Patients with high risk breast cancers (any locally advanced breast cancer patient defined as Stages IIB-III [excluding inflammatory breast cancer] with stage IIA being eligible for triple negative and HER2-positive breast cancers) will receive neoadjuvant radiation to any portion of their tumour in three fractions in order to act as an immune primer. Radiation will be delivered to a portion of the tumour in three fractions. The patient will be positioned prone as per the SIGNAL 2.0 protocol. The patient will then go on to standard of care treatment (neoadjuvant chemotherapy and surgery) followed by whole-breast radiation as needed. Pathologic complete response will be the primary outcome. Immune markers will also be evaluated.

Patients eligible for neoadjuvant chemotherapy for locally advanced stage III (non-inflammatory) breast cancer or stage IIb (triple negative or Her2+) breast cancers will be approached to participate in this single arm trial. Patients with staging investigations ruling out distant disease will be approached to participate and will undergo pre-treatment image guided core biopsy and blood samples for molecular correlative studies, followed by hypofractionated radiation (delivered prone) to entire tumor with dose constraints to skin, critical organs and contralateral breast, plus a 0.5 cm PTV. As much of the tumor that can receive planned dose of 8 Gy per fraction x 3 fractions every second day, with fall off dose to 4 Gy per fraction x 3 fractions for PTV margin. Two weeks following completion of radiation, patients will undergo a second image guided core needle biopsy of tumor and blood sample. They will then begin standard neoadjuvant chemotherapy (anthracycline and taxane based), followed by a third tissue biopsy under image guidance of any residual tumor and blood sample and then standard surgery (breast conserving or lumpectomy). This will be followed by standard whole breast radiation (50 Gy in 25 fractions). Herceptin therapy and hormonal therapy will be administered as per clinical standard when indicated. Primary outcome will be measured as pathological complete response to treatment, and secondary outcomes will include toxicity, immune markers (tumor infiltrating lymphocytes, PD-1 and PD-L1 up-regulation and changes to the circulating lymphocyte counts.

Inclusion Criteria:

1. Any biopsy-proven locally advanced breast cancer patient defined as Stages IIB-III (excluding inflammatory breast cancer). Stage IIA is eligible for triple negative and HER2-positive breast cancers
2. Invasive mammary carcinoma of any subtype excluding lobular, sarcomatous, or metaplastic subtypes, or with lobular features
3. Plan to be treated with neoadjuvant chemotherapy
4. Able to fit in/have MRI
5. 18 years of age or older
6. Able to tolerate core needle biopsies
7. Able to provide informed consent
8. No evidence of metastatic disease

Exclusion Criteria:

1. Any serious medical comorbidities or other contraindications to radiotherapy, chemotherapy, or surgery
2. Prior treatment for current breast cancer
3. Previous radiation therapy to the same breast
4. Inflammatory breast carcinoma
5. Invasive lobular carcinoma or invasive mammary carcinoma with lobular, sarcomatous, or metaplastic subtypes, or with lobular features
6. Recurrent breast cancer
7. Bilateral breast cancer
8. Evidence of distant metastatic disease
9. Collagen vascular disease (particularly lupus, scleroderma, dermatomyositis, psoriatic arthritis)
10. Any other malignancy at any site (except non-melanomatous skin cancer) <5 years prior to study enrollment
11. Inability to lay prone with arms above the head for extended periods of time
12. Inability to fit in/have an MRI
13. Inability to tolerate core needle biopsies
14. Pregnant or lactating
15. Under 18 years of age
16. Inability or unwillingness to provide informed consent