Testing the Addition of an Anti-cancer Drug, Berzosertib, to the Usual Treatment (Radiation Therapy) for Chemotherapy-Resistant Triple-Negative and Estrogen and/or Progesterone Receptor Positive, HER2 Negative Breast Cancer

PRIMARY OBJECTIVE: I. To determine the recommended phase 2 dose of twice weekly berzosertib administered concurrently with conventionally fractionated radiation therapy (RT) to the breast/chest wall and regional nodes. SECONDARY OBJECTIVES: I. To describe the nature of toxicity that develops when an ATR inhibitor is administered concurrently with RT for breast cancer using provider assessments. II. To assess long-term locoregional control, disease-free survival, distant disease-free survival, and overall survival of patients treated with this approach. III. To explore symptomatic adverse events and tolerability of berzosertib being administered concurrently with RT using patient-reported outcomes (PROs). IV. To assess for alterations in deoxyribonucleic acid (DNA) damage response and repair genes, including effectors and regulators of homologous recombination (HR), in pre-chemotherapy biopsy specimens and post-chemotherapy surgical resection specimens using whole exome sequencing (WES) and ribonucleic acid (RNA) sequencing (RNAseq), and to correlate HR deficiency with disease-free survival. V. To identify somatic alterations in circulating cell-free DNA (cfDNA) at baseline, mid-treatment, end-of-treatment, and follow-up and to correlate cfDNA with disease-free survival. EXPLORATORY OBJECTIVES: I. To compare the baseline and post-treatment skin microbiome and make exploratory correlations with severe provider and patient-reported toxicity. II. To explore dose-volume parameters associated with acute and late provider and patient-reported toxicity following berzosertib administration concurrent with RT. III. To identify circulating tumor cell (CTC) positivity at baseline, mid-treatment, end-of-treatment, and follow-up and to correlate CTC positivity or the combination of CTC positivity and cfDNA with disease-free survival. IV. To evaluate pre-treatment and post-treatment differential abundance of peripheral blood immune cell populations identified by cytometry by time-of flight (CyTOF). V. To evaluate associations of the pre-treatment and post-treatment peripheral blood immune phenotype (as assessed by CyTOF) with disease-free survival, distant disease-free survival and overall survival. VI. To explore the USP21-ATR pathway and its association with epithelial to mesenchymal transition (EMT) in therapeutically resistant breast cancer specimens at pre-treatment and post-treatment timepoints using immunohistochemistry (IHC) and RNAseq. OUTLINE: This is a dose-escalation study of berzosertib. Patients receive berzosertib intravenously (IV) over 60 minutes twice weekly (BIW) for 5 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo RT 5 days a week for 5-6 weeks depending on the type of surgery undergone. Patients also undergo a collection of blood on study. After completion of study treatment, patients are followed up weekly for 4 weeks, at 12 months, then yearly for up to 3 years.