Preoperative Chemotherapy, Pembrolizumab, and No, Low, or High Dose Radiation for the Treatment of Node-Positive, HER2-Negative Breast Cancer, P-RAD

Inclusion Criteria

• Age >= 18 years old
• Participant has non-metastatic, N1-3* and one of the following histologically confirmed disease subtypes: * Triple negative breast cancer is defined as estrogen receptor (ER) =< 10% cells, progesterone receptor (PR) =< 10% cells and HER2-negative (< 2+ HER2 IHC or < 2.2 HER2/CEP17 ratio by fluorescence in situ hybridization [FISH]), as per testing at local institution. * High-risk hormone receptor (HR)+/HER2-negative breast cancer is defined as ER >= 10%, HER2-negative (< 2+ Her2 IHC or < 2.2 HER2/CEP17 ratio by FISH) and either histologic grade III or a high-risk genomic assay score (Oncotype Recurrent Score [RS] > 25, Ki67 > 20%, high risk mammaprint, PAM-50, EndoPredict or ProSigna score).
• Primary breast tumor measuring >= 1.0 cm in maximal diameter as measured by any available standard of care imaging (mammogram, breast ultrasound, breast magnetic resonance imaging [MRI])
• Biopsy-proven, axillary lymph node-positive breast cancer at diagnosis. * Note: Clinically node-positive disease is classified as cN1-3. cN1: without matted nodes, even if several/multiple appear matted on ultrasound or MRI; cN2: clinically fixed or matted nodes on examination or clinically or imaging-detected internal mammary node involvement
• Clips or fiducial placement within the biopsy-proven axillary lymph node and breast primary tumor are required
• Multifocal and multicentric disease is permitted; more than one breast tumor may be boosted per doctor of medicine (MD) discretion * Note: For patients with multifocal/multicentric disease who are randomized to receive a preoperative RT boost, all sites of multifocal/multicentric disease do not have to be contained within the pre-operative boost volume. MDs may decrease coverage of multifocal/multicentric tumors in the boost volume in order to meet suggested normal tissue constraints as needed
• Synchronous bilateral invasive breast cancer is permitted; after discussion with the sponsor-investigator and study chair
• No indication of distant metastases. Staging scans are not required and are per the discretion of the treating physician
• Neoadjuvant chemotherapy (NAC) with paclitaxel, dose-dense doxorubicin and cyclophosphamide (dd AC) is planned * Note: For triple negative breast cancer (TNBC) patients, administration of carboplatin with paclitaxel, either weekly area under the curve (AUC) 1.5 or q3 wk AUC 5, is required
• The boost volume is determined to be able to meet study dose constraints by the treating radiation oncologist
• Breast-conserving surgery or mastectomy +/- reconstruction is planned following NAC
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
• Absolute neutrophil count (ANC) >= 1500/uL (within 14 days prior to registration)
• Platelets >= 100 000/uL (within 14 days prior to registration)
• Hemoglobin >= 9.0 g/dL or >= 5.6 mmol/L (within 14 days prior to registration) * Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks
• Creatinine =< 1.5 x upper limit of normal (ULN) OR Measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 30 mL/min for participant with creatinine levels > 1.5 x institutional ULN (within 14 days prior to registration) * Creatinine clearance (CrCl) should be calculated per institutional standard
• Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for participants with total bilirubin levels > 1.5 x ULN (within 14 days prior to registration)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN (within 14 days prior to registration)
• International normalized ratio (INR) OR prothrombin time (PT) activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants (within 14 days prior to registration)
• A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: * Not a woman of childbearing potential (WOCBP) as defined OR * A WOCBP who agrees to follow the contraceptive guidance 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 minimized
• A male participant must agree to use a contraception as detailed of this protocol during the treatment period and for at least 4 months after the last dose of after the last dose of study treatment and refrain from donating sperm during this period
• Willingness to adhere to the study visit schedule and the prohibitions and restrictions specified in this protocol
• Willingness to undergo mandatory research biopsy of the breast tumor at day 10-14 of cycle 1, prior to initiation of NAC
• Written informed consent obtained from participant and ability for participant to comply with the requirements of the study
• Patients unable to read/write English or Spanish are eligible to participate in the overall study, but will not be required to participate in the Patient-Reported Outcome questionnaires

Exclusion Criteria

• HER2-positive breast cancer by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines (HER2 IHC 3+ or >= 2.2 HER2/CEP17 ratio by FISH)
• Inflammatory (cT4d) breast cancer
• Metastatic breast cancer (M1)
• Contraindication(s) to breast-conserving therapy or mastectomy
• Contraindication to radiation therapy including: prior ipsilateral breast or mantle RT, active scleroderma, systemic lupus erythematosis and pregnancy * Note: All cardiac implantable electronic devices are permitted, provided that methods to assess radiation doses and minimize damage to the devices during RT is planned, per institutional guidelines
• Prior ipsilateral breast, chest wall or thoracic radiotherapy
• Prior ipsilateral invasive breast cancer, contralateral breast cancer or a known additional, invasive malignancy that is progressing or required active treatment in the last 5 years. * Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or cervical carcinoma in situ that has undergone potentially curative therapy and a previous diagnosis of ductal carcinoma in situ are not excluded
• Has a known history of active tuberculosis (Bacillus tuberculosis)
• 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 (e.g., CTLA-4, OX-40, CD137)
• Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to randomization. *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. If participant received major surgery, she/he must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment
• Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
• Has known severe hypersensitivity (>= grade 3) to pembrolizumab and/or any of its excipients
• Participants with active, known or suspected autoimmune disease. Participants with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
• Known history of human immunodeficiency virus (HIV). * Note: No HIV testing is required unless mandated by local health authorities
• 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) * Note: No testing for hepatitis B or hepatitis C is required, unless mandated by local health authorities or institutional guidelines
• Has received a live vaccine within 30 days prior to the first dose of study drug. Administration of killed vaccines is allowed.
• Has an active infection requiring systemic therapy
• Has had an allogenic tissue/solid organ transplant
• A WOCBP who has a positive urine pregnancy test within 14 days before study registration. If the urine test cannot be confirmed as negative, a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. *Note: If the screening pregnancy test was conducted > 72 hours prior to the first dose of study treatment, pregnancy status must be confirmed negative within 72 hours prior to treatment initiation.
• Prohibited Treatments and/or Therapies. Use of immunosuppressants and/or systemic corticosteroids is exclusionary, except the following in the absence of active autoimmune disease: * As premedication for chemotherapy * For the prevention of nausea in the three days following chemotherapy * Participants are permitted the use of corticosteroids with minimal systemic absorption (e.g. topical, ocular, intra-articular, intranasal and inhaled) * Systemic corticosteroids at physiologic doses < 10 mg/day of prednisone or equivalent permitted * Adrenal replacement steroid doses including doses > 10 mg daily prednisone is permitted * A brief (less than 3 weeks) course of corticosteroids for prophylaxis (e.g. computed tomography [CT] scan premedication against contrast dye allergy) or for treatment of non-autoimmune conditions (e.g. delayed-type hypersensitivity reaction caused by a contact allergen is permitted (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