Hormone Therapy Or Chemotherapy Before Surgery Based on Gene Expression Analysis in Treating Patients With Breast Cancer

OBJECTIVES:

I. To determine the feasibility of carrying out a large-scale multi-center trial in which RS
would be used to select treatment type in the neoadjuvant setting and whether patients with
intermediate RS are willing to be randomized between hormonal and chemotherapy.

II. To determine whether the type of neoadjuvant therapy (hormonal versus cytotoxic
chemotherapy) chosen on the basis of gene expression profiling will result in consistently
high rates of objective clinical responses in all patients.

III. To determine whether the type of neoadjuvant therapy (hormonal versus cytotoxic
chemotherapy) chosen on the basis of gene expression profiling will facilitate planned
breast-conserving therapy.

IV. To determine whether choosing the type of neoadjuvant therapy (hormonal versus cytotoxic
chemotherapy) on the basis of gene expression profiling will optimize the proportion of
patients overall who have a clinical complete response (cCR).

V. To determine whether choosing the type of neoadjuvant therapy (hormonal versus cytotoxic
chemotherapy) on the basis of gene expression profiling will optimize the pathologic
complete response (pCR) rate in the breast of patients receiving cytotoxic chemotherapy.

VI. To determine whether choosing the type of neoadjuvant therapy (hormonal versus cytotoxic
chemotherapy) on the basis of gene expression profiling will optimize the pCR rate in the
breast and nodes of patients receiving cytotoxic chemotherapy.

VII. To determine whether choosing the type of neoadjuvant therapy (hormonal versus
cytotoxic chemotherapy) on the basis of gene expression profiling will increase the
proportion of patients with Class 0 and 1 residual cancer burden (RCB) in patients receiving
cytotoxic chemotherapy.

OUTLINE: Patients are assigned to 1 of 3 groups based on recurrence score (RS) following
Oncotype Dx gene expression profiling.

GROUP I (Recurrence Score < 11): Patients receive neoadjuvant hormonal therapy comprising
tamoxifen (pre-menopausal women) or an aromatase inhibitor (post-menopausal women) for 4-6
months in the absence of disease progression or unacceptable toxicity.

GROUP II (Recurrence Score 11-25): Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive neoadjuvant hormonal therapy as in group I.

ARM II: Patients receive 6-8 courses of neoadjuvant chemotherapy comprising an
anthracycline/taxane based regimen over 4-6 months in the absence of disease progression or
unacceptable toxicity.

GROUP III (Recurrence Score > 25): Patients receive neoadjuvant chemotherapy as in arm II of
group II.

All patients then undergo surgery and receive hormonal therapy for at least 5 years.

After completion of study treatment, patients are followed up periodically.

Inclusion Criteria:

- The treating surgeon must determine that breast conservation therapy (BCT) would be
made more feasible by reducing tumor size using neoadjuvant systemic therapy

- The patient must have signed and dated an institutional review board (IRB)

- approved consent form that conforms to federal and institutional guidelines

- The patient must be female

- The patient must be greater than or equal to 18 years old

- The patient must have an Eastern Cooperative Oncology Group Score (ECOG) performance
status of 0 or 1

- The diagnosis of invasive carcinoma of the breast must have been made by core needle
biopsy

- The primary breast tumor must be >= 2 cm by physical exam or imaging

- Ipsilateral axillary lymph nodes must be evaluated by imaging (MRI or ultrasound)
within 6 weeks prior to randomization; If indicated for abnormal lymph nodes, fine
needle aspirate (FNA) or core biopsy must be performed.

- The tumor must have been determined to be HER2-negative as follows: fluorescent in
situ hybridization (FISH)-negative (defined by ratio of HER2 to Chromosome 17
centromere (CEP17) must be < 2.2) or, if a ratio was not performed, the HER2 gene
copy number must be < 4 per nucleus; or if Cytokine-inducible SH2-containing protein
(CISH) is performed, the result must indicate a HER2 gene copy number of < 6 per
nucleus; or immunohistochemistry (IHC) 0-1+; or IHC 2+ and FISH-negative or
CISH-negative

- The tumor must have been determined to be ER+ and/or progesterone positive (PgR+)
defined as > 10% tumor staining by immunohistochemistry

- The patient must be considered by the treating medical oncologist to be medically
able to tolerate standard cytotoxic chemotherapy regimens

Exclusion Criteria:

- FNA alone to diagnose the primary tumor

- Excisional biopsy or lumpectomy performed prior to randomization

- Surgical axillary staging procedure or sentinel node (SN) biopsy performed prior to
randomization

- Tumors clinically staged as including inflammatory breast cancer

- Ipsilateral cN2b or cN3 disease; (patients with cN1 or cN2a disease are eligible)

- Definitive clinical or radiologic evidence of metastatic disease; (Note: chest
imaging [mandatory for all patients] and other imaging [if required] must have been
performed within 6 weeks prior to randomization)

- Synchronous or metachronous contralateral invasive breast cancer; (patients with
synchronous and/or metachronous contralateral ductal carcinoma in situ (DCIS) or
lobular carcinoma in situ (LCIS) are eligible)

- HER2 test result of IHC 3+, regardless of FISH results, if performed

- Any history of ipsilateral invasive breast cancer or ipsilateral DCIS if treated with
radiation therapy (RT); (patients with synchronous or metachronous ipsilateral LCIS
are eligible)

- History of non-breast malignancies, except for in situ cancers treated only by local
excision and basal cell and squamous cell carcinomas of the skin, within 5 years
prior to randomization

- Treatment including RT, chemotherapy, and/or targeted therapy for the currently
diagnosed breast cancer prior to randomization

- Cardiac disease (history of and/or active disease) that would preclude the use of
chemotherapy

- Pregnancy or lactation at the time of randomization; (Note: pregnancy testing must be
performed within 2 weeks prior to randomization for women of childbearing potential)

- Other non-malignant systemic disease that would preclude the patient from receiving
study treatment or would prevent required follow-up

- Psychiatric or addictive disorders or other conditions that, in the opinion of the
investigator, would preclude the patient from meeting the study requirements

- Use of any investigational product within 30 days prior to randomization