Molecular Testing and Imaging in Improving Response in Patients With Stage I-III Triple-Negative Breast Cancer Receiving Chemotherapy MDACC Breast Moonshot Initiative

PRIMARY OBJECTIVES:

I. To conduct a prospective single arm, non-randomized trial to determine the impact of
implementation of a research platform that includes diagnostic imaging to assess response to
the initial phase of neoadjuvant chemotherapy combined with subtyping of TNBC in order to
select the appropriate targeted therapy trial to complete neoadjuvant chemotherapy in
patients found to have chemo-insensitive disease by imaging.

SECONDARY OBJECTIVES:

I. Measured as defined by Standardized Definitions for Efficacy End Points (STEEP) criteria
using the following prioritization: distant recurrence free interval (DRFI), recurrence free
survival (RFS), distant relapse-free survival (DRFS), overall survival (OS), invasive disease
free survival (IDFS), disease free survival including ductal carcinoma in situ (DFS-DCIS).

II. Compare the rates of enrollment into therapeutic clinical trials between the two arms of
the trial, i.e. those who do, versus do not, receive the results of molecular genomic
prediction of chemotherapy response.

III. Compare the frequency of pathologic response rates of tumors between the two arms of the
trial for the patients whose tumor was molecularly classified as chemotherapy-sensitive or
chemotherapy-insensitive, and in whose NACT followed the recommendation of the trial schema.

IV. Compare the estimates of DRFI, RFS, DRFS, IDFS and DFS-DCIS at 3 years, and OS at 5
years, between the two arms of the trial for the patients whose tumor was molecularly
classified as chemotherapy-sensitive or chemotherapy-insensitive, and for whose NACT followed
the recommendation of the trial schema.

V. Compare the pathologic response rates between the two arms of the trial for the patients
whose tumor was molecularly classified as a molecular subset (breast cancer
[BRCA]-associated, mesenchymal, androgen receptor positive, and other) between the two arms
of the trial, and whose NACT followed the recommendation of the trial schema.

VI. Compare the estimates of DRFI, RFS, DRFS, IDFS and DFS-DCIS at 3 years, and OS at 5
years, between the two arms of the trial for the patients whose tumor was molecularly
classified as a molecular subset (BRCA-associated, mesenchymal, androgen receptor positive,
and other), and whose NACT followed the recommendation of the trial schema.

VII. Subset analyses of pathologic response and 3-year DRFI, RFS, DRFS, IDFS and DFS-DCIS.
Estimate for the subsets where gene expression levels of receptor status (estrogen receptor
[ER], progesterone receptor [PR] and human epidermal growth factor receptor 2 [HER2]) were,
or were not concordant with TNBC status as defined by routine diagnostic tests
(immunohistochemistry and/or fluorescent in situ hybridization).

VIII. Compare the results of pathologic node-negative status (sentinel and/or non-sentinel
nodes) after neoadjuvant chemotherapy according to a genomic predictor of nodal response to
NACT, in subsets defined by pre-treatment clinical nodal status.

TERTIARY OBJECTIVES:

I. Future re-analysis of residual samples using a customized genomic diagnostic platform
(integrated "prospective-retrospective" biomarker analysis) to predict chemotherapy
sensitivity.

II. Generation and subsequent molecular characterization of patient derived xenograph (PDX)
models.

III. Clinical diagnostic development studies using residual samples (fresh and/or
formalin-fixed) within the Clinical Laboratory Improvement Amendments (CLIA)-compliant
Molecular Diagnostics Laboratory and patient derived xenographs (PDX), to formally evaluate
the clinical validity and utility of future clinical genomic diagnostic tests that would
predict both response and survival from the treatments used in this clinical trial
(correlative "retrospective-prospective" biomarker analyses).

IV. Correlative science studies to identify molecular therapeutic targets for
treatment-insensitive TNBC using residual samples and PDX models.

V. Correlation of changes in diagnostic imaging to determine potential predictions of
treatment responses.

OUTLINE:

Patients undergo baseline molecular and IHC evaluation of their tumor biopsy, and receive the
results. Patients then receive standard anthracycline-based chemotherapy and undergo standard
ultrasound at baseline, after 2 courses, and after 4 courses of treatment. Patients and
physicians are notified of the results of the molecular evaluation within 12 weeks. Patients
may then choose to continue with standard taxane +/- platinum-based chemotherapy or
participate in an experimental clinical trial designed to match the molecular profile and
triple-negative subtype. Patients with tumors predicted to be insensitive to chemotherapy are
advised to participate in a clinical trial treating their tumor subtype.

After completion of study treatment, patients are followed up for up to 5 years.

Inclusion Criteria:

- The patient can undergo biopsy or surgery of a primary tumor site for suspected or
proven invasive breast cancer of clinical stage I to III

- The clinical or radiologic primary tumor size is at least 1.5 cm diameter

- The patient was proven to have TNBC, defined from standard pathologic assays as
negative for ER and PR (< 10% tumor staining) and negative for HER2
(immunohistochemistry [IHC] score < 3, gene copy number not amplified)

- Primary tumor sample was collected before NACT began and was evaluated for genomic
testing (integral biomarker)

- Patients must have left ventricular ejection fraction (LVEF) > 50% by multi gated
acquisition scan (MUGA) or echocardiogram (ECHO) within 4 weeks prior to registration

- Leukocytes > 3,000/mcL

- Absolute neutrophil count > 1,500/mcL

- Platelets > 100,000/mcL

- Total bilirubin within normal institutional limits

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
< 2.5 x institutional upper limit of normal

- Creatinine within normal institutional limits OR creatinine clearance > 60 mL/min/1.73
m^2 for patients with creatinine levels above institutional normal

Exclusion Criteria:

- The patient has diagnosis of stage IV disease or is found to have stage IV disease
prior to randomization

- Prior history of invasive cancer within 5 years of study entry or history of
metastatic cancer; exceptions include non-metastatic, curatively treated basal and
squamous cell carcinoma of the skin

- Prior excisional biopsy of the primary invasive breast cancer

- Patients with hematomas or biopsy site changes that limit response assessment of the
primary tumor by diagnostic imaging

- Patients not eligible for chemotherapy with taxane and/or anthracycline based
chemotherapy regimens

- Prior therapy with anthracyclines

- Grade II or higher neuropathy

- Patients with Zubrod performance status of > 2

- Patients with history of serious cardiac events defined as:

- Patients with a history of New York Heart Association class 3 or 4 heart failure,
or history of myocardial infarction, unstable angina or cerebrovascular accident
(CVA) within 6 months of protocol registration

- Patients who have history of PR prolongation (grade 2 or higher) or
atrioventricular (AV) block