*Credentials required. Check your site's credentialing status.
CURRENT SITES CREDENTIALED:
SJMH, Sparrow, St. Alphonsus, SJMO, Livonia, St. John,  Macomb, Saginaw, Lehigh

-Diagnosis of rectal adenocarcinoma
-Radiologically measurable or clinically evaluable disease
-ECOG PS must be 0-2
-For this patient, the standard treatment recommendation in the absence of a clinical trial would be combined modality neoadjuvant chemoradiation followed by curative intent surgical resection
-Candidate for sphincter-sparing surgical resection prior to initiation of neoadjuvant therapy according to the primary surgeon
-Clinical stage: T2N1, T3N0, T3N1
-Tumor must not be adherent or invading the mesorectal fascia such that an R0 resection couldn't be performed
-Tumor must not be causing syptomatic bowel obstruction
-Patient must not have received chemotherapy within 5 years
-Patient must not have had prior pelvic RT

5-FU treatment:  5-day continuous infusion = 96 hrs; 7-day continuous infusion = 168 hrs 

Note: The required  biopsy for registration should be done 60 days, a new biopsy will be needed in order to comply with the test schedule requirements. The new biopsy does not need to be done prior to the registration, but it will need to be completed before treatment begins.

*Credentialing Required. Please check your site's credentialing status.
CURRENT SITES CREDENTIALED:
SJMH, St. Marys Saginaw
*Check for eligibility to DCP-001*

-Suspected MDS or MDS/MPN overlap disorders and undergoing diagnostic work-up with planned bone marrow assessments OR
-Diagnosed with de novo or therapy- related MDS within 6 months of enrollment per WHO criteria and undergoing clinical evaluation and planned bone marrow assessments to confirm MDS or evaluate disease status
-Bone marrow aspirate expected to be performed within 1 week of reg and no later than 4 weeks post enrollment
-No prior treatment for MDS at entry and through the time of the entry bone marrow aspirate
-No treatment with hematopoietic growth factors in prior 6 months
-No treatment with RT in past 2 years
-No non-hormonal treatment for malignancy in the past 2 years

For new registrations: Look for NHLBI-MDS BL study Aid under the IRB library and patient documents tabs - questionnaire will be needed for baseline data entry.

**Effective 12/20/16, the photon cohort of this study is closed to accrual. SJMH can no longer participate.
*Credentialing required. Please check your site's credentialing status.*
CURRENT SITES CREDENTIALED:
St. Alphonsus, SJMH
Please note: MCRC is not participating in the Advanced Imaging Substudy.

Step 1
-A diagnostic contrast-enhanced MRI (no other scan type allowed) of the brain must be performed postoperatively within 72 hours of resection. The enhancing tumor must have a maximal diameter of 5 cm. For cases where residual disease or postoperative surgical cavity is NOT identifiable, the patient will be excluded from the trial. 
-The GBM tumor must be located in the supratentorial compartment only (any component involving the brain stem or cerebellum is not allowed). 

Step 2:
-Patients must have histologically proven diagnosis of glioblastoma (WHO grade IV) confirmed by central review.
-Diagnosis must be made by surgical excision, either partial or complete. Stereotactic biopsy or CUSA technique are not allowed. 
-Karnofsky performance status must be greater than or equal to 70
-Patients must not have recurrent or multifocal malignant gliomas.
-Patients must not have any site of distant disease
-Patients must not have had prior chemotherapy or radiosensitizers for cancers of the head and neck region
-Prior use of Gliadel wafers or any other intratumoral or intracavitary treatment are not permitted. 
-Patients must not have had prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in overlap of radiation fields     

**DTL is required for this study- Physicians must sign the toxicity grids

Current sites credentialed: SJMH (Ann Arbor, Brighton, Canton, Chelsea), St. Mary's Livonia, Saginaw, Genesys, St. John Hospital, Macomb, LVHN

Eligibility Criteria:

Prior to Step 1 Registration:

3.1.1 No known IDH mutation. (If tested before step 1 registration, patients known to have IDH mutation in the tumor on local or other testing are ineligible and should not be registered).

3.1.2 Availability of FFPE tumor tissue block and H&E stained slide to be sent for central pathology review for confirmation of histology and MGMT promoter methylation status (See Sections 3.1.1, 3.1.2, and 10). Note that tissue for central pathology review and central MGMT assessment must be received by the NRG Oncology Biospecimen Bank on or before postoperative calendar day 23. If tissue cannot be received by postoperative calendar day 23, then patients may NOT enroll on this trial as central pathology review and stratification will not be complete in time for the patient to start treatment no later than 6 weeks following surgery. Results of central pathology review and central MGMT analysis will generally be conveyed to NRG Oncology within 10 business days of receipt of tissue.

3.1.3 Contrast-enhanced brain MRI within 72 hours after surgery.

• MRI with Axial T2 weighted FLAIR{preferred} or T2 TSE/FSE and 3D contrast-enhanced T1 sequences are required.

• 3D pre contrast-enhanced T1 sequences are strongly suggested.

3.1.4 Women of childbearing potential (WOCBP) and men who are sexually active with WOCBP must be willing to use an adequate method of contraception hormonal or barrier method of birth control; or abstinence during and after treatment (see Section 9.0).

3.1.5 The patient or a legally authorized representative must provide study-specific informed consent prior to study entry.

Prior to Step 2 Registration:

3.1.6 Histopathologically proven diagnosis of glioblastoma (or gliosarcoma as a subtype of glioblastoma) confirmed by central pathology review (See Section 10 for details);

3.1.7 MGMT promoter without methylation confirmed by central pathology review (See Section 10 for details). Note: Patients with tissue that is insufficient or inadequate for analysis, fails MGMT testing, or has indeterminate or methylated MGMT promoter are excluded.

3.1.8 IDH mutation testing by at least one method (such as immunohistochemistry for IDH1 R132H) must be performed as part of standard of care and no mutation must be found (i.e IDH wildtype). (If a mutation is identified then the patient will be ineligible and must be registered as ineligible at Step 2.)

3.1.9 History/physical examination within 28 days prior to Step 2 registration;

3.1.10 Karnofsky Performance Status (KPS) = 70 within 28 days prior to Step 2 registration;

3.1.11 Neurologic Function assessment within 28 days prior to Step 2 registration;

3.1.12 Age = 18 years;

3.1.13 Adequate hematologic, renal, and hepatic function within 7 days prior to Step 2 registration defined as follows:

- hemoglobin =10 g/dl (Note: the use of transfusion or other intervention to achieve Hgb =10.0 g/dl is acceptable)

- leukocytes =2,000/mm3

- absolute neutrophil count =1,500/mm3

- platelets =100,000/mm3

- total bilirubin =1.5× institutional/lab upper limit of normal (ULN)

-AST(SGOT) =.5 × ULN

-ALT(SGPT) =.5 × ULN

-serum creatinine =.5× ULN

OR

-creatinine clearance (CrCl) =0 mL/min (if using the Cockcroft-Gault formula

3.1.14 For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.

3.1.15 For women of childbearing potential (WOCBP), negative serum or urine pregnancy test within 7 days prior to Step 2 registration. Note that it may need to be repeated if not also within 72 hours prior to treatment start (see section 4)

• Women of childbearing potential (WOCBP) is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes.

Ineligibility Criteria

3.2.1 Prior therapy for tumor except for biopsy or resection. For example, prior chemotherapy, immunotherapy, or targeted therapy for GBM or lower grade glioma is disallowed (including but not limited to temozolomide, lomustine, bevacizumab, any viral therapy, ipilimumab or other CTLA-4 antibody, PD-1 antibody, CD-137 agonist, CD40 antibody, PDL-1 or 2 antibody, vaccine therapy, polio or similar viral injection as treatment for the tumor, and/or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) as is prior Laser interstitial thermal therapy (LITT), Gliadel wafer, radiotherapy, radiosurgery, gamma knife, cyber knife, vaccine or other immunotherapy, brachytherapy, or convection enhanced delivery;

• Note that 5-aminolevulinic acid (ALA)-mediated fluorescent guided resection (FGR) photodynamic therapy (PDT) or fluorescein administered prior to/during surgery to aid resection is not exclusionary and is not considered a chemotherapy or intracerebral agent

3.2.2 Current or planned treatment with any other investigational agents for the study cancer

3.2.3 Definitive clinical or radiologic evidence of metastatic disease outside the brain

3.2.4 Prior invasive malignancy (except non-melanomatous skin cancer, cervical cancer in situ and melanoma in situ) unless disease free for a minimum of 2 years

3.2.5 Prior radiotherapy to the head or neck that would result in overlap of radiation therapy fields

3.2.6 Pregnancy and nursing females due to the potential teratogenic effects and potential risk for adverse events in nursing infants.

3.2.7 History of severe hypersensitivity reaction to any monoclonal antibody.

3.2.8 History of allergic reactions attributed to compounds of similar chemical or biologic composition to ipilimumab, nivolumab, or temozolomide

3.2.9 On any dose of any systemically administered (oral, rectal, intravenous) corticosteroid within 3 days prior to Step 2 registration (see also section 4). Inhaled, topical, and ocular corticosteroids are allowed without limitation but must be recorded. Note that treatment with systemically administered corticosteroid after initiating study treatment is allowed as needed.

3.2.10 Patients with known immune impairment who may be unable to respond to anti-CTLA 4 antibody.

3.2.11 History of interstitial lung disease including but not limited to sarcoidosis or pneumonitis.

3.2.12 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, defined as New York Heart Association Functional Classification III/IV (Note: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification), unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

3.2.13 Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).

3.2.14 Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, are excluded. These include but are not limited to: patients with a history of immune-related neurologic disease, CNS or motor neuropathy, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as autoimmune vasculitis [e.g., Wegener’s Granulomatosis]), systemic lupus erythematosus (SLE), connective tissue diseases (e.g., systemic progressive sclerosis), scleroderma, inflammatory bowel disease (IBD), Crohn’s, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome, Hashimoto’s thyroiditis, autoimmune hepatitis are excluded because of the risk of recurrence or exacerbation of disease.

• Exceptions: patients with a history of the following conditions are not excluded: o vitiligo

• endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids

• rheumatoid arthritis and other arthropathies

• Sjögren’s syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA) ? anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible.

3.2.15 Patients who have evidence of active or acute diverticulitis, intra-abdominal abscess, GI obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation are also excluded

3.2.16 Current or planned therapy with warfarin

CREDENTIALING REQUIRED. Please check your site's credentialing status.

CURRENT SITES CREDENTIALED: SJMH (AA, Brighton, Canton, Chelsea), Livonia, LVHN, Sparrow, Saginaw, Oakland

Eligibility Criteria:

A patient cannot be considered eligible for this study unless ALL of the following conditions are met. Prior to Step 1 Registration

-No known IDH mutation. (If tested before step 1 registration, patients known to have IDH mutation in the tumor on local or other testing are ineligible and should not be registered).

- Availability of FFPE tumor tissue block and H&E stained slide to be sent for central pathology review for confirmation of histology and MGMT promoter methylation status (See Sections 3.1.1 and 10).

Note that tissue for central pathology review and central MGMT assessment must be received by the NYU Center for Biospecimen Research and Development (CBRD) on or before postoperative calendar day 23. If tissue cannot be received by postoperative calendar day 23, then patients may NOT enroll on this trial as central pathology review will not be complete in time for the patient to start treatment no later than 6 weeks following surgery. Results of central pathology review and central MGMT analysis will generally be conveyed to NRG Oncology within 10 business days of receipt of tissue. Note: In the event of an additional tumor resection(s), tissue must be received within 23 days of the most recent resection and the latest resection must have been performed within 30 days after the initial resection. Surgical resection is required; stereotactic biopsy alone is not allowed because it will not provide sufficient tissue for MGMT analysis.

- Contrast-enhanced brain MRI within 4 days after surgery.

• MRI with Axial T2 weighted FLAIR{preferred} or T2 TSE/FSE and 3D contrast\u0002enhanced T1 sequences are required.

• 3D pre contrast-enhanced T1 sequences are strongly suggested.

- Willing to use highly effective method of contraception for participants of childbearing potential (participants who may become pregnant or who may impregnate a partner) during therapy and for 6 months after completing treatment; this inclusion is necessary because the treatment in this study may be significantly teratogenic.(see Section 9 for definition of highly effective contraception).

- The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the U.S., authorization permitting release of personal health information.

Prior to Step 2 Registration

- Histopathologically proven diagnosis of glioblastoma (or gliosarcoma as a subtype of glioblastoma) confirmed by central pathology review (See Section 10 for details);

- MGMT promoter with methylation confirmed by central pathology review (See Section 10 for details). Note: Patients with tissue that is insufficient or inadequate for analysis, fails MGMT testing, or has indeterminate or unmethylated MGMT promoter are excluded. Patients with unmethylated MGMT may be considered for enrollment on NRG\u0002BN007. Please see Section 10 for additional information.

- IDH mutation testing by at least one method (such as immunohistochemistry for IDH1 R132H) must be performed as part of standard of care and no mutation must be found (i.e IDH wildtype). (If a mutation is identified then the patient will be ineligible and must be registered as ineligible at Step 2.)

- History/physical examination within 28 days prior to Step 2 registration;

- Karnofsky Performance Status (KPS) ≥ 70 within 28 days prior to Step 2 registration;

- Neurologic Function assessment within 28 days prior to Step 2 registration;

- Age 18-70 years;

Adequate hematologic, renal, and hepatic function within 7 days prior to Step 2 registration defined as follows:

- hemoglobin ≥10 g/dl (Note: the use of transfusion or other intervention to achieve Hgb ≥10.0 g/dl is acceptable)

- leukocytes ≥2,000/mm3

- absolute neutrophil count ≥1,500/mm3

- platelets ≥100,000/mm3

- total bilirubin ≤1.5× institutional/lab upper limit of normal (ULN)

- AST(SGOT) ≤2.5 × ULN

- ALT(SGPT) ≤2.5 × ULN

- serum creatinine ≤1.5× ULN OR

- creatinine clearance (CrCl) ≥50 mL/min

-For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

Note: Known positive test for hepatitis B virus surface antigen (HBV sAg) indicating acute or chronic infection would make the patient ineligible unless the viral load becomes undetectable on suppressive therapy. Patients who are immune to hepatitis B (anti-Hepatitis B surface antibody positive) are eligible (e.g. patients immunized against hepatitis B).

- For patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load. Note: Known positive test for hepatitis C virus ribonucleic acid (HCV RNA) indicating acute or chronic infection would make the patient ineligible unless the viral load becomes undetectable on suppressive therapy.

- Known human immunodeficiency virus (HIV) infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months prior to step 2 registration are eligible for this trial. Testing is not required for entry into protocol.

- Negative serum or urine pregnancy test (in persons of childbearing potential) within 7 days prior to Step 2 registration.

• Childbearing potential is defined as any person who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal.

Prior to Step 2 Registration

- Ineligibility Criteria Patients with any of the following conditions are NOT eligible for this study.

Prior therapy for tumor except for resection. For example, prior chemotherapy, immunotherapy, or targeted therapy for GBM or lower grade glioma is disallowed (including but not limited to temozolomide, lomustine, bevacizumab, any viral therapy, ipilimumab or other CTLA-4 antibody, PD-1 antibody, CD-137 agonist, CD40 antibody, PDL-1 or 2 antibody, vaccine therapy, polio or similar viral injection as treatment for the tumor, and/or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) as is prior Laser interstitial thermal therapy (LITT), Gliadel wafer, radiotherapy, radiosurgery, vaccine or other immunotherapy, brachytherapy, or convection enhanced delivery;

• Note: 5-aminolevulinic acid (ALA)-mediated fluorescent guided resection (FGR) photodynamic therapy (PDT) or fluorescein administered prior to/during surgery to aid resection is not exclusionary and is not considered a chemotherapy or intracerebral agent

- Current or planned treatment with any other investigational agents for the study cancer

- Definitive clinical or radiologic evidence of metastatic disease outside the brain

- Prior invasive malignancy (except non-melanomatous skin cancer, cervical cancer in situ and melanoma in situ) unless disease free for a minimum of 2 years

- Prior radiotherapy to the head or neck that would result in overlap of radiation therapy fields

- Pregnancy and individuals unwilling to discontinue nursing due to the potential teratogenic effects and potential risk for adverse events in nursing infants.

- History of allergic reactions attributed to compounds of similar chemical or biologic composition to temozolomide or lomustine.

- History of pulmonary fibrosis.

-Uncontrolled intercurrent illness including, but not limited to:

• Ongoing or active infection requiring IV antibiotics, IV antiviral, or IV antifungal treatment,

• Symptomatic congestive heart failure, defined as New York Heart Association Functional Classification III/IV (Note: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification),

• Unstable angina pectoris within 6 months prior to Step 2 registration,

• Uncontrolled cardiac arrhythmia,

• Psychiatric illness/social situations that would limit compliance with study requirements.

NIH Participant Population Inclusion Policy

NIH policy requires that participants regardless of gender identity and members of minority groups and their subpopulations be included in all NIH-supported biomedical and behavioral research projects involving NIH-defined clinical research unless a clear and compelling rationale and justification establishes to the satisfaction of the funding Institute & Center (IC) Director that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. Exclusion under other circumstances must be designated by the Director, NIH, upon the recommendation of an IC Director based on a compelling rationale and justification. Cost is not an acceptable reason for exclusion except when the study would duplicate data from other sources. Participants of childbearing potential should not be routinely excluded from participation in clinical research. Please see http://grants.nih.gov/grants/funding/phs398/phs398.pdf

SRS Head Phantom is credentialed to be done MI013 only

CREDENTIALING REQUIRED. Please check your site's credentialing status.
CURRENT SITES CREDENTIALED: Trinity Health Ann Arbor 

Eligibility Criteria:

3.2 Eligibility Criteria

A patient cannot be considered eligible for this study unless ALL of the following conditions are met. 3.2.1 Documentation of Disease Pathologically

(histologically or cytologically) proven diagnosis of one of the following solid tumor malignancies within 5 years prior to registration:

• non-small cell lung cancer

• melanoma

• breast cancer

• renal cell carcinoma

• gastrointestinal cancer

If the original histologic proof of malignancy is greater than 5 years, then more recent pathologic confirmation (e.g., from a systemic site or brain metastasis) or unequivocal imaging confirmation of extracranial metastatic disease (e.g. CT of the chest/abdomen/pelvis, PET/CT, etc.) is required.

3.2.2 Definition of Disease

• Patients must have at least 1 and up to 8 total intact brain metastases detected on a contrast-enhanced MRI (see Appendix I for imaging guidelines) performed ≤ 21 days prior to registration.

• At least 1 of the up to 8 lesions must be a study eligible lesion, defined as lesion with a maximum diameter as measured on any orthogonal plane (axial, sagittal, coronal) of ≥ 1.0 cm and ≤ 3.0 cm.

• All brain metastases must be located outside of the brainstem and ≥5 mm from the optic nerves or optic chiasm and ≤ 3.0 cm in maximum dimension.

Note: brainstem metastases per the MRI within 21 days of registration are an exclusion criterion; however, if the MRI used for treatment planning performed within 7 days of SRS/FSRS reveals a brainstem metastasis, the patient remains eligible if the patient is considered an appropriate radiosurgery candidate per the local investigator.

• Patients must have a diagnosis-specific graded prognostic assessment ≥1.5 (see Appendix II).

• No more than 2 lesions planned for resection if clinically indicated 

• No known leptomeningeal disease (LMD) 

Note: For the purposes of exclusion, LMD is a clinical diagnosis, defined as positive CSF cytology and/or unequivocal radiologic or clinical evidence of leptomeningeal involvement. Patients with leptomeningeal symptoms in the setting of leptomeningeal enhancement by imaging (MRI) would be considered to have LMD even in the absence of positive CSF cytology. In contrast, an asymptomatic or minimally symptomatic patient with mild or nonspecific leptomeningeal enhancement (MRI) would not be considered to have LMD. In that patient, CSF sampling is not required to formally exclude LMD, but can be performed at the investigator’s discretion based on level of clinical suspicion.

3.2.3 Age ≥ 18 years

3.2.4 Karnofsky performance status (KPS) ≥ 60

3.2.5 Not Pregnant and Not Nursing Negative urine or serum pregnancy test (in persons of childbearing potential) within 14 days prior to registration. Childbearing potential is defined as any person who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal

3.2.6 Prior Treatment No prior radiotherapy to the brain (partial or whole brain irradiation, SRS, FSRS, or prophylactic cranial irradiation [PCI]) 

** PLEASE SEE CURRENT VERSION OF PROTOCOL FOR FULL ELIGIBILITY LIST**

-ECOG PS must be 0-1
-The tumor must be unilateral invasive adenocarcinoma of the breast on histologic examination.
-The following staging criteria must be met:
--by pathologic evaluation, primary tumor must be pT1-3
--by pathologic evaluation, ipsilateral nodes must be pN0, pN1, pN2a, pN2b, pN3a, or pN3b
---if pN0, tumor must be greater than 3cm
-The tumor must be HER2-negative
-The tumor must have been determined to be ER/PR-negative
-The patient must have undergone either a mastectomy or lumpectomy. Margins must be negative.
-Patients must have completed one of the following procedures for evaluation of nodal status:
--sentinel lymphadenectomy alone-- if pN0 or pN1b; or, if pN1mi or pN1a and the patient has undergone breast conserving surgery and the primary tumor is T1-2 and nodal involvement is limited to 1-2 postitive nodes
--sentinel lymphadenectomy followed by removal of additional non-sentinel nodes if SN is positive
--axillary lymphadenectomy with or without SN isolation
-Interval between the last surgery for breast cancer and randomizatio must be no more than 60d.
-Patients must not have definitive clinical or radiologic evidence of metastatic disease.
-Patients must not have synchronous or previous contralateral or ipsilateral breast cancer (including ipsilateral DCIS).
-Patients must not have had previous therapy with anthracyclines or taxanes for any malignancy.
-Patients must not have had any previous chemotherapy for the currently diagnosed breast cancer.

**Effective 04/24/23, HRQOL sub study is closed to accrual**

**ePRO training required prior to first patient enrollment.** 

CREDENTIALING REQUIRED. Please check your site's credentialing status.
CURRENT SITES CREDENTIALED: Saginaw St. Mary's, and SJMO; St. John, Macomb, Genesys, 

Eligibility Criteria:

Patient Pre-Entry and Randomization

For the NRG-BR007 study, patients with a T1a tumor (≤0.5 cm in size) who do not have an Oncotype DX Recurrence Score must have a tissue sample sent to Genomic Health for a Recurrence Score to determine eligibility. For these patients, Genomic Health will cover the cost of the test.

 Pre-Entry (ALL patients)

• Step 1: All patients will have to be registered in NRG-BR007 before being randomized.

• The authorized site staff must obtain a signed consent form from the potential patients before any study specific procedures are performed.

• The authorized site staff must determine patient eligibility. See Sections 3.2 and 3.3.

• During Pre-Entry in OPEN, patients will be assigned a unique patient identifier which will be used to identify the sample to be sent for central Oncotype DX Recurrence Score testing (for patients with a T1a tumor (≤0.5 cm in size) who have not had a Recurrence Score), the eCRFs in Medidata RAVE, and any other trial-related communications. See Section 10.0 and the NRG-BR007 Pathology and Correlative Science Instructions for ordering the Oncotype DX Recurrence Score test.

• Patients who already have a Recurrence Score result of ≤ 18, will be registered in Step 1 and go straight to randomization in Step 2.

• When a Recurrence Score result of ≤ 18 is received on central testing for patients with a T1a tumor (≤ 0.5 cm in size), the patient should be randomized. Patients who do not have a Recurrence Score result of ≤ 18 by central testing will not be randomized, will be treated per investigator discretion, and will not be followed on BR007. 

Randomization (ALL patients)

• Step 2: If a patient meets all eligibility requirements, the authorized site staff will randomize the patient using OPEN.

• OPEN will randomly assign treatment (breast radiation therapy + endocrine therapy or no breast radiation + endocrine therapy) 

**A patient cannot be considered eligible for this study unless ALL of the following conditions are met. -The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the U.S., authorization permitting release of personal health information.  

- The patient must be ≥ 50 years and < 70 years of age.

- The trial is open to female and male patients.

- The patient must have an ECOG performance status of 0 or 1.

- The patient must have undergone a lumpectomy and the margins of the resected specimen or re\u0002excision must be histologically free of invasive tumor and DCIS with no ink on tumor as determined by the local pathologist. If pathologic examination demonstrates tumor at the line of resection, additional excisions may be performed to obtain clear margins. (Patients with margins positive for LCIS are eligible without additional resection.)

- The tumor must be unilateral invasive adenocarcinoma of the breast on histologic examination.

- Patient must have undergone axillary staging (sentinel node biopsy and/or axillary node dissection).

- The following staging criteria must be met postoperatively according to AJCC 8th edition criteria:

• By pathologic evaluation, primary tumor must be pT1 ( ≤ 2 cm).

• By pathologic evaluation, ipsilateral nodes must be pN0. (Patients with pathologic staging of pN0(i+) or pN0(mol+) are NOT eligible.)

- Oncotype DX Recurrence Score of ≤ 18 on diagnostic core biopsy or resected specimen.**

** For patients with a T1a tumor (≤ 0.5 cm in size) who do not already have an Oncotype DX Recurrence Score at study entry, a specimen (unstained blocks or slides) must be sent to the Genomic Health centralized laboratory.

- The tumor must have been determined to be ER and/or PgR positive assessed by current ASCO/CAP Guideline Recommendations for hormone receptor testing. Patients with ≥ 1% ER or PgR staining by IHC are considered positive.

- The tumor must have been determined to be HER2-negative by current ASCO/CAP guidelines.

- Patients may be premenopausal or postmenopausal at the time of study entry. For study purposes, postmenopausal is defined as:

• Age 56 or older with no spontaneous menses for at least 12 months prior to study entry; or a documented hysterectomy; or

• Age 55 or younger with no spontaneous menses for at least 12 months prior to study entry (e.g., spontaneous or secondary to hysterectomy) and with a documented estradiol level in the postmenopausal range according to local institutional/laboratory standard; or

• Documented bilateral oophorectomy.

- The interval between the last surgery for breast cancer (including re-excision of margins) and study entry must be no more than 70 days. 

-The patient must have recovered from surgery with the incision completely healed and no signs of infection.

- Bilateral mammogram or MRI within 6 months prior to study entry.

- HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.

- Patients must be intending to take endocrine therapy for a minimum 5 years duration (tamoxifen or aromatase inhibitor). The specific regimen of endocrine therapy is at the treating physician’s discretion.  Ineligibility Criteria Patients with any of the following conditions are NOT eligible for this study.

- Definitive clinical or radiologic evidence of metastatic disease.

- pT2 - pT4 tumors including inflammatory breast cancer.

- Pathologic staging of pN0(i+) or pN0(mol+), pN1, pN2, or pN3 disease.

- Patient had a mastectomy.

- Palpable or radiographically suspicious ipsilateral or contralateral axillary, supraclavicular, infraclavicular, or internal mammary nodes, unless there is histologic confirmation that these nodes are negative for tumor.

- Suspicious microcalcifications, densities, or palpable abnormalities (in the ipsilateral or contralateral breast) unless biopsied and found to be benign.

- Non-epithelial breast malignancies such as sarcoma or lymphoma.

- Proven multicentric carcinoma (invasive cancer or DCIS) in more than one quadrant or separated by 4 or more centimeters. (Patients with multifocal carcinoma are eligible.) .

- Paget's disease of the nipple.

- Any history, not including the index cancer, of ipsilateral invasive breast cancer or ipsilateral DCIS treated or not treated. (Patients with synchronous or previous ipsilateral LCIS are eligible.)

- Synchronous or previous contralateral invasive breast cancer or DCIS. (Patients with synchronous and/or previous contralateral LCIS are eligible.)

- Surgical margins that cannot be microscopically assessed or are positive at pathologic evaluation. (If surgical margins are rendered free of disease by re-excision, the patient is eligible.)

- Treatment plan that includes regional nodal irradiation.

- Any treatment with radiation therapy, chemotherapy, biotherapy, and/or endocrine therapy administered for the currently diagnosed breast cancer prior to study entry. (Short course endocrine therapy of < 6 weeks duration is acceptable post core biopsy pre surgery if the Oncotype DX Recurrence Score is assessed on the biopsy core and is < 18.)

- History of non-breast malignancies (except for in situ cancers treated only by local excision and basal cell and squamous cell carcinomas of the skin) within 5 years prior to study entry.

Current therapy with any endocrine therapy such as raloxifene (Evista®), tamoxifen, or other selective estrogen receptor modulators (SERMs), either for osteoporosis or breast cancer prevention. (Short course endocrine therapy of < 6 weeks duration is acceptable post core biopsy pre surgery if the Oncotype DX Recurrence Score is assessed on the biopsy core and is < 18.)

- Patients intending to continue on oral, transdermal, or subdermal estrogen replacement (including all estrogen only and estrogen-progesterone formulas) are not eligible. Patients that discontinue oral, transdermal, or subdermal estrogen replacement prior to registration are eligible.

- Prior breast or thoracic RT for any condition.

- Active collagen vascular disease, specifically dermatomyositis with a CPK level above normal or with an active skin rash, systemic lupus erythematosis, or scleroderma 

-Pregnancy or lactation at the time of study entry or intention to become pregnant during treatment. (Note: Pregnancy testing according to institutional standards for women of childbearing potential must be performed within 2 weeks prior to study entry.)

- Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of study therapy or that may affect the interpretation of the results or render the patient at high risk from treatment complications.

- Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements or interfere with interpretation of study results.

- Use of any investigational product within 30 days prior to study entry.  

Eligibility Criteria:

3.2.1 The patient or a legally authorized representative must provide study-specific informedconsent prior to pre-entry and, for patients treated in the U.S., authorization permitting release of personal health information. 

3.2.2 Female patients must be ≥ 18 years of age.

3.2.3 Patients must be premenopausal (evidence of functioning ovaries) at the time of pre-entry. For study purposes, premenopausal is defined as:

• Age 50 years or under with spontaneous menses within 12 months; or

• Age > 50-60 years with spontaneous menses within 12 months plus follicle-stimulating hormone (FSH) and estradiol levels in the premenopausal range; or

• Patients with amenorrhea due to IUD or prior uterine ablation must have FSH and estradiol levels in the premenopausal range; or

• Patients with prior hysterectomy must have FSH and estradiol levels in the premenopausal range. 3.2.4 The patient must have an ECOG performance status of ≤ 2 (or Karnofsky ≥ 60%).

3.2.5 Patients may have ipsilateral or contralateral synchronous breast cancer if the highest stage tumor meets entry criteria, and the other sites of disease would not require chemotherapy or HER2-directed therapy.

3.2.6 Patients may have multicentric or multifocal breast cancer if the highest stage tumor meets entry criteria, and the other sites of disease would not require chemotherapy or HER2-directed therapy.

3.2.7 Patient may have undergone a total mastectomy, skin-sparing mastectomy, nipple-sparing mastectomy, or a lumpectomy.

3.2.8 For patients who undergo a lumpectomy, the margins of the resected specimen or re-excision must be histologically free of invasive tumor and DCIS with no ink on tumor as determined by the local pathologist. If pathologic examination demonstrates tumor at the line of resection, additional excisions may be performed to obtain clear margins. Positive posterior margin is allowed if surgeon deems no further resection possible. (Patients with margins positive for LCIS are eligible without additional resection.)

3.2.9 For patients who undergo mastectomy, the margins must be free of residual gross tumor. (Patients with microscopic positive margins are eligible if post-mastectomy RT of the chest wall will be administered.)

3.2.10 Patient must have undergone axillary staging with sentinel node biopsy (SNB), targeted axillary dissection (TAD), or axillary lymph node dissection (ALND).

3.2.11 The following staging criteria must be met postoperatively according to AJCC 8 th edition criteria:

• By pathologic evaluation, primary tumor must be pT1-3. (If N0, must be T1c or higher.)

• By pathologic evaluation, ipsilateral nodes must be pN0 or pN1 (pN1mi, pN1a, pN1b, pN1c).

• Patients with positive isolated tumor cells (ITCs) in axillary nodes will be considered N0 for eligibility purposes. 

• Patients with micrometastatic nodal involvement (0.2-2 mm) will be considered N1

. 3.2.12 Oncotype DX RS requirements*:

• If node-negative:

- Oncotype DX RS must be RS 21-25, or

- Oncotype DX RS must be 16-20 and disease must be high clinical risk, defined as: low histologic grade with primary tumor size > 3 cm, intermediate histologic grade with primary tumor size > 2 cm, or high histologic grade with primary tumor size > 1 cm.

• If 1-3 nodes involved:

- Oncotype DX RS must be 26.

* Patients with a “Low Risk” or “MP1” MammaPrint result must have eligibility assessed with an Oncotype DX RS at pre-entry (see Section 3.1). Blocks or unstained slides must be sent to the Genomic Health centralized laboratory for testing at no cost to these patients. If MammaPrint High Risk or MP2, these patients are not eligible.

3.2.13 The tumor must be ER and/or PgR-positive by current ASCO/CAP guidelines based on local testing results. Patients with ≥ 1% ER and/or PgR staining by IHC will be classified as positive. 

**PLEASE SEE THE CURRENT VERSION OF PROTOCOL FOR FULL ELGIBILITY LIST**