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.

Tumour necrosis factor-α expression is associated with increased severity of periprosthetic breast capsular contracture.

BACKGROUND: The pathogenesis of periprosthetic capsular contracture following breast implant surgery is unclear. The aim of this study was to identify the expression of tumour necrosis factor-α (TNF-α), collagen type III α(1) (COL3A1), transforming growth factor-ß(1) (TGF-ß(1)) and connective tissue growth factor (CTGF) in different Baker grades of breast capsular contracture. METHODS: Seven periprosthetic breast capsule specimens were collected from 6 patients. TNF-α, COL3A1, TGF-ß(1) and CTGF gene expression were analysed using real-time quantitative polymerase chain reaction. Immunohistolocalisation of TNF-α was performed on paraffin-embedded sections. Significant correlations were analysed using the Pearson correlation coefficient. RESULTS: TNF-α expression was associated with increased Baker grade of capsular contracture (Pearson correlation, r = 0.558; p = 0.02). COL3A1 gene expression was reduced with increasing severity of contracture (r = -0.490; p = 0.05). There were no significant correlations between TGF-ß(1) and CTGF expression with Baker grade. Positive TNF-α staining in breast capsules was localised to fibroblasts, macrophages, and extracellularly close to the prosthesis. CONCLUSION: The increased expression of TNF-α may play a key role in the inflammatory response associated with capsular contracture. The corresponding decrease in COL3A1 may contribute to the change in capsular physical properties seen in capsular contracture.

Screening younger women with a family history of breast cancer--does early detection improve outcome?

Women with a family history are often offered mammographic surveillance at an earlier age and with greater frequency than those in the National Breast Screening Programme. In this study, we compared the survival of 62 breast cancer patients diagnosed in the context of a family history clinic offering 12-18 monthly mammographic screening with that of 1108 patients of the same age range but having no exposure to screening. We subtracted the expected additional observation time due to lead time from the survival of the screen-detected cases. Survival was significantly better in the family history group with relative hazards of 0.19 (95% CI 0.07-0.52, P<0.001) for breast cancer death and 0.19 (95% CI 0.08-0.43, P<0.001) for disease-free survival. After correcting for lead-time, the relative hazards were 0.24 (95% CI 0.09-0.66, P=0.005) for breast cancer death and 0.25 (95% CI 0.11-0.57, P<0.001) for disease-free survival. These results strongly suggest that screening younger women with a family history of breast cancer leads to improved survival. More precise estimates of the benefit will accrue from further follow-up and other such studies.

Assessment of hormone dependence of comedo ductal carcinoma in situ of the breast.

BACKGROUND: Ductal carcinoma in situ (DCIS) represents 20%-30% of breast cancers detected by clinical screening (i.e., mammography). More than 50% of DCIS lesions may be estrogen receptor negative and, therefore, hormone independent. However, the role of estrogen in the natural history of DCIS is unknown. PURPOSE: A novel in vivo (i.e., xenograft) model was developed to determine to what degree DCIS lesions depend on estrogen for growth. METHODS: Specimens of breast tissue were collected from 52 women during diagnostic or therapeutic surgical procedures. Portions of each specimen were randomly selected and analyzed by histology and thymidine labeling (to measure cell proliferation). The remainder of each specimen was implanted into five to 18 athymic BALB/c nu/nu mice (depending on the amount of tissue available), with eight pieces of approximately 2 mm x 2 mm x 1 mm implanted at different locations on the back of each mouse. Half of the mice received implants containing estrogen (2 mg 17 beta-estradiol), and the other half received placebo implants. Levels of cell proliferation in xenografts, recovered after 14, 28, 42, or 56 days in the mice, were measured by thymidine labeling or by immunohistochemistry through use of an antibody specific for the Ki-67 nuclear antigen. Immunohistochemistry was also used to measure the levels of estrogen receptor in the tissue specimens. Serum 17 beta-estradiol levels in the mice were measured by radioimmunoassay. RESULTS: Initial levels of cell proliferation were approximately 10-fold higher in 10 specimens with estrogen receptor-negative, comedo (i.e., more malignant in appearance) DCIS than in four specimens with estrogen receptor-positive DCIS (mean proliferation indices: 22% versus 1.9%, respectively; two-sided P < .001). Xenografts from the majority of specimens survived up to 56 days in the mice and maintained good architectural and cellular preservation. Estrogen treatment of the xenograft-bearing mice had no effect on the high level of cell proliferation observed in estrogen receptor-negative, comedo DCIS specimens (two-sided P = .89). In contrast, increased levels of cell proliferation in response to estrogen supplementation were measured in three estrogen receptor-positive, noncomedo DCIS specimens (two-sided P < .001). However, even with estrogen treatment, cell proliferation levels in estrogen receptor-positive DCIS specimens did not reach those seen in estrogen receptor-negative DCIS specimens. CONCLUSION AND IMPLICATION: Estrogen receptor-negative, comedo DCIS lesions appear to be estrogen independent; therefore, antiestrogen (e.g., tamoxifen) therapy may not benefit patients with comedo DCIS.

Endocrine therapy for advanced carcinoma of the breast: relationship between the effect of tamoxifen upon concentrations of progesterone receptor and subsequent response to treatment.

In some cell lines and tumors of mammary origin, tamoxifen causes an increase of progesterone receptor (PR) as a result of its partial estrogen agonist activity. In this study we have assessed the effect of tamoxifen on PR in patients with advanced carcinoma of the breast in order to test if those with a rise in PR are more likely to respond to endocrine therapy. PR was measured before and a median of 13 days after treatment with tamoxifen in a group of 52 patients with either locally advanced (n = 28) or recurrent (n = 24) carcinoma of the breast. Controls were a group of patients with operable disease who had two biopsies with no intervening tamoxifen (n = 51) or with intervening tamoxifen (n = 58). In the test group PR was higher in the second biopsy than the first in 21 patients, and 19 of these responded to continued endocrine therapy (90%). In the remaining 31 patients PR was either lower in the second biopsy (n = 19) or was negative in both biopsies (n = 12), and 11 of the total of 31 patients (35%) responded to continued endocrine therapy. The prediction of response and time to progression was better when both biopsies were taken into account than either the first or the second alone. The prediction of survival was similar for the group selected by an increase in the second biopsy and the group with PR present in the second biopsy. The controls without tamoxifen showed a marked variation in the level of PR in the first and second biopsies, suggesting heterogeneity of PR across the tumors studied. However, the PR level was significantly higher in the second biopsy in the controls given tamoxifen and in the test group compared with those with no intervening treatment (p = 0.031). This study indicates that some effect of tamoxifen upon PR can be demonstrated in human mammary tumors in vivo and that, by taking a second biopsy for PR estimation during treatment with tamoxifen, a more precise indication of subsequent response is obtained. The value of a single estimation of PR before treatment on secondary deposits is limited, and if one biopsy only is performed, it is of greater predictive value if taken after a few days treatment with tamoxifen.

Surgical decisions made by 158 women with hereditary breast cancer aged <50 years.

AIM: To establish the uptake of contralateral risk reducing mastectomy in women informed of their risks and options at time of diagnosis of their primary unilateral breast cancer. METHODS: We have assessed the surgical choices of 70 women diagnosed with breast cancer <50 years as part of a family history surveillance program and fully informed about their contralateral risks and surgical options. We have compared this to women from other surgical clinics who were subsequently found to harbour a pathogenic BRCA1/2 mutation. RESULTS: Sixty-five percent (13/20) of BRCA1/2 mutation carriers and 59% (n=20/34) of those at the highest level of risk pre-diagnosis (33+% lifetime risk) opted for contra-lateral mastectomy in the study sample. In contrast only 10% (n=9/88) women identified as mutation carriers from other clinics opted for such surgery. CONCLUSIONS: We would suggest that women with a significant family history and therefore a high contra-lateral breast cancer risk, should have these risks and management options discussed at the time of diagnosis of breast cancer.

Mixed apocrine/endocrine ductal carcinoma in situ of the breast coexistent with lobular carcinoma in situ.

An unusual mixed form of ductal carcinoma in situ (DCIS) of the breast is described, which exhibits a biphenotypic morphology encompassing a range of differential diagnostic DCIS subtypes. In addition, immunophenotypic and ultrastructural studies demonstrate neuroendocrine and apocrine differentiation, raising questions regarding appropriate classification and biological behaviour. In two cases, coexistence of this mixed form of DCIS with lobular carcinoma in situ (LCIS) in the same duct lobular units is an additional unusual feature that might, at least in some cases, indicate a closer relation between them.

A protocol for preventative mastectomy in women with an increased lifetime risk of breast cancer.

This paper describes a protocol for women at high risk of breast cancer wishing to undergo preventative mastectomy. The protocol described is a holistic approach to each woman involving the use of a multidisciplinary team. The protocol takes a number of months from initiation to surgery. A time delay is deliberate to allow women to fully address the issues involved with a decision for surgery. Early evidence suggests that this prepares the women emotionally and physically for their surgery.

Long term results of a randomised prospective study of preservation of the intercostobrachial nerve.

AIM: We have previously reported in a randomised controlled trial comparing intercostobrachial nerve (ICBN) preservation with division that no difference in symptoms was seen between the groups at 3 months follow-up although a reduced area of sensory loss was measured on the arm. To determine if longer follow-up provides evidence for ICBN preservation, follow-up of patients in the trial at 3 years (range 32-38 months) postoperatively was performed. METHODS: Sensory symptoms and deficits, pain, shoulder movements, arm circumference and the presence of neuromas were documented in 73 patients from the original group of 120. RESULTS: No difference in survival or axillary recurrence was observed. The only symptom which differed between the two groups was a subjective assessment of 'different sensation' (P=0.006). No significant difference was observed in other sensory symptoms, pain, shoulder movement, arm circumference or presence of neuromas. A larger area of sensory deficit was measured in women with sacrificed nerves compared to preserved (P=0.009). CONCLUSION: Preservation of the intercostobrachial nerve does not affect patient survival. It improves patient sensory deficit significantly and modestly improves long-term symptoms.

Increased soluble intercellular adhesion molecule-1, breast cancer and the acute phase response.

Abnormal levels of soluble intercellular adhesion molecule-1 (sICAM-1), C-reactive protein (CRP) and von Willebrand factor (vWf) are commonly found in breast and other cancers. However, the relationship between these molecules is unclear as raised sICAM-1 and vWf may simply reflect an acute phase response. We tested the hypothesis that raised sICAM-1 and vWf are related to the acute phase response by measuring both markers by enzyme-linked immunosorbent assay, and CRP by dry chemistry, in 40 women with breast cancer (cases) and 40 age-matched controls. All three markers were raised in the cases compared with the controls [sICAM-1 (mean +/- SD), 281 +/- 70 versus 230 +/- 40 ng/ml; vWf (mean +/- SD), 139 +/- 33 versus 106 +/- 16 IU/dl; CRP (median), 7 (interquartile range, 5-11) versus 5 (4-6) mg/dl; all P < 0.01]. However, sICAM-1 correlated strongly with CRP (r = 0.67, P < 0.001) in the cases but there was no significant relationship between vWf and CRP (r = -0.15, P = 0.351). There were no significant correlations in the controls. We conclude that raised sICAM-1 in breast cancer, like the acute phase response, reflects inflammation, and that raised vWf seems likely to be independent of the acute phase response.

Is it acute cholecystitis?

In a prospective study of 100 patients presenting with acute right hypochondrial pain and diagnosed clinically by a qualified surgeon as having acute cholecystitis, we have shown that the diagnostic error can be considerable. Twenty-five of these patients were found to have a different diagnosis on subsequent investigation and in a further 11 patients, no definite diagnosis could be established. This emphasises the need for careful investigation of patients with this presenting complaint.

Can preoperative factors predict for residual malignancy after breast biopsy for invasive cancer?

The presence of malignancy at the resection margins of a malignant breast biopsy requires difficult therapeutic decisions about whether a re-excision biopsy is necessary. The aim of this study was to determine the factors predisposing to the involvement of the resection margins in 280 women undergoing breast biopsy for invasive malignancy from a single breast screening practice. Resection margins were assessed independently by a single pathologist who noted either the presence of tumour at the margins of the biopsy specimen or in the shavings taken from the biopsy cavity. Resection margin involvement (RMI) occurred in 113 patients. Mammographic microcalcification (MM) was seen in 87 women with invasive cancer and RMI occurred in 53 (61%) compared with 60/193 invasive cancers without MM (P < 0.001). If RMI was present the patients underwent a second procedure to ensure complete tumour excision, and 68% of re-excision specimens from tumours with MM and 36% of tumours without MM contained residual malignancy (P < 0.005). Statistical analysis demonstrated that these observations were independent of tumour size, grade, type, and axillary node status. The presence of mammographic microcalcification therefore indicates that wider than usual surgical resection margins should be taken.

Abdominal lymphoma--the place for surgery.

Gastrointestinal lymphoma (GIL) is rare but may be cured by surgery and chemotherapy. Because symptoms frequently mimic common abdominal conditions, presentation is often to a surgeon. Fifty-five patients with GIL were treated between 1975 and 1984: all underwent operations before the correct diagnosis was made, 22 (40%) as emergencies. Misdiagnosis in 23 (42%) led to a delay in correct treatment of greater than or equal to 6 months from the start of symptoms: in 17 (31%) the delay was greater than or equal to one year. Endoscopy and radiology were inaccurate and suggested peptic ulceration, Crohn's disease or irritable bowel syndrome. The site of disease was usually stomach and duodenum (26, 47%) or ileum and jejunum (29, 53%). The extent of surgical resection was associated with survival at greater than or equal to 3 years-in 16 (29%) who underwent 'complete resection' 14 survived, but only one of 28 survived when the operation was limited to diagnostic biopsy (P less than 0.0001). Most deaths occurred within one year of operation, commonly from perforation or haematemesis from residual mural disease during chemotherapy. In 5 of 11 patients who had biopsy only, CT scans suggested localized disease, and 'complete resection' was achieved at a second laparotomy. Complete resection should be attempted wherever possible before chemotherapy. The place for surgeons with experience is clearly central to the management of this disease.

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

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.

Effects of oestrogens and anti-oestrogens on normal breast tissue from women bearing BRCA1 and BRCA2 mutations.

There is considerable interest in whether anti-oestrogens can be used to prevent breast cancer in women bearing mutations in the BRCA1 and BRCA2 genes. The effects of oestradiol (E2), tamoxifen (TAM) and fulvestrant (FUL) on proliferation and steroid receptor expression were assessed in normal breast epithelium taken from women at varying risks of breast cancer and implanted into athymic nude mice, which were treated with E2 in the presence and absence of TAM or FUL. Tissue samples were taken at various time points thereafter for assessment of proliferative activity and expression of oestrogen and progesterone receptors (ERalpha and PgR) by immunohistochemistry. Oestradiol increased proliferation in the breast epithelium from women carrying mutations in the BRCA1/2 genes, those otherwise at increased risk and those at population risk of breast cancer. This increase was reduced by both TAM and FUL in all risk groups. In the absence of E2, PgR expression was reduced in all risk groups but significantly more so in the BRCA-mutated groups. Subsequent E2 treatment caused a rapid, complete induction of PgR expression in the population-risk group but not in the high-risk or BRCA-mutated groups in which PgR induction was significantly delayed. These data suggest that the mechanisms by which E2 induces breast epithelial PgR expression are impaired in BRCA1/2 mutation carriers, whereas those regulating proliferation remain intact. We conclude that early anti-oestrogen treatment should prevent breast cancer in very high-risk women.

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.