Atezolizumab + Stereotactic Radiation in Triple-negative Breast Cancer and Brain Metastasis

Inclusion Criteria:

* Participants must have histologically or cytologically confirmed Stage IV invasive breast cancer. Participants without pathologic or cytologic confirmation of metastatic disease should have unequivocal evidence of metastasis from physical examination or radiologic evaluation.
* Either the primary tumor and/or metastatic tumor must be triple-negative as defined below:

  * Hormone receptor status: the invasive tumor must be ER- and PR-negative, or staining present in \<1% by immunohistochemistry (IHC)
  * HER2 status: the invasive tumor must be Human Epidermal Growth Factor Receptor 2 Negative (HER2-negative) by the ASCO CAP guidelines
* In cases where both primary tumor and metastatic sample(s) have been tested for ER, PR, and HER2, the triple-negative status of the most recent sample should be used.
* Participants must have a diagnosis of brain metastases for which SRS is indicated, as determined by a radiation oncologist.
* The contrast-enhancing intraparenchymal brain metastases(s) must be well circumscribed and must have a maximum diameter of ≤ 3.0 cm in any direction on the enhanced scan.
* Participants must not have more than 5 new or progressive lesions in the brain requiring SRS treatment (greater than 5 total brain lesions are allowed as long as no more than 5 lesions require SRS treatment).
* Participants must have measurable extracranial disease as defined by RECIST 1.1.
* Participants must be willing to undergo a research biopsy at baseline and at Cycle 2 Day 1 if extracranial metastases are safely accessible. Participants for whom biopsies cannot be safely performed must be willing to submit an archival primary and/or metastatic specimen. The biopsies may be waived with prior PI approval for the first 6 participants enrolled to the safety run in phase.
* Prior systemic therapy:

  * Participants must have discontinued systemic therapy at least 14 days prior to initiating protocol therapy.
  * There is no limit to the number of prior lines of systemic therapy. Participants who have not received any systemic therapy for metastatic disease are also eligible.
  * Participants may initiate or continue bisphosphonate therapy on study.
* Prior local therapy:
* Prior surgery, whole brain radiation or SRS is allowed as long as the most recent brain progression is amenable to SRS treatment.
* Resolution of all chemotherapy-related or radiation-related toxicities to Grade 1 severity or lower, except for stable sensory neuropathy (≤ Grade 2 allowed) and alopecia (of any grade).
* Participant is ≥18 years old.
* ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)
* Stable dose of dexamethasone 2mg or less for at least 7 days prior to initiation of treatment
* Participants must have normal organ and marrow function as defined below:

  * absolute neutrophil count ≥1,000/μl
  * platelets ≥75,000/μl
  * hemoglobin ≥9 g/dL
  * total bilirubin ≤1.5mg/dL (≤2.0 in patients with known Gilberts syndrome)
  * AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN. ≤5.0 × institutional ULN for patients with documented liver metastases.
  * albumin \>2.5mg/dL
  * serum creatinine ≤1.5mg/dL or calculated GFR ≥60 mL/min
* Female subjects of childbearing potential must have a negative serum or urine pregnancy test within 8 days of initiating protocol therapy.
* For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of \< 1% per year during the treatment period and for at least 90 days after the last dose of study treatment. A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of \< 1% per year include bilateral tubal ligation, male sterilization, established, proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. The effects of atezolizumab on the developing human fetus are unknown and radiotherapy has known teratogenic effects so women of child-bearing potential and men must agree to use adequate contraception (barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and 4 months after completion of atezolizumab administration.
* The subject is capable of understanding and complying with the protocol and has signed the informed consent document

Exclusion Criteria:

* CNS complications for whom urgent neurosurgical intervention is indicated (e.g., resection, shunt placement).
* Known leptomeningeal or brainstem metastases. The presence of leptomeningeal enhancement alone, without associated clinical manifestations and/or positive CSF cytology, will not be constituted as known leptomeningeal metastases.
* Treatment with high dose systemic corticosteroids defined as dexamethasone \>2mg/day or bioequivalent within 7 days of initiating therapy.
* Patients unable to undergo gadolinium contrast-enhanced MRI or receive IV contrast for any reason (e.g., due to pacemaker, ferromagnetic implants, claustrophobia, extreme obesity, hypersensitity).
* Participants who are receiving any other investigational agents.
* Previous treatment with any anti-PD-1, PD-L1, or PD-L2 agent.
* Subjects with a history of hypersensitivity to compounds of similar biologic composition to atezolizumab or any constituent of the product
* The participant has an uncontrolled intercurrent illness, including, but not limited to uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, congestive heart failure-New York Heart Association Class III or IV, active ischemic heart disease, myocardial infarction within the previous six months, uncontrolled diabetes mellitus, gastric or duodenal ulceration diagnosed within the previous 6 months, severe malnutrition or psychiatric illness/social situations that would limit compliance with study requirements.
* Participant has a medical condition that requires chronic systemic steroid therapy or on any other form of immunosuppressive medication. For example, patients with autoimmune disease that requires systemic steroids or immunosuppression agents should be excluded. Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
* Has evidence of active, noninfectious pneumonitis that requires treatment with steroids.
* Has a history of interstitial lung disease.
* The participant is known to be positive for the human immunodeficiency virus (HIV), HepBsAg, or HCV RNA. HIV-positive participants on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with atezolizumab.
* Individuals with a history of different malignancy are ineligible except for the following circumstances. Individuals with a history of other malignancies are eligible if they have been disease-free for at least 3 years or are deemed by the principal investigator to be at low risk for recurrence of that malignancy.
* Has received a live vaccine within 28 days of planned start of study therapy.
* The participant is pregnant or breast-feeding.