Investigation of immunoregulatory mechanisms relating to poor surgical wound healing and breast cancer recurrence

Background

The factors leading to breast cancer recurrence are incompletely understood. We recently carried out a retrospective study of treatment and outcome for 1,065 breast cancer patients for which we examined factors correlating with cancer recurrence. We found that infection of surgical wounds after surgery for primary disease positively correlated with cancer recurrence [1]. Patients with wound complications were almost threefold more likely to have systemic recurrences than those without over the follow-up period (P < 0.0001). The aim of our current study is to determine mechanisms responsible for this correlation. Our approach is based on two possible theories. First, patients may have an underlying immune dysfunction that predisposes them to developing both wound complications and also recurrence. This may be as a result of the tumour itself suppressing the activity of immune regulatory cells including dendritic cells, T cells and NK cells via increased levels of some critical cytokines (for example, vascular endothelial growth factor, IL-10, IL-6). Secondly, factors released at sites of wound complications may have direct influences on the remaining occult tumour cells, thereby increasing the likelihood of metastases. This model is supported by observations that cytokines released at sites of infection as part of inflammatory/immune responses are capable of enhancing growth and survival of tumour cells [2]. Also there is evidence that bacterial components may stimulate metastatic growth, most probably via cytokine mediators [3].

Methods and results

Patients with primary operable breast cancer are recruited prospectively. Blood samples are collected from patients preoperatively, 4 hours and 16 hours postoperatively and again at 2 weeks, 3 months and 6 months postoperatively. A variety of investigations are carried out on each sample to establish the immune status of the patient at that time point, and to identify potential mediators of crosstalk between the immune system, the wound and any occult tumour cells. These investigations include: full blood count; detailed immune cell phenotyping (absolute numbers/frequency of B-cell, T-cell and NK-cell subtypes using multicolour flow cytometry); and cytokine profiling (using fluid-phase cytometric multiplex immunoassays for 27 critical cytokines and growth factors). Patients are followed up and monitored for postoperative wound complications and evidence of recurrence. We shall determine whether patients that develop wound complications and/or metastases show immune defects from the outset, and whether systemic changes in immune regulators during wound complications reflect the development of metastases. Recruitment is ongoing with samples from >100 patients expected to be collected and processed by the end of 2007. Preliminary data concerning immune status and wound complications will be presented.