Tamoxifen Citrate, Letrozole, Anastrozole, or Exemestane With or Without Chemotherapy in Treating Patients With Invasive RxPONDER Breast Cancer
Tamoxifen Citrate, Letrozole, Anastrozole, or Exemestane With or Without Chemotherapy in Treating Patients With Invasive RxPONDER Breast Cancer
This randomized phase III clinical trial studies how well tamoxifen citrate, anastrozole,
 letrozole, or exemestane with or without chemotherapy work in treating patients with breast
 cancer that has spread from where it began in the breast to surrounding normal tissue
 (invasive). Estrogen can cause the growth of breast cancer cells. Hormone therapy, using
 tamoxifen citrate, may fight breast cancer by blocking the use of estrogen by the tumor
 cells. Aromatase inhibitors, such as anastrozole, letrozole, and exemestane, may fight breast
 cancer by lowering the amount of estrogen the body makes. Drugs used in chemotherapy work in
 different ways to stop the growth of tumor cells, either by killing the cells, by stopping
 them from dividing, or by stopping them from spreading. It is not yet known whether giving
 tamoxifen citrate, anastrozole, letrozole, or exemestane is more effective with combination
 chemotherapy in treating patients with 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