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

Inclusion Criteria:

• Patients must have a histologically confirmed diagnosis of node positive (1-3 nodes)invasive breast carcinoma with positive estrogen and/or progesterone receptorstatus, and negative HER-2 status; estrogen and progesterone receptor positivitymust be assessed according to American Society of Clinical Oncology (ASCO)/Collegeof American Pathologists (CAP) guidelines as either estrogen receptor (ER) orprogesterone receptor (PR) >= 1% positive nuclear staining; HER-2 test resultnegativity must be assessed as per ASCO/CAP 2013 guidelines usingimmunohistochemistry (IHC), in situ hybridization (ISH) or both; HER-2 is negativeif 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 copynumber < 4.0 signals per cell by single probe or HER-2/CEP ration < 2.0 with anaverage 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 benegative; 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 areallowed

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

• Multicentric disease is defined as more than one invasive cancer >= 2 cm fromthe largest lesion within the same breast quadrant or more than one lesion indifferent quadrants (NOTE: Oncotype DX testing should be completed on alltumors and the determination for eligibility should be made on the highestrecurrence score)

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

• Patients will have undergone axillary staging by sentinel node biopsy or axillarylymph nodes dissection (ALND); patients must have at least one, but no more thanthree known positive lymph nodes (pN1a, pN1b or pN1c); patients with micrometastasesas the only nodal involvement (pN1mi) are not eligible; patients with positivesentinel node are not required to undergo full axillary lymph node dissection; thisis at the discretion of the treating physician; axillary node evaluation is to beperformed per the standard of care at each institution

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

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

• Registration of patients who have not yet undergone Oncotype DX screening must occurno later than 56 days after definitive surgery; (for all patients, Step 2Registration must occur within 84 days after definitive surgery); if the Oncotype DXBreast Cancer Assay has not been performed, patients must be willing to submittissue samples for testing to determine the Recurrence Score value; a representativeblock or unstained sections from the representative block are sent directly toGenomic Health for Oncotype DX Breast Cancer Assay which will be performed accordingto the standard commercial process

• If the Oncotype DX Recurrence Score is already known and is 25 or less, thepatient 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 be females >= 18 years of age. As the Oncotype DX recurrence score hasnot been validated in men with breast cancer, men are not eligible for this study

• Patients must have a complete history and physical examination within 28 days priorto 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 received an aromatase inhibitor (AI) or a selective estrogenreceptor modulator (SERM) such as tamoxifen or raloxifene within 5 years prior toregistration

• No other prior malignancy is allowed except for adequately treated basal cell (orsquamous cell) skin cancer, in situ cervical cancer, or other cancer for which thepatient 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 completeQOL forms per their expectation report; patients who are able to complete aquestionnaire in English must be offered the opportunity to participate in theQuality of Life and Economic Substudy; (The Quality of Life and Economic Substudy isavailable to U.S. INSTITUTIONS ONLY); patients who are not able to complete aquestionnaire in English are registered to S1007 without participating in theQuality of Life and Economic Substudy

• Patients who consent to participate in the Quality of Life and EconomicSubstudy and who do not yet know the results of their Oncotype DX screeningmust 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 EconomicSubstudy 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 S1007Health-Related Quality of Life Questionnaire Enrollment Form (but will completethe S1007 Health-Related Quality of Life Questionnaire: Randomized Study Form)

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

• As a part of the Oncology Patient Enrollment Network (OPEN) registration process thetreating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study hasbeen 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 breastcancer prior to randomization

• Patients randomized to either arm may also co-enroll in phase III trials thatcompare local therapies, or compare systemic therapies (such as chemotherapy, ifrandomized 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 ofLife and Economic Substudy must agree to complete the S1007 Health-Related Qualityof Life Questionnaire: Randomized Study Form after Recurrence Score results andrandomized treatment status are known but before treatment has been initiated

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

• STEP 3 REGISTRATION CBALR TM Substudy

• Patients must be disease-free, with no prior invasive recurrence at time ofregistration to Step 3

• Patients must be registered to Step 3 no more than 8 years after randomization (Step 2 Registration) and must agree to have samples drawn within 28 days afterregistration to Step 3

• Patients must agree to have blood samples collected at up to 3 timepoints: 1) within 28 days after registration to Step 3, 2) 2-3 years after time of registration toStep 3, and 3) At time of invasive recurrence (if applicable). Patients must alsoagree to have tissue submitted at time of invasive recurrence (if applicable) fromthe invasive recurrence biopsy (where tissue is available)

Exclusion Criteria:

• Patients must not have inflammatory breast cancer and must not have metastaticdisease

• Patients must not have begun chemotherapy or endocrine therapy for their breastcancer prior to registration

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

• Patients must not be pregnant or nursing; women of reproductive potential must haveagreed 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 12consecutive months; in addition to routine contraceptive methods, "effectivecontraception" also includes heterosexual celibacy and surgery intended to preventpregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy,bilateral oophorectomy or bilateral tubal ligation; however, if at any point apreviously celibate patient chooses to become heterosexually active during the timeperiod for use of contraceptive measures outlined in the protocol, he/she isresponsible for beginning contraceptive measures