Standard of Care Therapy With or Without Stereotactic Radiosurgery and/or Surgery in Treating Patients With Limited Metastatic Breast Cancer

PRIMARY OBJECTIVES:

I. To determine whether ablation (through stereotactic body radiation therapy [SBRT]
[stereotactic radiosurgery] and/or surgical resection of all known metastases) in
oligometastatic breast cancer patients provides a sufficient signal for improved
progression-free survival (PFS) to warrant full accrual to the Phase III portion of the
trial. (Phase II-R) II. To determine whether ablation (through SBRT and/or surgical resection
of all known metastases) in oligometastatic breast cancer patients significantly improves
overall survival (OS). (Phase III)

SECONDARY OBJECTIVES:

I. To evaluate treated metastasis control according to tumor receptor status (estrogen
receptor [ER], progesterone receptor [PR], human epidermal growth factor receptor [HER]-2),
use of chemotherapy, surgery vs. ablative therapy, and solitary metastasis vs. 2 metastasis
(may expand to >= 2 to =< 4 following completion of a Phase I trial).

II. To evaluate whether the addition of ablative metastasis directed therapy significantly
reduces the number of distant recurrences (new metastases) in patients who progress according
to tumor receptor status (ER, PR, HER-2); use of chemotherapy, and solitary metastasis vs. 2
metastases (may expand to >= 2 to =< 4 following completion of the Phase I NRG-BR001 trial).

III. To evaluate adverse events in patients who receive ablative metastasis-directed therapy
to all known metastases in addition to standard medical therapy alone.

IV. To explore the most appropriate and clinically relevant technological parameters to
ensure quality and effectiveness throughout the radiation therapy processes, including
imaging, simulation, target and critical structure definition, treatment planning, image
guidance, and delivery.

TERTIARY OBJECTIVES:

I. To determine whether < 5 circulating tumor cells (CTCs) (per 7.5 ml of blood) is an
independent prognostic (outcome) marker for improved PFS and OS in oligometastatic breast
cancer.

II. To determine whether < 5 CTCs (per 7.5 ml of blood) is an independent predictive
(response to therapy) marker for improved PFS and OS in oligometastatic breast cancer.

III. To determine whether eliminating CTCs (0/7.5 ml of blood in patients with at least 2
CTCs at registration) is both a prognostic and predictive marker for improved PFS and OS.

IV. To evaluate the prognostic and predictive properties of CTC count as a continuous measure
of PFS and OS.

V. To store material for retrospective analysis of circulating tumor deoxyribonucleic acid
(ctDNA).

VI. To store material for retrospective analysis of circulating micro-ribonucleic acid (RNA).

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM 1: Patients continue to receive their current planned systemic therapy at the discretion
of the treating physician.

ARM 2: Patients continue to receive their current planned systemic therapy at the discretion
of the treating physician. Patients also undergo stereotactic radiosurgery in 1, 3, or 5
fractions within 3 weeks and/or surgery at the discretion of the treating physician.

ARM 1: Patients are followed every 3 months from randomization to 2 years. ARM 2: Patients
are followed 25-35 days post-ablation, every 3 months from randomization to 2 years, and then
yearly thereafter.

Inclusion Criteria:

- Pathologically confirmed metastatic breast cancer

- Known estrogen, progesterone, and HER2 status of either primary tumor or metastasis

- ≤ 4 metastases seen on standard imaging within 60 days prior to registration when all
metastatic disease is located within the following sites:

- peripheral lung

- osseous (bone)

- spine

- central lung

- abdominal-pelvic(lymph node/adrenal gland)

- liver

- mediastinal/cervical lymph node

- All known disease amenable to metastasis-directed therapy with either SBRT or
resection

- NOTE: Symptomatic bone metastasis are allowed if ablative therapy can be
delivered

- NOTE: Sites for possible surgical excision include lung, liver, adrenal gland,
bone, small intestine, large intestine, ovary, and amenable nodal disease sites

- NOTE: Surgical stabilization is allowed for a metastasis if it is followed by
conventionally fractionated external beam radiotherapy

- Maximum diameter of individual metastasis in any dimension ≤ 5 cm

- There are no restrictions on distance between the metastases

- Patients must be registered within 365 days of the initial metastatic breast cancer
diagnosis. First-line standard systemic therapy (chemotherapy, anti-endocrine therapy,
anti-HER2 or other standard targeted therapy) for metastatic breast cancer must be
given or planned to be given. If given before study entry, it cannot have exceeded a
duration of 12 months at the time of registration. (Note: Sequencing of ablative
therapy (surgery or SBRT) relative to systemic therapy, for patients randomized to Arm
2, is at the discretion of the treating physician.)

- The primary tumor site must be controlled prior to registration

- For those who present with synchronous primary and oligometastatic disease:

Primary must be controlled prior to registration. The definition of control is definitive
surgery by excision or mastectomy (+/- radiotherapy) per institution preference

- For those who present with local recurrence and oligometastatic disease, local
recurrence must be controlled prior to registration The definition of control is
definitive surgery by excision or mastectomy (+/- radiotherapy) per institution
preference

- Appropriate stage for study entry based on the following diagnostic workup:

- History/physical examination within 60 days prior to registration

- Clinical grade computed tomography (CT) scans of the chest, abdomen, and pelvis with
radionuclide bone scan OR whole body positron emission tomography (PET)/CT within 60
days prior to study registration

- Zubrod performance status ≤ 2 within 60 days prior to registration

- Absolute neutrophil count (ANC) ≥ 500 cells/mm^3

- Platelets ≥ 50,000 cells/mm^3

- Hemoglobin ≥ 8.0 g/dl (note: the use of transfusion or other intervention to
achieve hemoglobin [Hgb] ≥ 8.0 g/dl is acceptable)

- For females of child-bearing potential, negative serum or urine pregnancy test
within 14 days prior to study registration

Exclusion Criteria:

- Pathologic evidence of local/regional breast tumor recurrence at the time of
registration

- Co-existing or prior invasive malignancy (except non-melanomatous skin cancer), unless
disease free for a minimum of 3 years; previous RT dose, date, fraction size, must be
reported

- Metastases with indistinct borders making targeting not feasible

- NOTE: A potential issue with bone metastases is that they often are not discrete.
Since many patients on this protocol will have bone metastases, this will be an
important issue. Theoretically, Houndsfield units might provide an appropriate
measure; however, a sclerotic lesion against dense cortical bone will not have a
sharp demarcation based on Houndsfield units (HU). Therefore, we acknowledge that
such determinations will pose a challenge and thus the physician's judgment will
be required

- Prior palliative radiation treatment for metastatic disease (including
radiopharmaceuticals)

- Metastases located within 3 cm of the previously irradiated structures:

- Spinal cord previously irradiated to > 40 Gy (delivered in ≤ 3 Gy/fraction)

- Brachial plexus previously irradiated to > 50 Gy (delivered in ≤ 3 Gy/fraction)

- Small intestine, large intestine, or stomach previously irradiated to > 45 Gy
(delivered in ≤ 3 Gy/fraction)

- Brainstem previously irradiated to > 50 Gy (delivered in ≤ 3 Gy/fraction)

- Whole lung previously irradiated with prior V20Gy > 30% (delivered in ≤ 3
Gy/fraction)

- Primary tumor irradiated with SBRT

- Metastasis irradiated with SBRT

- Brain metastases

- Exudative, bloody, or cytological proven malignant effusions

- Severe, active co-morbidity defined as follows:

- Unstable angina and/or congestive heart failure requiring hospitalization within
the last 6 months

- Transmural myocardial infarction within the last 6 months

- Acute bacterial or fungal infection requiring intravenous antibiotics at the time
of registration

- Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy at the time of registration

- Pregnancy; lactating females must cease expression of milk prior to signing consent to
be eligible

- Human immunodeficiency virus (HIV) positive with cluster of differentiation (CD)4
count < 200 cells/microliter; note that patients who are HIV positive are eligible,
provided they are under treatment with highly active antiretroviral therapy (HAART)
and have a CD4 count ≥ 200 cells/microliter within 30 days prior to registration; note
also that HIV testing is not required for eligibility for this protocol