  and either an Oncotype DX® RS > 25 (screened via S1007 or otherwise) or tumor
                  tissue with pathological Grade III following local practice. If Oncotype DX is
                  done, then RS must be > 25. If the test is not done, but the patient has Grade
                  III disease then the patient is eligible and Oncotype DX does not need to be
                  performed.

               -  Completion of adjuvant chemotherapy and pathologically 4 or more positive lymph
                  nodes.

               -  Completion of neoadjuvant chemotherapy and 1 or more positive nodes
                  pathologically determined prior to or after chemotherapy

          -  Patients must have completed either breast-conserving surgery or total mastectomy,
             with negative margins and appropriate axillary staging; a negative margin is defined
             as no evidence of tumor or ductal carcinoma in situ (DCIS) at the line of resection;
             additional operative procedures may be performed to obtain clear margins

               -  Patients who had breast-conserving surgery must have completed whole-breast
                  radiation; use of regional nodal-basin radiation will be at the discretion of the
                  investigator according to institutional guidelines

               -  Patients with ≥ 4 positive lymph nodes must have completed breast/chest wall and
                  nodal-basin radiation therapy according to standard-of-care guidelines before
                  randomization; omission of radiation therapy is not allowed in this high-risk
                  population of patients

               -  Patients must be registered no sooner than 21 days after completion of radiation
                  therapy and must have recovered (≤ grade 1) from any of the effects of radiation

          -  Patients must have undergone axillary staging by sentinel-node biopsy or axillary
             lymph node dissection (ALND)

               -  For patients with 1-3 positive lymph nodes, sentinel-node biopsy alone is allowed
                  provided that the patient completed either whole-breast or chest-wall radiation
                  and the primary tumor is < 5 cm

               -  All patients with ≥ 4 positive lymph nodes must have completed ALND (with or
                  without prior sentinel-node biopsy)

        PATIENT CHARACTERISTICS:

          -  Absolute Neutrophil Count ≥ 1,500/mL

          -  Hemoglobin ≥ 9 g/dL

          -  Platelet count ≥ 100,000/mL

          -  Bilirubin ≤ 1.5 mg/dL (≤ 3.0 mg/dL if due to Gilbert syndrome)

          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 1.5 times
             institutional upper limit of normal (IULN)

          -  Alkaline phosphatase ≤ 1.5 times IULN

          -  Serum creatinine level ≤ IULN

          -  Fasting cholesterol ≤ 300 mg/dL and triglycerides ≤ 2.5 times IULN; patients may be on
             lipid-lowering agents to reach these values

          -  Patients must have a performance status of 0-2 by Zubrod criteria

          -  Patients must not have any grade III/IV cardiac disease as defined by the New York
             Heart Association Criteria (i.e., patients with cardiac disease resulting in marked
             limitation of physical activity or resulting in inability to carry on any physical
             activity without discomfort), unstable angina pectoris, myocardial infarction within 6
             months, or serious uncontrolled cardiac arrhythmia

          -  Patients previously diagnosed with diabetes must not have uncontrolled diabetes
             (defined as a hemoglobin [Hg] A1C > 7% within 28 days prior to registration)

          -  Patients known to be human immunodeficiency virus (HIV) positive may be enrolled if
             baseline CD4 count is > 500 cells/mm³ and they are not taking anti-retroviral therapy

          -  Patients with known hepatitis are not eligible

          -  Patients must not have any known uncontrolled, underlying pulmonary disease

          -  Patients must be able to take oral medications

          -  Patients may not have any impairment of gastrointestinal function or gastrointestinal
             disease that may significantly alter the absorption of blinded drug (e.g., ulcerative
             disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small
             bowel resection)

          -  Patients must not be pregnant or nursing

          -  Women/men of reproductive potential must have agreed to use an effective non-hormonal
             contraceptive method during and for 8 weeks after completion of study therapy

               -  In addition to routine contraceptive methods, "effective contraception" also
                  includes heterosexual celibacy and surgery intended to prevent pregnancy (or with
                  a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral
                  oophorectomy, or bilateral tubal ligation; corresponding procedures for men
                  include castration, vasectomy, and barrier-contractive devices

               -  If at any point a previously celibate patient chooses to become heterosexually
                  active during the protocol therapy, he/she is responsible for beginning
                  contraceptive measures

          -  No other prior malignancy is allowed except for adequately treated basal cell or
             squamous cell skin cancer, in situ cervical cancer, or other cancer for which the
             patient has been disease-free for 5 years

        PRIOR CONCURRENT THERAPY:

          -  See Disease Characteristics

          -  Patients must have completed standard neoadjuvant or adjuvant chemotherapy prior to
             randomization; completion of chemotherapy will be determined by the treating
             oncologist, but should include a minimum of 4 cycles (a cycle of weekly paclitaxel is
             considered 3 doses); patients must be registered within 42 weeks after the last dose
             of chemotherapy; patients may have started endocrine therapy at any time after the
             diagnosis of the current breast cancer

          -  Patients must not be receiving or planning to receive trastuzumab

          -  Concurrent bisphosphonate therapy is allowed

          -  Patients must not have prior exposure to mTOR inhibitors (rapamycin, everolimus,
             temsirolimus, deforolimus)

          -  Patients must not have prior treatment with any investigational drug within the
             preceding 28 days and must not be planning to receive any other investigational drug
             for the duration of the study

          -  Patients must not be planning to receive any other anticancer drug for the duration of
             the study

          -  Patients must not have an organ allograft or other history of immune compromise;
             patients must not be receiving chronic, systemic treatment with corticosteroids or
             other immunosuppressive agent; topical or inhaled corticosteroids are allowed

          -  Patients must not have received immunization with an attenuated live vaccine (e.g.,
             intranasal influenza, measles, mumps, and rubella [MMR], oral polio, varicella,
             zoster, yellow fever, and Bacillus Calmette-Guérin [BCG] vaccines) within seven days
             prior to registration nor have plans to receive such vaccination while on protocol
             treatment

          -  Patients must not have taken within 14 days prior to registration, be taking, nor plan
             to take while on protocol treatment, strong cytochrome P450 3A4 (CYP3A4) inhibitors
             and/or CYP3A4 inducers