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

Tracking Information
First Submitted Date ICMJE	January 6, 2011
First Posted Date ICMJE	January 7, 2011
Last Update Posted Date	June 12, 2018
Actual Study Start Date ICMJE	January 15, 2011
Estimated Primary Completion Date	February 1, 2022 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: March 19, 2014)	RS, as measured by Oncotype DX [ Time Frame: Up to 15 years ]; The interaction of the linear RS term and chemotherapy benefit will be tested in a Cox regression model of DFS. If the interaction is statistically significant and there is a point of equivalence between the two randomized treatments for some RS value in the range 0-25, a clinical cutpoint for recommending chemotherapy will be estimated. This estimated cutpoint is the upper bound of the 95% confidence interval on the point of equivalence. Kaplan-Meier curves comparing randomized arms generated separately for RS values below and above this cutpoint and tested with stratified log-rank tests.
Original Primary Outcome Measures ICMJE; (submitted: January 6, 2011)	Invasive disease-free survival (DFS) of women with node-positive breast cancer treated with endocrine therapy with vs without chemotherapy
Change History	Complete list of historical versions of study NCT01272037 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: March 2, 2018)	OS [ Time Frame: The time from the second registration (randomization) to death due to any cause, assessed up to 15 years ]; DDFS [ Time Frame: The time from second registration to distant recurrence, new invasive primary, or death due to any cause, assessed up to 15 years ]; Local disease-free interval [ Time Frame: The time from second registration to local/regional recurrence, assessed up to 15 years ]; Toxicities using standard National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 5 years ]Compared between the two arms using logistic regression.
Original Secondary Outcome Measures ICMJE; (submitted: January 6, 2011)	Overall survival; Distant DFS; Local disease-free interval; Toxicities using standard NCI-CTCAE version 4.0
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Tamoxifen Citrate, Letrozole, Anastrozole, or Exemestane With or Without Chemotherapy in Treating Patients With Invasive RxPONDER Breast Cancer
Official Title ICMJE	A Phase III, Randomized Clinical Trial of Standard Adjuvant Endocrine Therapy +/- Chemotherapy in Patients With 1-3 Positive Nodes, Hormone Receptor-Positive and HER2-Negative Breast Cancer With Recurrence Score (RS) of 25 or Less. RxPONDER: A Clinical Trial Rx for Positive Node, Endocrine Responsive Breast Cancer
Brief Summary	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.
Detailed Description	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.
Study Type ICMJE	Interventional
Study Phase	Phase 3
Study Design ICMJE	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	Ductal Breast Carcinoma In Situ; Estrogen Receptor and/or Progesterone Receptor Positive; HER2/Neu Negative; Invasive Breast Carcinoma; Multicentric Breast Carcinoma; Multifocal Breast Carcinoma; Synchronous Bilateral Breast Carcinoma
Intervention ICMJE	Drug: Anastrozole Given PO Other Names: Anastrazole Arimidex ICI D1033 ICI-D1033 ZD-1033; Drug: Exemestane Given PO Other Names: Aromasin FCE-24304; Other: Laboratory Biomarker Analysis Correlative studies; Drug: Letrozole Given PO Other Names: CGS 20267 Femara; Other: Quality-of-Life Assessment Ancillary studies (closed as of 12/1/12) Other Name: Quality of Life Assessment; Drug: Systemic Chemotherapy Given IV; Drug: Tamoxifen Citrate Given PO Other Names: Apo-Tamox Clonoxifen Dignotamoxi Ebefen Emblon Estroxyn Fentamox Gen-Tamoxifen Genox ICI 46,474 ICI-46474 Jenoxifen Kessar Ledertam Lesporene Nolgen Noltam Nolvadex Nolvadex-D Nourytam Novo-Tamoxifen Novofen Noxitem Oestrifen Oncotam PMS-Tamoxifen Soltamox TAM Tamax Tamaxin Tamifen Tamizam Tamofen Tamoxasta Tamoxifeni Citras Zemide
Study Arms	Experimental: Arm I (chemotherapy and endocrine therapy) 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. Interventions: Drug: Anastrozole Drug: Exemestane Other: Laboratory Biomarker Analysis Drug: Letrozole Other: Quality-of-Life Assessment Drug: Systemic Chemotherapy Drug: Tamoxifen Citrate; Experimental: Arm II (endocrine therapy) 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. Interventions: Drug: Anastrozole Drug: Exemestane Other: Laboratory Biomarker Analysis Drug: Letrozole Other: Quality-of-Life Assessment Drug: Tamoxifen Citrate
Publications *	Not Provided
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Active, not recruiting
Estimated Enrollment ICMJE; (submitted: June 30, 2016)	10000
Original Estimated Enrollment ICMJE; (submitted: January 6, 2011)	4000
Study Completion Date	Not Provided
Estimated Primary Completion Date	February 1, 2022 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	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
Sex/Gender	Sexes Eligible for Study: Female
Ages	18 Years and older (Adult, Older Adult)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	Canada, Colombia, France, Ireland, Korea, Republic of, Mexico, Puerto Rico, Saudi Arabia, Spain, United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT01272037
Other Study ID Numbers ICMJE	NCI-2011-02623; NCI-2011-02623 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); CDR0000692475; PS1007_A11PAMDREVW01; SWOG-S1007; S12-03603; S1007 ( Other Identifier: SWOG ); S1007 ( Other Identifier: CTEP ); U10CA180830 ( U.S. NIH Grant/Contract ); U10CA180888 ( U.S. NIH Grant/Contract ); U10CA032102 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee	Yes
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	National Cancer Institute (NCI)
Study Sponsor ICMJE	National Cancer Institute (NCI)
Collaborators ICMJE	Not Provided
Investigators ICMJE	Principal Investigator: Kevin Kalinsky Southwest Oncology Group
PRS Account	National Cancer Institute (NCI)
Verification Date	March 2018
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP