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Cytogenetic and fluorescent in situ hybridization (FISH) analysis has been performed on consecutive samples, taken 4 weeks apart, from a phyllodes breast tumor. This revealed the presence of two different chromosome 1 derivatives, namely a dic(1;10) (q10;q24) in the first sample and an i(1) (q10) in the second. In one cell out of 25 from the second sample both derivative chromosomes were seen. A chromosome 21 was lost in both samples. These results are consistent with phyllodes tumors having a clonal origin.

Summary points There is now unequivocal evidence that a small proportion of breast cancer cases, perhaps 4-5%, are due to highly penetrant dominant genes.*RF 1-4* The recent publicity surrounding breast cancer in general, the national screening programme,5 and trials of prevention have heightened awareness in families where the disease has already occurred. This has led to demands for advice about risks and what to do about them. Women wish to know not only their own risks but also the risks to their daughters. The needs of these women are being met by general practitioners, surgeons, oncologists, and an increasing number of specialist cancer family history clinics. Access to such clinics is now possible in most regions. In this article we consider how best to give advice and what to do with regard to prevention and screening for women at high risk of developing cancer. The new potential for precise genetic diagnosis in some families raises important additional psychological and ethical issues. From studies of the pattern of distribution of breast and other cancers in families it has been known for some time that inheritance is usually dominantly transmitted.6,7 To find the defective gene …

Christina C. Dahm*, Ruth H. Keogh , Marleen A.H. Lentjes , Elizabeth A. Spencer , Tim J. Key , Darren C. Greenwood , Janet E. Cade , Victoria J. Burley , Martin J. Shipley , Eric J. Brunner , Alison M. Stephen , Gita Mishra , Diana Kuh , Ian S. Fentiman , Ian R. White , Robert Luben , Kay Tee Khaw , Sheila A. Rodwell (Bingham) a,1 Medical Research Council Centre for Nutritional Epidemiology in Cancer Prevention and Survival, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, United Kingdom MRC Biostatistics Unit, Institute of Public Health, University of Cambridge, Cambridge CB2 0SR, United Kingdom Cancer Epidemiology Unit, University of Oxford, Oxford OX3 7LF, United Kingdom Centre for Epidemiology & Biostatistics, Level 8, Worsley Building, University of Leeds, Leeds LS2 9JT, United Kingdom Department of Epidemiology and Public Health, University College London, London WC1E 6BT, United Kingdom MRC Human Nutrition Research, Elsie Widdowson Laboratory, Cambridge CB1 9NL, United Kingdom MRC Unit for Lifelong Health and Ageing, Department of Epidemiology and Public Health, University College London, 33 Bedford Place, London WC1B 5JU, United Kingdom Academic Oncology Unit, Guy’s Hospital, London SE1 9RT, United Kingdom Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, United Kingdom

The association with breast cancer of menstrual and reproductive events, family history of breast cancer, and body size have been studied on two cohorts of 6,706 volunteers on the island of Guernsey (United Kingdom), 168 of whom had breast cancer detected during follow-up. The median follow-up time of the non-cases was 21 years in the first study and 10 years in the second. A time-dependent Cox regression model was fitted to the data with age as the time-dependent variable in order to represent the effect of changing menopausal status. Other variables examined in the model were age at menarche, parity, age at first birth, family history of breast cancer, height, weight (both directly measured), relative weight (weight [kg]/height[m]), and Quetelet's body mass index (weight[kg]/height[m]2). Interactions between age and all other covariates also were examined. Family history was found to be the most important risk factor for women aged less than 51 years (relative risk [RR] = 3.5, 95 percent confidence interval [CI] = 2.0-6.0), and intervals between menarche and first birth longer than 14 years were found to increase significantly the risk of breast cancer in women older than 61 years (RR = 2.4, CI = 1.3-4.4). Height was the only indicator of body size which was associated significantly with risk of breast cancer, the estimated regression coefficient indicating an increase in risk of about 70 percent for women on the 90th centile of height relative to those on the 10th centile. A survey of the literature showed that the association between risk of breast cancer and height was found in those studies which used direct measurements of height but not in others which used self-reported values.

Work in this laboratory has established the presence of IGF-I and IGF-II BCF although at levels at about 5%–10% of those found in the peripheral circulation. This is unlike EGF where we confirm that the concentration is very much higher than that found in blood. The amount of TGF-α is uncertain since this depended on which of the commercially available kits was used; the average results from the two kits being in the order of 100ng/ml and 1ng/ml, respectively. There is evidence that binding proteins for IGF-I and IGF-II are present in BCF although these proteins are non-specific having high capacities and low affinities for these ligands. The levels of these growth factors appear to be host-dependent. There is a highly significant (P

The dilemma of increasing costs of medical care and shrinking health budgets has stimulated attempts to implement stricter control on expenditure without affecting the quality of care. This study shows that in patients with operable breast cancer, a policy of early discharge after a mastectomy did not have deleterious effects on wound healing and was well accepted by patients. In a randomized trial, drains were removed after either 3 or 6 days postmastectomy, and in both groups of patients there was no difference between the mean volumes of seromas aspirated or the number of aspirations and return visits to the hospital. This suggests that a policy of early discharge is safe, acceptable, economical, and may improve bed utilization. © 1992 Wiley-Liss, Inc.

A consecutive series of 197 women under 70 years of age with operable breast cancer, randomised to treatment by a conservation technique in comparison to mastectomy, were assessed using structured interviews. The prevalence of cases of anxiety and depression was high before treatment commenced, there were fewer cases in the conservation group but no significant difference at 3 or 12 months in the number of new cases, social adjustment, or capacity to return to work. Attitudes to treatment showed significant differences between the groups, more women in the conservation group were able to wear their usual clothes and most women rated the cosmetic result highly. Patients were more likely to stop sexual intercouse completely after mastectomy. An effective conservation technique should be an attractive treatment choice available to selected women with early breast cancer.

Background: Initial results of the UK/ANZ DCIS trial found that adjuvant radiotherapy reduced the recurrence of ipsilateral invasive breast cancer (BC) and ductal carcinoma in situ (DCIS) by 55% and 64% respectively, but the effect of tamoxifen was smaller (Lancet 2003, 362: 95-102). Here, we report an updated analysis of this trial.Methods: 1701 women with completely locally excised DCIS were enrolled in a randomised 2x2 trial of radiotherapy, tamoxifen or both. Elective decision to withhold or provide one of the treatments was also permitted and long-term follow-up was performed by treating hospitals. Seven patients were excluded due to protocol violations leaving 1694 patients available for analysis.Results: After a median follow-up of 12.7 years, a total of 376 breast cancers were diagnosed; 162 invasive (122 ipsilateral; 39 contralateral) and 197 DCIS (173 ipsilateral; 17 contralateral). Radiotherapy continued to reduce the incidence of ipsilateral invasive disease (HR=0.32 (0.19-0.56), P Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 34.

While operating upon the elderly, and even the very elderly, for cardiac, orthopaedic or vascular diseases is increasingly accepted, there is continued reluctance to recommend aggressive interventions for several malignancies, other than those arising in the colon [1]. Surgical resection is accepted as the only curative therapy for most solid tumours [2], but elderly subjects may be denied surgery because of their presumed higher mortality and morbidity; the situation that existed at the beginning of this century [3]. Surprisingly, reluctance to advise or to accept an operation is often unrelated to the presence of co-existing debilitating conditions or impaired functional status [4]. In the first half of this century operative mortality was high for patients ]70 years of age (19%) [5]. The increasing size of the elderly population meant a parallel increase in need for surgery in the elderly. A report in 1975 by Greenfield showed that operative mortality was halved during a 40-year period among the same age group [6]. This was the consequence of improvements in anaesthetic and surgical techniques, the availability of new drugs and optimised post-operative care. However, common clinical practice and scientific reporting continue to exclude the aged from optimal surgical treatment [7]. While the incidence of post-operative myocardial infarction and bronchopneumonia have remained unchanged among colorectal cancer patients treated before and after 1980, the mortality rate associated with these complications was dramatically reduced from 100 to 38% and from 55 to 15% (PB0.005), respectively, due to earlier diagnosis and aggressive treatment of post-operative complications [8]. A protocol of pre-operative evaluation, intra-operative haemodynamic monitoring and post-operative intensive care has been formalised for use in the elderly poor-risk subjects [9]. Mortality rates among a group of non-cancer patients \90 years old were 2.3% in elective surgery, 16% in urgent and 45% for emergency cases [1]. An Italian study on 435 patients \80 years old confirmed these figures; a significant difference was recorded between emergency and elective operations (morbidity 42 vs. 20%, mortality 18 vs. 6%) [2]. In a selected series of colorectal cancer patients there was a 2-fold increase in mortality in patients aged between 69 and 74 years and a 4-fold increase in those \74 years old operated on emergency basis and also operative deaths were significantly increased after emergency surgery (26 vs. 11.6%) [9]. Age-related changes are most evident under physical/ psychological stress and elderly people are slower to react and recover [10]. While anaesthesiological guidelines for management (pre-operative evaluation, intraoperative monitoring and post-operative intensive care) of elderly people at high risk for surgery are to be further developed [11,8], detailed evaluation of major organ function helps in choosing anaesthetic and pharmacological agents. Despite this wide experience, only two risk factors for peri-operative cardiac morbidity have been definitively identified: recent myocardial infarction and current congestive heart failure [12]. In the past years, multivariate analyses have identified combinations of risk factors allowing the organisation of scoring systems [13]. These scores are generally based on costly clinical and laboratory tests, often referring to further investigations. Most recently it has been argued that routine clinical evaluation before surgery is neither sufficiently sensitive nor specific and that higher costs are justified if specialised testing provides otherwise unavailable information. The topic of pre-operative assessment of cardiovascular patients is addressed for both, elderly and non elderly patients, by the recent overview by Mangano [14,15]. For these reasons the results of retrospective evaluation of large surgical series aimed at the * Corresponding author. MultiMedica 300, via Milanese, Sesto S. Giovanni, 20099 Milan, Italy. Tel.: +39 2 24209481; fax: +39 2 224209313.

For more than a decade, results frompublished studies have indicated that therisk of breast cancer may be loweramong heavy premenopausal womenthan among their less obese counterparts(1-8). In heavy postmenopausal women,however, this risk is either increased orunchanged in comparison with non-obese postmenopausal women (9,10).The mechanism explaining this reversalin risk is unknown, although theoreticalexplanations have been proposed. Obesepostmenopausal women may have ele-vated risk from higher levels of circulat-ing estrogens secondary to increasedconversion of androgen to estrogen inadipose tissue (11) and a higher propor-tion of bioavailable estrogen due to thelow levels of sex hormone-bindingglobulin (SHBG) (12,13). Obese pre-menopausal women may exhibit agreater degree of anovulation, resultingin lower levels of both progesterone andestradiol, lower breast cell divisionrates, and, consequently, a lower risk ofbreast cancer (13-15).We had the opportunity to evaluatethe relation of body mass and hormonalprofiles in a group of 195 communityand 103 hospital control subjects from astudy of endometrial cancer describedelsewhere (16,17). Results of both con-trol groups were similar; therefore, thetwo groups were combined. Body massindex (BMI) (kg/m

Carcinoma in situ is the earliest histologically recognisable form of malignancy and as such provides an opportunity to treat the disease in a curative way. However, due to the comparative rarity of in situ breast carcinoma, there is no available information derived from controlled clinical trials. The two major variants, ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS) will be considered separately as the two conditions have divergent natural histories. DCIS is increasing in incidence since microcalcification, which is a frequent accompaniment, may be detected radiologically in the screening of asymptomatic women. The extent of microcalcification may not indicate the extent of disease. It has yet to be determined whether there is a difference in behaviour of the tumour forming and the asymptomatic types of DCIS. After a biopsy has shown DCIS there will be residual DCIS at the biopsy site in one-third of patients, and multifocal DCIS in another third. A coexistent infiltrating carcinoma may be present in up to 16%. Due to sampling problems areas of invasion may be missed. Axillary nodal metastases are found in only 1% of patients with histological DCIS. Radical surgery by total or modified mastectomy is almost curative, but 3% of patients will die of metastases. Taking results of uncontrolled trials, local relapse rates are as follows: excision alone 50%, wide excision 30%, wide excision plus radiotherapy 20%. Two prospective trials are underway run by the EORTC and NSABP in which patients with DCIS are treated by wide excision with or without external radiotherapy. LCIS is usually an incidental finding with a bilateral predisposition to subsequent infiltrating carcinomas. Curative procedures such as bilateral mastectomy with reconstruction may represent overtreatment. A systemic rather than local approach would seem appropriate and a trial is now underway run by the EORTC in which patients with histologically confirmed LCIS are randomised to observation alone or to receive tamoxifen 20 mg daily for 5 years. Cooperative studies will provide the way of acquiring important data on treatment regimens of both DCIS and LCIS. It is timely that treatment regimens for in situ carcinoma of the breast be examined by controlled clinical trials.

Presentation data on 607 breast cancer patients treated by a variety of modalities at Guy's Hospital, London, have been analysed using the Cox proportional hazards model, to identify factors associated with length of overall survival. When deaths attributable to causes other than breast cancer were treated as censoring events, the significant factors were found to be stage, mode of treatment, menstrual status and tumour size. The analysis was repeated for the subgroup of 326 patients treated by modified radical mastectomy. Four variables: stage, age at menarche, menstrual status and age were found to be significantly associated with both overall survival and length of distant recurrence-free interval. These factors have been combined to create a prognostic index which has been used to define subgroups of patients with different prognosis. The index has been validated on a separate group of 457 modified radical mastectomy patients treated at the same hospital.

This paper reviews 105 patients with breast cancer who had a pleural effusion as a direct consequence of metastatic disease. The mean lag time between diagnosis of primary tumor and presentation of the effusion was 41.5 months. Mean survival time after development of an effusion was 15.7 months. Of the 99 patients with unilateral breast tumors, 50% had ipsilateral effusions, 40% were contralateral, and 10% were bilateral. Forty-two percent of the patients had pleural effusion as the first evidence of recurrence. No particular group of women, based on age, menopausal status, or parity could be identified as being at risk of developing a subsequent effusion. However, there was a significantly higher proportion of patients who had central and medial tumors and who had Stage III cancers. Other tumor features, such as size, histologic type, or grade, did not predict the development of pleural metastasis. The success rate of a variety of treatment methods, local, general, or a combination of both, was 17% in achieving control of effusions. There may be a place for more aggressive treatment of pleural effusion at first presentation so that the quality of life could be improved during the patient's remaining months of survival.

A study has been conducted to compare the nature and severity of post-operative sensory changes (sensory loss, paraesthesiae, and pain) among patients with breast cancer treated by either modified radical mastectomy or a conservative procedure (tumourectomy, axillary clearance, iridium implant, and external radiotherapy). There was a similar incidence of post-operative sensory loss in the two groups, reported by 82% of the mastectomy group and 77% of the iridium group, and an equivalent rate of improvement (76 and 80% respectively). Post-operative paraesthesiae occurred in 61% of the mastectomy group and 63% of the iridium group; maximum severity of paraesthesiae was similar as was the percentage improving. Among the mastectomy group 55% reported phantom breast sensation and 61% of the iridium group had post-operative breast pain. Improvement occurred in 58% of those with breast pain. These findings may have implications for the counseling of patients with breast cancer who are going to be treated by certain conservative procedures.

This review of the epidemiologic and endocrinologic literature aims to improve understanding of the etiology of premalignant breast disease. Although there are inconsistencies regarding the clinical symptoms defined as benign breast disease, there are 2 major clinical categories: cysts treated by aspiration and solid lesions treated by excision or incision biopsy. A necessary research approach is to determine which patients with benign breast disease have an increased risk of breast cancer and study them to determine whether they carry any endocrine or biologic stigmata. Epithelial hyperplasia is the lesion with greatest premalignant potential. Both population and case-control studies have examined the association between benign breast disease and the risk factors of age, reproductive history, family history of breast cancer, obesity, socioeconomic status, race, oral contraceptive use, and methylxanthines. No clear or consistent endocrine or hormonal abnormalities have been detected in women with benign breast disease. On the other hand, cyst fluid studies have revealed high amounts of androsterone sulfate and DHA-sulfate compared with serum levels. Carcinoembryonic antigen levels are highest in women with fibrocystic disease. At this point, it is unclear whther the progression from normal epithelium through atypia and hyperplasia and then in in situ carcinoma or invasive carcinoma is under hormonal control. Inconsistencies within the research literature may reflect the heterogeneity of conditions encompassed within the benign breast disease category. Since epithelial hyperplasia is likely a forerunner of breast cancer, such patients should be monitored to determine whether they exhibit a consistently abnormal pattern of hormonal production, e.g., subnormal androgen levels or elevation of free estradiol.

VARIOUS small molecules, up to 1,600 molecular weight1, can pass directly between certain animal cells in contact, probably through gap junctions2,3. Such communication may partly mediate growth control in multicellular organisms and cultured cells, so that disturbances in the normal pattern of communication could be related to malignant growth4,5. The 3H-nucleotide transfer method6, based on metabolic cooperation7 has shown that communication is not always an all-or-none phenomenon, but may be selective8,9. For example, human mammary epithelial cells from benign tumours or milk do not communicate with human breast fibroblasts (HumF), although either type can communicate well with homologous cells. We have examined the communication between cancer cells from several human breast cancer sources and found that, unlike normal mammary epithelium, they do not show selectivity in communication. The cancer cells fall into one or other of the two functional groups we have defined as non-selective communicators (communicate with all cells capable of communication) or non-communicators (unable to communicate with homologous or heterologous cells) suggesting that the change to malignancy involves some change in the pattern of cell communication.

The clinical and pathologic features of 35 patients who had ipsilateral supraclavicular node (SCF) recurrence after radical mastectomy were reviewed. These were compared with the features of 70 patients who had a local skin recurrence after radical mastectomy, 48 of whom had a single nodule and 22 of whom had multiple skin nodules. There were no significant differences between age at diagnosis, disease-free interval, menstrual status, tumor type and grade, and extent and location of axillary node metastases in the three groups. Survival of the SCF group was intermediate between those of the single-nodule and multiple-nodule groups. SCF recurrence is an almost invariable signal of micrometastatic disease; thus, such patients are ideal candidates for trials of adjuvant therapy.

The growth of human mammary epithelial cells is stimulated by cholera toxin and analogues of cyclic AMP, while the growth of breast derived fibroblasts is inhibited. These compounds have little effect on DNA synthesis in the absence of other mitogens but show a synergistic effect with serum and/or EGF. The results suggest that high intracellular levels of cyclic AMP in human mammary epithelial cells increase the growth response of the cell to mitogens.

To elucidate the association between stressful life events and the development of cancer the influence of life stress on relapse in operable breast cancer was examined in matched pairs of women in a case-control study. Adverse life events and difficulties occurring during the postoperative disease free interval were recorded in 50 women who had developed their first recurrence of operable breast cancer and during equivalent follow up times in 50 women with operable breast cancer in remission. The cases and controls were matched for the main physical and pathological factors known to be prognostic in breast cancer and sociodemographic variables that influence the frequency of life events and difficulties. Severely threatening life events and difficulties were significantly associated with the first recurrence of breast cancer. The relative risk of relapse associated with severe life events was 5.67 (95% confidence interval 1.57 to 37.20), and the relative risk associated with severe difficulties was 4.75 (1.58 to 19.20). Life events and difficulties not rated as severe were not related to relapse. Experiencing a non-severe life event was associated with a relative risk of 2.0 (0.62 to 7.47), and experiencing a non-severe difficulty was associated with a relative risk of 1.13 (0.38 to 3.35). These results suggest a prognostic association between severe life stressors and recurrence of breast cancer, but a larger prospective study is needed for confirmation.

• A review was conducted of 401 women who presented with breast lumps that proved to be cysts by yielding fluid on aspiration. The aim was to determine the proportion of patients with cancers that masqueraded as cysts and to establish whether short-term follow-up was necessary. After the first visit, six patients had biopsies because of a residual mass or a bloodstained aspirate. Of these patients, two were found to have cancer. After the follow-up visit, 20 further biopsies were carried out for presence of a mass, bloodstained fluid, or recurrent fluid, and two more cancers were diagnosed. Of the four patients with malignancy, only one had an intracystic carcinoma, two had necrotic grade 3 ductal carcinomas, and one had a malignant phyllode tumor. These findings underline the value of a single return visit after cyst aspiration. ( Arch Surg 1989;124:253-255)

• Outpatient needle biopsy of suspected breast cancers has been performed on 151 patients. Of 135 who were ultimately diagnosed as having a malignant tumor, 107 were correctly diagnosed on the initial needle biopsy, a success rate of 79%. The procedure is well tolerated by most patients and enables family support during a very stressful period. Furthermore, outpatient histopathologic confirmation of cancer allows adequate preoperative investigation and more efficient use of operating theater time. ( Arch Surg 115:652-653, 1980)