Andrew D Baildam

Energy balance in early breast cancer patients receiving adjuvant chemotherapy.

Weight gain is a common problem amongst women receiving adjuvant chemotherapy for early breast cancer. We undertook a study to determine the causes of this weight gain. Prospective measurements of body mass and composition (skinfolds, bioelectrical impedance, total body potassium), energy balance (resting energy expenditure dietary intake, and physical activity), were determined in 17 women during and in the 6 months after commencing adjuvant chemotherapy. Women gained significant amounts of weight (5.0 ± 3.8; p < 0.01) and body fat (7.1 kg ± 4.5; p < 0.01) over the year. Waist circumference (5.1 ± 4.5 cm; p < 0.01) and abdominal skinfold (16.2 ± 10 mm; p < 0.01) were also increased but there was a decline in fat free mass (FFM); 1.7 ± 2.5 kg. Women due to receive adjuvant chemotherapy had a greater resting energy expenditure (REE) compared with healthy subjects (n = 21); 100.5 ± 8.0% Harris Benedict compared to 94.5 ± 8.4% Harris Benedict (p = 0.05). REE declined by 3% during adjuvant chemotherapy (p < 0.05), and remained depressed until at least 3 months posttreatment. There were no significant changes in dietary intake or physical activity over the year. Failure of women to reduce their energy intake to compensate for the decreased energy requirement may account for some of the weight gain. Treatment of adjuvant chemotherapy causes gain of body fat because of reduced energy expenditure, and the failure of women to reduce their energy intake to compensate for the decline in energy requirement during and in the 6 months posttreatment. Since weight gain impacts on survival, patients should be counselled to reduce energy intake and exercise during and after adjuvant treatment.

Clinical follow‐up after bilateral risk reducing (‘prophylactic’) mastectomy: mental health and body image outcomes

Background: In Manchester, approximately 120 women at ≥1: 4 lifetime risk of breast cancer have considered preventative surgery since 1992. Women treated within the Manchester protocol receive two genetic counselling sessions, a psychological assessment and a surgical consultation pre‐operatively and annual follow‐up post‐operatively. The vast majority of women have breast reconstruction.

Randomised controlled trial of effects of early discharge after surgery for breast cancer

Abstract Objective : To determine the effect of early discharge from hospital after surgery for breast cancer on physical and psychological illness. Design : Randomised controlled trial comparing discharge two days after surgery (before removal of drain) with standard management (discharge after removal of drain). Setting : Regional breast unit. Subjects : 100 women with early breast cancer undergoing mastectomy and axillary node clearance (20) or breast conservation surgery (80). Main outcome measures : Physical illness (infection, seroma formation, shoulder movement) and psychological illness (checklist of concerns, Rotterdam symptom questionnaire, hospital anxiety and depression scale) preoperatively and at one month and three months postoperatively. Results : Women discharged early had greater shoulder movement (odds ratio 0.28 (95% confidence interval 0.08 to 0.95); P=0.042) and less wound pain (odds ratio 0.28 (0.10 to 0.79); P=0.016) three months after surgery compared with women given standard management. One month after surgery scores were significantly lower on the Rotterdam symptom questionnaire in patients who were discharged early (ratio of geometric mean scores 0.73 (0.55 to 0.98); P=0.035), but rates of psychological illness generally did not differ between groups. Conclusions : Increased rates of physical or psychological illness did not result from early discharge after surgery for breast cancer. This policy can be recommended for patients with support at home.

Uptake of Risk-Reducing Surgery in Unaffected Women at High Risk of Breast and Ovarian Cancer Is Risk, Age, and Time Dependent

Purpose: The uptake of risk-reducing surgery in women at increased risk of breast and ovarian cancer is highly variable between countries and centers within countries. We have investigated the rate, timing, and age of uptake of surgery in the northwest of England to report the results after up to 7 years in a Regional Genetics center. Methods: Uptake was documented in 211 known unaffected BRCA1/2 mutation carriers from 509 families and in 3,515 women at >25% lifetime risk of breast cancer without known mutations. Results: Of the 211 mutation carriers, 40% opted for bilateral risk-reducing mastectomy (BRRM) and 45% underwent bilateral risk-reducing salpingo-oophorectomy (BRRSPO). Uptake of BRRM was significantly related to lifetime risk and age but continued over several years. In women not known to carry a BRCA mutation, 6.4% of women at 40% to 45% lifetime risk, 2.5% of women at 33% to 39% lifetime risk, and 1.8% of women at 25% to 32% lifetime risk underwent BRRM (P < 0.005). BRRSPO uptake was greater in BRCA1 (52%) than BRCA2 (28%) carriers but in both groups tended to occur within the first 2 years after gene test (except in the youngest age group) and in women between the ages of 35 and 45. Conclusion: To truly assess the uptake of risk-reducing surgery, longer-term follow-up is necessary particularly in younger women who are likely to delay BRRSPO. Careful risk counseling does seem to influence womens decisions for surgery, although the effect is not immediate. (Cancer Epidemiol Biomarkers Prev 2009;18(8):2318–24)

The importance of complete excision in the prevention of local recurrence of ductal carcinoma in situ.

Mastectomy probably represents over-treatment for the majority of women with screen detected ductal carcinoma in situ (DCIS) and breast-conserving surgery is now widely advocated. In this study, biopsy cavity shavings were used to ensure complete excision in 129 women undergoing breast-conserving surgery for screen detected DCIS. A margin was considered clear if DCIS was > 1 mm from any margin of excision and shavings were clear. Patients with involved margins (DCIS at resection margin) underwent re-excision, irrespective of shaving status. After re-excision, 101 women (78%) had clear margins and 28 (22%) close margins (DCIS < or = 1 mm from resection margin). Cavity shavings were histologically clear of DCIS in all cases. Ipsilateral DCIS recurrence occurred in 12 (9.3%) patients. Two recurrences also contained invasive carcinoma. The median time to diagnosis was 14 months and all recurrences occurred at the site of the previous biopsy. Seven recurrences were detected at the first annual mammogram, four at the second and one at the third. Ipsilateral recurrence was related to margin status; only 2 out of 101 (2%) patients with clear margins recurred, compared with 10 out of 28 (36%) patients with close margins. Local recurrence and close margin status both correlated with a high modified Van Nuys prognostic index score. Our results indicate that local relapse represents residual DCIS rather than true recurrence in the majority of cases. Cavity shavings have proved ineffective in ensuring complete excision. We now ensure a minimum 10 mm margin of excision around all screen-detected DCIS lesions.

Risk reducing mastectomy: outcomes in 10 European centres

Background: Increasingly women at high risk of breast cancer are opting for risk reducing surgery. The aim of this study was to assess the effectiveness of this approach in women at high risk in both carriers and non-carriers of BRCA1/2. Methods: Data from 10 European centres that offer a genetic counselling and screening service to women at risk were obtained prospectively from 1995. Breast cancer risks were estimated from life tables and a control group of women at risk who did not undergo surgery. Results: The combined centres have data on 550 women who have undergone risk reducing mastectomy with greater than 3334 women years of follow-up. Operations were carried out on women with lifetime risks of 25–80%, with an average expected incidence rate of 1% per year. No breast cancers have occurred in this cohort in the “at risk” unaffected breast, whereas >34 would have been expected. A high rate (2–3.6%) of occult disease was identified in the at risk breast at the time of surgery. Interpretation: We conclude that risk reducing surgery is highly effective.

Late Toxicity Is Not Increased in BRCA1/BRCA2 Mutation Carriers Undergoing Breast Radiotherapy in the United Kingdom

Purpose: To undertake the first substantial clinical study of breast radiotherapy toxicity in BRCA1 and BRCA2 mutation carriers in the United Kingdom. Experimental Design: Acute and late radiation effects were evaluated in a retrospective study of 55 BRCA1 and BRCA2 mutation carriers treated with radiotherapy for breast cancer at four centers between 1983 and 2002. Individual matching with controls who had sporadic breast cancer was undertaken for age at diagnosis, time since completion of radiation, and treatment variables. Detailed assessments were undertaken by one examiner. Median follow-up was 6.75 years for carriers and 7.75 years for controls. Rates of late events (rib fractures, lung fibrosis, necrosis of soft tissue/bone, and pericarditis) as well as LENT-SOMA scores and clinical photography scores of breast size, shape, and skin telangiectasia were the primary end points. Results: No increase in clinically significant late toxicity was seen in the mutation carriers. Conclusions: These data add substantial weight to the evidence that the outcomes in the treated breast from radiotherapy in women with BRCA1 or BRCA2 mutations are comparable with those in women with sporadic breast cancer.

Epidermal and transforming growth factor alpha in patients with breast tumours.

Measurements of transforming growth factor alpha (TGF-alpha) in cancer patients have produced variable results. We have now used a specific radioimmunoassay (RIA) and a mitogenic assay to evaluate TGF-alpha content of tumour and urine samples separated by an analytical HPLC system. Urine samples from patients with breast tumours and from age matched controls gave TGF-alpha amounts ranging from 0 to 61.5 ng 24 h-1 compared to urogastrone epidermal growth factor figures of 3.0-26.2 micrograms 24 h-1. The quantities of TGF-alpha in patient and control groups were not significantly different. The majority of breast tumour extracts contained mitogenic material eluting from the HPLC system at the TGF-alpha calibration point. Measurement by RIA of combined samples from each group showed that steroid receptor positive tumours had a mean figure of 14.8 ng g-1 tissue and steroid receptor negative 7.4 ng g-1. Receptor positive tumours from patients treated with an antioestrogen, tamoxifen citrate (Nolvadex), had 0.16 ng g-1. Thus TGF-alpha is found in tumours as a biologically active entity and in quantities sufficient to promote cell division. In addition the observation that tamoxifen causes a significant reduction in the content of TGF-alpha may be an additional beneficial action.

Cyclooxygenase-2 inhibition does not improve the reduction in ductal carcinoma in situ proliferation with aromatase inhibitor therapy: Results of the ERISAC randomized placebo-controlled trial

Purpose: Tamoxifen reduces risk of recurrence after breast conservation surgery for ductal carcinoma in situ (DCIS), but no data exists on the effectiveness of aromatase inhibitors for DCIS. Cyclooxygenase-2 (COX-2) is overexpressed in DCIS, representing another potential therapeutic target. The aim of the study was to determine the effect of aromatase and/or COX-2 inhibition on epithelial proliferation and apoptosis in a presurgical study of estrogen receptor (ER)–positive DCIS. Methods: Postmenopausal women with ER-positive DCIS diagnosed by core biopsy were randomized to a 2 × 2 design of either 14 days of exemestane or placebo and celecoxib, or placebo immediately before surgery. Paired baseline and end point biopsies were analyzed for proliferation (Ki67), apoptosis, human epidermal growth factor receptor 2 (HER2), COX-2, and progesterone receptor (PR) expression by immunohistochemistry. The primary end point was a decrease in Ki67 between diagnosis and surgical excision. Results: Ninety women were randomized: all were ER positive, 49 (54%) had grade III tumors, and 29 (32%) were HER2 positive (3+). Exemestane reduced proliferation compared with placebo with a median reduction of 9% (95% confidence interval, 6-14; P < 0.001). Progesterone receptor was reduced by exemestane (mean decrease, 19%; 95% confidence interval, 9-28; P = 0.011). The effect of exemestane on proliferation was seen regardless of grade, HER2, or PR expression. Celecoxib had no effect on proliferation or apoptosis alone, or in combination with exemestane. Conclusions: Exemestane reduces proliferation in ER-positive DCIS. Aromatase inhibition is a potential alternative to tamoxifen in patients who have undergone breast conservation for ER-positive DCIS. Clin Cancer Res; 16(5); 1605–12

Energy balance in patients with advanced NSCLC, metastatic melanoma and metastatic breast cancer receiving chemotherapy - A longitudinal study

Chemotherapy exerts a variable effect on nutritional status. It is not known whether loss of body fat or fat-free mass (FFM) during chemotherapy relates to diminished dietary intake, failure to meet elevated energy requirements, or to the presence of an acute-phase response. We sought to determine prospective measurements of body mass and composition, resting energy expenditure, energy and protein intake, and C-reactive protein over a course of chemotherapy in 82 patients with advanced cancer. There was a large dropout from the study. Prospective measurements were obtained in 19 patients with non-small-cell lung cancer (NSCLC), 12 with metastatic melanoma and 10 with metastatic breast cancer. There were significant increases in energy intake among patients with metastatic breast cancer, 873 (266–1480) kJ (mean 95% CI; P<0.01), and metastatic melanoma, 2513 (523–4503) kJ (P<0.01). Breast cancer patients gained percentage body fat over the course of treatment, 2.1 (0.8–3.5%). Gain or loss of body fat correlated to mean energy intake throughout chemotherapy in patients with NSCLC (Rs=0.751; P<0.01) and metastatic breast cancer (Rs=0.617; P<0.05). The ability to meet or exceed energy requirements led to gains in body fat among patients with metastatic breast cancer and NSCLC, but did not prevent loss of FFM in these groups.