Trial Of PreoperAtive Radiation (TOPAz): A Randomized Trial Comparing Hypofractionated Versus Conventionally Fractionated Preoperative Radiation Followed by Mastectomy With Immediate Autologous Breast Reconstruction With Integrated Nanomechanical Biomarker Evaluation

Inclusion Criteria:

* Age 18 years or older
* Histologic diagnosis of invasive breast cancer (cytologic or histologic confirmation of nodal metastasis is sufficient to establish this eligibility criteria).
* Clinical and/or pathologic stage T3-T4c OR N1-N3; for the IBC pilot cohort only, the stage requirement is T4d, any N, M1
* Mastectomy is the planned oncologic surgery but has not yet been performed at the time of protocol enrollment
* Autologous (i.e. tissue-based) reconstruction is planned with either a free or rotational flap.
* For patients with HER2 positive, non-IBC breast cancer treated with neoadjuvant chemotherapy, one of the following criteria must be met:

  1. Residual invasive disease should be documented in either the breast or a regional nodal metastasis after neoadjuvant chemotherapy. This specific eligibility criteria can be satisfied by the post-chemotherapy standard of care breast biopsy. For this matter, the patient may be enrolled on the trial prior to biopsy. If the biopsy does not show residual invasive disease, then the patient will not proceed with protocol-directed therapy and will be removed and replaced from the study.
  2. Medical oncologist has documented a discussion in the chart about potential risks of proceeding with PreMRT with regard to impact on adjuvant systemic therapy decisions and the patient has opted to proceed with trial enrollment
* For T4d pilot cohort patients, post-chemotherapy, pre-radiation ultrasound must demonstrate at least partial response in the breast and regional lymph nodes and no suspicious infraclavicular, internal mammary, and supraclavicular lymph nodes.
* Ability to provide written informed consent in accordance with institutional policies.

Exclusion Criteria:

* Patients undergoing treatment for recurrent breast cancer in the index breast or lymph nodes.
* History of therapeutic irradiation to the breast, lower neck, mediastinum or other area(s) that will overlap with the affected breast.
* Presence of active scleroderma
* Patients who are pregnant.