Targeted Intraoperative Radiotherapy Impairs the Stimulation of Breast Cancer Cell Proliferation and Invasion Caused by Surgical Wounding

Abstract

Purpose: After apparently successful excision of breast cancer, risk of local recurrence remains high mainly in the area surrounding the original tumor, indicating that wound healing processes may be implicated.The proportional reduction of this risk by radiotherapy does not depend on the extent of surgery, suggesting that radiotherapy, in addition to killing tumor cells, may influence the tumor microenvironment. Experimental Design: We studied how normaland mammary carcinoma cell growth and motility are affectedby surgical wound fluids (WF), collectedover 24 hfollowingbreast-conserving surgery in 45 patients, 20 of whomhadreceivedadditionalTARGeted Intraoperative radioTherapy (TARGIT), immediately after the surgical excision. The proteomic profile of the WF and their effects on the activation of intracellular signal transduction pathways of breast cancer cells were also analyzed. Results: WF stimulated proliferation, migration, and invasion of breast cancer cell lines.The stimulatory effect was almost completely abrogated when fluids from TARGIT-treated patients were used. These fluids displayed altered expression of several cytokines and failed to properly stimulate the activation of some intracellular signal transduction pathways, when compared with fluids harvested from untreated patients. Conclusions: Delivery of TARGIT to the tumor bed alters the molecular composition and biological activity of surgical WF. This novel antitumoral effect could, at least partially, explain the very low recurrence rates found in a large pilot study using TARGIT. It also opens a novel avenue for identifying new molecular targets and testing novel therapeutic agents.

An international randomised controlled trial to compare TARGeted Intraoperative radioTherapy (TARGIT) with conventional postoperative radiotherapy after breast-conserving surgery for women with early-stage breast cancer (the TARGIT-A trial)

“…It suggests that the difference in non-breast-cancer mortality could arise from an increase in mortality from EBRT toxicity, as one would think conventionally, as well as a reduction in mortality because of a potential beneficial effect of TARGIT. The latter is a radically new hypothesis that the local effect of TARGIT on the tumour bed by inhibiting cancer-stimulating cytokines 17 may spill over to reduce the systemic inflammatory response to trauma and have significant long-term systemic beneficial effects that might be protective against cardiac and cancer mortality ( Figure 28). This remarkable finding, albeit a non-randomised comparison, could potentially have far-reaching implications.…”

“…13,15,16 This is perhaps surprising given evidence from three-dimensional whole-organ analyses of mastectomy specimens, > 60% of which host additional cancer foci, with 80% of these foci found remote from the index quadrant. 17 It appears that these cancers in other quadrants lie dormant, rarely manifesting clinically, and recurrences develop in the tissues immediately surrounding the primary tumour. This could be because of a tumour-promoting effect of the microenvironment of the surgical wound, 18 or the presence of morphologically normal cells in the peritumoural tissues, which may already be on the path of malignant progression, as evidenced by their loss of heterozygosity.…”

“…33,34 This could be because of the radiotherapy limiting breast cancer cell proliferation normally caused by the trauma of surgery. 17 The biological, economical and technical advantages of TARGIT distinguish this trial from other trials that have since been launched with a similar aim to irradiate only the index quadrant, such as the ELectron IntraOperative radiotherapy (ELIOT) trial in Italy, 35 Thus, the TARGIT-A trial was an investigator-initiated trial that was launched in March 2000. 36 At the time of our successful funding application to the Health Technology Assessment (HTA) programme it was already recruiting from 21 centres (increased from 16 in the previous 12 months) and 1301 patients had already been recruited.…”

Preclinical validation of a novel compound targeting p70S6 kinase in breast cancer

“…Our previous studies demonstrated that wound fluids , drained from BC patients for 24 hours post-surgery (hereafter WF), are very rich in cytokines and growth factors and very efficiently stimulate proliferation, motility and invasion and that activation of p70S6K signaling is a common event following exposure of breast cancer cells to WF [10,24]. Figure 1), suggesting that the spectrum of activity for this inhibitor may vary depending from the cancer subtypes.…”

A multicentre observational study evaluating image-guided radiotherapy for more accurate partial-breast intensity-modulated radiotherapy: comparison with standard imaging technique

“…Advocates for IORT cite several potential advantages of using this approach: including delivery of radiation immediately after surgery to prevent tumour cell proliferation; change in cytokines pattern into a less stimulating microenvironment, which is expected to reduce the local recurrence rates; and reduced risk of geographical miss 29,30 .…”