title: Preoperative Single-Fraction Partial Breast Radiation Therapy: A Novel Phase 1, Dose-Escalation Protocol With Radiation Response Biomarkers.
abstract: OBJECTIVE
  Women with biologically favorable early-stage breast cancer are increasingly treated with accelerated partial breast radiation (PBI). However, treatment-related morbidities have been linked to the large postoperative treatment volumes required for external beam PBI. Relative to external beam delivery, alternative PBI techniques require equipment that is not universally available. To address these issues, we designed a phase 1 trial utilizing widely available technology to 1) evaluate the safety of a single radiation treatment delivered preoperatively to the small-volume, intact breast tumor and 2) identify imaging and genomic markers of radiation response.
  
  
  METHODS
  Women aged ≥55 years with clinically node-negative, estrogen receptor-positive, and/or progesterone receptor-positive HER2-, T1 invasive carcinomas, or low- to intermediate-grade in situ disease ≤2 cm were enrolled (n=32). Intensity modulated radiation therapy was used to deliver 15 Gy (n=8), 18 Gy (n=8), or 21 Gy (n=16) to the tumor with a 1.5-cm margin. Lumpectomy was performed within 10 days. Paired pre- and postradiation magnetic resonance images and patient tumor samples were analyzed.
  
  
  RESULTS
  No dose-limiting toxicity was observed. At a median follow-up of 23 months, there have been no recurrences. Physician-rated cosmetic outcomes were good/excellent, and chronic toxicities were grade 1 to 2 (fibrosis, hyperpigmentation) in patients receiving preoperative radiation only. Evidence of dose-dependent changes in vascular permeability, cell density, and expression of genes regulating immunity and cell death were seen in response to radiation.
  
  
  CONCLUSIONS
  Preoperative single-dose radiation therapy to intact breast tumors is well tolerated. Radiation response is marked by early indicators of cell death in this biologically favorable patient cohort. This study represents a first step toward a novel partial breast radiation approach. Preoperative radiation should be tested in future clinical trials because it has the potential to challenge the current treatment paradigm and provide a path forward to identify radiation response biomarkers.
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina. Electronic address: janet.horton@duke.edu.
authors.forename: Janet K
authors.initials: JK
authors.lastname: Horton
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Blitzblau
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Sua
authors.initials: S
authors.lastname: Yoo
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Joseph
authors.initials: J
authors.lastname: Geradts
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Chang
authors.affiliation: Department of Radiology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Jay A
authors.initials: JA
authors.lastname: Baker
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina.
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Georgiade
authors.affiliation: Department of Bioinformatics: Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Sharareh
authors.initials: S
authors.lastname: Siamakpour-Reihani
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Chunhao
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Biostatistics: Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina.
authors.forename: Gloria
authors.initials: G
authors.lastname: Broadwater
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Jeff
authors.initials: J
authors.lastname: Groth
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Manisha
authors.initials: M
authors.lastname: Palta
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Mark
authors.initials: M
authors.lastname: Dewhirst
authors.affiliation: Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina; Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: William T
authors.initials: WT
authors.lastname: Barry
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Eileen A
authors.initials: EA
authors.lastname: Duffy
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina; Center for Genomic and Computational Biology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Jen-Tsan A
authors.initials: JT
authors.lastname: Chi
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina.
authors.forename: E Shelley
authors.initials: ES
authors.lastname: Hwang
mesh_terms: D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy* / Q000601:surgery; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy* / Q000601:surgery; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy* / Q000601:surgery; D005240:Feasibility Studies; D005260:Female; D015870:Gene Expression; D005819:Genetic Markers; D006801:Humans; D015412:Mastectomy, Segmental; D008875:Middle Aged; D011300:Preoperative Care; D011832:Radiation Injuries / Q000473:pathology; D011879:Radiotherapy Dosage; D050397:Radiotherapy, Intensity-Modulated / Q000379:methods*
chemical_list: D005819:Genetic Markers