The goal of this study is to evaluate the safety and effectiveness of adjuvant chemoradiation therapy in high-risk breast cancer patients who had received neoadjuvant chemotherapy before their lumpectomy and/or mastectomy and were found to have residual disease. As well as examine the effects of this treatment combination on the immune system.

Breast cancer is often treated with a combination of surgery, chemotherapy and radiation. In patients with advanced breast cancer, (neoadjuvant) chemotherapy is often given prior to surgical removal (lumpectomy and/or mastectomy). Neoadjuvant chemotherapy has been consistently shown to down-stage primary breast tumors and convert positive underarm lymph nodes to pathologically negative nodes. Residual disease discovered after receiving neoadjuvant chemotherapy indicates an increased risk for recurrence and poor overall survival. The combination of concurrent chemotherapy and radiation after surgery (adjuvant chemoradiation) may improve local and distant recurrence outcomes in high risk breast cancer patients. Chemoradiation is a standard treatment for many cancers and is universally associated with improvements in local recurrence, however, it has not historically been given as post-surgery breast cancer treatment.

The study will evaluate the safety, feasibility, and effectiveness of chemoradiation therapy in high-risk breast cancer patients. Radiation has been associated with various effects on immune cells. The study will also examine the effects of this combination on the immune cells.

Participants on this trial will be treated (per approved clinical guidelines) with capecitabine or Trastuzumab emtansine (T-DM1) depending on Her2 status while receiving radiation at the same time. Participants will have their blood drawn at various timepoints during treatment and follow up. Participants will also be asked to complete surveys asking about overall health and wellbeing.

Inclusion Criteria:

1. Provision of signed and dated informed consent form

2. Stated willingness to comply with all study procedures and availability for the duration of the study

3. Male or female, aged 18 or older

4. Diagnosis of stage I-IIIB breast cancer

5. Received neoadjuvant chemotherapy (minimum of 3 cycles) and surgical resection (lumpectomy and/or mastectomy)

6. Discovered to have residual disease at least ypT1aNx or ypTxN1mic at surgical resection

7. Candidate for adjuvant chemoradiation as part of standard clinical care

8. Planned initiation of radiation within 12 weeks of their final oncologic surgery

9. ECOG performance status ≤2

10. Adequate cardiac function, with LVEF greater or equal to 45% (only for patients who will receive TDM-1 therapy)

11. Adequate organ function per the following criteria within 21 days before the start of treatment. If a laboratory value required for study eligibility does not meet the below requirements, the value may be retested.

    • Absolute neutrophil count ≥1.5 k/uL
    • Platelets ≥100 k/uL
    • Hemoglobin ≥ 10 g/dL
    • Serum Creatinine ≤ 1.5 x ULN
    • Bilirubin ≤ 1.5 x ULN (except in patients with Gilbert's disease, where bilirubin to 4x ULN is allowed).
    • AST and ALT ≤ 2.5 x ULN
    • Alkaline phosphatase ≤ 2.5 x ULN

12. For females and males of reproductive potential: agreement to use adequate contraception during study participation and for an additional 6 months after the end of chemoradiation administration or until advised by their medical oncologist

13. Agreement to adhere to Lifestyle Considerations throughout study duration

14. Subjects taking warfarin and plan to receive capecitabine will need their anticoagulant management assessed before starting treatment.

Exclusion Criteria:

1. Had a mastectomy with expander placement or immediate reconstructions
2. Diagnosed with systemic lupus
3. Diagnosed with scleroderma
4. Diagnosed with a genetic mutation associated with increased sensitivity to radiation (e.g. ataxia-telangectasias (AT)). AT heterozygotes without known radiation sensitivity may be included.
5. Acute bacterial or fungal infection requiring intravenous antibiotics at time of registration.
6. Pathologic evidence of metastatic disease, or strong clinical/radiological evidence of metastatic disease, at the investigator's judgment.
7. Pregnancy or lactation
8. Incarceration
9. Presence of cardiac pacemaker on side of the body that is being treated unless the pacemaker can be moved prior to treatment.
10. Anthracycline exposure exceeding a cumulative doxorubicin dose of 264 mg/m2 (240 mg/m2 plus a 10% threshold)
11. Known allergic reactions to components of capecitabine or T-DM1
12. Known DPD deficiency for patients prescribed capecitabine
13. Febrile illness within a week of starting treatment
14. Incomplete healing of chest wall or breast in the treatment field within 12 weeks from surgery.
15. Known HIV or active hepatitis.
16. Unwilling to discontinue endocrine therapy if currently taking endocrine therapy.

Participants, clinical research staff, and treating clinicians will be aware of arm assignment. The labels on research blood will not include the treatment arm on which the participant is assigned and this information will not be provided to lab investigators and staff.