S1007: 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

Summary

this trial will use the regimens that have proven to be of greater benefit than earlier chemotherapy regimens in modern randomized trials. The study will use a simple parallel two-group randomization to chemotherapy followed by endocrine therapy or endocrine therapy alone in a lower risk, 1-3 node-positive population (identified by intermediate or low Recurrence Score) to determine if modern chemotherapy is efficacious and to identify those patients who will
benefit from the addition of chemotherapy.

Participant Eligibility

-->If patient has previously been tested by Oncotype DX(RegisteredTM), then she still must satisfy these eligibility criteria to be considered for randomization.
a. 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 ASCO/CAP guidelines as
either ER or PR >= 1% positive nuclear staining. HER-2 test result negativity must
be assessed as per ASCO/CAP 2013 guidelines using IHC, 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.
b. 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(RegisteredTM) 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(RegisteredTM) 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(RegisteredTM) testing should be completed on both tumors and the tumor with the highest
recurrence score should be used.)
c. 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), see Section 4.0
for definitions. 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
insititution.
d. 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. Partial breast irradiation (including brachytherapy) is not allowed.
e. 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 (as per local institutional guidelines).
f. Registration of patients who have not yet undergone Oncotype DX(RegisteredTM) 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(RegisteredTM) 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(RegisteredTM) Breast Cancer Assay which will be performed according to the standard commercial process (see Section 15.1).

If the Oncotype DX(RegisteredTM) 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(RegisteredTM) Recurrence Score is already known and is greater than 25, the patient is ineligible.
g. Patients must be females >= 18 years of age. As the Oncotype DX(RegisteredTM) Recurrence Score has not been validated in men with breast cancer, men are not eligible for this study.
h. Patients must have a complete history and physical examination within 28 days
prior to registration.
i. Patients must have a performance status of 0-2 by Zubrod criteria
j. Patients must be able to receive taxane and/or anthracycline based chemotherapy.
k. Patients must not have begun chemotherapy or endocrine therapy for their
breast cancer prior to registration.
l. Patients must not require chronic treatment with systemic steroids (inhaled
steroids are allowed) or other immunosuppressive agents.
m. 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.
n. Patients must not be pregnant or nursing due to the possibility of harm to a fetus
or nursing infant from this treatment regimen. 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.
o. 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.
p. 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(RegisteredTM)
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(RegisteredTM) 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) as outlined in Section 5.2d.
q. 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(RegisteredTM) 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.
r. As a part of the OPEN registration process (see Section 13.4 for OPEN access
instructions) 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.5.2 STEP 2 REGISTRATION (Randomization)
The following additional criteria must be met in order for a patient to be considered
eligible for registration to the randomized trial. For each criterion requiring test results
and dates, please record this information on the S1007 Prestudy Form-Randomized
Study and submit to the Data Operations Center in Seattle (see Section 14.0). Any
potential eligibility issues should be addressed to the Data Operations Center in Seattle
at 206/652-2267 prior to registration.

5.2 STEP 2 REGISTRATION (Randomization)
The following additional criteria must be met in order for a patient to be considered
eligible for registration to the randomized trial. For each criterion requiring test results
and dates, please record this information on the S1007 Prestudy Form-Randomized
Study and submit to the Data Operations Center in Seattle (see Section 14.0). Any
potential eligibility issues should be addressed to the Data Operations Center in Seattle
at 206/652-2267 prior to registration.
a. Recurrence score (RS) by Oncotype DX(RegisteredTM) must be <= 25.
b. 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.
c. 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).
d. 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.
e. 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 Form.