Overview

Newly diagnosed post-menopausal women with clinical stage II-III, HR+HER2- breast cancer are eligible to a randomized trial, concurrently open at five US academic institutions. Patients receiving 4 months of standard neoadjuvant hormonal therapy with letrozole are randomly assigned to one of 4 arms of a trial testing focal hypo-fractionated RT alone or with immunotherapy combinations.

Eligibility

Inclusion Criteria:

• Post-menopausal female ≥ 18 years of age (Post-menopausal status defined as either 1) at least 2 years without menstrual period or 2) or patients older than 50 with serological evidence of post-menopausal status or 3) hysterectomized patients of any age with FSH confirmation of post-menopausal status.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Biopsy proven diagnosis of ER+ PR+ or PR- HER2- breast cancer.
• Clinical stage I(>1.5cm, if N0) - III breast cancer, as per AJCC staging 8th edition.
• Patient needs to be able to understand and demonstrate willingness to sign a written informed consent document.

Adequate bone marrow reserve and liver function:

        WBC ≥ 2000/uL Absolute neutrophil count (ANC) ≥1500/μL Platelets ≥100 000/μL Hemoglobin
        ≥9.0 g/dL or ≥5.6 mmol/La Creatinine OR Measured or calculated creatinine clearance (GFR
        can also be used in place of creatinine or CrCl) ≤1.5 × ULN OR ≥30 mL/min for participant
        with creatinine levels >1.5 × institutional ULN Total bilirubin ≤1.5 ×ULN OR direct
        bilirubin ≤ULN for participants with total bilirubin levels >1.5 × ULN AST (SGOT) and ALT
        (SGPT) ≤2.5 × ULN (≤5 × ULN for participants with liver metastases) International
        normalized ratio (INR) OR prothrombin time (PT) Activated partial thromboplastin time
        (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or
        aPTT is within therapeutic range of intended use of anticoagulants
        Exclusion Criteria:
          -  Active connective tissue disorders, such as lupus or scleroderma requiring flare
             therapy
          -  Current use of systemic chemotherapy, endoctine therap or HER2-neu targeted therapy
          -  Post surgical excision of breast cancer.
          -  Previous radiotherapy of the same breast.
          -  Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with
             an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4,
             OX-40, CD137).
          -  Inability to obtain histologic proof of breast cancer
          -  Has received a live vaccine within 30 days prior to the first dose of study drug.
        Examples of live vaccines include, but are not limited to, the following: measles, mumps,
        rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin
        (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed
        virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are
        live attenuated vaccines and are not allowed.
          -  Is currently participating in or has participated in a study of an investigational
             agent or has used an investigational device within 4 weeks prior to the first dose of
             study treatment. Note: Participants who have entered the follow-up phase of an
             investigational study may participate as long as it has been 4 weeks after the last
             dose of the previous investigational agent.
          -  Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
             (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
             immunosuppressive therapy within 7 days prior to the first dose of study drug.
          -  Has a known additional malignancy (second primary) that is progressing or has required
             active treatment within the past 3 years. Note: Participants with basal cell carcinoma
             of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. cervical
             cancer in situ) that have undergone potentially curative therapy are not excluded.
          -  Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
          -  Has active autoimmune disease that has required systemic treatment in the past 2 years
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs). 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 a history of (non-infectious) pneumonitis that required steroids or has current
             pneumonitis.
          -  Has an active infection requiring systemic therapy.Has a known history of Human
             Immunodeficiency Virus (HIV). Note: No HIV testing is required unless mandated by
             local health authority.
          -  Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg]
             reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is
             detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required
             unless mandated by local health authority.
          -  Has a known history of active TB (Bacillus Tuberculosis). Note: optional based on
             country.
          -  Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.