This is a phase II trial with an initial safety lead-in evaluating the efficacy, safety, neurocognitive, and quality-of-life outcomes of anti-cytomegalovirus (CMV) therapy and standard-of-care (SOC) in patients with anti-human cytomegalovirus (HCMV)-reactivated brain metastases. Male and female patients, aged ≥18 years, who have metastatic breast cancer with progressive brain metastases and CMV viremia (> 250 copies/ml) or positive CMV IgG or IgM will be eligible to participate in the trial.

Patients can proceed with SRS as long as at least 1 lesion which is 2 cm or less in a noncritical area in the brain is spared as per the discretion of treating neurosurgeon/radiation oncologist. At least 10 patients will be enrolled in the initial safety lead-in followed by the Phase II trial which will include 18 patients.

Anti-HCMV therapy, oral Valganciclovir will be given to patients at 900 mg twice a day for 2 weeks. After the induction period, the maintenance will be continued with valganciclovir at 450 mg twice daily for 4 weeks (28 days).

This is a phase II trial with an initial safety lead-in evaluating the efficacy, safety, neurocognitive, and quality-of-life outcomes of anti-cytomegalovirus (CMV) therapy and standard-of-care (SOC) in patients with anti-human cytomegalovirus (HCMV)-reactivated brain metastases. Male and female patients, aged ≥18 years, who have metastatic breast cancer with progressive brain metastases and CMV viremia (> 250 copies/ml) or positive CMV IgG or IgM will be eligible to participate in the trial. Patients can proceed with SRS as long as at least 1 lesion which is 2 cm or less in a noncritical area in the brain is spared as per the discretion of treating neurosurgeon/radiation oncologist. Multidisciplinary discussion with neurosurgery and radiation oncology will be needed to determine which patients may be safely enrolled on the trial. At least 10 patients will be enrolled in the initial safety lead-in followed by the Phase II trial which will include 18 patients. The primary endpoint will be to determine the objective response rate after the start of the treatment (anti-HCMV therapy and SOC). Anti-HCMV therapy, oral Valganciclovir will be given to patients at 900 mg twice a day for 2 weeks. Patients will be followed with weekly labs for viral clearance, hematological toxicity, and electrolyte imbalances. CMV PCR, IgG and IgM will be checked at the end of two weeks to monitor for viral clearance. After the induction period, the maintenance will be continued with valganciclovir at 450 mg twice daily for 4 weeks (28 days). Patients will be followed with every 2 weekly labs for hematological toxicity, and electrolyte imbalances. CMV PCR, IgG and IgM will be checked at the end of these four weeks. Pill counting will be done at each follow up to ensure compliance with oral valganciclovir. Patients will be followed with physical examinations and assessment of laboratory parameters as required per standard-of-care treatment. Quality-of-life, neurocognitive questionnaires, and MRI brain (if asymptomatic) every 2 months until subsequent intracranial progression or end of study, whichever comes first. MRI brain will be performed at any symptom onset regardless of study schedule. All MRIs will be evaluated for tumor response and progression using RANO-BM for intracranial and extracranial response using RECIST V1.1.

Patients will be followed for 24 months. Adverse events will be recorded for up to 2 months after treatment discontinuation according to (NCI CTAE) v5. After end of study patients will be followed for survival only.

Correlative studies will include HCMV-DNA copies in serum, and whole-blood based immunophenotyping from baseline to end of anti-CMV treatment. Any craniotomy brain metastatic tissue sample or lumbar puncture done as part of standard of care treatment will also be used for correlative studies. Exploratory blood samples will be transported to Dr Hong Zhao's lab at Fondren building floor 6 in < 4 hours at Room Temperature (RT, 18-25°C) post-collection. Freeze the stabilized blood at -80 °C. The samples will be thawed and lysed using the SmartTube lysis protocol before adding to MDIPA tubes for analysis. Specimens will be stored for up to 3 years after collection. Specimen samples will be accessed by Dr. Hong Zhao's lab for analysis.

Written informed consent is required before performing any trial-specific tests or procedures. Signing of the informed consent form can occur outside the 28-day screening period. All screening evaluations must be completed and reviewed to confirm that patients meet all eligibility criteria before trial entry. Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 7-28 days prior to trial entry (except where otherwise specified) may be used for screening assessments rather than repeating such tests. The investigator or qualified designer will maintain a screening log to record details of all patients screened and to confirm eligibility or record reasons for screening failure, as applicable.

Neurocognitive testing will consist of the Rey Auditory Verbal Learning Test (RAVLT), Trail Making Test (TMT), and Delis-Kaplan Executive Function System (DKEFS) letter fluency test at baseline and every 8 weeks until end of study or until subsequent intracranial progression, whichever comes first These tests were selected based on the recommendation of the International Cognition and Cancer Task Force (ICCTF). Testing will require approximately 1 hour to complete and will be conducted by the research assistant.

Inclusion Criteria:

1. Male or female aged >18 years at the time of consent

2. Breast cancer with progressive brain metastases supra and/or infratentorial. Patients can proceed with SRS as long as at least 1 lesion which is 2 cm or less in a noncritical area in the brain is spared as per the discretion of treating neurosurgeon/radiation oncologist.

3. At least one non irradiated, untreated progressive brain metastases site

4. Serum HCMV DNA by real time PCR > 250 copies/ml or positive CMV Ig G or Ig M.

5. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form and in this protocol. If the patient is unable to consent for any reason a legally authorized guardian may provide consent on their behalf. Written informed consent and any locally required authorization (e.g., Health Insurance Portability and Accountability Act) will be obtained from the patient prior to performing any protocol-related procedures, including screening evaluations.

6. Metastatic breast cancer who has systemically no evidence of disease, complete remission, partial remission, stable or progressive disease

7. Eastern Cooperative Oncology Group (ECOG) performance score of 0-2

8. Adequate hematology without ongoing transfusion support (hemoglobin > 9 g/dl, absolute neutrophil count (ANC) > 1500 per mm3 , platelets > 100,000 per mm3)

9. Adequate renal and hepatic function (creatinine clearance [CrCL] > 60 mL/min, bilirubin x:≤1.5 upper limit of normal (ULN), aspartate aminotransferase [AST] and alanine aminotransferase [ALT] ≤ 2.5 x ULN and serum albumin ≥ 3 g/dl.

10. Other CMV treatment if clinically indicated per physician's choice

11. Evidence of postmenopausal status or negative serum pregnancy test for premenopausal female patients. Negative serum β-human chorionic gonadotropin pregnancy test within 7 days prior to the first dose of study treatment for premenopausal patients. Women will be considered postmenopausal if they have been amenorrheic for 12 months without an alternative medical cause.

    The following age-specific requirements apply:

12. Women <50 years of age would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the postmenopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).

13. Women ≥50 years of age would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy).

14. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow-up.

Exclusion Criteria:

1. Single resectable intracranial lesion
2. Last intracranial progression free survival > 12 months
3. All progressive brain metastases have been radiated
4. Brain metastases needing immediate local intervention such as mass effect, herniation, active neurological symptoms, increased intracranial pressure, those near vital structures like the motor cortex, proximity to the optic nerve/chiasm or brain stem etc (can still be included if there are any other non-radiated progressive brain metastases) Multidisciplinary discussion with neurosurgery and radiation oncology will be needed to determine which patients may be safely enrolled on the trial.
5. Active pregnancy or breast feeding
6. Women of childbearing potential or fertile men unwilling to use effective contraception (Section 6.2, Table 6) during study and up to three months after treatment discontinuation.
7. Known psychiatric disorder that causes poor cooperation with the trial requirements.
8. Participants with previous other malignancies must have had at least a 3-year disease free interval, except those with non-melanoma skin cancer or carcinoma in situ of cervix
9. Participation in another clinical study with an investigational product within 28 days prior to the first dose of study treatment.
10. Concurrent enrollment in another clinical study unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.
11. Unresolved or unstable adverse events (AEs) from prior administration of another investigational drug, per investigators' discretion.
12. Major surgical procedure (as defined by the investigator) within 28 days prior to the first dose of study treatment.
13. Non-English-speaking subjects will not be enrolled in this study since the neurocognitive tests including DKEFS, RAVLT and TMT are not validated to be scored in other languages.