How breast cancer presents.

A study of 501 new breast cancers in patients seen in a consulting surgical practice revealed that 87% were in patients 45 years of age or older. The patients had found 83% of the cancers. The distributions of size and stage were the same for the tumours found by the patients and those found by the referring physicians. Two thirds of the cancers had an associated visible clinical sign, demonstrating the importance of inspection in the examination of the breast. Dimpling, sometimes apparent only on manipulation of the tumour, was present with 264 of the cancers and was often associated with "minimal" lesions. Mammography was done for 63 of the breast cancers but it missed 27. Of the physician-found cancers 15 were in patients who had already had breast cancer, 4 were in patients presenting with symptomatic metastases and 14 were in women presenting with other disorders. Of the 52 cancers found by periodic examination 3 were locally advanced and 21 had axillary metastases, while among the 28 "early" cancers 12 were in women who were senile, mentally defective or psychotic. Only four of the cancers found by the physicians were in women under age 45; two were rapidly fatal, one had an axillary metastasis, and the fourth was in a woman who had had cancer of the opposite breast. The remaining 284 lesions found by periodic or routine examination in women under age 45 were benign. Thus, periodic or routine examination for unsuspected breast cancer in women under age 45 seems unjustified except in those who have already had breast cancer.     

Preventive health care, 1999 update: 3. Follow-up after breast cancer

OBJECTIVE: To make recommendations to physicians who provide follow-up care for women who have been treated for early-stage breast cancer. OPTIONS: Combination of blood tests, bone scans, liver echography and chest radiography for detection of distant disease; physical examination with or without mammography for detection of contralateral breast cancer; and physical examination with or without mammography for detection of ipsilateral recurrent disease after breast-conserving therapy. OUTCOMES: Survival, disease recurrence and quality-of-life measures for distant disease, local recurrence of disease and disease in the contralateral breast. EVIDENCE: A MEDLINE search for relevant articles published between January 1966 and January 1998 with the MeSH terms "breast neoplasms" and "neoplasm recurrence" (local and distant) with limits to "human" was done. A subsequent MEDLINE search using the MeSH terms "breast neoplasms," "neoplasm recurrence," "local/diagnosis" and "mammography" was done to address issues of mammography. The literature search was reviewed by a medical librarian and 2 breast cancer specialists to ensure completeness. BENEFITS, HARMS AND COSTS: Breast cancer is the most common cancer in Canadian women and is the second leading cause of death after lung cancer. Even with early-stage breast cancer, recurrence after treatment for primary breast cancer is frequent. Traditionally, follow-up has been felt to facilitate early detection and improve survival. Randomized controlled trials (RCTs) have shown that routine screening (blood tests and diagnostic imaging) for distant disease does not alter survival or quality of life over routine physical examination. In an underpowered secondary analysis of RCT data, the detection of contralateral breast cancer did not affect survival. However, there have been no RCTs examining the role of mammography and physical examination and their effect on survival in the detection of contralateral breast cancer. The sensitivity and specificity of mammography after local excision and radiotherapy is unknown. There have been no RCTs examining the role of mammography or physical examination, or both, and their effect on survival in the detection of ipsilateral breast recurrence. VALUES: The strength of evidence was evaluated using the methods of the Canadian Task Force on Preventive Health Care. A high value was placed on interventions that changed survival. When evidence was available, high value was also placed on interventions that affected quality of life. RECOMMENDATIONS: There is good evidence not to include blood work and diagnostic imaging as part of screening for distant disease (grade E recommendation). There is no evidence to suggest that mammography decreases mortality by detecting ipsilateral disease in the conservatively treated breast; however, there is indirect evidence that it may be beneficial (grade C recommendation). There is no direct evidence to suggest that physical examination or mammography, or both, should be used to detect contralateral breast cancer; however, there is indirect evidence that it may be beneficial (grade C recommendation). VALIDATION: The findings of this analysis were reviewed through an iterative process by the members of the Canadian Task Force on Preventive Health Care.     

A cohort study of breast cancer risk in breast reduction patients.

Surgical reduction of the female breast (reduction mammaplasty) is very common in plastic surgery. The purpose of this study was to determine whether women who have undergone breast reduction surgery are at the same, greater, or lesser risk of developing breast cancer than women who have not undergone breast reduction surgery. This study incorporates a population-based, non-concurrent cohort linkage methodology. The Canadian Institute for Health Information hospital records were used to identify all Ontario women who had undergone breast reduction surgery in Ontario between 1979 and 1992. Three computerized probabilistic record linkages were performed. The first linkage was between a file of the 28,042 Ontario women who had undergone bilateral breast reduction surgery between April 1, 1979, and December 31, 1992, and a file of incident cancer cases among Ontario women for the calendar period 1979 to 1993. Follow-up of the cohort was undertaken starting from the date of breast reduction surgery, and vital status was ascertained as of December 31, 1993, by record linkage with the Ontario Mortality Database maintained at the Ontario Cancer Registry. The incidence of cancer in the Ontario breast reduction cohort was compared with the cancer incidence of the general Ontario population after appropriate adjustments for age and calendar time period. The expected number of cancers was calculated using the "PERSON YEARS" computer program. Within the cohort, followed for an average of 6.5 years after bilateral breast reduction surgery, 101 breast cancers were observed and 165.8 were expected, for a standardized incidence ratio of 0.61 (0.50 to 0.74, 95 percent confidence interval). This effect was independent of patient age at breast reduction. This study demonstrates that there is no increased risk of breast cancer after bilateral breast reduction surgery and, in fact, a significant decreased risk existed in women followed for an average of 6.5 years.     

Risk of breast cancer in women with history of benign disease of the breast.

A consecutive series of 791 women who had attended diagnostic breast clinics during 1967-70 and been found to be free of malignant disease were later traced to determine their subsequent incidence of breast cancer. Of the 770 (97%) successfully traced, 22 had developed breast cancer. Based on data from the Welsh Cancer Registry only eight cases of breast cancer had been expected, so that the excess risk for the group was 2.7. The increased risk occurred in all age groups and in women deemed "essentially normal" as well as in those who had had a pathological abnormality. The risk was increased when epithelial hyperplasia was present. No excess mortality from breast cancer was apparent, but follow up was short. More breast symptoms were experienced and more biopsies performed than expected in this group of women. Women with a past history of benign breast disease have a slightly increased risk of breast cancer. Selective screening of these women, however, may be uneconomic and a cause of groundless anxiety.     

Fat content of expressed breast milk: a case for quality control.

Expressed breast milk used to feed preterm infants is precious and so, despite heterogeneity of composition, all available milk is used. A study of 274 samples of expressed breast milk supplied by preterm mothers and National Childbirth Trust donors showed pronounced variation in fat content as measured by the "creamatocrit" method. This was not due to differences between term and preterm mothers or between transitional and mature milk. The composition was affected by diurnal variation and method of collection. Substantial amounts of fat were also wasted as a result of continuous nasogastric feeding. Several milk samples did not contain enough fat to supply even a fraction of the recommended energy requirements of these infants. Some type of quality control over samples of expressed breast milk is clearly essential. The creamatocrit method is simple and feasible.     

Immunohistochemical analysis of MUC5B apomucin expression in breast cancer and non-malignant breast tissues.

A deregulation of several MUC genes (MUC1, MUC2, MUC3, MUC5AC, and MUC6) was previously demonstrated in breast carcinomas. Considering that recently we found the "non-mammary" MUC5B mRNA in primary breast tumors (Berois et al. 2003), we undertook the present study to evaluate the expression profile of MUC5B protein product in breast tissues, using LUM5B-2 antisera raised against sequences within the non-glycosylated regions of this apomucin. Expression of MUC5B by breast cancer cells was confirmed by immunocytochemistry, in situ hybridization, and Western blot on MCF-7 cancer cells. Using an immunohistochemical procedure, MUC5B apomucin was detected in 34/42 (81%) primary breast tumors, in 13/14 (92.8%) samples of non-malignant breast diseases, in 8/19 (42.1%) samples of normal-appearing breast epithelia adjacent to cancer, and in 0/5 normal control breast samples. The staining pattern of MUC5B was very different when comparing breast cancer cells (cytoplasmic) and non-malignant breast cells (predominantly apical and in the secretory material). We analyzed MUC5B mRNA expression using RT-PCR in bone marrow aspirates from 22/42 patients with breast cancer to compare with MUC5B protein expression in the primary tumors. Good correlation was observed because the six MUC5B-positive bone marrow samples also displayed MUC5B expression in the tumor. Our results show, for the first time at the protein level, that MUC5B apomucin is upregulated in breast cancer. Its characterization could provide new insights about the glycobiology of breast cancer cells.     

Recurrent Hodgkin's disease in the breast. Diagnosis of a case by fine needle aspiration and immunocytochemistry

Recurrent Hodgkin's disease involving the breast in a 17-year-old girl was diagnosed by fine needle aspiration (FNA) biopsy of a solitary mass that developed one year after "curative" radiation. Benign breast disease and breast carcinoma were ruled out upon cytologic examination of the FNA smears, which contained diagnostic Reed-Sternberg cells and the characteristic polymorphic background elements. Follow-up immunoperoxidase staining for Leu-M1 on destained smears confirmed the diagnosis. Definitive therapeutic measures were initiated after the FNA diagnosis.     

Four decades of discovery in breast cancer research and treatment--an interview with V. Craig Jordan. Interview by Marc Poirot

V. Craig Jordan is a pioneer in the molecular pharmacology and therapeutics of breast cancer. As a teenager, he wanted to develop drugs to treat cancer, but at the time in the 1960s, this was unfashionable. Nevertheless, he saw an opportunity and through his mentors, trained himself to re-invent a failed "morning-after pill" to become tamoxifen, the gold standard for the treatment and prevention of breast cancer. It is estimated that at least a million women worldwide are alive today because of the clinical application of Jordan's laboratory research. Throughout his career, he has always looked at "the good, the bad and the ugly" of tamoxifen. He was the first to raise concerns about the possibility of tamoxifen increasing endometrial cancer. He described selective estrogen receptor modulation (SERM) and he was the first to describe both the bone protective effects and the breast chemopreventive effects of raloxifene. Raloxifene did not increase endometrial cancer and is now used to prevent breast cancer and osteoporosis.The scientific strategy he introduced of using long term therapy for treatment and prevention caused him to study acquired drug resistance to SERMs. He made the paradoxical discovery that physiological estrogen can be used to treat and to prevent breast cancer once exhaustive anti-hormone resistance develops. His philosophy for his four decades of discovery has been to use the conversation between the laboratory and the clinic to improve women's health.     

Clinical practice guidelines for the care and treatment of breast cancer: 14. The role of hormone replacement therapy in women with a previous diagnosis of breast cancer

Objective

To provide information and recommendations to women with a previous diagnosis of breast cancer and their physicians regarding hormone replacement therapy (HRT).

Outcomes

Control of menopausal symptoms, quality of life, prevention of osteoporosis, prevention of cardiovascular disease, risk of recurrence of breast cancer, risk of death from breast cancer.

Evidence

Systematic review of English-language literature published from January 1990 to July 2001 retrieved from MEDLINE and CANCERLIT.

Recommendations

· Routine use of HRT (either estrogen alone or estrogen plus progesterone) is not recommended for women who have had breast cancer. Randomized controlled trials are required to guide recommendations for this group of women. Women who have had breast cancer are at risk of recurrence and contralateral breast cancer. The potential effect of HRT on these outcomes in women with breast cancer has not been determined in methodologically sound studies. However, in animal and in vitro studies, the development and growth of breast cancer is known to be estrogen dependent. Given the demonstrated increased risk of breast cancer associated with HRT in women without a diagnosis of breast cancer, it is possible that the risk of recurrence and contralateral breast cancer associated with HRT in women with breast cancer could be of a similar magnitude. · Postmenopausal women with a previous diagnosis of breast cancer who request HRT should be encouraged to consider alternatives to HRT. If menopausal symptoms are particularly troublesome and do not respond to alternative approaches, a well-informed woman may choose to use HRT to control these symptoms after discussing the risks with her physician. In these circumstances, both the dose and the duration of treatment should be minimized.

Validation

Internal validation within the Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer; no external validation.

Sponsor

The steering committee was convened by Health Canada.

Completion date

October 2001.Hormone replacement therapy (HRT) connotes treatment with either estrogen alone or estrogen with progesterone in postmenopausal women. Menopausal symptoms, such as hot flashes and vaginal dryness, and the potential long-term effects of estrogen deprivation are a concern to women with breast cancer, particularly those in whom menopause develops early as a result of adjuvant chemotherapy.Traditionally, the use of HRT has been contraindicated in women with breast cancer because of the notion that the development and growth of breast cancer is estrogen dependent and that the introduction of HRT may increase the risk of breast cancer recurrence. The focus of this guideline is on whether it is safe to give HRT to women with breast cancer.     

Secretion of immunoreactive calcitonin by human breast carcinomas.

Twenty-three out of 28 patients with metastatic breast carcinoma and one out of 13 patients with localised disease had raised levels of plasma immunoreactive calcitonin. Monolayer cultures of breast carcinomas maintained for up to 10 weeks released immunoreactive calcitonin, and a primary breast carcinoma passaged in "nude" mice for over a year contained material immunologically and chromatographically resembling the monomeric form of human calcitonin. These studies indicate that breast carcinomas can produce calcitonin and that plasma calcitonin measurements may be useful in staging patients with breast carcinomas.     

Life events and breast cancer prognosis.

OBJECTIVE--To determine whether psychosocial stress, in the form of adverse life events and social difficulties, depressive illness, or lack of confiding relationships, shortens the postoperative disease free interval in breast cancer patients. DESIGN--Prospective follow up of a cohort of newly diagnosed breast cancer patients for 42 months after primary surgical treatment, using a life events and social difficulties schedule (LEDS) and assessment of depressive symptomatology (DSM-III). SETTING--Patients recruited from breast clinics in Southampton and Portsmouth were interviewed in their homes. PATIENTS--204 women (83% of 246 consecutive cases) treated either by mastectomy or wide excision followed by radiotherapy interviewed four, 24, and 42 months after operation. MAIN OUTCOME MEASURES--Hazard ratios for relapse of breast cancer in relation to various measures of psychosocial stress. Relapse was defined as local recurrence or distant metastasis, or both, with histological or radiological confirmation and timed from the month when clinical symptoms began. RESULTS--After adjustment for age and axillary lymph node involvement, the hazard ratio associated with severe life events or social difficulties (excluding "own health" ones), or both, during the year before breast cancer surgery was 0.43 (95% confidence interval 0.20 to 0.93); for those during the follow up period it was 0.88 (0.48 to 1.64). For prolonged major depression before surgery and during the follow up period, hazard ratios were 1.26 (0.49 to 3.26) and 0.85 (0.41 to 1.79) respectively. For absence of a full confidant the figures were 0.93 (0.42 to 2.09) and 0.86 (0.38 to 1.93). CONCLUSION--These results give no support to the theory that psychosocial stress contributes to relapse of breast cancer.     

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.     

Fine needle aspiration cytology of breast fibroadenoma. A cytohistologic correlation study of 405 cases.

OBJECTIVE: To evaluate the cytohistologic correlation of breast fibroadenoma (FA) in order to assess the value of cytology in the conservative management of this lesion. STUDY DESIGN: A retrospective analysis of all aspirates diagnosed as FA or fibroadenomatous lesion (n = 1,549) for which a histologic follow-up study was available (n = 362). Forty-three aspirates, including 14 nonrepresentative smears, from histologically proven FAs with a different cytologic report were also included in the study. RESULTS: Cytohistologic agreement was present in 287 of the 362 cytodiagnoses. Lack of correlation was observed in 75 cases. Most diagnostic errors accumulated in the older patient group. The sensitivity of the cytologic diagnosis of FA was 86.9% (90.8% excluding nonrepresentative cases), with a positive predictive value of 79.3%. In 43 cases a histologic diagnosis of FA was given after previous erroneous (n = 29) or nonrepresentative cytodiagnoses (n = 14). The specificity of the cytologic diagnosis of FA reached 93.8%, with a negative predictive value of 96.3% (97.5% excluding nonrepresentative cases). Regarding malignancy, five tumors were diagnosed as FA and were malignant. No false positive diagnoses of malignancy were given, but nine aspirates were included in the category "suspicious for carcinoma." CONCLUSION: FA of the breast remains a diagnostic challenge for the cytopathologist. A considerable amount of benign breast lesions can mimic FA on cytology, and such diagnostic categories as "fibroadenomatous lesion" or "consistent with FA" are associated with low diagnostic accuracy. While the cytologic requisites for entering a program of conservative management of FA are established, it seems that strict diagnostic criteria should be applied even at the expense of diminishing sensitivity.     

Inflammatory myofibroblastic tumor of the breast. A case report

BACKGROUND: Inflammatory myofibroblastic tumor (IMT) of the breast is a very rare tumor like lesion with only 6 previously reported cases. Very little is known about the cytology of IMT. We present the fine needle aspiration (FNA) cytology of a case of recurrent, bilateral IMT of the breast and detail the clinical course, radiologic findings, morphologic appearances and immunohistochemical profile of the lesion. CASE: A 79-year-old female was initially seen in 1991 because of a suspicious mammographic abnormality in her right breast. Ultrasound-guided FNA cytology showed an unusual "inflammatory" lesion with occasional aggregates of cellular connective tissue fragments, sheets of uniform ductal epithelial cells with myoepithelial cells, spindle cells, lymphocytes and histiocytelike cells. The lesion was excised, and histology confirmed a benign process with spindle cells, lymphocytes and histiocytes. No malignant features were noted. During follow-up many new lesions appeared in both breasts, and after several FNA procedures and local excisions, bilateral mastectomy was performed at the patient's urging. She remained disease free. CONCLUSION: Although IMT of the breast has benign cytology and histology, clinically and on imaging, it resembles carcinoma. Awareness of the condition may help prevent a false diagnosis of carcinoma.     

Fine needle aspiration cytology in the management of palpable benign and malignant breast disease. Correlation with clinical and mammographic findings

Two surgeons in a health maintenance organization group practice performed 280 fine needle aspirations (FNAs) on 257 palpable breast lesions in 200 patients. The cytology was interpreted by four pathologists at a community hospital. FNA cytology had a sensitivity of 96% and a specificity of 94% in these cases; there were no false-positive diagnoses of cancer. FNA cytology improved the identification of benign disease and decreased the risk of missing cancers. FNA cytology also improved the predictive value of mammographic information and was more helpful than mammography in demonstrating the need for biopsy of small palpable lesions that turned out to be "minimal" breast cancers.     

Basic fibroblast growth factor (bFGF): mitogenic activity and binding sites in human breast cancer.

We investigated binding characteristics of basic fibroblast growth factor (bFGF) on membranes prepared from 4 human breast cancer cell lines and 38 primary BC biopsies. Competitive binding experiments were performed and analyzed using the "Ligand" program. Furthermore bFGF mitogenic activity was measured by [3H]thymidine incorporation into DNA from breast cancer cell lines. The presence of high-affinity binding sites was demonstrated in each cell type (MCF-7: Kd = 0.60 nM; T-47D: Kd = 0.55 nM; BT-20: Kd = 0.77 nM; MDA-MB-231: Kd = 0.34 nM). The presence of these high-affinity binding sites was confirmed with saturation experiments. A second class of low-affinity binding sites was detected in the 2 hormone-independent cells (BT-20: Kd = 2.9 nM; MDA-MB-231: Kd = 2.7 nM). bFGF stimulated the proliferation of MCF-7, T-47D, BT-20 but not MDA-MB-231 cell lines. With competition experiments, binding sites were detectable in 36/38 breast cancers; high-affinity binding sites (Kd less than 1 nM) were present in 19/36 cases and low-affinity binding sites (Kd greater than 2 nM) were present in 29/36 cases (the two classes of binding sites were present in 12 breast cancers). No relation between bFGF binding sites and node involvement, histologic type or grading of the tumor was evidenced. There were negative correlations (Spearman test) between total bFGF binding sites and estradiol receptor (P = 0.05) or progesterone receptor (P = 0.009). The demonstration of (1) bFGF specific binding sites in breast cancer membranes, and (2) bFGF growth stimulation of some breast cancer cell lines indicates that this factor may be involved directly in the growth of some breast cancers.     

CCAAT/Enhancer binding protein delta (c/EBPdelta) regulation and expression in human mammary epithelial cells: I. "Loss of function" alterations in the c/EBPdelta growth inhibitory pathway in breast cancer cell lines

"Loss of function" alterations in growth inhibitory signal transduction pathways are common in cancer cells. In this study, we show that growth arrest (GA) treatments--serum and growth factor withdrawal and growth inhibitory IL-6 family cytokines (Interleukin-6 and Oncostatin M (OSM))--increase STAT3 phosphorylation (pSTAT3), increase CCAAT enhancer binding protein delta (C/EBPdelta) gene expression and induce GA of primary, finite-lifespan human mammary epithelial cells (HMECs), and immortalized breast cell lines (MCF-10A and MCF-12A). In contrast, serum and growth factor withdrawal from human breast cancer cell lines (MCF-7, SK-BR-3, T-47D, and MDA-MB-231) for up to 48 h induced a relatively modest increase in pSTAT3 levels and C/EBPdelta gene expression and resulted in varying levels of GA. In most breast cancer cell lines, IL-6 family cytokine treatment increased pSTAT3 levels and C/EBPdelta gene expression, however, growth inhibition was cell line dependent. In addition to "loss of function" alterations in growth inhibitory pathways, breast cancer cell lines also exhibit "gain of function" alterations in growth signaling pathways. The Akt growth/ survival pathway is constitutively activated in T-47D and MCF-7 breast cancer cells. The Akt inhibitor LY 294,002 significantly enhanced T-47D growth inhibition by serum and growth factor withdrawal or IL-6 family cytokine treatment. Finally, we show that activation of the pSTAT3/C/EBPdelta growth control pathway is independent of estrogen receptor status. These results demonstrate that "loss of function" alterations in the pSTAT3/C/EBPdelta growth inhibitory signal transduction pathway are relatively common in human breast cancer cell lines. Defective activation of the pSTAT3/ C/EBPdelta growth inhibitory signal transduction pathway, in conjunction with constitutive activation of the Akt growth stimulatory pathway, may play a synergistic role in the etiology or progression of breast cancer.     

A breast-halving incision for subcutaneous mastectomy.

A new "breast-halving incision" for subcutaneous mastectomy is described. It has particular advantages in the large breast, where the incidence of complications is much higher. Its main disadvantage is the length of the incision, which runs across the equator of the breast. However, subcutaneous mastectomy is not primarily a cosmetic operation. The improved results in immediate reconstruction would seem to justify this approach.     

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."