Tamoxifen Citrate, Letrozole, Anastrozole, or Exemestane With or Without Chemotherapy in Treating Patients With Invasive RxPONDER Breast Cancer

PRIMARY OBJECTIVES:

I. To determine the effect of chemotherapy in patients with node positive breast cancer who
do not have high recurrence scores (RS) by Oncotype DX.

SECONDARY OBJECTIVES:

I. To compare overall survival (OS), distant disease-free survival (DDFS) and local
disease-free interval (LDFI) by receipt of chemotherapy or not and its interaction with RS.

II. To compare the toxicity across the treatment arms. III. To perform other assays or tests
(in particular the prediction analysis of microarray [PAM50] risk of relapse score), as they
are developed and validated that measure potential benefit of chemotherapy and compare them
to Oncotype DX.

IV. To determine the impact of management with Oncotype DX on patient-reported anxiety
(co-primary Health-Related Quality of Life [HRQL] outcome) prior to screening, after
disclosure of test results, and during the randomized trial.

V. To determine the impact of Oncotype DX on the initial management cost of node-positive,
hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative
breast cancer.

VI. To compare patient-reported utilities (e.g., quality of life [QOL]) for those randomized
to chemotherapy versus no chemotherapy.

VII. Using modeling and DFS information from the trial, to estimate the cost-effectiveness of
management with Oncotype DX vs usual care.

VIII. To determine the role of other assays (e.g., PAM50) as predictors of DFS, DDFS, and
LDFI for patients randomized to chemotherapy versus no chemotherapy.

IX. To determine the impact of treatment with chemotherapy versus no chemotherapy on
patient-reported fatigue and cognitive concerns (secondary HRQL outcomes).

X. To determine the impact of management with Oncotype DX on patient-reported decision
conflict, perceptions regarding Oncotype DX testing, and survivor concerns prior to
screening, after disclosure of test results, and during the randomized trial (secondary HRQL
outcomes).

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive a protocol-approved chemotherapy regimen based on the patient and/or
physician preference. Patients then receive a protocol-approved adjuvant endocrine therapy
comprising tamoxifen citrate, an aromatase inhibitor (anastrozole, letrozole, or exemestane),
or both for 5-10 years in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive a protocol-approved endocrine therapy comprising tamoxifen citrate,
an aromatase inhibitor (anastrozole, letrozole, or exemestane), or both for 5-10 years in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year,
every 6 months for 4 years, and then yearly for 15 years.

Inclusion Criteria:

- Patients must have a histologically confirmed diagnosis of node positive (1-3 nodes)
invasive breast carcinoma with positive estrogen and/or progesterone receptor status,
and negative HER-2 status; estrogen and progesterone receptor positivity must be
assessed according to American Society of Clinical Oncology (ASCO)/College of American
Pathologists (CAP) guidelines as either estrogen receptor (ER) or progesterone
receptor (PR) >= 1% positive nuclear staining; HER-2 test result negativity must be
assessed as per ASCO/CAP 2013 guidelines using immunohistochemistry (IHC), in situ
hybridization (ISH) or both; HER-2 is negative if a single test (or all tests)
performed in a tumor specimen show: a) IHC negative (0 or 1+) or b) ISH negative using
single probe or dual probe (average HER-2 copy number < 4.0 signals per cell by single
probe or HER-2/CEP ration < 2.0 with an average copy number < 4.0 signals per cell by
dual probe); if HER-2 IHC is 2+, evaluation for gene amplification (ISH) must be
performed and the ISH must be negative; ISH is not required if IHC is 0 or 1+; HER-2
equivocal is not eligible

- Patients with multifocal, multicentric and synchronous bilateral breast cancers are
allowed

- Multifocal disease is defined as more than one invasive cancer < 2 cm from the
largest lesion within the same breast quadrant; (NOTE: the Oncotype DX testing
must be completed on the largest lesion)

- Multicentric disease is defined as more than one invasive cancer >= 2 cm from the
largest lesion within the same breast quadrant or more than one lesion in
different quadrants (NOTE: Oncotype DX testing should be completed on all tumors
and the determination for eligibility should be made on the highest recurrence
score)

- Synchronous bilateral disease is defined as invasive breast cancer with positive
lymph nodes (axillary or intramammary) in at least one breast, diagnosed within
30 days of each other; (NOTE: the Oncotype DX testing should be completed on both
tumors and the tumor with the highest recurrence score should be used)

- Patients will have undergone axillary staging by sentinel node biopsy or axillary
lymph nodes dissection (ALND); patients must have at least one, but no more than three
known positive lymph nodes (pN1a, pN1b or pN1c); patients with micrometastases as the
only nodal involvement (pN1mi) are not eligible; patients with positive sentinel node
are not required to undergo full axillary lymph node dissection; this is at the
discretion of the treating physician; axillary node evaluation is to be performed per
the standard of care at each institution

- Patients must not have inflammatory breast cancer and must not have metastatic disease

- Patients with a prior diagnosis of contralateral ductal carcinoma in situ (DCIS) are
eligible if they underwent a mastectomy or lumpectomy with whole breast radiation;
prior partial breast irradiation, including brachytherapy, is not allowed; patients
with a prior diagnosis of ipsilateral DCIS or invasive breast cancer who received
radiation to that breast are not eligible

- Patients must have had either breast-conserving surgery with planned radiation therapy
or total mastectomy (with or without planned postmastectomy radiation); patients must
have clear margins from both invasive breast cancer and DCIS (as per local
institutional guidelines); lobular carcinoma in situ (LCIS) at the margins is allowed

- Registration of patients who have not yet undergone Oncotype DX screening must occur
no later than 56 days after definitive surgery; (for all patients, Step 2 Registration
must occur within 84 days after definitive surgery); if the Oncotype DX Breast Cancer
Assay has not been performed, patients must be willing to submit tissue samples for
testing to determine the Recurrence Score value; a representative block or unstained
sections from the representative block are sent directly to Genomic Health for
Oncotype DX Breast Cancer Assay which will be performed according to the standard
commercial process

- If the Oncotype DX Recurrence Score is already known and is 25 or less, the
patient must be registered to Step 2 immediately following Step 1 registration;
if the Oncotype DX Recurrence Score is already known and is greater than 25, the
patient is ineligible

- Patients must have a complete history and physical examination within 28 days prior to
registration

- Patients must have a performance status of 0-2 by Zubrod criteria

- Patients must be able to receive taxane and/or anthracycline based chemotherapy

- Patients must not have begun chemotherapy or endocrine therapy for their breast cancer
prior to registration

- Patients must not require chronic treatment with systemic steroids (inhaled steroids
are allowed) or other immunosuppressive agents

- Patients must not have received an aromatase inhibitor (AI) or a selective estrogen
receptor modulator (SERM) such as tamoxifen or raloxifene within 5 years prior to
registration

- Patients must not be pregnant or nursing; women of reproductive potential must have
agreed to use an effective contraceptive method; a woman is considered to be of
"reproductive potential" if she has had menses at any time in the preceding 12
consecutive months; in addition to routine contraceptive methods, "effective
contraception" also includes heterosexual celibacy and surgery intended to prevent
pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy,
bilateral oophorectomy or bilateral tubal ligation; however, if at any point a
previously celibate patient chooses to become heterosexually active during the time
period for use of contraceptive measures outlined in the protocol, he/she is
responsible for beginning contraceptive measures

- No other prior malignancy is allowed except for adequately treated basal cell (or
squamous cell) skin cancer, in situ cervical cancer, or other cancer for which the
patient has been disease-free for 5 years

- The Quality of Life and Economic Substudy is permanently closed to accrual effective
12/1/12; patients who consented to QOL prior to 12/1/12 should continue to complete
QOL forms per their expectation report; patients who are able to complete a
questionnaire in English must be offered the opportunity to participate in the Quality
of Life and Economic Substudy; (The Quality of Life and Economic Substudy is available
to U.S. INSTITUTIONS ONLY); patients who are not able to complete a questionnaire in
English are registered to S1007 without participating in the Quality of Life and
Economic Substudy

- Patients who consent to participate in the Quality of Life and Economic Substudy
and who do not yet know the results of their Oncotype DX screening must agree to
complete the S1007 Health-Related Quality of Life Questionnaire: Enrollment
between 14 days prior to and 7 days after Step 1 Registration

- Patients who consent to participate in the Quality of Life and Economic Substudy
and who do already know their Oncotype DX Recurrence Score (and it is 25 or less)
will proceed to Step 2 Registration without completing the S1007 Health-Related
Quality of Life Questionnaire Enrollment Form (but will complete the S1007
Health-Related Quality of Life Questionnaire: Randomized Study Form)

- Patients or their legally authorized representative must be informed of the
investigational nature of this study and must sign and give written informed consent
in accordance with institutional and federal guidelines; for Step 1 registration of
patients who have not yet submitted specimens for the Oncotype DX Breast Cancer Assay,
the appropriate consent form is the Step 1 Consent Form; for both Step 1 and Step 2
registration of patients whose Recurrence Score is already known and is 25 or less,
the appropriate consent form is the Step 2 Consent Form

- As a part of the Oncology Patient Enrollment Network (OPEN) registration process the
treating institution's identity is provided in order to ensure that the current
(within 365 days) date of institutional review board approval for this study has been
entered in the system

- STEP 2 REGISTRATION

- Recurrence score (RS) by Oncotype DX must be =< 25

- Step 2 Registration must take place within 84 days after definitive surgery; patients
must not have begun chemotherapy or endocrine therapy for their breast cancer prior to
randomization

- Patients randomized to either arm may also co-enroll in phase III trials that compare
local therapies, or compare systemic therapies (such as chemotherapy, if randomized to
Arm I of S1007)

- The Quality of Life and Economic Substudy is permanently closed to accrual effective
12/1/12; patients at U.S. INSTITUTIONS who consent to participate in the Quality of
Life and Economic Substudy must agree to complete the S1007 Health-Related Quality of
Life Questionnaire: Randomized Study Form after Recurrence Score results and
randomized treatment status are known but before treatment has been initiated

- Patients or their legally authorized representative must be informed of the
investigational nature of this study and must sign and give written informed consent
in accordance with institutional and federal guidelines; for all patients the
appropriate consent form for this registration is the Step 2 Consent