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

To compare the outcomes of and responses to 2 different radiation therapy schedules (the standard radiation amount and number of doses versus less radiation and fewer doses) that are being given before having breast cancer surgery (cancer removal and reconstruction).

Primary Objectives: --To compare BREAST-Q satisfaction with breasts 18 months after reconstructive surgery for patients randomized to HF-PreMRT versus CF-PreMRT. We hypothesize that HF-PreMRT will be superior to CF-PreMRT with regard to this endpoint. Secondary Objectives: * To compare oncologic outcomes following HF-PreMRT versus CF-PreMRT, including residual cancer burden, local-regional control, disease-free survival, and overall survival. * To compare surgical outcomes following HF-PreMRT versus CF-PreMRT, including surgical complications, flap loss, difficulty of reconstructive surgery, number of reoperations, and aesthetic outcomes including photographic assessment of the reconstructed breast. * To compare radiation outcomes following HF-PreMRT versus CF-PreMRT, including acute and late toxicities and fibrosis. * To compare health services research outcomes following HF-PreMRT versus CF-PreMRT, including financial toxicity, work productivity and disability, total cost of care, complicationrelated cost of care, and health utility. * To compare patient-reported quality of life and toxicities following HF-PreMRT versus CFPreMRT. * To compare patient-reported quality of life and toxicities following HF-PreMRT versus CFPreMRT. * To evaluate associations between the radiation treatment plan parameters and surgical, radiation, health services, and patient-reported outcomes. * To evaluate nanomechanical properties of the breast cancer before and after radiation and their association with oncologic outcomes * To evaluate nanomechanical properties of the breast normal tissue after radiation and their association with surgical and radiation outcomes. * To evaluate the association of germline polymorphisms, including the pro-fibrotic cytokine transforming growth factor-beta (TGF-β), with circulating serum TGF- levels during and after radiation and toxicities of radiation and reconstruction, particularly fibrotic complications. * To characterize pre- and post-radiation tumor and nodal tissue by single cell sequencing, whole genome, whole exome, and targeted sequencing, and digital spatial profiling for immune landscape, radiation resistance signatures, microenvironmental and tumor genome profiles and correlate radiation induced changes to tumor and patient characteristics and residual cancer burden. * To characterize pre- and post-radiation tumor and nodal tissue by single cell sequencing, whole genome, whole exome, and targeted sequencing, and digital spatial profiling for immune landscape, radiation resistance signatures, microenvironmental and tumor genome profiles and correlate radiation induced changes to tumor and patient characteristics and residual cancer burden. * To characterize irradiated normal breast and nodal tissues for genomic, proteomic, and metabolomic profiles and correlate these to tumor and patient characteristics, tumor burden, and toxicity * To characterize irradiated normal breast and nodal tissues for genomic, proteomic, and metabolomic profiles and correlate these to tumor and patient characteristics, tumor burden, and toxicity. * To compare surgical, radiation, and health services outcomes for patients treated with PreMRT on this trial to a matched cohort of patients treated with standard post-mastectomy radiation with breast reconstruction on the SAPHIRE protocol (2016-0142). * To compare translational data for patients treated with PreMRT on this trial to a matched cohort of patients treated with standard post-mastectomy radiation with breast reconstruction on the SAPHIRE protocol (2016-0142).