Trastuzumab and Pertuzumab or Bevacizumab With Combination Chemotherapy in Treating Patients With Stage II-III Breast Cancer

PRIMARY OBJECTIVES:

I. To determine if genomically derived 'molecular subtypes' predict pathological complete
response to combination chemotherapy and targeted therapy for HER2 early stage breast cancer.

SECONDARY OBJECTIVES:

I. To explore the ability of trastuzumab or pertuzumab response signatures to predict pCR in
HER2 positive tumors treated with brief exposure to trastuzumab or pertuzumab followed by
combination chemotherapy.

II. To explore the value of immune signatures as well as AKT and IGF signatures to predict
pCR in HER2 tumors treated with brief exposure to trastuzumab and pertuzumab.

III. To explore if comprehensive annotation of genomic alterations (mutations, copy number
alternations, gene fusions, non-coding RNA and splice variants) can further sub-stratify
subtype-based classifiers for prediction of response to targeted therapy in early stage
breast cancer IV. To explore if circulating RNA expression levels are associated with
treatment response V. To explore changes in cardiac function and identify early cardiac
injury using strain echocardiograms and cardiac biomarkers during treatment VI. To explore
immunohistochemistry-based markers of response to treatment

Objectives for Imaging Sub-Study: Secondary Objectives I. Evaluate the visualization of
primary breast tumors using analog and digital positron emission tomography (PET) with FDG
and FLT. II. Evaluate the quantification of FDG-uptake in primary breast tumors using analog
and digital PET with FDG and FLT. III. Compare the levels and changes in metabolic tumor
activity from analog and digital FDG-PET/CT or FLT-PET/CT with clinical follow up and other
procures include into CASE 14112 (such as DCE-MRI, genetic testing, etc.)

OUTLINE: Patients are assigned to 1 of 2 treatment cohorts based on HER2 status.

COHORT I (HER2 positive): Patients receive trastuzumab intravenously (IV) over 30-60 minutes,
and pertuzumab IV over 30-60 minutes, docetaxel IV, and carboplatin IV on day 1. Treatment
repeats every 3 weeks for 6 courses in the absence of disease progression or unacceptable
toxicity. As part of standard of care, each patient will receive three MRIs pre-treatment,
before biopsy is taken, and before surgery. Ten additional patients will be added to cohort 1
to take part in the imaging sub-study. These ten patients will follow the same procedure as
the other participants in cohort I but will have a PET/CT in place of the DCE-MRI

COHORT II (HER2 negative): Patients receive bevacizumab IV over 30-60 minutes on day 1 of
weeks 1, 3, 5, 7, 9, and 11; doxorubicin IV and cyclophosphamide IV over 30-60 minutes on day
1 of weeks 1, 3, 5, and 7; and paclitaxel IV over 3 hours on day 1 of weeks 9, 11, 13, and
15. Prior to receiving paclitaxel patients will receive the anti-nausea medication

After completion of study treatment, patients are followed up for 30 days.

Inclusion Criteria:

- Histologically confirmed adenocarcinoma of the breast, with sufficient tissue
available for estrogen receptor (ER), progesterone receptor (PR), and HER 2 testing

- HER2 must be positive by IHC or ISH testing by laboratory standard.

- Needle biopsy or incisional biopsy

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1

- Resectable disease-clinical stage I (T/0/N0miT1N0-N0mi), IIA-IIIA (T2 N0/T3N0 or T1-3
N1-N2a) or unresectable disease - clinical stage IIIB/IIIC (T4 or T1-3 N2b-3); no
evidence of metastatic disease

- No prior chemotherapy, hormonal therapy, or radiation therapy for this cancer

- Absolute neutrophil count (ANC) ≥1000/ul

- Platelet count ≥ 100,000/ul

- Hemoglobin ≥ 9 g/dl

- Serum creatinine ≤ 1.5 mg/dl or measured creatinine clearance of > 30 ml/min

- Total bilirubin ≤ upper limit of normal (ULN)

- Aspartate aminotransferase (AST) ≤ 2.5 x ULN

- Patients with multiple foci of invasive cancer in the same breast are eligible if any
single lesion meets the above size criteria and all sampled lesions are histologically
similar (whether radiographically detected lesions separate from the target lesion are
sampled for histologic evaluation is left to the discretion of the treating
physicians); the presence of ductal carcinoma in situ (DCIS) or lobular carcinoma in
situ (LCIS) in either breast will not render a patient ineligible; patients with a
small focus of invasive cancer detected the contralateral breast (clinical T1N0) are
eligible, however only the histologic response in the breast containing the target
lesions will be considered in determining the patient's pathologic response

- Measurable disease in the breast or axilla that measures at least 1 cm by either
clinical or radiographic measurement

Exclusion Criteria:

- Excisional biopsy

- Pregnant and lactating women are not eligible; all participants of reproductive age
must have a negative serum pregnancy test at baseline and agree to use an effective
barrier method of contraception during the entire period of treatment on the study

- Patients with New York Heart Association (NYHA) grade 2 or higher congestive heart
failure, myocardial infarction within the last 6 months, unstable angina pectoris, or
arterial thrombotic event with the past 12 months, uncontrolled hypertension (systolic
blood pressure > 150 and/or diastolic blood pressure > 100 on antihypertensive
medications; patients not on medication for high blood pressure who are found to have
systolic blood pressure [SBP] > 150 and/or diastolic blood pressure [DBP] > 100 should
have 3 documented episodes of elevated blood pressure before being considered
'uncontrolled', if they have 3 documented episodes of elevated blood pressure, then
can be started on antihypertensive medications; patients currently on antihypertensive
medications with elevated blood pressures as defined above may have their medications
adjusted; if patients have persistent [3 episodes] of high blood pressure despite
medication adjustment they will be considered ineligible for study participation; each
measured episode should be 24 hours apart), prior history of hypertensive crisis or
hypertensive encephalopathy, uncontrolled or clinically significant arrhythmia, grade
II or greater peripheral vascular disease or prior history of stroke or transient
ischemic attack (TIA); patient must have a pretreatment multi gated acquisition scan
(MUGA) scan or echocardiogram with left ventricular ejection fraction (LVEF) above
lower limit of normal

- No non-breast malignancy within the past 5 years other than treated squamous or basal
cell carcinoma of the skin or CIS of the cervix

- Patients known to be human immunodeficiency virus (HIV) positive are not eligible for
the study given their potentially compromised immune systems and increased risk of
treatment-related toxicity

- Advanced (T1N1-4/T2-3 N any) invasive cancer in the contralateral breast

- Any known history of cerebrovascular disease including TIA, stroke or subarachnoid
hemorrhage

- Patients must not have a non-healing wound or fracture

- Patients with an abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 6 months

- Patients must not have a bleeding diathesis, hereditary of acquired bleeding disorder
or coagulopathy

- Patients on therapeutic doses of Coumadin or Lovenox are ineligible to participate in
study

- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to study enrollment or anticipation of need for major surgical procedure during
the course of the study; core biopsy or other minor surgical procedure, for example
placement of a vascular access device, are excluded from this requirement

- No known hypersensitivity to any component of bevacizumab