Trial to Evaluate Genomic Expression Profiles to Direct Preoperative Chemotherapy in Early Stage Breast Cancer

Primary Objective 1 was to test for an arm difference in pathological complete response
rates. Secondary Objective 2 was to estimate and test the difference in pathologic complete
response rates between drug-sensitive patients who received their preferred drug and
drug-resistant patients randomized to AC or TC.

Secondary objectives included: to determine the 60% cutoff for the genomic profiles resulted
in a larger pathologic CR rate for the guided arm than for the unguided arm; to compare the
pathologic CR rates of patients whose genomic predictive probabilities indicated that they
were resistant to both chemotherapy regimens with the pathologic CR rates of patients whose
genomic predictive probabilities indicated that they were sensitive to only one treatment
and who were then randomly assigned to a treatment for which they were resistant (combining
AC and TC subgroups); Secondary Objective 3 in patients with T2 and T3 tumors classified as
requiring mastectomy at baseline, compare the guided and non-guided treatment arms on rates
of breast conserving surgery with negative final margins; Secondary Objective in patients
with T2 tumors classified as potential candidates for breast conservation, compare the
guided and non-guided arms on rates of breast conserving surgery at first attempt; Secondary
Objectives 5, 6, 7 and 8 to correlate genomic profiles (i.e., genomic predictive
probabilities) with clinical response, disease-free survival, sites of recurrence, and
overall survival; Secondary Objective 9:to compare the mean cost of guided versus non-guided
treatment; and Secondary Objective 10 to assess patient perceptions of participating in a
clinical trial that evaluated cancer genomics for preoperative systemic therapy of
early-stage breast cancer.

Objective 10 details: Due to space limitations in the Outcome Measure Description field,
details are supplied here:

To assess patient motivation and participation for study participation in a clinical trial
evaluating cancer genomics for treatment patients provided responses for the following
questions at both baseline (the day of chemotherapy start) and following post-surgical
medical oncology evaluation:

One of the goals of this study is to tailor your cancer treatments for you based upon a
genomic analysis of your tumor. How much did the knowledge that the treatment is potentially
tailored specifically for your tumor influence your decision to participate in this study?
(Select One)

Response 1: I did not know that the treatment was tailored.

Response 2: I do not understand what "tailored treatment based upon genomic analysis of "my
tumor" means.

Response 3: The information that this was a tailored treatment based upon genomic analysis
of my tumor decreased my willingness to participate in this study.

Response 4: The information that this was a tailored treatment based upon genomic analysis
of my tumor was of neutral value in the decision making process to participate in this study
and did not influence my decision to participate.

Response 5: The information that this was a tailored treatment based upon genomic analysis
of my tumor played a minor role in helping me decide to participate in the study.

Response 6: The information that this was a tailored treatment based upon genomic analysis
of my tumor played a major role in helping me decide to participate in the study.

Response 7: The information that this was a tailored treatment based upon genomic analysis
of my tumor was the primary reason that I decided to participate in the study.

Inclusion Criteria:

1. Histologic Documentation: Patients must have a histologic (i.e., not just cytologic)
diagnosis of invasive breast cancer by core biopsy. Excisional biopsy or incisional
biopsy is not allowed. All breast cancer histologic types are allowed.

2. Stage: Any patient with a clinical T1c (>1.5 cm) to T3 invasive breast cancer by the
revised TNM staging system (AJCC 6th edition) will be eligible. Any N stage disease
is allowed. No distant metastases allowed.

3. Tumor Site: Patients must have invasive cancer in the breast. Multifocal disease
(i.e. confined to a single quadrant in the same breast) is allowed. Multicentric
disease (i.e. disease in multiple breast quadrants) is not allowed. Determination of
multifocal and multicentric disease status will be made by the evaluating surgeon;
ambiguous cases will be reviewed by the principal investigator. Patients with
synchronous contralateral invasive breast cancers are not eligible; prior
contralateral breast cancer allowed as long as patient has not received prior
chemotherapy or radiation therapy in the past 5 years.

4. Measurable Disease: Patients must have measurable disease in the breast by imaging
studies (mammogram, ultrasound, or MRI), and must be greater than 1.5 cm in at least
one dimension by one or more of the imaging assessments.

5. Conventional Biomarker Status: Standard clinical biomarkers for ER, PR, and HER2 must
be obtained on the initial diagnostic core biopsy. The invasive cancer must be HER2
negative (i.e. immunohistochemistry score 1-2+ and/or FISH non-amplified). Any ER/PR
status is allowed. Patients who are HER2 2+ on initial immunohistochemistry
assessment will be further assessed by FISH. In this instance, patient will be
consented and further screened for eligibility and have tissue acquired for genomic
profiling. If the standard of care additional FISH testing is positive for HER2 gene
amplification, the patient will not be randomized and will be treated in the same
manner as screen failures.

6. Must be deemed a surgical candidate.

7. Fresh tissue biopsy material must be available for genomics analysis.

8. No prior chemotherapy, radiotherapy, or biologic/targeted therapy for the currently
diagnosed breast cancer, or any other malignancy in the past 5 years, is allowed. No
prior anthracycline or taxane therapy.

9. Prior malignancies are allowed if the patient is considered to be disease-free for 5
or more years and is deemed to be at low risk for recurrence. Patients with any prior
diagnosis of in situ malignancies (melanoma, bladder, colon, cervical, basal cell, or
squamous carcinoma) are eligible regardless of time from diagnosis.

10. Aged at least 18 years.

11. ECOG Performance Status 0-1.

12. Adequate Organ Function:

1. Total bilirubin ≤1.0 x the institutional ULN

2. Hepatic enzymes (AST (SGOT), ALT (SGPT)) ≤1.5x the institutional ULN

3. Alkaline Phosphatase ≤2.5 x ULN

4. Serum creatinine ≤2.0 mg/dl

5. Neutrophil count (ANC or AGC) ≥1000/ μL

6. Platelets ≥100,000/ μL

7. Cardiac Ejection Fraction ≥50% by MUGA, Echo or MRI.

13. Significant cardiac disease that would preclude the use of anthracyclines: No
myocardial infarction in the last 6 months; history of congestive heart failure,
serious cardiac arrhythmia requiring medication, active coronary artery
disease/angina pectoris requiring therapy, uncontrolled hypertension defined as BP
>150/90 despite medication; any other unstable cardiac condition as perceived by
treating physician or study PI.

14. No other serious medical or psychiatric illness.

15. Pregnancy: Patients may not be pregnant or nursing at the time of enrollment and
other restrictions apply.

16. Signed written informed consent including HIPAA.

Exclusion Criteria:

1. Patients who have received investigational drugs within 4 weeks prior to starting study
drug and/or who have not recovered from side effects of such therapy are not eligible.