Hormone Therapy With or Without Combination Chemotherapy in Treating Women Who Have Undergone Surgery for Node-Negative Breast Cancer (The TAILORx Trial)

Study Overview
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Brief Summary
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This randomized phase III trial studies the best individual therapy for women who have node-negative, estrogen-receptor positive breast cancer by using a special test (Oncotype DX), and whether hormone therapy alone or hormone therapy together with combination chemotherapy is better for women who have an Oncotype DX recurrence score of 11-25. Estrogen can cause the growth of breast cancer cells. Hormone therapy may fight breast cancer by blocking the use of estrogen by the tumor cells or 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. Giving hormone therapy together with more than one chemotherapy drug (combination chemotherapy) has been shown to reduce the chance of breast cancer recurrence, but the benefit of adding chemotherapy to hormone therapy for women with node-negative, estrogen-receptor positive breast cancer is small. New tests may provide information about which patients are more likely to benefit from chemotherapy.

Detailed Description
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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. GROUP 2 (PRIMARY STUDY GROUP; ODRS 11-25): Patients are randomized to receive either hormonal therapy alone or combination chemotherapy and hormonal therapy. ARM I (EXPERIMENTAL): Patients receive hormonal therapy as in Group 1 at the discretion of the treating physician. ARM II (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 II followed by hormonal therapy as in Group 1. 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. After completion of study treatment, patients are followed up every 3-6 months for 5 years and then annually for 15 years.

Official Title
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Program for the Assessment of Clinical Cancer Tests (PACCT-1): Trial Assigning Individualized Options for Treatment:The TAILORx Trial

Conditions
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Breast Adenocarcinoma, Hormone Receptor Positive, Stage IA Breast Cancer AJCC v7, Stage IB Breast Cancer AJCC v7, Stage IIA Breast Cancer AJCC v6 and v7, Stage IIB Breast Cancer AJCC v6 and v7, Stage IIIB Breast Cancer AJCC v7

Intervention / Treatment
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* Drug: Anastrozole
* Drug: Exemestane
* Other: Laboratory Biomarker Analysis
* Drug: Letrozole
* Other: Quality-of-Life Assessment
* Radiation: Radiation Therapy
* Drug: Tamoxifen Citrate


Participation Criteria
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Eligibility Criteria
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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 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 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 (Oncotype DX recurrence score =< 10)<br>Patients in this group receive hormone therapy with tamoxifen, anastrozole, letrozole, or exemestane PO for up to 5 years. Some patients then continue to receive hormone therapy for an additional 5 years. | Drug: Anastrozole<br>* Given PO<br>* Other names: ZD-1033;Drug: Exemestane<br>* Given PO<br>* Other names: FCE-24304;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Letrozole<br>* Given PO<br>* Other names: Fempro;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Radiation: Radiation Therapy<br>* Undergo radiation therapy or partial breast irradiation<br>* Other names: Therapy, Radiation;Drug: Tamoxifen Citrate<br>* Given PO<br>* Other names: Zemide;|
| Experimental: Group 2, Arm I (experimental)<br>Patients receive hormonal therapy as in Group 1 at the discretion of the treating physician. | Drug: Anastrozole<br>* Given PO<br>* Other names: ZD-1033;Drug: Exemestane<br>* Given PO<br>* Other names: FCE-24304;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Letrozole<br>* Given PO<br>* Other names: Fempro;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Drug: Tamoxifen Citrate<br>* Given PO<br>* Other names: Zemide;|
| Active Comparator: Group 2, Arm II (standard)<br>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. | Drug: Anastrozole<br>* Given PO<br>* Other names: ZD-1033;Drug: Exemestane<br>* Given PO<br>* Other names: FCE-24304;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Letrozole<br>* Given PO<br>* Other names: Fempro;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Radiation: Radiation Therapy<br>* Undergo radiation therapy or partial breast irradiation<br>* Other names: Therapy, Radiation;Drug: Tamoxifen Citrate<br>* Given PO<br>* Other names: Zemide;|
| Experimental: Group 3 (Oncotype DX recurrence score >= 26)<br>Patients in this group receive combination chemotherapy followed by hormone therapy similar to the patients in group two who are assigned to receive both types of treatment. | Drug: Anastrozole<br>* Given PO<br>* Other names: ZD-1033;Drug: Exemestane<br>* Given PO<br>* Other names: FCE-24304;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Letrozole<br>* Given PO<br>* Other names: Fempro;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Radiation: Radiation Therapy<br>* Undergo radiation therapy or partial breast irradiation<br>* Other names: Therapy, Radiation;Drug: Tamoxifen Citrate<br>* Given PO<br>* Other names: Zemide;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 5-year Disease-free Survival | Disease-free survival (DFS) is defined to be time from randomization to first event, where the first event is any of ipsilateral breast tumor recurrence, local recurrence, regional recurrence, distant recurrence, contralateral second primary invasive cancer, second primary non-breast invasive cancer (excluding non-melanoma skin cancers), or death without evidence of recurrence. The distribution of DFS (eg, 5-year DFS rate) is estimated using Kaplan-Meier method, and compared between the two randomized arms (arm B vs. arm C) using stratified log rank test and stratified Cox proportional hazard model. | Assessed every 6 months within 5 years from registration and then annually up to 20 years, DFS rate estimated at 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 5-year Distant Recurrence-free Interval | Distant recurrence-free interval (DRFI) is defined as time from date of randomization or registration to the date of distant recurrence of breast cancer, or of death with distant recurrence, if death is the first manifestation of distant recurrence. The distribution of DRFI (eg, 5-year DRFI rate) is estimated using Kaplan-Meier method. | Assessed every 6 months within 5 years from registration and then annually up to 20 years, DRFI rate estimated at 5 years | 
| 5-year Recurrence-free Interval | Recurrence-free interval (RFS) is defined as time from date of randomization or registration to the date of first recurrence of breast cancer (ipsilateral breast tumor recurrence, local/regional recurrence, distant recurrence) or to the date of death with recurrence, if death is the first manifestation of recurrence. The distribution of RFS (eg, 5-year RFS rate) is estimated using Kaplan-Meier method. | Assessed every 6 months within 5 years from registration and then annually up to 20 years, RFS rate estimated at 5 years | 
| 5-year Overall Survival | Overall survival (OS) is defined as time from date of randomization or registration to date of death from any cause. The distribution of OS (eg, 5-year OS rate) is estimated using Kaplan-Meier method. | Assessed every 6 months within 5 years from registration and then annually up to 20 years, OS rate estimated at 5 years | 
| 5-year Disease-free Survival by Age and Recurrence Score Groups | Disease-free survival (DFS) is defined to be time from randomization to first event, where the first event is any of ipsilateral breast tumor recurrence, local recurrence, regional recurrence, distant recurrence, contralateral second primary invasive cancer, second primary non-breast invasive cancer (excluding non-melanoma skin cancers), or death without evidence of recurrence. DFS is evaluated by recurrence score (0-10 vs. 11-15 vs. 16-20 vs. 21-25 vs. >25) and age groups (<=50 vs. 51-65 vs. 65-75). The distribution of DFS (eg, 5-year DFS rate) is estimated using Kaplan-Meier method. | Assessed every 6 months within 5 years from registration and then annually up to 20 years, DFS rate estimated at 5 years | 
| To Compare the Outcomes Projected at 10 Years by Adjuvant! With Those Made by the Genomic Health Oncotype DX Test | Adjuvant! is not currently available; additional work combining classical information with genomic tests will be reported separately. | Assessed at 10 years after study entry | 
| 5-year Disease-free Survival by Individual RS Gene Groups | Disease-free survival (DFS) is defined to be time from randomization to first event, where the first event is any of ipsilateral breast tumor recurrence, local recurrence, regional recurrence, distant recurrence, contralateral second primary invasive cancer, second primary non-breast invasive cancer (excluding non-melanoma skin cancers), or death without evidence of recurrence. The distribution of DFS (eg, 5-year DFS rate) is estimated using Kaplan-Meier method. 5-year DFS by individual RS gene groups (Proliferation Gene Group, HER2 Gene Group, ER Gene Group, Invasion Gene Group, and Other Genes) will be estimated in each arm. | Assessed every 6 months within 5 years from registration and then annually up to 20 years |