With more than 1 million new cases diagnosed yearly worldwide, breast cancer is a global
public health burden. Over the past decade, molecular subtyping of breast cancer has
identified intrinsic subtypes that may be at enhanced risk for both local and distant
recurrence. This study focuses on the immunogenicity of high-risk breast cancer subtypes that
are likely to display a dense lymphocytic infiltration including including TNBC and HR+/HER2-
Immune build up via immune co-stimulatory molecules permits the ensuing immune response to
strengthen and destroy cancer systemically. Thus, the effect of the anti-tumor immune
response initiated by the radiation to an intact tumor by combination with checkpoint
blockade is increased.
Pembrolizumab is an optimal immunotherapy agent to study, as this agent has recently been FDA
approved for use in multiple tumor types. It is therefore ready to be tested for efficacy in
other disease sites and in combination with other treatments.
- Confirmed histologic diagnosis of invasive adenocarcinoma of the breast, and
- ER, PR and HER2 testing (on outside or Cedars-Sinai biopsy report), and
- High-risk, ER-positive and HER2-negative breast cancer patients. ER-positive
disease is defined as ER>10%, any PR and HER2-negative by ASCO CAP guidelines.
High-risk disease will be defined by the presence of at least 2 of the following
3 criteria: histologic grade II-III, Ki-67 > 20%, ER expression < 75% by IHC)
- TNBC patients (defined as ER<10%, PR<10%, HER2-neu 0-1+ by IHC or FISH-negative;
or as per MD discretion)
- Operable tumor measuring ≥2 cm in maximal diameter as measured by any available
standard of care imaging (mammogram, breast ultrasound, breast MRI)
- Any nodal status
- Multifocal disease is permitted; largest focus must measure ≥2 cm
- Synchronous bilateral invasive breast cancer is permitted
- No indication of distant metastases
- Breast-conserving therapy is planned
- Tumor amenable to preoperative radiation therapy boost as determined by radiation
- ECOG performance status score of 0 or 1
- Screening laboratory values must meet the following criteria:
i. White blood cells (WBCs) ≥ 2000/μL ii. Absolute neutrophil count (ANC) ≥ 1500/μL
iii. Platelets ≥ 100 x 103/μL iv. Hemoglobin ≥ 11.0 g/dL v. Serum creatinine ≤ 2 mg/dL
(or glomerular filtration rate ≥ 40 ml/min) vi. AST ≤ 2.5 x upper limit of normal
(ULN) vii. ALT ≤ 2.5 x ULN viii. Total bilirubin within normal limits (except subjects
with Gilbert's syndrome, who must have total bilirubin < 3.0 mg/dL) ix. INR ≤ 1.5 x
ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is
within therapeutic range of intended use of anticoagulant(s) x. Negative HIV screening
test xi. Negative screening tests for Hepatitis B and Hepatitis C. Patients with
positive results that do not indicate true active or chronic infection may enroll
after discussion and consensus agreement by the treating physician and principal
- Women of childbearing potential (WOCBP) must be using an acceptable method of
contraception to avoid pregnancy throughout the study and for at least 4 months after
the last dose of pembrolizumab in such a manner that the risk of pregnancy is
- WOCBP must have a negative serum pregnancy test within 14 days prior to the first dose
- Women must not be breastfeeding.
- Willingness to adhere to the study visit schedule and the prohibitions and
restrictions specified in this protocol.
- Willingness to undergo mandatory Week 4 research biopsy
- Written informed consent obtained from subject and ability for subject to comply with
the requirements of the study.
- HER2-positive breast cancer defined as IHC3+ or IHC2+ with FISH>2 AND copy number >4
OR FISH <2 AND copy number >6
- Inflammatory breast cancer
- Contraindication(s) to breast-conserving therapy
- Contraindication to radiation therapy or planned partial breast irradiation
- Patients with cosmetic breast augmentations, specifically sub glandular implants with
altered breast tissue, at the time of diagnosis
- Evidence of metastatic disease.
- 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.
- Known additional malignancy 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. breast carcinoma,
cervical cancer in situ) that have undergone potentially curative therapy are not
- Medical history and concurrent diseases
- 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.
- History of (non-infectious) pneumonitis that required steroids or has current
- Active infection requiring systemic therapy.
- Any serious or uncontrolled medical disorder that, in the opinion of the
investigator, may increase the risk associated with study participation or study
drug administration, impair the ability of the subject to receive protocol
therapy, or interfere with the interpretation of study results.
- Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
- Known history of Hepatitis B (e.g., HBsAg reactive) or known active Hepatitis C
(e.g., HCV RNA [qualitative] is detected).
- Prohibited Treatments and/or Therapies
- Chronic use of immunosuppressants and/or systemic corticosteroids (used in the
management of cancer or non-cancer-related illnesses). However, use of
corticosteroids is allowed for the treatment of immune related Adverse Events
(irAEs), or adrenal insufficiency.
- Live vaccines within 30 days prior to the first dose of study treatment and while
participating in the study. Examples of live vaccines include, but are not
limited to, the following: measles, mumps, rubella, varicella/zoster, yellow
fever, rabies, 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
- Prior treatment 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)
- Prior systemic anti-cancer therapy including investigational agents within 4
weeks prior to study start. Note: Participants must have recovered from all AEs
due to previous therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2
neuropathy may be eligible. Note: If participant received major surgery, they
must have recovered adequately from the toxicity and/or complications from the
intervention prior to starting study treatment.
- Prior radiotherapy within 2 weeks of start of study treatment to sites outside
the breast. Participants must have recovered from all radiation-related
toxicities, not require corticosteroids, and not have had radiation pneumonitis.
- 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.
- For subjects who agree to the research breast MRI sub-study: Four or more previous
gadolinium contrast scans due to the risk of brain deposits following repeated use of
gadolinium-based contrast agents.