Hormone Therapy With or Without Combination Chemotherapy in Treating Node-Negative Breast Cancer (The TAILORx Trial)

PRIMARY OBJECTIVES:

I. To determine whether adjuvant hormonal therapy is not inferior to adjuvant chemohormonal
in women whose tumors meet established clinical guidelines for adjuvant chemotherapy and fall
in the "primary study group" category (Oncotype DX Recurrence Score 11-25).

II. To create a tissue and specimen bank for patients enrolled in this trial, including
formalin fixed paraffin embedded tumor specimens, tissue microarrays, plasma, and
deoxyribonucleic acid (DNA) obtained from peripheral blood.

SECONDARY OBJECTIVES:

I. To determine whether adjuvant hormonal therapy is sufficient treatment (i.e. 10 year
distant disease-free survival of at least 95%) for women whose tumors meet established
clinical guidelines for adjuvant chemotherapy and who fall into the "Secondary Study Group-1"
category (Oncotype DX Recurrence Score =< 10).

II. To compare the outcomes projected at 10 years by Adjuvant (with outcomes projected using
classical pathologic information including tumor size, hormone receptor status, and
histologic grade) with those made by the Genomic Health Oncotype DX test. Classical
pathologic information and outcome results will also be used to create and refine models that
would use classical information instead of or in combination with genomic tests.

III. To estimate failure rates as a function of recurrence score (RS) separately in the
chemotherapy (arms C, D) and no chemotherapy (arms A, B) groups. The purpose of the analysis
is to develop more precise estimates of the relationship between recurrence score and
chemotherapy treatment effect, if any, at the upper range of the RS 11 - 25 group.

IV. To determine the prognostic significance of the Oncotype DX recurrence score and of the
individual RS gene groups (proliferation gene group, human epidermal growth factor receptor
[HER]2 gene group, estrogen receptor [ER] gene group, invasion gene group, and other genes).

TERTIARY OBJECTIVES:

I. To evaluate the effects of chemotherapy and hormonal therapy vs hormonal therapy alone on
perceived cognitive impairment, fatigue, fear of recurrence among pre-menopausal patients,
endocrine symptoms and sexual dysfunction, and overall health-related quality of life (HRQL).

II. To determine whether perceived cognitive impairment, fatigue, fear of recurrence,
endocrine symptoms, and overall HRQL are similar for patients receiving chemotherapy plus
hormonal therapy in secondary study group 2 as for those in the primary study group (arm D vs
C).

III. To determine whether perceived cognitive impairment, fatigue, fear of recurrence,
endocrine symptoms, and overall HRQL are similar for patients receiving hormonal therapy
alone in secondary study group 1 as for those in the primary study group (arms A vs B).

IV. To determine whether age will be inversely associated with a fear of recurrence,
independent of treatment assignment.

V. Among participants receiving hormonal treatment alone on arm A and arm B, to determine
whether Oncotype DX Recurrence score will be inversely correlated with fear of recurrence.

VI. To create a biospecimen repository including plasma, serum and CellSearch cassettes
containing circulating tumor cells (CTC) for evaluating determinants of late relapse,
including candidate biomarkers reflecting occult tumor burden (e.g., CTCs and plasma tumor
DNA) and host factors (e.g., estrogen, insulin growth factor-[IGF] axis, inflammation, etc).

VII. To create a biorepository of metastatic tumor samples in patients who have had a late
relapse.

VIII. To determine body mass index (BMI) and comorbidity burden in patients with operable
breast cancer five or more years after diagnosis.

IX. To determine whether there is a relationship between late relapse and BMI at diagnosis
and at 5 years after diagnosis, and whether BMI-associated inflammatory and/or metabolic
biomarkers are associated with early and late recurrence.

OUTLINE: This is a partially randomized study. Patients are assigned to 1 of 3 treatment
groups.

GROUP 1 (SECONDARY STUDY GROUP 1; ONCOTYPE DX RECURRENCE SCORE [ODRS] =< 10): Patients
receive standard hormonal therapy (e.g., tamoxifen alone orally (PO), aromatase inhibitor
[e.g., anastrozole, letrozole, or exemestane] alone PO, or tamoxifen PO followed by aromatase
inhibitor PO) at the discretion of the treating physician for 5 or 10 years (Arm A).

GROUP 2 (PRIMARY STUDY GROUP; ODRS 11-25): Patients are randomized to receive either hormonal
therapy alone (Arm B) or combination chemotherapy and hormonal therapy (Arm C).

Arm B (EXPERIMENTAL): Patients receive hormonal therapy as in Group 1 at the discretion of
the treating physician.

Arm C (STANDARD): Patients receive standard combination chemotherapy at the discretion of the
treating physician. Within 4 weeks after the last dose of chemotherapy, patients receive
hormonal therapy as in Group 1 at the discretion of the treating physician.

GROUP 3 (SECONDARY STUDY GROUP 2; ODRS >= 26): Patients receive combination chemotherapy as
in Group 2, Arm C followed by hormonal therapy as in Group 1. (Arm D)

Patients in all groups who have had breast-conservation surgery are also treated with
radiotherapy. Radiotherapy should begin within 4 weeks of registration for patients receiving
hormonal therapy alone or within 8 weeks after completion of chemotherapy. Patients
participating in National Surgical Adjuvant Breast and Bowel Project (NSABP) and/or Radiation
Therapy Oncology Group (RTOG) partial irradiation trial(s) may receive partial breast
radiation.

PROJECTED ACCRUAL: 11248 patients

FOLLOW UP: After completion of study treatment, patients are followed up every 3-6 months for
5 years and then annually up to 20 years.

Inclusion Criteria:

- Patients with operable histologically confirmed adenocarcinoma of the female breast
who have completed primary surgical treatment and meet the following criteria:

- ER and/or progesterone receptor (PR)-positive: Estrogen and/or progesterone
receptor positive disease (as defined by local pathology laboratory)

- Negative axillary nodes: As assessed by a sentinel lymph node biopsy, an axillary
dissection, or both, and as defined by the Sixth Edition of the American Joint
Committee on Cancer (AJCC) staging criteria

- Tumor size 1.1-5.0 cm (or 5 mm-1.0 cm plus unfavorable histological features):

- Unfavorable features defined as intermediate or poor nuclear and/or
histologic grade, or lymphovascular invasion

- NOTE: Definition of tumor size: The tumor size used for determination of
eligibility is the pathologic tumor size, which is usually determined by the
size of the tumor as measured by inspection of the gross specimen; if the
tumor size is measured microscopically and the tumor includes ductal
carcinoma in-situ, the measurement should include only the invasive
component of the tumor

- The tumor must be human epidermal growth factor receptor 2 (Her2)/neu negative by
either fluorescent in-situ hybridization (FISH) or immunohistochemistry (e.g. 0
or 1+ by DAKO Herceptest)

- The patient and physician must be agreeable to initiate standard chemotherapy and
hormonal therapy as adjuvant therapy

- A tissue specimen from the primary breast cancer has been located and is ready to be
shipped to the appropriate laboratory after consent is obtained and within 3 days
following pre-registration; NOTE: For determination of the Oncotype Recurrence Score,
tissue must be shipped to Genomic Health; if the Oncotype DX Recurrence Score was
previously performed by Genomic Health (prior to pre-registration), tissue must be
submitted to the Eastern Cooperative Oncology Group (ECOG)-American College of
Radiology Imaging Network (ACRIN) Central Biorepository and Pathology Facility upon
randomization

- Leukocyte count >= 3500/mm^3

- Platelets >= 100,000/mm^3

- Serum creatinine =< 1.5 mg/dL

- Serum aspartate transaminase (AST) that is =< 3-fold the upper institutional limits of
normal

- Patients must be disease-free of prior invasive malignancies for >= 5 years with the
exception of curatively-treated basal cell or squamous cell carcinoma of the skin or
carcinoma in situ of the cervix; patients with a previous ipsilateral or contralateral
invasive breast cancer, or with bilateral synchronous cancers, are not eligible;
patients with previous ipsilateral or contralateral ductal in situ carcinoma (DCIS)
are not eligible

- Prior treatment

- Mandatory prior surgery criteria:

- Patient must pre-register within 84 days from the final surgical procedure
required to adequately treat the primary tumor (please note that if margins
are not clear and a resection has to be conducted after pre-registration but
before randomization, the patient will be deemed to be within the 84 day
window allowed by protocol and therefore eligible)

- All tumors should be removed by either a mastectomy or local excision plus
an acceptable axillary procedure (i.e., sentinel lymph node biopsy, axillary
dissection, or both); there must be adequate (at least 1 mm if margin width
specified) tumor-free margins of resection (for invasive and ductal
carcinoma in-situ) in order for the patients to be eligible; patients with
lobular carcinoma in-situ involving the resection margins are eligible

- Criteria re: other prior treatments:

- No prior chemotherapy for this malignancy

- No prior radiation therapy for this malignancy; this includes no prior
MammoSite Brachytherapy radiation therapy (RT)

- Hormonal therapy: Patients who develop breast cancer while receiving a
selective estrogen-receptor modulator (SERM; e.g., tamoxifen, toremifene,
raloxifene) or an aromatase inhibitor (e.g., anastrazole, letrozole,
exemestane) for breast cancer prevention or a SERM for other indications
(e.g., raloxifene for osteoporosis) are not eligible; however, patients may
have received up to 8 weeks of a SERM or aromatase inhibitor for this
malignancy and still be eligible for study entry

- Patients must have an anticipated life expectancy of at least 10 years

- Women must not be pregnant or breast-feeding; all females of childbearing potential
must have a blood test or urine study within 2 weeks prior to pre-registration to rule
out pregnancy

- Women of childbearing potential must be strongly advised to utilize an accepted
and effective form of non-hormonal contraception (e.g. intrauterine device,
condoms, diaphragm, abstinence)

- Patients must not have previously had the Oncotype DX Assay performed, with the
exception of patients who have had the assay performed and have a recurrence score of
11-25

Exclusion Criteria:

- Patients with the following medical conditions should not be enrolled on the study:

- Chronic obstructive pulmonary disease requiring treatment

- Chronic liver disease (e.g., cirrhosis, chronic active hepatitis)

- Previous history of a cerebrovascular accident

- History of congestive heart failure or other cardiac disease that would represent
a contraindication to the use of an anthracycline (e.g., doxorubicin or
epirubicin)

- Chronic psychiatric condition or other condition that would impair compliance
with the treatment regimen