Preoperative Single-Fraction Partial Breast Radiation Therapy: A Novel Phase 1, Dose-Escalation Protocol With Radiation Response Biomarkers

Abstract

Purpose: 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 and materials: 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.

Figure 1

Preoperative radiation to the intact tumor. Sagittal view (A) of a prone treatment planning MRI (left) and CT (right). (B) Sagittal (left) and axial (right) treatment planning images with dose distribution in the same patient.

Figure 2

Cosmetic outcomes for single-dose, definitive pre-operative partial breast irradiation. (A) Patient and physician-reported cosmetic outcomes in patients treated with preoperative radiation only. (B) Two women with more than 3 years of follow-up. Red arrows highlight the region of lumpectomy.

Figure 3

Paired pre and post-radiation MRI images demonstrate evidence of increased vascular permeability. (A) Pre- (left) and post-treatment (right) DCE-MRI images. (B) Pre- (left) and post-treatment (right) images highlighting contrast agent distribution with the planning target volume.

Figure 4

Changes in gene expression following radiation in early-stage favorable breast tumors (ER+). (A) Principal component analysis suggests that gene expression profiles following radiation are significantly and consistently distinct from that noted prior to radiation. (B) The primary effect of increasing dose is to enhance, rather than repress, gene expression in the subset of 27 genes experiencing significant and dose-related change with radiation. (C) The impact of radiation on relative gene expression increases (n=24 of 27) with each incremental increase in dose. (D) The cohort of genes demonstrating significant dose-response is enriched for modulators of immunity and inflammation.