Mitigation of Radiation Induced Type I Collagen Dermal Disorganization Utilizing Amifostine in a Murine Breast Reconstruction Model

Purpose: In the United States, breast cancer is the most common cancer diagnosis with treatment often combining surgery with adjuvant radiation (XRT). While XRT is effective as a cancer therapy, it has detrimental effects on the surrounding healthy tissues. This collateral damage leads to reconstructive complications limiting patient candidacy for expander-based reconstruction. Radiation’s direct damage to the structural organization of dermal type I collagen can lead to impairment of cutaneous strength and elasticity. To assuage the pernicious effects of radiation, we utilized the cytoprotectant amifostine (AMF) as a preemptive therapeutic with the objective of improving dermal type I collagen organization within a murine model of breast reconstruction.

Methods: Female Sprague-Dawley rats (n=15) were divided into 3 groups (n= 5 per group): 1)  Expander placement (Control); 2) Expander placement + XRT (XRT); 3) Expander + AMF +XRT (AMF). Expanders were surgically placed in a sub-musculocutaneous plane in the right upper back with a subsequent 15 cc fill volume. Control specimens received no additional intervention, XRT group received a breast cancer human-equivalent dose of radiation, and the AMF group received AMF 30 minutes prior to each radiation dose. After a 20 day recovery period skin was harvested, sectioned, and Atomic Force Microscopy (AFM) was used to acquire 10x10 um images of type I collagen dermal sheets. Image J analysis was utilized to quantify AFM images with respect to dermal collagen organizational structure.

Results: Image J evaluation of the XRT group demonstrated a significant increase in skin ulceration when compared to the Control group (p=0.001). Pre-radiation treatment with AMF was associated with improved collagen sheet organization when compared to the XRT group (p=0.001). AFM images of the XRT group exhibited a significant increase in collagen fibril disorganization when compared to Control (p=0.001) and AMF (p=0.001). No statistical differences were identified between Control and AMF groups (p=0.122) as both had similar parallel, organized collagen sheets.

Conclusions: Pre-treatment with AMF resulted in a significant improvement in type I collagen fibril organization in a murine model of expander-based breast reconstruction. Type I collagen organization directly impacts the architectural integrity of skin as well as providing the substrate environment for cell proliferation for proper wound healing. Retaining this type I collagen sheet structure is paramount to facilitating improved reconstructive outcomes. If these findings translate into clinical practice then utilizing AMF has the potential to reduce radiation associated type I collagen dermal change. More broadly, this therapeutic has potential to increase candidacy for breast reconstruction, improve surgical outcomes, and enhance quality of life for breast cancer patients undergoing reconstruction.