Intraoperative radiotherapy (IORT) impairs surgical wound-stimulated breast cancer cell invasion

Abstract

21139 Background: Risk of local recurrence after complete excision of breast cancer is higher in the area around the original tumor, suggesting that wound healing may be implicated. Methods: We collected blood samples (BS) before surgery and wound fluid (WF) in the 24 hours after breast conserving surgery from 50 patients. Twenty five of these patients were also treated with TARGeted Intraoperative radioTherapy (TARGIT, 20Gy to tumor bed surface in one session), immediately after the surgical excision. The ability of the BS and WF to stimulate growth and motility of a panel of normal and mammary carcinoma cells was studied. A proteomic approach was used to analyze the expression pattern of WF and BS. Results: We assayed five cell lines in a transwell based assay using individual patient BS and wound fluids WF as potential chemo-attractants. WF strongly attracted cells from all 5 types of breast cancer cell lines that we tested including MDA- MB 231, MCF-7, MDA-MB 453, T47D and SKBR-3. The WF attracted the cells better than both the respective BS. Importantly, in all tested cell lines TARGIT significantly impaired the ability of WF to attract cancer cells (p=0.03 MDA-MB 231 and MCF-7. p=0.01 for MDA-MB 453, and SKBR-3). Moreover, while BS did not stimulate 3D motility over the control WF strongly stimulated 3D movement of MDA-MB 231 and MDA-MB- 453 cells. This stimulatory effect was abrogated in the WF taken from patients who had received TARGIT (p=0.01 for MDA-MB 231 and p<0.0001 for MDA-MB 453). Similar results were obtained when cell proliferation was evaluated using the same cell lines and BS or WF samples. Finally, proteomics analyses demonstrated that TARGIT modifies the expression levels of several key proteins involved in tumor cell growth and dissemination. Conclusion: TARGIT delivered to the tumor bed alters the cytokines and growth factors expression patterns in the surgical wound and abrogates its stimulatory effect on cancer cell growth and motility. This novel mechanism of action of radiotherapy could partly explain the very low recurrence rates found in large pilot studies of this technique and open new avenues for peri-operative therapies. No significant financial relationships to disclose.