Nodal Pathologic Complete Response rate(pCR)

Nodal pCR is defined in a patient with no residual cancer cells in all sampled regional lymph nodes following completion of neoadjuvant systemic therapy as assessed by the study pathologist at the time of definitive surgery. Nodal pCR rates will be calculated and analyzed separately for patients receiving low versus high dose RT. A pooled analysis, incorporating the corresponding (3Gyx3 or 8Gyx3) patient cohort from the P-RAD trial, will be performed.

Time of surgery (24 week)

The CD3+/CD8+ T cell Breast post-treatment biopsy

The CD3+/CD8+ T cell Breast Immunoscore of post-treatment biopsy samples represents an average of percentage ranked scores for (i) CD3+ density in intra-tumoral region, (ii) CD3+ density in peri-tumoral region, (iii) CD8+ density in intra-tumoral region, and (iv) CD8+ density in peri-tumoral region. The reference cohort for determining percentage ranks will be the pre-treatment biopsy samples.

Time of surgery (24 week)

Composite pathologic complete response (pCR) (ypT0/Tis ypN0)

Composite pCR =T0/Tis and pN0 will be defined as the percentage of patients with Tis/T0 disease in the breast and 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.

Time of surgery (24 week)

Total residual cancer burden (RCB)

RCB will be evaluated by the study pathologist and defined based on residual tumor size and/or area, overall cellularity, and extent of lymph node involvement.

Time of surgery (24 week)

Nodal pathologic complete response (pCR)

Nodal pCR is defined as absence of residual cancer cells in all sampled regional lymph nodes.

Time of surgery (24 week)

Composite pathologic complete response (pCR)

Composite pCR rate is measured by ypTis/T0 disease in the breast and the absence of residual cancer cells in all sampled regional lymph nodes.

Time of surgery (24 week)

Changes in pre- versus post-treatment intra-tumoral, peri-tumoral, and stromal CD3+ or CD8+ T cell percentages

Intra-tumoral, peri-tumoral, and stromal CD3+ and CD8+ T-cell densities will be measured in biopsy and surgical specimens and compared. Pan-cytokeratin staining will be used to identify tumor regions, and the percentages will be analyzed.

Time of surgery (24 week)

Change in tumor-infiltrating lymphocyte (TIL)

Tumor-infiltrating lymphocyte (TIL) counts will be assessed on hematoxylin and eosin (H\&E)-stained biopsy and surgical specimens using the Salgado criteria, which evaluate the percentage of stromal area occupied by lymphocytes following standardized guidelines. The values in biopsy and surgical specimens and compared.

Time of surgery (24 week)

Change in Programmed cell death 1 ligand 1(PD-L1)

Changes in PD-L1 expression levels will be assessed using the U.S. FDA-approved 22C3 pharmDx companion diagnostic assay to determine the Combined Positive Score (CPS). A CPS greater than 1 will be considered PD-L1 positive. The values in biopsy and surgical specimens and compared.

Time of surgery (24 week)

Changes in intratumoral, peri-tumoral, and stromal CD4+Foxp3+ T regulatory cell densities

Changes in intratumoral, peri-tumoral, and stromal CD4+FOXP3+ regulatory T-cell densities will be quantified using quantitative immunofluorescence (QIF) for CD4 and FOXP3 in formalin-fixed, paraffin-embedded (FFPE) tumor biopsy and surgical specimens. Pan-cytokeratin staining will be used to identify tumor regions.

Time of surgery (24 week)

Adverse Events

Adverse events will be classified and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI-CTCAE v5.0), at 30 days after investigational pembrolizumab administration. The number of observed AEs will be reported.

Up to 60 weeks

Invasive disease-free survival (iDFS)

iDFS will be defined as the 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.

Up to 5 years

Event-free survival (EFS)

EFS will be 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.

Up to 5 years

Quality of life Global Health PROMIS in Low Dose Radiotherapy Boost Group

Quality of life will be assessed by Patient-Reported Outcomes Measurement Information System (PROMIS) tool developed by the National Institutes of Health (NIH) before and after treatment. It is designed to measure a patient's overall physical, mental, and social health using a brief and standardized questionnaire. Responses are collected using a 5-point Likert scale (1 = Poor, 5 = Excellent), summed into raw scores, and converted to standardized T-scores (mean = 50, SD = 10; range \~20-80), with higher scores indicating better health.

Baseline, Week 2, Week 8, Week 14, and Week 20, 6 months post-surgery, and monthly for up to 3 years

Quality of life BREAST-Q in Low Dose Radiotherapy Boost Group

Patient-reported outcomes related to breast surgery will be assessed using the BREAST-Q questionnaire, a validated instrument measuring satisfaction with breasts, psychosocial well-being, physical well-being, and sexual well-being. Most items are answered on a 4- to 5-point Likert scale, for example: Satisfaction: "Very dissatisfied" → "Very satisfied" or Frequency/impact: "Never" → "Always" or "Not at all" → "Very much. "Responses are scored according to the BREAST-Q scoring system and transformed to a 0-100 scale, with higher scores indicating greater satisfaction or better quality of life.

Baseline, Week 2, Week 8, Week 14, and Week 20, 6 months post-surgery, and monthly for up to 3 years

The Was It Worth It (WIWI) in Low Dose Radiotherapy Boost Group

The Was It Worth It (WIWI) instrument, also called the Trial Satisfaction survey, is a validated patient-reported outcome measure designed to assess participants' experiences and satisfaction with clinical trial participation. It evaluates whether patients feel that joining the trial was worthwhile and captures their overall perception of the trial experience. Responses are collected using a Likert-type scale (3 to 5 points) or categorical options, with higher scores indicating a more positive perception of trial participation. Scores will be summarized to assess overall patient satisfaction and the perceived value of trial involvement.

Baseline, Week 2, Week 8, Week 14, and Week 20, 6 months post-surgery, and monthly for up to 3 years

Quality of life Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) in Low Dose Radiotherapy Boost Group

PRO-CTCAE, which collects information on the frequency, severity, interference, and presence or absence of symptoms such as pain, fatigue, nausea, and cutaneous side effects including rash and hand-foot syndrome. These toxicities are selected because they can be meaningfully reported from the patient perspective. PRO-CTCAE responses are scored from 0 to 4, or 0/1 for absent/present items. If the first response in an item set is the lowest on the scale (e.g., 'Never' for frequency or 'None' for severity), any conditionally branched items are scored as 0 and not treated as missing.

Baseline, Week 2, Week 8, Week 14, and Week 20, 6 months post-surgery, and monthly for up to 3 years

Comparison tumor-infiltrating lymphocyte (TIL)

Differences in tumor-infiltrating lymphocyte (TIL) between low and high dose levels will be assessed by hematoxylin and eosin (H\&E)-stained biopsy and surgical specimens using the Salgado criteria, which evaluate the percentage of stromal area occupied by lymphocytes following standardized guidelines. The values in biopsy and surgical specimens and compared. Differences in TIL between low and high dose levels (3Gyx3 or 8Gyx3) will be assessed by H\&E.

Time of surgery (24 week)