Neoadj ph 2 AI Plus Everolimus in Postmenopausal Women w/ ER Pos/HER2 Neg, Low Risk Score

This is a single arm open-labeled neoadjuvant phase II clinical trial evaluating everolimus
in combination with an aromatase inhibitor in postmenopausal women with hormone receptor
positive/HER2 negative breast cancers with low and intermediate risk (< 25) Recurrence Scores
by Oncotype Dx.

Inclusion Criteria:

- Patients must have a histologically confirmed diagnosis of hormone receptor positive,
HER2 negative invasive breast carcinoma.

- Tumors must be estrogen and/or progesterone receptor positive according to ASCO/CAP
2010 guidelines as either ER or PR ≥ 1% positive nuclear staining by
immunohistochemistry. Estrogen and/or progesterone receptor results by Oncotype Dx
will not be accepted.

- Tumors must be HER2 negative as defined according to ASCO/CAP 2013, as HER2 0 - 1+ by
IHC or non-amplified FISH or CISH. If HER2 IHC is 2+, FISH/CISH must be performed and
must not be positive (must be a ratio of < 2), but otherwise FISH/CISH is not required
if IHC is 0 or 1+ by institutional standards.

- Patients must not have had prior ipsilateral breast-conserving surgery or total
mastectomy and be eligible for neoadjuvant treatment.

- Clinical Stage II-IIIC (T2-4 N0-3 M0) by mammogram, ultrasound or MRI

- Baseline Oncotpye Dx recurrence score < 25.

- Staging studies with a CT scan of the chest and abdomen and bone scan, or a PET/CT is
required for clinical stage III, and are considered optional for stage II breast
cancers.

- Patients with multifocal, multicentric and synchronous bilateral 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 in both
breasts, diagnosed within 30 days of each other.

- In patients with multicentric or bilateral invasive breast cancers, all sampled
lesions must be hormone receptor-positive and HER2-negative. Any lesion measuring
> 1 cm must have an Oncotype Dx and the score must be < 25. Lesions less than 1
cm in size are not required to have an Oncotype Dx. One lesion (typically the
largest) should be designated as the target lesion for which clinical and
radiographic response to the neoadjuvant therapy will be judged.

- Patients with a hormone receptor-positive, HER2-negative invasive cancer that
meets study criteria may have ductal carcinoma in situ in another quadrant of the
same breast or in the contralateral breast even if the DCIS is hormone
receptor-negative.

- Patients must have adequate bone marrow function, as defined by peripheral granulocyte
count of ≥ 1,500/mL, hemoglobin ≥ 9 g/dL and a platelet count ≥ 100,000/ mL within 28
days prior to registration.

- Patients must have adequate hepatic function obtained within 28 days prior to
registration and documented by all of the following:

- Bilirubin ≤ 1.5 mg/dL (or ≤ 3.0 mg/dL if due to Gilbert's Syndrome)

- ALT and AST ≤ 1.5 x Institutional Upper Limit of Normal (IULN)

- Alkaline phosphatase ≤ 1.5 x IULN

- Patients must have adequate renal function with serum creatinine level ≤ IULN within
28 days prior to registration.

- Patients must have a fasting cholesterol ≤ 300 mg/dl OR ≤7.75 mmol/L and triglycerides
≤ 2.5 x IULN obtained within 28 days prior to registration. Patients may be on lipid
lowering agents to reach these values.

- Patients must have a ECOG performance status of 0-2.

- Patients must be able to take oral medications.

- Postmenopausal women (women are considered post-menopausal and not of child-bearing
potential if they are > 18 years of age and have had 12 months of natural
(spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate,
history of vasomotor symptoms or biochemically postmenopausal by estradiol and FSH
levels) prior to enrollment, or have had surgical bilateral oophorectomy (with or
without hysterectomy) prior to registration. Medical ovarian suppression with LHRH
agonists to render a patient postmenopausal will not be acceptable.

16. Patients or their legally authorized representative must be informed of the
investigational nature of this study and must sign and give written informed consent
prior to any screening procedures in accordance with institutional and federal
guidelines.

Exclusion Criteria:

- Patients must not have inflammatory breast cancer (T4d) and must not have metastatic
breast cancer (Stage IV disease).

- Patients must not have prior exposure to mTOR inhibitors (e.g. rapamycin, everolimus,
sirolimus, 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.

- Patient may not have any impairment of gastrointestinal function or gastrointestinal
disease that may significantly alter the absorption of the drug (e.g. ulcerative
disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small
bowel resection).

- Uncontrolled diabetes mellitus as defined by HbA1c >8% within 28 days prior to
registration despite adequate therapy.

- Patients who have any severe and/or uncontrolled cardiac disease within ≤ 6 months
prior to start of everolimus, including: unstable angina pectoris, Symptomatic
congestive heart failure of New York heart Association Class III or IV, myocardial
infarction, serious uncontrolled cardiac arrhythmia, or any other clinically
significant cardiac disease

- 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 a known history of HIV seropositivity

- Patients must not have a known diagnosis of hepatitis B or C. Patients with the
following risk factors must have hepatitis screening pre-treatment:

- Blood transfusions prior to 1990

- Current or prior IV drug users

- Current or prior dialysis

- Household contact with a hepatitis B or C patient

- Current or prior high-risk sexual activity

- History of jaundice.

- Patients must not have any known uncontrolled underlying pulmonary disease or severely
impaired lung function (spirometry and DLCO 50% or less of normal and O2 saturation
88% or less at rest on room air),

- Active (acute or chronic) or uncontrolled severe infection.

- Patients who have received live attenuated vaccines within 1 week of start of
Everolimus, or have plans to receive such vaccination while on protocol treatment.
Patient should also avoid close contact with others who have received live attenuated
vaccines. Examples of live attenuated vaccines include intranasal influenza, measles,
mumps, rubella, oral polio, BCG, yellow fever, varicella and TY21a typhoid vaccines;

- Patients who are currently part of or have participated in any clinical investigation
with an investigational drug within 1 month prior to dosing;

- Patients must not have taken within 14 days prior to registration , be taking, nor
plan to take while on protocol treatment, strong CYP3A4 inhibitors, and/or CYP3A4
inducers.

- Patients with active bleeding diathesis.