test

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

Conditions

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

Trial Phase

Phase 3

Trial Purpose and Description

Trial Purpose

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.


Trial 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. In patients with 1-3 positive nodes,
and hormone receptor (HR)-positive, human epidermal growth factor receptor (HER)2-negative
breast cancer with RS =< 25 treated with endocrine therapy we will test whether the
difference in disease-free survival for patients treated with chemotherapy compared to no
chemotherapy depends directly on the magnitude of RS. If benefit depends on the RS score,
the trial will determine the optimal cutpoint for recommending chemotherapy or not.

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: 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.

Participation Guidelines

Age:
18 Years - N/A
Gender:
Female

Eligibility Criteria


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 (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 ductal carcinoma in situ (DCIS) are
eligible if they received mastectomy alone (no therapeutic radiation, intraoperative
radiation, or endocrine therapy); radiation in the opposite breast is acceptable;
partial breast irradiation (including brachytherapy) is not allowed

- Patients must have had breast-conserving surgery with planned radiotherapy or total
mastectomy (with or without planned post mastectomy radiation); patients must have
clear margins (as per local institutional guidelines)

- 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 concurrent 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 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

- 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 (not including chemotherapy); patients
randomized to chemotherapy may also co-enroll in Phase III trials that compare
chemotherapies (including S1207)
Sponsor:
National Cancer Institute (NCI)
Dates:
January 2011
Last Updated:
March 19, 2014
Study HIC#:

Clinicaltrials.gov ID: NCT01272037