S1207 Hormone Therapy With or Without Everolimus in Treating Patients With Breast Cancer

OBJECTIVES:

Primary

- To compare whether the addition of one year of everolimus (10 mg daily) to standard
adjuvant endocrine therapy improves invasive disease-free survival (IDFS) in patients
with high-risk, hormone-receptor (HR)-positive, and human epidermal growth factor
receptor (HER)2-negative breast cancer.

Secondary

- To compare whether the addition of one year of everolimus to standard adjuvant endocrine
therapy improves overall survival (OS) and distant recurrence-free survival (DRFS) in
this patient population.

- To evaluate the safety, toxicities, and tolerability of one year of everolimus in
combination with standard adjuvant endocrine therapy and to compare it with standard
adjuvant endocrine therapy plus placebo in this patient population.

- To determine whether the benefit of one year of everolimus use in addition to standard
adjuvant endocrine therapy varies by recurrence score (RS), nodal status, or other
commonly used prognostic factors.

- To evaluate adherence to 1-year treatment of everolimus in comparison to placebo in
addition to standard adjuvant endocrine therapy in this patient population.

- To collect specimens in order to evaluate biomarkers of therapeutic efficacy.
(exploratory)

OUTLINE: This is a multicenter study. Patients are stratified according to risk level
(node-negative and recurrence score [RS] > 25 in the primary tumor, and a tumor measuring ≥ 2
cm in greatest diameter treated with adjuvant therapy vs 1-3 positive lymph nodes and RS > 25
treated with adjuvant therapy vs ≥ 4 positive lymph nodes [any RS value] treated with
adjuvant therapy vs ≥ 4 positive lymph nodes [any RS value] prior to or after neoadjuvant
chemotherapy). Patients are randomized to 1 of 2 treatment arms.

- Arm I: Patients receive an approved endocrine therapy comprising tamoxifen citrate*,
goserelin acetate** or leuprolide acetate**, or aromatase inhibitor (anastrozole,
letrozole, or exemestane) for 2-5 years. Patients also receive a placebo orally (PO)
daily for 1 year in the absence of disease progression or unacceptable toxicity.

- Arm II: Patients receive an approved endocrine therapy regimen as in arm I. Patients
also receive everolimus PO daily for 1 year in the absence of disease progression or
unacceptable toxicity.

NOTE: *Men receive tamoxifen citrate PO for 5 years.

NOTE: **Goserelin acetate or leuprolide acetate is given if patient is or becomes
postmenopausal.

Blood and tissue samples are collected for biomarker studies.

After completion of study treatment, patients are followed up every 6 months for 2 years and
then yearly thereafter for 10 years.

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