HER2-positive Breast Cancer With Brain Metastasis (GCC 1345)

Metastatic breast cancer is a leading cause of death for women. HER2(human epidermal growth
factor receptor type 2)-positive disease represents a more aggressive type of breast cancer
which often afflicts younger patients. As many as one-third of patients with HER2-positive
breast cancer develop brain metastasis[1]. The development of brain metastasis in this young
female population is particularly devastating as they are often highly functional and may
have young children. Improvement in quality of life by preventing neurocognitive decline
from disease progression and/or treatment related side effects is paramount.

Patients with 1-10 brain metastasis from HER2+ breast cancer, after informed consent, will
be treated with:

Radiosurgery: Gamma-knife, Cyberknife, or linac-based SRS is followed by anti-HER2 based
systemic therapy, with the treatment selection of approved agents at the physician's
discretion. Possible anti-HER2 agents include trastuzumab, pertuzumab,
trastuzumab-emtansine, or lapatinib. Anti-HER2 therapy will be delivered in combination with
appropriate cytotoxic therapy as per FDA indications.

Anti-HER2 based systemic therapy will continue until progression, patient discontinuation,
unacceptable toxicity or if, in the view of the physician it is no longer indicated.

MRI and neurocognitive testing will be done prior to SRS and repeated every 3 months during
the first 6 months from enrollment.

Patients can only be enrolled after all eligibility criteria are met. The date of
registration/enrollment is considered to be the day the Eligibility Checklist is signed by
the verifying physician. Once a patient is enrolled, a unique case number will be assigned
to the patient.

Inclusion Criteria:

- Histologically proven diagnosis HER2-positive breast cancer. Her2-positive is defined
as follows:

* Validated IHC assay score of 3+ (defined as uniform, intense staining of >30% of
invasive tumor cells)

- OR- Average HER2 gene copy number of >6

- OR- Gene amplified (HER2:D17Z1 ratio >2.20).

- Patients with 1-10 newly diagnosed brain metastases

- The contrast-enhancing intraparenchymal brain tumor must be well circumscribed and
must have a maximum diameter of ≤ 4.0 cm in any direction on the enhanced scan. If
multiple lesions are present and one lesion is at the maximum diameter, the other(s)
must not exceed 3.0 cm in maximum diameter.

- History and physical with neurological examination, steroid documentation, height,
and weight within 14 days of registration.

- A diagnostic contrast-enhanced MRI of the brain must be performed within 28 days
prior to registration.

- Eligibility for treatment with SRS confirmed by a radiation oncologist.

- Performance Status 0-2

- Age ≥ 18.

- CBC with differential obtained within 14 days prior to registration, with adequate
bone marrow function defined as follows:

- Absolute neutrophil count (ANC) ≥ 1,100 cells/mm3.

- Platelets ≥ 75,000 cells/mm3.

- Hemoglobin ≥ 9.0 g/dl (Note: The use of transfusion or other intervention to achieve
Hgb ≥9.0 g/dl is acceptable).

- Adequate renal function within 14 days prior to registration, as defined below:

- BUN ≤ 30 mg/dl.

- Creatinine ≤ 1.5 x ULN

- Creatinine clearance ≥30 mL/min.

Adequate hepatic function within 14 days prior to registration, as defined below:

- Total Bilirubin ≤1.5 x ULN

- ALT/AST ≤ 2.5 x upper limit of normal (ULN).

- Systolic blood pressure ≤ 160 mg Hg or diastolic pressure ≤ 90 mg Hg within 14 days
prior to registration.

- Prothrombin time/international normalized ratio (PT INR) < 1.4 for patients not on
warfarin confirmed by testing within 14 days prior to registration. Patients on
full-dose anticoagulants (e.g., warfarin or LMW heparin) must meet both of the
following criteria:

- No active bleeding or pathological condition that carries a high risk of bleeding
(e.g., tumor involving major vessels or known varices).

- In-range INR (between 2.5 and 3.5) on a stable dose of warfarin-based oral
anticoagulant; or on a stable dose of low molecular weight heparin; or INR between
1.5 and 2 if a Greenfield filter is in place.

- Patient must provide study specific informed consent prior to study entry.

- For women of child-bearing potential, negative serum pregnancy test within 14 days
prior to registration.

- Women of childbearing potential and male participants must practice adequate
contraception.

- Echocardiogram or MUGA scan with ejection fraction within normal institution limits
within 28 days of registration

Exclusion Criteria:

- Prior invasive malignancy (except for non-melanomatous skin cancer) unless disease
free for ≥ 3 years. For example, carcinoma in situ of the oral cavity and cervix are
all permissible.

- Leptomeningeal metastases

- Previous treatment with all of the following: lapatinib, trastuzumab, pertuzumab, and
trastuzumab emtansine. (Patients are eligible if treated with 3 or less of these
agents.)

- Prior cranial radiotherapy.

- Prior resection of cerebral metastases

- Allergy to gadolinium

Severe, active co-morbidity, defined as follows:

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

- Transmural myocardial infarction within the last 6 months.

- New York Heart Association grade II or greater congestive heart failure requiring
hospitalization within 12 months prior to registration.

- History of stroke, cerebral vascular accident (CVA) or transient ischemic attack
within 6 months.

- Serious and inadequately controlled cardiac arrhythmia.

- Significant vascular disease (e.g., aortic aneurysm, history of aortic dissection) or
clinically significant peripheral vascular disease.

- Evidence of bleeding diathesis or coagulopathy.

- Serious or non-healing wound, ulcer, or bone fracture or history of abdominal
fistula, gastrointestinal perforation or intra-abdominal abscess, major surgical
procedure or significant traumatic injury within 28 days prior to registration, with
the exception of the craniotomy for tumor resection or follow-on craniotomies to
manage complications of brain tumor management such as hemorrhage or infection.

- 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.

- Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects;
note, however, that laboratory tests for coagulation parameters are not required for
entry into this protocol.

- Active connective tissue disorders, such as lupus or scleroderma, that in the opinion
of the treating physician may put the patient at high risk for radiation toxicity.

- Any other major medical illnesses or psychiatric impairments that in the
investigator's opinion will prevent administration or completion of protocol therapy.

- Cognitive impairment that precludes a patient from acting as his or her own agent to
provide informed consent.

- Women of childbearing potential who are sexually active and not willing/able to use
medically acceptable forms of contraception; this exclusion is necessary because the
chemotherapeutic treatment involved in this study is potentially teratogenic.

- Pregnant or lactating women, due to possible adverse effects on the developing fetus
or infant due to study treatment.

- Patients treated on any other therapeutic clinical protocols within 30 days prior to
study entry or during participation in the study.

- Inability to undergo MRI (e.g., due to safety reasons, such as presence of a
pacemaker).

- Inability to undergo SRS due to claustrophobia