A Phase II Trial of Neoadjuvant PD 0332991, a Cyclin-Dependent Kinase (Cdk) 4/6 Inhibitor, in Combination With Anastrozole in Women With Clinical Stage 2 or 3 Estrogen Receptor Positive and HER2 Negative Breast Cancer

Inclusion Criteria:

Patients who were pre-registered to NCI 9170 trial (Phase II Trial of Neoadjuvant MK-2206
in Combination with either Anastrozole if Postmenopausal or Anastrozole and Goserelin if
Premenopausal in Women with Clinical Stage 2 or 3 PIK3CA Mutant Estrogen Receptor Positive
and HER2 Negative Invasive Breast Cancer), started anastrozole (or anastrozole plus
goserelin if premenopausal) < 4 weeks, and were found negative for PIK3CA hotspot
mutations are eligible to be screened for this trial.

-Clinical T2-T4c, any N, M0 invasive ER+ (Allred Score of 6-8) and HER2 negative (0 or 1+
by IHC or FISH negative for amplification) breast cancer, by AJCC 7th edition clinical
staging, with the goal being surgery to completely excise the tumor in the breast and the
lymph node.

Note: If the patient has invasive or DCIS in the contralateral breast the patient is
ineligible

- Pre-registered to the NCI 9170 trial (A Phase II Trial of Neoadjuvant MK-2206 in
Combination with either Anastrozole if Postmenopausal or Anastrozole and Goserelin if
Premenopausal in Women with Clinical Stage 2 or 3 PIK3CA Mutant Estrogen Receptor
Positive and HER2 Negative Invasive Breast Cancer), but negative for PIK3CA hotspot
mutations.

- Female ≥18 years of age.

- ECOG performance status of 0, 1 or 2.

- Life expectancy > 4 months.

- If premenopausal, serum estradiol level must be in the postmenopausal range per
institutional standard within 7 days prior to registration.

- If premenopausal, patient must be willing to comply with pregnancy requirements

- Adequate organ and marrow function as defined below:

- leukocytes ≥ 3,000/mcL

- absolute neutrophil count ≥ 1,500/mcL

- platelets ≥ 100,000/mcL

- total bilirubin within normal institutional limits

- AST(SGOT)/ and ALT(SGPT) ≤ 2.5 X institutional upper limit normal

- Creatinine within normal institutional limits

- Serum potassium within normal institutional limits

- Magnesium within normal institutional limits

- Calcium within normal institutional limits

- Able to understand and willing to sign an IRB-approved written informed consent
document.

Exclusion Criteria:

- The following for treatment of this cancer including:

- Surgery

- Radiation therapy

- Chemotherapy

- Biotherapy

- Hormonal therapy (except anastrozole and GnRH agonist within 42 days prior to
registration)

- Investigational agent prior to study entry (except MK-2206 on NCI9170 trial).

- Receiving any other investigational agents.

- Prior therapy with any Cdk4 inhibitor.

- Corrected QT (QTc) interval >470 msec.

- Receiving medications (within the last 7 days prior to registration) that hve the
potential of prolonging the CT interval.

- Current use or anticipated need for food or drugs that are known strong CYP3A4
inhibitors (i.e. grapefruit juice, verapamil, ketoconazole, miconazole, itraconazole,
posaconazole, erythromycin, clarithromycin, telithromycin, indinavir, saquinavir,
ritonavir, nelfinavir, lopinavir, atazanavir, amprenavir, fosamprenavir, nefazodone,
diltiazem, and delavirdine).

- Any of the following in the previous 6 months:

- myocardial infarction

- severe/unstable angina

- coronary/peripheral artery bypass graft

- symptomatic congestive heart failure

- cerebrovascular accident

- transient ischemic attack

- symptomatic pulmonary embolism.

- Uncontrolled intercurrent illness including, but not limited to:

- ongoing or active infection

- symptomatic congestive heart failure

- unstable angina pectoris

- uncontrolled symptomatic cardiac arrhythmia,

- psychiatric illness/social situations that would limit compliance with study
requirements.

- Pregnant/nursing.

- Unwilling to employ adequate contraception.

- Known HIV-positive on combination antiretroviral therapy.

NOTE: HIV-positive patients on combination antiretroviral therapy are ineligible because
of the potential for pharmacokinetic interactions with PD 0332991. In addition, these
patients are at increased risk of lethal infections when treated with marrow-suppressive
therapy.

- Evidence of inflammatory cancer (clinical presentation of skin erythema involving
more than one third of the breast or pathological evidence of dermal lymphatic
involvement)

- Known metastatic disease.

- Current use of anticoagulation therapy.

- Previous excisional biopsy of the breast cancer or sentinel lymph node biopsy.

- Any condition that impairs patient's ability to swallow PD 0332991 tablets (e.g.,
gastrointestinal tract disease resulting in an inability to take oral medication or a
requirement for IV alimentation, prior surgical procedures affecting absorption)

- History of other malignancy ≤ 5 years previous with the exception of basal cell or
squamous cell carcinoma of the skin which were treated with local resection only or
carcinoma in situ of the cervix.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to PD 0332991 or other agents used in the study.

- Inclusion of Women and Minorities: Women and members of all races and ethnic groups
are eligible for this trial.