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

• Overall survival [ Time Frame: Up to 15 years ] [ Designated as safety issue: No ]
  Defined as the time from the second registration (randomization) to death due to any cause. Survival times are censored at time of last follow-up for individuals who are not known to have died.
• Distant DFS [ Time Frame: Up to 15 years ] [ Designated as safety issue: No ]
  Defined as the time from second registration to distant recurrence, new invasive primary, or death due to any cause. Patients who have local or regional recurrence are continued to be followed for a distant event or death. Survival times are censored at time of last follow-up for individuals who are not known to have died and have not had a distant recurrence or new primary.
• Local disease-free interval [ Time Frame: Up to 15 years ] [ Designated as safety issue: No ]
  Defined as the time from second registration to local/regional recurrence. Patients who have distant recurrence or a new primary or who die without recurrence are censored at time of this event. The analysis of this endpoint must account for informative censoring using a competing risk framework. Survival times are also censored at time of last follow-up for individuals who are not known to have died and have had a recurrence or new primary.
• Toxicities using standard NCI-CTCAE version 4.0 [ Time Frame: Up to 15 years ] [ Designated as safety issue: Yes ]

• Overall survival [ Designated as safety issue: No ]
• Distant DFS [ Designated as safety issue: No ]
• Local disease-free interval [ Designated as safety issue: No ]
• Toxicities using standard NCI-CTCAE version 4.0 [ Designated as safety issue: Yes ]

This phase III clinical trial is studying how well giving tamoxifen citrate, anastrozole, letrozole, or exemestane with or without chemotherapy works in treating patients with invasive breast cancer. 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 or by stopping them from dividing. 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 endocrine therapy with versus without 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 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, HR-positive, HER2-negative breast cancer.

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

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

VIII. To determine the role of other assays (e.g., PAM50) as predictors of DFS, DDFS, and LDFI of 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: This is a multicenter study. Patients are stratified according to Recurrence Score (0-13 vs 14-25), menopausal status (pre-menopausal vs post-menopausal), and type of nodal dissection (axillary lymph node dissection [with or without sentinel node mapping] vs sentinel node biopsy without axillary lymph node dissection). 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.

Patients may complete health-related quality-of-life (QOL) questionnaires at baseline and periodically during study. Information on Medicare and/or insurance coverage and on health coverage decisions may also be collected periodically.

After completion of study therapy, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then yearly for at least 15 years.

• Estrogen Receptor-positive Breast Cancer
• HER2-negative Breast Cancer
• Progesterone Receptor-positive Breast Cancer
• Stage II Breast Cancer
• Stage IIIA Breast Cancer
• Stage IIIB Breast Cancer
• Stage IIIC Breast Cancer

• Drug: systemic chemotherapy
  Given IV
• Drug: tamoxifen citrate
  Given PO
  Other Names:

  • Nolvadex
  • TAM
  • tamoxifen
  • TMX
• Drug: anastrozole
  Given PO
  Other Names:

  • ANAS
  • Arimidex
  • ICI-D1033
• Drug: exemestane
  Given PO
  Other Names:

  • Aromasin
  • FCE-24304
  • PNU 155971
• Drug: letrozole
  Given PO
  Other Names:

  • CGS 20267
  • Femara
  • LTZ

• 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: systemic chemotherapy
  • Drug: tamoxifen citrate
  • Drug: anastrozole
  • Drug: exemestane
  • Drug: letrozole
• 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: tamoxifen citrate
  • Drug: anastrozole
  • Drug: exemestane
  • Drug: letrozole

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, as determined by IHC or gene amplification evaluation (e.g. FISH, CISH, etc.); estrogen and progesterone receptor positivity must be assessed according to ASCO/CAP guidelines as either ER or PR >= 1% positive nuclear staining; if HER2 IHC is 2+, an evaluation for gene amplification must be performed and must not be amplified, but otherwise gene amplification evaluation is not required if IHC is 0 or 1+ by institutional standards
• Patients must not have inflammatory breast cancer and must not have metastatic disease; patients with a prior diagnosis of DCIS are eligible if they received mastectomy alone (no therapeutic radiation, intraoperative radiation, or endocrine therapy); radiation in the opposite breast is acceptable
• Must have had breast-conserving surgery with planned radiotherapy or total mastectomy (with or without planned post mastectomy radiation) with clear margins within the past 28-84 days
• Menopausal status: pre- or post-menopausal
• Zubrod performance status 0-2
• Not pregnant or nursing
• Fertile patients must use an effective non-hormonal contraception method while on treatment and for ≥ 3 months after completion of protocol treatment
• No other prior malignancy except adequately treated basal cell or squamous cell skin cancer; in situ cervical cancer; adequately treated stage 0, I, or II cancer from which the patient is currently in complete remission; or any other cancer from which the patient has been disease-free for the past 5 years
• LVEF ≥ 50% if an anthracycline-based regimen is planned
• Patients randomized to chemotherapy may also co-enroll in Phase III trials that compare chemotherapies
• No prior chemotherapy or endocrine therapy for breast cancer
• No prior preventive tamoxifen or raloxifene
• No prior therapeutic breast radiotherapy
• Not requiring concurrent chronic treatment with systemic steroids or other immunosuppressive agents
• Patients randomized to either arm may also co-enroll in Phase III trials that compare local therapies or compare systemic therapies (not including chemotherapy)

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

• The Quality of Life and Economic Substudy is permanently closed to accrual effective 12/1/12; 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