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No RT boost plus pembrolizumab, followed by pembrolizumab plus paclitaxel, doxorubicin and cyclophosphamide chemotherapy.There will be up to a total of 8 cycles of pembrolizumab (4 cycle before surgery and 4 cycles after surgery at the discretion of the study doctor).

Low-dose RT boost plus pembrolizumab, followed by pembrolizumab plus paclitaxel, doxorubicin and cyclophosphamide chemotherapy. There will be up to a total of 8 cycles of pembrolizumab (4 cycle before surgery and 4 cycles after surgery at the discretion of the study doctor).

High-dose RT boost plus pembrolizumab followed by pembrolizumab plus paclitaxel, doxorubicin and cyclophosphamide chemotherapy. There will be up to a total of 8 cycles of pembrolizumab (4 cycle before surgery and 4 cycles after surgery at the discretion of the study doctor).

Participants randomized to the low-dose or high-dose RT boost group will be receiving treatment on Day 1-3 of Cycle 1 of pembrolizumab. Proton therapy may be used in the high dose RT group.

Radiation Therapy Boost

Neoadjuvant Phase: Day 1 (once every 6 weeks) of Cycles 1-4 (by intravenous infusion) over about 30 minutes.

Adjuvant Phase: Pembrolizumab may be given post-surgery for up to 4 cycles (once every 6 weeks) by intravenous infusion over about 30 minutes. Pembrolizumab after surgery is optional and should be discussed with the study doctor.

Starting Week 3 and administered once per week for 12 weeks (up to 12 doses) by intravenous infusion over about 30 minutes.

Carboplatin is optional for TNBC patients and should be discussed with the study doctor.

Starting Week 3 and administered once per week for 12 weeks (up to 12 doses) by intravenous infusion over about 30 minutes.

Starting Week 15 and administered every 2 weeks for 4 cycles (up to 4 doses) into your vein (by intravenous infusion).

Starting Week 15 and administered every 2 weeks for 4 cycles (up to 4 doses) into your vein (by intravenous infusion). Doxorubicin will be administered after pembrolizumab.

Capecitabine after surgery is optional for TNBC patients and should be discussed with the study doctor.

Starting 3-6 weeks after surgery, administered orally twice daily for 6 courses, each 3 weeks long (for a total of 18 weeks).

Laura M Spring, MD

Cesar Santa-Maria, MD

Laura Warren, MD

Robert Mutter, MD

Jana Fox, MD

Atif Khan, MD

Gaorav Gupta, MD, PhD

Rachel Blitzblau, MD

Shelley Hwang, MD, MPH

Haven Garber, MD, PhD

This research trial is studying a combination of neoadjuvant radiotherapy (RT), immunotherapy (pembrolizumab) and chemotherapy for lymph node-positive, triple negative (TN) or hormone receptor positive/HER2-negative breast cancer.

The names of the study interventions involved in this study are:

* Radiation Therapy (RT)
* Immunotherapy: Pembrolizumab (MK-3475)
* Chemotherapies:

  * Paclitaxel
  * Doxorubicin (also called Adriamycin)
  * Cyclophosphamide
  * Carboplatin (optional, and in TN only)
  * Capecitabine (optional, and in TN only)

The main purpose of this study is to find out what is the best dose of preoperative RT when combined with pembrolizumab and chemotherapy. The study will assess if combining the RT with the immunotherapy agent, pembrolizumab, will increase the ability of the immune system to destroy cancer cells.

The research study procedures include: screening for eligibility and study treatment, including evaluations and follow-up visits.

The study aims to assess the effectiveness of pembrolizumab (study drug) with or without RT directed to the breast tumor. Participants will then undergo neoadjuvant chemotherapy with pembrolizumab, followed by treatment that can consist of one or more of the following:

* Pembrolizumab (optional, per MD discretion)
* Standard of Care Treatment

  * Breast surgery (lumpectomy or mastectomy) and axillary surgery
  * Adjuvant radiation to the entire breast or chest wall, plus or minus the lymph nodes after surgery
  * Adjuvant chemotherapy (optional Capecitabine for TNBC patients)
  * Hormone therapy

Participants will be randomized to 1 of 3 groups. Neither the participant not the research doctor will choose the group that the participant is assigned to. However, the participant will be notified of the group prior to the start of study treatment. Participants will receive study treatment for up to 13 months. Participants will be followed for 2 years after the end of the study treatment.

It is expected that a total of 120 people will be participating in total.

This research study is a randomized, phase II study. The U.S. Food and Drug Administration (FDA) has not approved pembrolizumab for your specific disease, but it has been approved for other uses. The U.S. Food and Drug Administration (FDA) has approved the chemotherapies being used in this study (Paclitaxel, Doxorubicin, Cyclophosphamide, Carboplatin, Capecitabine).

Pre-op Pembro + Radiation Therapy in Breast Cancer (P-RAD)

P-RAD: A Randomized Study of Preoperative Chemotherapy, Pembrolizumab and No, Low or High Dose RADiation in Node-Positive, HER2-Negative Breast Cancer

The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to Sponsor Investigator or designee. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.

Quantitative immunofluorescence in post-treatment tumor biopsy samples collected on day 14-21 of C1 of Pembrolizumab.

Defined as the percentage of patients no evidence of residual cancer cells in all sampled regional lymph nodes following completion of neoadjuvant systemic therapy assessed by the study pathologist at the time of definitive surgery.

RCB is a measure of residual cancer burden in the breast and regional lymph nodes at the time of definitive surgery following completion of neoadjuvant systemic therapy.

Pathologic response rate is measured by the presence or absence of residual cancer cells in all sampled regional lymph nodes. RCB measures residual disease in the breast and lymph nodes at the time of definitive surgery. CD3+/CD8+ T cell Breast Immunoscore greater than 75% versus patients with Post-treatment CD3+/CD8+ T cell Breast Immunoscore less than or equal to 75%.

Intra-tumoral, peri-tumoral and stromal CD3+, CD8+, and CD3+CD8+ T cell densities will be measured using pan-cytokeratin staining and multiplexed QIF

TIL counts by H\&E in pre-treatment versus post-RT boost tumor biopsy specimens in each RT dose and breast cancer subtype cohort.

H\&E will be performed according to Salgado Criteria \[1\].

To quantify changes in PD-L1 expression levels after treatment with Pembro + no, low or high RT boost (at the time of the time of interval biopsy).

QIF for PD-L1 will be performed in pre- and post-treatment FFPE tumor biopsy samples.

To quantify changes in intratumoral, per-tumoral, and stromal CD4+Foxp3+ T regulatory cell densities in response to treatment with preoperative Pembro + no, low, or high dose RT boost (at the time of interval biopsy).

QIF for CD4 and Foxp3 will be performed in pre- and post-treatment FFPE tumor biopsy samples. Pan-cytokeratin staining will be used to identify tumor regions

iDFS is defined as time from completion of surgery to the first occurrence of the following events: invasive ipsilateral, local, regional, or distant recurrence, or death due to breast cancer.

EFS is defined as the time from the initiation of the study treatment to any of the following events: progression of disease (precluding surgery), recurrence (local or distant), or death due to any cause.

PROMIS Global Health Measure Quality of life (e.g., global, physical, mental, and social health) outcomes will be measured by two PROMIS (Patient-Reported Outcomes Measurement Information System) short forms consisting of 4 questions total. This instrument has demonstrated content-validity, cross-sectional validity, and responsiveness to change in numerous publications\[93\].

(Breast-Q), four domains will be evaluated both before and after surgery: satisfaction with breasts, psychosocial, sexual, and physical well-being. Scores for each domain range from 0-100, with higher scores indicative of better quality of life

PRO-CTCAE will evaluate symptom burden in the previous week using a Likert scale to assess presence/absence, frequency, severity and/or interference for different symptoms. Each symptom will be presented descriptively, using summary statistics and graphical representations across time points.

Recently coined term used to describe the potential financial burden patients experience while receiving medical care. Two questions were adapted from the National Health Interview Survey\[95\] and a survey administered to caregivers of participants of the Cancer Car Outcomes Research and Surveillance (CanCORS) study\[96\] to assess financial burden and impact on employment-related metrics (e.g., sick leave, unpaid time off work). Financial burden will be assessed at the post-surgery visit.

The Was It Worth It (WIWI) instrument, also called the "Trial Satisfaction" survey, was developed to investigate the patient experience on clinical trials. Multiple cooperative group studies have utilized this instrument at the completion of treatment to measure patient satisfaction relating to clinical trial enrollment, although formal validity and reliability data is not yet available\[

Spots Global Cancer Trial Database for radiation therapy boost