A follow-up study of 105 women with breast cancer following reduction mammaplasty.

Reduction mammaplasty is one of the most common procedures performed by plastic surgeons in Canada. In a recent study of 27,500 women in the province of Ontario who underwent breast reduction surgery, 105 women were identified who developed breast cancer after reduction mammaplasty. The purpose of this study was to compare women who had breast cancer and had a previous breast reduction with women who had breast cancer but did not have a breast reduction. Specifically, we wanted to document patient demographics, cancer type, surgical and nonsurgical treatment, and eventual outcome. A comparison group of non-breast reduction women was taken from the cohort of breast cancer patients in the province of Ontario, and the two groups were matched for age, year of diagnosis, and place of diagnosis. It was found that (1) the average age at diagnosis of breast cancer is significantly younger for women who have had previous breast reduction surgery than for those who have not; (2) the median interval between breast reduction and cancer is 5 years; (3) the type, location, and side of breast cancers are similar in the two groups of women; (4) breast reduction does not significantly increase or decrease survival rate from breast cancer; and (5) women who have had breast reduction receive the same treatment for their breast cancer as women who have not had reduction mammaplasty.     

Metabolism of estrogens in breast cancer.

This extensive literature compilation reviews major studies on estrogen metabolism in cancer, studies which have led to proposed possible etiological roles of estrogens in human breast cancer. Urinary and plasma estrogen excretion patterns and profiles in women with breast cancer are the topics of part 1. Studies of estrogen profiles in women who are at high-risk for breast cancer are critiqued. The estriol hypothesis is presented and criticised in a chapter. The effects of endocrine ablation on urinary estrogen profiles in breast cancer patients are compiled. Production and metabolism of estrogens in women with breast cancer are rendered, including in vivo biotransformation rates and in vitro transformation data. And the search for estrogen metabolites in women with breast cancer is reviewed. In conclusion it is obvious that the question of whether breast cancer patients have an abnormal metabolism of estrogen has not been answered, but further investigations of estrogen metabolism in breast cancer should be continued because: 1) the possibility that estrogens are carcinogenic has not been ruled out; 2) receptors have been discovered which do correlate with hormone dependency of tumors; 3) present evidence suggests that neoplasm may induce abnormal estrogen metabolism; 4) directional changes of estrogen metabolism that occur in pregnancy may also occur in women with target tissue neoplasia; 5) hepatic tissue's relationship to breast cancer has not received attention; and 6) the role of peripheral aromatization in the pathogenesis of mammary cancer is not yet understood.     

Efficiency of palpation in clinical detection of breast cancer.

An annual clinical screening test for breast cancer must be simple, brief and efficient. The traditional physical examination of the breast is time-consuming, mainly because of the complicated maneuvers necessary to inspect for retraction. Palpation with the patient supine, however, can be performed quickly. Of 286 primary breast cancers 96% (275) were palpable as a lump, and this was the only clinical sign in 55%. Retraction was the sole clinical sign in only 1%. The combination of retraction and a solid lump is a very specific but not very sensitive test for breast cancer. Retraction in this series was not related to the size of the primary tumour but among the women with a cancerous breast lump was significantly more likely to be found in those over 44 years of age, being present in 52% of these women but only 10% of the younger women. Inspection of the breast can therefore safely be detected from screening breast examinations, whether performed by the physician or the patient.     

Stress and relapse of breast cancer.

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.     

Functional analysis of Csk and CHK kinases in breast cancer cells.

In this report, we analyzed the expression and kinase activities of Csk and CHK kinases in normal breast tissues and breast tumors and their involvement in HRG-mediated signaling in breast cancer cells. Csk expression and kinase activity were abundant in normal human breast tissues, breast carcinomas, and breast cancer cell lines, whereas CHK expression was negative in normal breast tissues and low in some breast tumors and in the MCF-7 breast cancer cell line. CHK kinase activity was not detected in human breast carcinoma tissues (12 of 12) or in the MCF-7 breast cancer cell line (due to the low level of CHK protein expression), but was significantly induced upon heregulin (HRG) stimulation. We have previously shown that CHK associates with the ErbB-2/neu receptor upon HRG stimulation via its SH2 domain and that it down-regulates the ErbB-2/neu-activated Src kinases. Our new findings demonstrate that Csk has no effect on ErbB-2/neu-activated Src kinases upon HRG treatment and that its kinase activity is not modulated by HRG. CHK significantly inhibited in vitro cell growth, transformation, and invasion induced upon HRG stimulation. In addition, tumor growth of wt CHK-transfected MCF-7 cells was significantly inhibited in nude mice. Furthermore, CHK down-regulated c-Src and Lyn protein expression and kinase activity, and the entry into mitosis was delayed in the wt CHK-transfected MCF-7 cells upon HRG treatment. These results indicate that CHK, but not Csk, is involved in HRG-mediated signaling pathways, down-regulates ErbB-2/neu-activated Src kinases, and inhibits invasion and transformation of breast cancer cells upon HRG stimulation. These findings strongly suggest that CHK is a novel negative growth regulator of HRG-mediated ErbB-2/neu and Src family kinase signaling pathways in breast cancer cells.     

Breast cancer--a woman's perspective.

This paper is bound to arouse controversy. It already has. No article in this special issue has been more thoroughly reviewed or had more widely divergent opinions. Some reviewers thought it expressed unrelieved anger; others felt it described the experience, perceptions, and feelings of many women with breast cancer. The paper seemed important to publish, however, because breast cancer is the second most common tumor occurring in American women. It is important to note that the author is a successful teacher and health professional who has a full and active family and social life. She describes encounters with breast cancer in an uncommonly fervent and articulate way. These encounters have clearly left deep scars. The essay is not scientific and not balanced in this issue by a paper by a women who had a wonderful experience with breast cancer. Such a paper may never be written. Read on!     

Value of the history in the office diagnosis of breast cancer.

A review of the histories of 1059 patients with breast problems seen consecutively in office consultation revealed an incidence of breast cancer of 13%. Patients over 50 years of age or whose mother or sister had had breast cancer had a substantially greater likelihood of having breast cancer. The finding of the problem on routine examination, a family history of breast cancer in a relative other than the mother or a sister, or prominent breast pain or nipple discharge made the diagnosis of cancer less likely. Menstrual status, a history of previous benign disease, nulliparity, current hormone therapy and duration of symptoms did not help identify the patient likely to have breast cancer. Much time could be saved for both doctor and patient in taking the history from patients with breast disorders. Only the patient''s age and the history of the mother and sisters with regard to breast cancer will help identify the "high-risk" patient. Other historical findings are either valueless or should be used to reassure these usually anxious women.     

Spontaneous in vitro immortalization of breast epithelial cells from a patient with Li-Fraumeni syndrome.

Individuals with germ line mutations in the p53 gene, such as Li-Fraumeni syndrome (LFS), have an increased occurrence of many types of cancer, including an unusually high incidence of breast cancer. This report documents that normal breast epithelial cells obtained from a patient with LFS (with a mutation at codon 133 of the p53 gene) spontaneously immortalized in cell culture while the breast stromal fibroblasts from this same patient did not. Spontaneous immortalization of human cells in vitro is an extremely rare event. This is the first documented case of the spontaneous immortalization of breast epithelial cells from a patient with LFS in culture. LFS patient breast stromal fibroblasts infected with a retroviral vector containing human papillomavirus type 16 E7 alone were able to immortalize, whereas stromal cells obtained from patients with wild-type p53, similarly infected with human papillomavirus type 16 E7, did not. The present results indicate a protective role of normal pRb-like functions in breast stromal fibroblasts but not in breast epithelial cells and reinforces an important role of wild-type p53 in the regulation of the normal growth and development of breast epithelial tissue.     

Influence of postmenopausal hormone replacement therapy on an estrogen metabolite biomarker of risk for breast cancer.

Whether postmenopausal hormone-replacement therapy (HRT) increases the risk of breast cancer remains controversial, despite numerous epidemiological studies. We approached the question from a biochemical rather than an epidemiological direction - we hypothesized that if estrogen administration increases the risk of breast cancer, it should also alter a known estrogen biomarker of risk towards what has been observed in patients who already have breast cancer. The specific biomarker we studied was the ratio of the urinary excretion of two principal estradiol metabolites, 2-hydroxyestrone and 16 alpha-hydroxyestrone, which is markedly decreased in women with breast cancer and women with familial risk for breast cancer. We studied 34 healthy postmenopausal women not on HRT and 19 women on HRT (Premarin 0.625 mg daily plus Provera, 2.5 mg daily, in women with a uterus and Premarin alone in women without a uterus); treatment duration ranged from 3 months to 15 years. We also studied four women with recently diagnosed, untreated breast cancer. The women with breast cancer showed a significantly lower 2-hydroxyestrone to 16 alpha-hydroxyestrone ratio than control women on HRT (1.35 +/- 0.13 vs. 2.71 +/- 0.84; p < 0.0001). There was no significant difference in the metabolite ratio between healthy women on HRT and women not on HRT (2.82 +/- 0.92 vs. 2.71 +/- 0.84). There was no significant difference between women receiving Premarin alone and women receiving Premarin plus Provera (2.46 +/- 0.84 vs. 3.13 +/- 0.90), and neither differed significantly from women not on HRT (2.71 +/- 0.84). The finding that the ratio of women on HRT was not decreased to or toward the ratio in women with breast cancer can be interpreted, we believe, as a suggestive item of biochemical evidence that HRT is not a risk for breast cancer.     

Neurilemoma of the breast in a man. A case report.

A case of neurilemoma of the left breast in an 83-year-old man is presented, including the fine needle aspiration and biopsy diagnosis. A review of the literature did not reveal the existence of such a tumor in a man's breast. The aspirate yielded a cellular smear composed of clusters of spindle-shaped cells showing minimal atypia and Verocay bodies. The final diagnosis was established on the excised mass through histopathologic study.     

Screening and self examination for breast cancer.

Breast cancer is the major form of cancer in women, with nearly 30,000 new cases and over 15,000 deaths in the United Kingdom each year. Breast screening by mammography has been shown in randomised trials to reduce mortality from breast cancer in women aged 50 and over. An NHS breast screening programme has been in operation in the United Kingdom since 1988. Its aim is to reduce mortality from breast cancer by 25% in the population of women invited to be screened. The uptake of mammography among the eligible population may be the single most important determinant if the programme is to be effective. Primary care teams have an important part to play in encouraging women to attend for screening and in providing information, advice, and reassurance at all stages of the screening process. To date, routine breast self examination has not been shown to be an effective method of screening for breast cancer and should not therefore be promoted as a primary screening procedure. There is, however, a case to be made for women to become more "breast aware."     

Etiology of breast cancer. II. Epidemiologic aspects

The epidemiology of breast cancer is reviewed with particular emphasis on its etiology. A number of studies suggest that differences in breast cancer incidence are associated with differences in marital status, number of pregnancies, age at menarche, age at menopause, height and weight, socioeconomic status, geographic location and residence. However, in no case is the evidence adequate to establish a “cause and effect” relationship. The genetic component of these associations may be of primary importance, while other conditions such as marital status are probably indirect reflections of the operation of more fundamental factors.There is a general consensus that endocrine factors play an important part in mammary cancer occurrence. At present, the association between breast cancer and the presence of the virus-like (type B) particles in human milk is not established.     

Influence of maternal diet during lactation and use of formula feeds on development of atopic eczema in high risk infants.

OBJECTIVE--To examine the effects of maternal diet during lactation and the use of formula feeds on the development of atopic eczema in infants at risk. DESIGN--Mothers who planned to breast feed exclusively were randomly allocated to either a restricted diet (avoiding milk and other dairy products, eggs, fish, peanuts, and soybeans) or a diet without restrictions. Mothers who did not plan to breast feed were randomly allocated to using one of three formula feeds. SETTING--Child health centre in Canada. SUBJECTS--97 Mothers who chose to breast feed and 124 mothers who did not. INTERVENTIONS--Restricted diet for 49 mothers who breast fed. Casein hydrolysate formula, soy milk formula, or cows'' milk formula for infants not breast fed. MAIN OUTCOME MEASURE--Development of eczema in babies. RESULTS--Infants were followed up over 18 months and examined for eczema. Eczema was less common and milder in babies who were breast fed and whose mothers were on a restricted diet (11/49 (22%) v 21/48 (48%)). In infants fed casein hydrolysate, soy milk, or cows'' milk 9/43 (21%), 26/41 (63%), and 28/40 (70%), respectively, developed atopic eczema. CONCLUSIONS--In families with a history of atopic disease [corrected] mothers who breast feed should avoid common allergenic foods during lactation. If they choose not to breast feed a hydrolysate formula should be used.     

Differential cytology of breast cancer.

The aim of the study was to investigate the possibility of predicting the histologic type of different breast cancers by semi-quantitative screening of cytologic criteria. Cytologic material was obtained by the aspiration technique. The frequency of ten cytologic criteria was correlated to five histologic types of breast cancer. Hitherto, it has not been possible to define histologic types of breast carcinomas on the basis of cytologic criteria alone. While the occurrence of cellularity, intercellular cohesion, foam cells and necroses often varies from slide to slide within one particular carcinoma, other features such as nuclear diameter, polymorphism, anisonucleosis, apocrine carcinoma cells, and enlarged nucleoli are more or less uniformly distributed. The application of these cytologic criteria thus uniformly represented in a tumour may prove to be a more reliable method for classifying breast carcinomas than the use of histologic growth patterns which are often inhomogenous within each individual neoplasm.     

Granulomatous angiopanniculitis of the breast. A case report

BACKGROUND: Granulomatous angiopanniculitis (GAP) is a rare benign condition of the breast of unknown etiology. Clinically and by fine needle examination, GAP may simulate breast carcinoma. The cytologic characteristics have not been described before. CASE: A 63-year-old female exhibited a palpable mass in her left breast. The fine needle aspirate contained both epithelioid and stromal elements. The epithelioid component consisted of dissociated individual cells and small groups and clusters of atypical cells. The stromal component showed a uniform, not-atypical pattern. The lumpectomy specimen showed nonnecrotizing granulomatous panniculitis and lymphoid angiitis without involvement of ducts or lobules. CONCLUSION: Granulomatous lesions should be borne in mind in the differential diagnosis of breast cancer in fine needle aspiration cytology. GAP must be histopathologically distinguished from granulomatous inflammation in the breast of autoimmune or infectious origin as specific medical therapy may be available for these latter diseases.     

Parity and breast cancer: evidence of a dual effect.

Epidemiological studies have shown that early first pregnancy reduces the risk of developing breast cancer, which indicates that initiation of the disease occurs at an early age. Thus the subclinical lesion of breast cancer might already be present in the breast before childbearing begins and the growth of any such focus might be modified by the endocrine changes of pregnancy. To test this hypothesis the relation between parity and age at presentation was studied in 341 unselected patients with breast cancer presenting to a single clinic. The mean age at presentation was 5.2 years lower in parous than nulliparous women (p < 0.001) and fell with increasing parity. It is concluded that reproductive history influences not only the risk of breast cancer but also the latent interval of a proportion of breast carcinomas.     

Randomised controlled trial of breast shells and Hoffman's exercises for inverted and non-protractile nipples.

OBJECTIVE--To determine the value of recommending breast shells or Hoffman''s exercises, or both, to pregnant women with inverted or non-protractile nipples who intend to breast feed. DESIGN--Randomised controlled trial with a two treatment by two level factorial design. SETTING--Antenatal clinics in a district general hospital and the community. SUBJECTS--96 nulliparous women recruited between 25 and 35 completed weeks in a singleton pregnancy with at least one inverted or non-protractile nipple. MAIN OUTCOME MEASURES--Anatomical change of nipples, judged blindly before first breast feeding, and success of breast feeding reported by postal questionnaire six weeks postnatally. RESULTS--Sustained improvement in nipple anatomy was more common in the untreated groups but the differences were not significant (52% (25/48) shells v 60% (29/48) no shells; difference -8% (95% confidence interval -28% to 11%) and 54% (26/48) exercises v 58% (28/48) no exercises; -4% (-24% to 16%)). 24 (50%) women not recommended shells and 14 (29%) recommended shells (21%; 40% to 2%) were breast feeding six weeks after delivery (p = 0.05), reflecting more women recommended shells both deciding to bottle feed before delivery and discontinuing breast feeding. The same number of women in exercise and no exercise groups were successfully breast feeding (0%; -20% to 20%). 13% of women approached about the trial (and planning to breast feed) did not attempt breast feeding. CONCLUSIONS--Recommending nipple preparation with breast shells may reduce the chances of successful breast feeding. While there is no clear evidence that the treatments offered are effective antenatal nipple examination should be abandoned.     

Down-regulation of laminin-5 in breast carcinoma cells.

BACKGROUND: Laminin-5 (ln-5), a large heterotrimeric glycoprotein consisting of an alpha 3, beta 3, and gamma 2 chain, is a component of epithelial cell basement membranes that functions as a ligand of the alpha 3 beta 1 and alpha 6 beta 4 integrins to regulate cell adhesion, migration, and morphogenesis. The ln-5 chains show tissue-specific patterns of regulation in tumors derived from different tissues. For example, ln-5 is often up-regulated in gliomas, gastric carcinomas, and squamous carcinomas and down-regulated in prostate and basal cell carcinomas. Ln-5 expression patterns may represent useful tumor markers and help to elucidate the role of ln-5 in tumor progression in different tissue types. MATERIALS AND METHODS: We have studied ln-5 expression patterns in the breast. mRNA levels were examined in tumor and normal breast epithelial cell lines, tissue samples, and immunomagnetically sorted primary cultures using differential display, Northern blotting, and hybridization arrays. Protein levels were examined by immunoprecipitation. Gene integrity was assessed by Southern blotting of representative cell types. RESULTS: Ln-5 alpha 3, beta 3, and gamma 2 mRNA expression was found to be markedly down-regulated in a panel of breast tumor cell lines when compared with normal breast epithelial cells. Ln-5 mRNA was expressed at relatively high levels in MCF-10A immortal normal breast epithelial cells, long-term cultures of normal breast cells, and sorted primary cultures of normal breast luminal epithelial and myoepithelial cells. Reduced, but detectable, levels of ln-5 tended to be expressed in cell lines derived from early-stage breast tumors, whereas expression was generally not detected in cell lines derived from later-stage tumors. In breast tumor tissue specimens, expression of ln alpha 3 and beta 3 mRNAs tended to be reduced relative to levels observed in adjacent nontumor tissue, whereas in gamma 2 levels were elevated in specimens with increased amounts of myoepithelial cells. These ln-5 expression changes could not be attributed to large-scale mutations or gene rearrangements. Ln-5 protein levels were found to reflect mRNA levels in representative cell lines. At senescence, a growth state believed to suppress tumorigenesis, expression of all three ln-5 mRNAs was up-regulated. CONCLUSION: The down-regulation of ln-5 mRNA expression in breast tumors cells provides a new molecular marker and suggests that ln-5 functions to control tumor progression in the breast.     

Breast self-examination: importance of technique in early diagnosis.

Shortly after diagnosis of breast cancer 416 patients were interviewed about their use of screening procedures and the method of tumour detection. Although 72% reported that they performed breast self-examination (BSE), only 12% actually inspected and palpated their breasts monthly. BSE was not significantly associated with tumour size or involvement of the lymph nodes; however, thorough inspection was associated with smaller tumours, and careful palpation with the absence of palpable nodes. Of those who no longer or never had examined their breasts 40% reported having annual breast examinations by their physician and had significantly smaller tumours than did the others. Most of the women (86%) reported having detected their own tumours, and BSE did not significantly increase the likelihood of self-detection. The frequency of use of screening procedures was similar in a sample of women without breast cancer.