J.C. Doughty

Evaluation of an inflammation-based prognostic score (GPS) in patients with metastatic breast cancer

Prediction of outcome in patients with metastatic breast cancer remains problematical. The present study evaluated the value of an inflammation-based score (Glasgow Prognostic Score, GPS) in patients with metastatic breast cancer. The GPS was constructed as follows: patients with both an elevated C-reactive protein (>10 mg l−1) and hypoalbuminaemia (<35 g l−1) were allocated a score of 2. Patients in whom only one or none of these biochemical abnormalities was present were allocated a score of 1 or 0, respectively. In total, 96 patients were studied. During follow-up 51 patients died of their cancer. On multivariate analysis of the GPS and treatment received, only the GPS (HR 2.26, 95% CI 1.45–3.52, P<0.001) remained significantly associated with cancer-specific survival. The presence of a systemic inflammatory response (the GPS) appears to be a useful indicator of poor outcome independent of treatment in patients with metastatic breast cancer.

Guidance for the management of breast cancer treatment-induced bone loss: A consensus position statement from a UK Expert Group

In postmenopausal women, the use of aromatase inhibitors increases bone turnover and induces bone loss at sites rich in trabecular bone at an average rate of 1-3% per year leading to an increase in fracture incidence compared to that seen during tamoxifen use. The bone loss is much more marked in young women with treatment-induced ovarian suppression followed by aromatase inhibitor therapy (average 7-8% per annum). Pre-treatment with tamoxifen for 2-5 years may reduce the clinical significance of the adverse bone effects associated with aromatase inhibitors, particularly if this leads to a shortening in the duration of exposure to an aromatase inhibitor. However, skeletal status should still be assessed at the commencement of aromatase inhibitor therapy. The rate of bone loss in women who experience a premature menopause before the age of 45 or are receiving ovarian suppression therapy is accelerated by the concomitant use of aromatase inhibitors. These patients are considered to be at high risk of clinically important bone loss and should have a baseline dual energy X-ray absorptiometry (DXA) assessment of bone mineral density (BMD). Randomised clinical trials in postmenopausal women indicate that bisphosphonates prevent the bone loss and accelerated bone turnover associated with aromatase inhibitor therapy and are a promising strategy for the prevention and treatment of osteoporosis in this setting. Treatment initiation recommendations are based on a combination of risk factors for osteoporotic fracture and BMD levels. Bisphosphonates, along with a healthy lifestyle and adequate intake of calcium and vitamin D are the treatments of choice to prevent bone loss. Due to the rate of bone loss associated with breast cancer treatments, and uncertainties about the interaction between aromatase inhibitor use and BMD for fracture risk, the threshold for intervention has been set at a higher level than that generally recommended for postmenopausal osteoporosis. Management recommendations have been summarised in two algorithms, one for women experiencing a premature menopause and the other for postmenopausal women requiring adjuvant aromatase inhibitor therapy.

Poor survival outcomes in HER2 positive breast cancer patients with low grade, node negative tumours

We present a retrospective analysis on a cohort of low-grade, node-negative patients showing that human epidermal growth factor receptor 2 (HER2) status significantly affects the survival in this otherwise very good prognostic group. Our results provide support for the use of adjuvant trastuzumab in patients who are typically classified as having very good prognosis, not routinely offered standard chemotherapy, and who as such do not fit current UK prescribing guidelines for trastuzumab.

The relationship between components of tumour inflammatory cell infiltrate and clinicopathological factors and survival in patients with primary operable invasive ductal breast cancer

Background:The importance of the components of host local inflammatory response in determining outcome in primary operable ductal invasive breast cancer is not clear. The aim of this study was to examine the relationship between components of the tumour inflammatory cell infiltrate and standard clinicopathological factors including hormone status (oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER)-2), Ki-67 and survival in patients with primary operable invasive ductal breast cancer.Methods:Tumour inflammatory cell infiltrate, hormone status (ER, PR and HER-2), Ki-67 and standard clinicopathological factors were determined using routine pathological and immuno-histochemical techniques in 468 patients.Results:The large majority (94%) of ductal tumours had evidence of inflammatory cell infiltrate. The general inflammatory cell infiltrate was positively associated with high grade (P<0.001), the absence of ER (P<0.001), the absence of PR (P<0.01), the presence of vascular invasion (P<0.05) and high lymphocytic infiltrate, plasma cell infiltrate, other inflammatory cell infiltrate and macrophage infiltrate (all P<0.001). The median follow-up of the survivors was 165 months. During this period, 93 patients died of their cancer. On univariate analysis, stratified for ER status, tumour size (P<0.01), lymph node involvement (P<0.001), tumour plasma cell infiltrate (P<0.001), other inflammatory cell infiltrate (P<0.05) and treatment (P<0.05) were associated with poorer cancer-specific survival whereas lymphocyte infiltrate (P<0.001) was associated with improved cancer-specific survival. On multivariate analysis, stratified for ER status, lymph node involvement (P<0.05) was independently associated with poorer cancer-specific survival whereas increased tumour lymphocyte infiltrate (P<0.001) was independently associated with improved cancer-specific survival.Conclusion:The results of this study show that, using routine histology, the general inflammatory cell infiltrate was a common feature and was positively associated with high grade, the absence of ER, the absence of PR, the presence of vascular invasion and high-grade infiltration of lymphocytes, plasma cells, other inflammatory cells and macrophages. Also, that within a mature cohort of patients, a high lymphocytic infiltrate was associated with improved survival, independent of clinicopathological characteristics including ER status, in primary operable ductal invasive breast cancer. These results rationalise previous work and provide a sound basis for future studies in this important area of breast cancer research.

Comparison of visual and automated assessment of Ki-67 proliferative activity and their impact on outcome in primary operable invasive ductal breast cancer.

Background:Immunohistochemistry of Ki-67 protein is widely used to assess tumour proliferation, and is an established prognostic factor in breast cancer. There is interest in automating the assessment of Ki-67 labelling index (LI) with possible benefits in handling increased workload, with improved accuracy and precision.Patients and methods:Visual and automated assessment of Ki-67 LI and survival were examined in patients with primary operable invasive ductal breast cancer. Tissue microarrays (n=379 patients) immunostained for Ki-67 were scored visually and automatically with the Slidepath Tissue IA system.Results:Visual and automated Ki-67 LI were in excellent agreement (ICCC=0.96, P<0.001). On univariate analysis, visual (P<0.001) and automated Ki67 LI (P<0.05) were associated with cancer-specific survival in patients with invasive ductal breast cancer overall and in patients who received endocrine therapy (Tamoxifen) (P<0.01 for visual and P<0.05 for automated scoring).Conclusion:Automated assessment of Ki-67 LI would appear to be comparable to visual Ki-67 LI. However, automated Ki-67 LI assessment was inferior in predicting cancer survival in patients with breast cancer, including patients who received Tamoxifen.

The relationship between the systemic inflammatory response, tumour proliferative activity, T-lymphocytic and macrophage infiltration, microvessel density and survival in patients with primary operable breast cancer.

The significance of the inter-relationship between tumour and host local/systemic inflammatory responses in primary operable invasive breast cancer is limited. The inter-relationship between the systemic inflammatory response (pre-operative white cell count, C-reactive protein and albumin concentrations), standard clinicopathological factors, tumour T-lymphocytic (CD4+ and CD8+) and macrophage (CD68+) infiltration, proliferative (Ki-67) index and microvessel density (CD34+) was examined using immunohistochemistry and slide-counting techniques, and their prognostic values were examined in 168 patients with potentially curative resection of early-stage invasive breast cancer. Increased tumour grade and proliferative activity were associated with greater tumour T-lymphocyte (P<0.05) and macrophage (P<0.05) infiltration and microvessel density (P<0.01). The median follow-up of survivors was 72 months. During this period, 31 patients died; 18 died of their cancer. On univariate analysis, increased lymph-node involvement (P<0.01), negative hormonal receptor (P<0.10), lower albumin concentrations (P<0.01), increased tumour proliferation (P<0.05), increased tumour microvessel density (P<0.05), the extent of locoregional control (P<0.0001) and limited systemic treatment (P⩽0.01) were associated with cancer-specific survival. On multivariate analysis of these significant covariates, albumin (HR 4.77, 95% CI 1.35–16.85, P=0.015), locoregional treatment (HR 3.64, 95% CI 1.04–12.72, P=0.043) and systemic treatment (HR 2.29, 95% CI 1.23–4.27, P=0.009) were significant independent predictors of cancer-specific survival. Among tumour-based inflammatory factors, only tumour microvessel density (P<0.05) was independently associated with poorer cancer-specific survival. The host inflammatory responses are closely associated with poor tumour differentiation, proliferation and malignant disease progression in breast cancer.

Evaluation of the relationship between the systemic inflammatory response and cancer-specific survival in patients with primary operable breast cancer.

The relationship between the systemic inflammatory response (as evidenced by elevated C-reactive protein and lowered albumin concentrations), clinico-pathologic status and relapse-free, cancer-specific and overall survival was examined in patients with invasive primary operable breast cancer (n=300). The median follow-up of the survivors was 46 months. During this period, 37 patients relapsed and 25 died of their cancer. On multivariate analysis, only tumour size (P<0.05), albumin (P<0.01) and systemic treatment (P<0.0001) were significant independent predictors of relapse-free, cancer-specific and overall survival. Lower serum albumin concentrations (⩽43 g l−1) were associated with deprivation (P<0.05), hormonal receptor negative tumours (P<0.01) and significantly poorer 3-year relapse-free (85 vs 93%, P=0.001) cancer-specific (87 vs 97%, P<0.0001) and overall survival (84 vs 94%, P=0.001) rates. The results of the present study suggest that lower preoperative albumin concentrations, but not elevated C-reactive protein concentrations, predict relapse-free, cancer-specific and overall survival, independent of clinico-pathologic status and treatment in patients undergoing potentially curative surgery for primary operable breast cancer.

Expression of sphingosine 1-phosphate receptor 4 and sphingosine kinase 1 is associated with outcome in oestrogen receptor-negative breast cancer

Background:We previously reported that sphingosine 1-phosphate receptor 4 (S1P4) is expressed and stimulates the ERK-1/2 pathway via a human epidermal growth factor receptor 2 (HER2)-dependent mechanism in oestrogen receptor-negative (ER−) MDA-MB-453 breast cancer cells.Methods:Clinical relevance of S1P4 and sphingosine kinase 1 (SK1, which catalyses the formation of S1P) was assessed in a cohort of 140 ER− breast tumours by immunohistochemistry (IHC) and the weighted histoscore method. Additional evidence for a functional interaction between S1P4 and SK1 and between HER2 and SK1 was obtained using MDA-MB-453 cells.Results:High S1P4 expression is associated with shorter disease-free (P=0.014) and disease-specific survival (P=0.004), and was independent on multivariate analysis. In addition, patients with tumours that contain high and low levels of SK1 and S1P4, respectively, have a significantly shorter disease-free survival (P=0.043) and disease-specific survival (P=0.033) compared with patients whose tumours contain both low S1P4 and SK1 levels. In addition, high tumour expression of SK1 was significantly associated with shorter disease-specific survival (P=0.0001) in patients with HER2-positive tumours. Treatment of MDA-MB-453 cells with the SK1 inhibitor, SKi (2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole) reduced the basal and S1P/S1P4-induced activation of ERK-1/2 and altered HER2 trafficking in these cells.Conclusion:These findings highlight an important role for S1P4 and SK1 in ER− breast cancer progression.

Seroma formation related to electrocautery in breast surgery: a prospective randomized trial

Abstract Seroma formation is one of the commonest complications following breast cancer surgery. Prospective audit in our unit had identified an increased rate of postoperative seromas, and this seemed to coincide with the introduction of diathermy dissection of the skin flaps. This prospective randomized trial was designed to assess the contribution of diathermy to postoperative seroma formation. Fifty consecutive patients undergoing either wide local excision or mastectomy, with a level 11 axillary clearance, were assigned to either diathermy or scalpel dissection. The incidence of wound seroma was significantly higher in the diathermy group (38% vs 10%, P = 0.03, Fishers exact test). There was no significant difference between groups with respect to age, type of procedure, length of operation, weight of breast specimen or pathological staging. We conclude that diathermy dissection in breast surgery is associated with an increased incidence of seroma formation and cannot be recommended.

A comparison of serum and plasma levels of vascular endothelial growth factor during the menstrual cycle in healthy female volunteers.

Angiogenesis is the formation of new blood vessels from the existing vasculature, and is essential for the growth and metastasis of most solid tumours. One of the most important growth factors involved in the angiogenesis process is vascular endothelial growth factor. Vascular endothelial growth factor expression has been shown to be regulated by female hormones in breast cancer cell lines, and two previous authors have reported on cyclical variations in serum vascular endothelial growth factor concentrations with conflicting results. No work has been performed on variations in plasma levels of vascular endothelial growth factor during the menstrual cycle. We therefore conducted the first prospective trial to compare serum and plasma levels of vascular endothelial growth factor in healthy pre-menopausal volunteers. Twenty healthy pre-menopausal women were recruited and had blood samples taken over one menstrual cycle with an average of eight samples taken per patient. Plasma and serum samples were then analysed for sex hormones and vascular endothelial growth factor 165. Serum vascular endothelial growth factor levels were found to be significantly higher than plasma vascular endothelial growth factor levels (P<0.005). We found no significant difference between serum and plasma vascular endothelial growth factor in the luteal and follicular phases of the cycle. The majority of the measurements for plasma levels of vascular endothelial growth factor at all phases of the cycle were under the limit of detection of the vascular endothelial growth factor ELISA kit. We found no significant correlation between plasma or serum levels of vascular endothelial growth factor and either FSH, LH, Oestradiol or Progesterone levels. This study has demonstrated no difference in serum concentrations of vascular endothelial growth factor during the different phases of the menstrual cycle in a group of healthy volunteers. We also demonstrated no obvious difference in plasma concentrations of vascular endothelial growth factor between the phases of the cycle, but most of the measurements were below the level of accuracy reported by the ELISA kit manufacturer. With the sensitivity of this ELISA test, therefore, we must still regard the question of whether there is a variation in plasma concentrations of vascular endothelial growth factor throughout the menstrual cycle as unanswered.