Increased risk of breast cancer in women with false-positive test: The role of misclassification

IntroductionStudies have shown that women with a false-positive result from mammography screening have an excess risk for breast cancer compared with women who only have negative results. We aimed to assess the excess risk of cancer after a false-positive result excluding cases of misclassification, i.e. women who were actually false-negatives instead of false-positives.MethodWe used data from the Copenhagen Mammography Screening Programme, Denmark. The study population was the 295 women, out of 4743 recalled women from a total of 58,003 participants, with a false-positive test during the screening period 1991–2005 and who later developed breast cancer. Cancers that developed in the same location as the finding that initially caused the recall was studied in-depth in order to establish whether there had been misclassification.ResultsSeventy-two cases were found to be misclassified. When the women with misclassified tests had been excluded, there was an excess risk of breast cancer of 27% (RR = 1.27, 95% confidence interval (CI), 1.11–1.46) among the women with a false-positive test compared to women with only negative tests. Women with a false-positive test determined at assessment had an excess risk of 27%, while false-positives determined at surgery had an excess risk of 30%.ConclusionsThe results indicate that the increased risk is not explained only by misclassification. The excess risk remains for false-positives determined at assessment as well as at surgery, which favours some biological susceptibility. Further research into the true excess risk of false positives is warranted.     

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.     

Postoperative radiotherapy and late mortality: evidence from the Cancer Research Campaign trial for early breast cancer.

OBJECTIVE--To identify any excess mortality caused by adjuvant radiotherapy for early breast cancer. DESIGN--Prospective randomised clinical trial. Two thousand subjects needed for study to have a 90% chance of detecting a difference in survival rate of 7% with 95% significance. Patients were followed up until June 1988, giving follow up of 158-216 months. SETTING--A multicentre trial mainly drawing patients from centres in the United Kingdom. PATIENTS--2800 Women presenting with clinical stage I or II carcinoma of the breast from June 1970 to April 1975. INTERVENTIONS--One group of women (n = 1376) had simple mastectomy followed by immediate postoperative radiotherapy (1320 to 1510 rets). The remaining women (n = 1424) had simple mastectomy with subsequent careful observation of the axilla, radiotherapy being delayed until there was obvious progression or recurrence of disease locally. END POINT--Increased mortality in patients treated with radiotherapy from causes other than breast cancer. MEASUREMENTS AND MAIN RESULTS--Survival was measured from time of first treatment to death or last follow up. Deaths from any cause and from specified causes were counted as events. Comparison over the whole follow up showed a slight excess mortality in the group treated with radiotherapy (relative risk 1.04; 95% confidence interval 0.94 to 1.15). The relative risk of death from breast cancer was 0.97 (0.87 to 1.08) but that of death from other causes was 1.37 (1.09 to 1.72), the increase mainly being in women who had had tumours of the left breast (1.61 (1.17 to 2.24)) and had been treated with orthovoltage (1.85 (1.27 to 2.71)). Analysis of causes of death after five years showed a relative risk of 2.11 (1.25 to 3.59) for new malignancies and of 1.65 (1.05 to 2.58) for cardiac disease, the increase in cardiac mortality being most pronounced in patients who had had tumours of the left breast and whose treatment had included orthovoltage radiation (relative risk 2.67 (1.28 to 5.55)). CONCLUSIONS--Adjuvant radiotherapy after simple mastectomy for early breast cancer produces a small excess late mortality from other cancers and cardiac disease. The risk has to be balanced against the higher risk of local recurrence when immediate postoperative radiotherapy is not given. The balance has to be assessed for each patient, and for many patients radiotherapy will still be desirable in the initial treatment of their early breast cancer.     

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.     

Reproductive events and family history as risk factors for breast cancer in northern Alberta.

Reproductive events and family history as risk factors for breast cancer in northern Alberta were investigated with the use of data from a computerized population-based registry. Women aged 30 to 79 years attending diagnostic breast clinics at the Cross Cancer Institute from 1971 through 1975 constituted the two study groups; 1232 women had diagnosed breast cancer (malignant disease group) and 602 women were clinically free of all types of breast disease (control group). An increased relative risk of breast cancer was found in women with a family history of breast cancer, those who gave birth to their first term infant at age 30 years or older, those in whom more than 15 years elapsed between menarche and that birth, and those with a late natural menopause. There was a decreased risk, relative to nulliparity, in the postmenopausal women who first gave birth to a term infant 5 years or less after menarche. Artificial menopause (bilateral oophorectomy), parity and age at menarche had no apparent effect on the risk. The pattern of risk factors in northern Alberta differed from that reported for other geographic areas, including other provinces of Canada, thus emphasizing the need for local studies in the planning of screening programs.     

Bilateral breast cancer in northern Alberta: risk factors and survival patterns.

Of 2231 women with stage I, II or III breast cancer who were registered and seen between 1971 and 1979 and followed to the end of 1981, 48 (2.2%) had synchronous and 58 (2.6%) asynchronous bilateral breast cancer. The unadjusted incidence rate for a second breast cancer was 6.4/1000 breast-years at risk, compared with a rate of 0.70 for the risk of a first breast cancer in women. When calculated from the date of diagnosis of the first breast cancer the survival rate was better for the group with asynchronous disease than for the group with synchronous disease or for a group with unilateral disease, but when calculated from the date of diagnosis of the second cancer the rate was the same in all three groups. Comparison of known risk factors showed a significant association between the development of bilateral cancer and a later age at the birth of the first child and a longer interval between menarche and that birth. There was a trend towards greater age and more stage III cancer in the group with synchronous disease. There was no correlation between receiving radiotherapy for the first breast cancer and development of the second cancer. Annual mammography and clinical examination of asymptomatic women at a cancer centre resulted in the detection of a significantly higher proportion of minimal breast cancers in the second breast compared with the first. Such screening practices should be even more valuable in the earlier detection of unilateral breast cancer in asymptomatic women who have not had breast cancer.     

Long-term survival of patients with breast cancer: a study of the curability of the disease.

A retrospective analysis was made of 3878 cases of breast carcinoma first seen in Edinburgh from 1954 to 1964. During this time there was a policy to treat breast cancer by simple mastectomy and x-ray therapy, and over 90% of cases classified as international stages I and II were so treated. The mortality in these women was compared with that in an equivalent normal population using Scottish national age-specific death rates. For every year of follow-up within 20 years of initial treatment there was an excess mortality from all causes. There was an overall excess mortality of 58% among patients with breast cancer 15-20 years after initial treatment, and 20 times more deaths occurred in this period from breast cancer than in a normal population. For patients disease-free after 15 years there was still a 28% excess mortality from all causes. Factors known to be of major prognostic significance for five-year survivorship had less influence than might have been expected when the ratio of observed to expected deaths was considered for longer periods of follow-up. The effect of clinical staging (I, II, or III), though initially marked, largely disappeared by the 10th year of follow-up, and after allowing for age there was no evidence beyond 10 years of an effect on survival of the original stage of the disease. Similarly, the effect of tumour size on survival disappeared after 10 years. Women who were premenopausal at presentation still had a significant excess of deaths in the fourth quinquennium of follow-up. In the menopausal and postmenopausal groups combined there was still a small non-significant excess of deaths from all causes after 15 years but this almost disappeared when patients who had already relapsed were excluded. In terms of overall mortality only patients who have undergone the menopause before presentation and who are disease-free 15 years after primary treatment may prove to be cured by conventional techniques such as simple mastectomy and postoperative radiotherapy.     

Depot medroxyprogesterone (Depo-Provera) and risk of breast cancer.

OBJECTIVE--To determine whether use of the injectable contraceptive depot medroxyprogesterone acetate (Depo-Provera) affects the risk of breast cancer in women. DESIGN--A population based case-control study. SETTING--Nationwide community study. SUBJECTS--891 Women aged 25-54 with newly diagnosed breast cancer were compared with 1864 women selected at random from the electoral rolls. INTERVENTION--Women were interviewed by telephone about past use of contraceptives and about possible risk factors for breast cancer. MAIN OUTCOME MEASURE--Relative risk of breast cancer in women who had used medroxyprogesterone. RESULTS--Medroxyprogesterone had been used by 110 patients and 252 controls. Overall, the relative risk of breast cancer associated with any duration of use was 1.0 (95% confidence interval 0.80 to 1.3). In women aged 25-34 the relative risk was 2.0 (1.0 to 3.8). The relative risk was highest in women aged 25-34 who had used the drug for six years or longer, although there were few women in this category. Women who had used it for two years or longer before age 25 had an increased risk of breast cancer (relative risk 4.6; 1.4 to 15.1). CONCLUSION--Despite the lack of an overall association these findings suggest that medroxyprogesterone may increase the risk of breast cancer in young women.     

Risk of connective tissue disease and related disorders among women with breast implants: a nation-wide retrospective cohort study in Sweden.

OBJECTIVE: To examine the relation between connective tissue disease and related conditions and breast implants. DESIGN: Retrospective cohort study of all women in the Swedish national inpatient registry who underwent breast augmentation surgery with artificial implants during 1964-93, compared with women who underwent breast reduction surgery during the same period. SETTING: Sweden. SUBJECTS: 7442 women with implants for cosmetic reasons or for reconstruction after breast cancer surgery and 3353 women with breast reduction surgery. MAIN OUTCOME MEASURES: Subsequent hospitalisation for definite connective tissue diseases (rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, dermatomyositis, and Sjögren''s syndrome) or related disorders. RESULTS: 29 women with implants were hospitalised for definite connective tissue disease compared with 25.5 expected based on general population rates (standardised hospitalisation ratio 1.1 (95% confidence interval 0.8 to 1.6)). There were no diagnoses of systemic sclerosis, and no significant excess in risk for polymyalgia rheumatica, fibromyalgia, and several related disorders. Among women who underwent breast reduction surgery, 14 were hospitalised for definite connective tissue disease compared with 10.5 expected (standardised hospitalisation ratio 1.3 (0.7 to 2.2)). Compared with the breast reduction group, women with breast implants showed a slight reduction for all definite connective tissue disease (relative risk 0.8 (95% confidence interval 0.5 to 1.4)). CONCLUSIONS: This large nationwide cohort study shows no evidence of association between breast implants and connective tissue disease.     

Frequent chest X-ray fluoroscopy and breast cancer incidence among tuberculosis patients in Massachusetts

The incidence of breast cancer was determined in 4940 women treated for tuberculosis between 1925 and 1954 in Massachusetts. Among 2573 women examined by X-ray fluoroscopy an average of 88 times during lung collapse therapy and followed for an average of 30 years, 147 breast cancers occurred in contrast to 113.6 expected [observed/expected (O/E) = 1.29; 95% confidence interval (CI) = 1.1-1.5]. No excess of breast cancer was seen among 2367 women treated by other means: 87 observed versus 100.9 expected. Increased rates for breast cancer were not apparent until about 10 to 15 years after the initial fluoroscopy examination. Excess risk then remained high throughout all intervals of follow-up, up to 50 years after first exposure. Age at exposure strongly influenced the risk of radiation-induced breast cancer with young women being at highest risk and those over age 40 being at lowest risk [relative risk (RR) = 1.06]. Mean radiation dose to the breast was estimated to be 79 cGy, and there was strong evidence for a linear relationship between dose and breast cancer risk. Allowing for a 10-year minimum latent period, the relative risk at 1 Gy was estimated as 1.61 and the absolute excess as 10.7 per 10(4) woman-years per gray. When compared to other studies, our data suggest that the breast is one of the most sensitive tissues to the carcinogenic force of radiation, that fractionated exposures are similar to single exposures of the same total dose in their ability to induce breast cancer, that risk remains high for many years after exposure, and that young women are especially vulnerable to radiation injury.     

Multiple fluoroscopy of the chest: carcinogenicity for the female breast and implications for breast cancer screening programs.

The risk of radiation carcinogenesis has been established for breast tissue from experience with total body irradiation and multiple fluoroscopy of the chest with the patient prone. The doubling dose has been estimated to lie between 20 and 50 rads. Before undertaking radiologic screening programs for breast cancer, therefore, it is necessary to determine whether exposures below this range are safe. Of 792 women who had had tuberculosis and were followed for a minimum of 20 years, 451 had had multiple fluoroscopy while supine; 341 had not had fluoroscopy. The first group received a total radiation dose to the breast averaging 17 rads (141.5 fluoroscopies); the incidence of breast cancer in this group was not increased. Had fluoroscopy been performed with the patient prone the total radiation dose would have averaged 308 rads. The difference is thought to explain the increased incidence of breast cancer attributable to fluoroscopy given with the patient prone. Mid-breast exposure with mammography or xeroradiography varies between 3 and 6 rads. Repetitive screening would, therefore, appear safe provided total exposure did not exceed 20 rads. With this restriction there would appear to be no reason to curtail screening of women for breast cancer.     

Are infertility treatments a potential risk factor for cancer development? Perspective of 30 years of follow-up

The aim of the present study was to evaluate the possible risk for cancer development in infertile women with over 30 years of follow-up. Cancer development was assessed through linkage with the National Cancer Registry updated to 31 December 2005 in a cohort of 2431 women who were treated for infertility at the Sheba Medical Center in Israel during the period 1964-1974 and contributed more than 84,000 women years of follow-up. Standardized incidence ratios (SIR) were calculated between the observed cancer cases and the expected cancer rates in the general population. The mean age at the end of follow-up was 62.7 years. Eighteen cases of ovarian cancer were observed as compared to 18.1 expected (SIR = 1.0; 95% CI = 0.59-1.57). For breast cancer, 153 cases were observed as compared to 131.9 expected (SIR = 1.16; 95% CI = 0.98-1.36), and for endometrial cancer, 30 cases were observed as compared to 17.8 expected cases (SIR = 1.69; 95% CI = 1.14-2.41). No excess risk associated with exposure to gonadotropins was observed. Infertility was found to be associated with significant increased risk for endometrial cancer and borderline increased risk for breast cancer. Ovarian cancer risk was not found to be elevated. No significant excess risk was associated with treatment with ovulation induction.     

Risk factors for breast cancer in women biopsied for benign breast disease: A nested case-control study

Aim: Women with a history of benign breast disease are at increased risk of subsequent breast cancer. However, few studies have examined whether established breast cancer risk factors other than histology are associated with an altered risk of breast cancer in women with benign breast disease. We used a nested case-control design within a large, multi-center cohort of women biopsied for benign breast disease (BBD) to estimate odds ratios for breast cancer in association with exposure to a range of personal and lifestyle factors. Methods: Cases were women biopsied for BBD who subsequently developed breast cancer; controls were individually matched to cases on center and age at diagnosis and were women biopsied for BBD who did not develop breast cancer in the same follow-up interval as that for the cases. After excluding women with prevalent breast cancer, 1357 records (661 case records and 696 records) were available for analysis. We used conditional logistic regression to obtain crude and multivariable-adjusted estimates of the association between specific factors and risk of breast cancer. Results: In multivariable analyses age at first live birth, number of pregnancies, and postmenopausal status were inversely associated with risk of breast cancer. The odds ratio for women with age at first birth <25 years and ≥3 pregnancies, relative to nulliparous women, was 0.49, 95% confidence interval 0.13–0.79, and that for postmenopausal women relative to premenopausal women was 0.60, 95% CI 0.37–0.99. Conclusions: Further study of personal factors influencing the risk of breast cancer in women with BBD may help to identify subgroups of the population at increased risk of invasive disease.     

Obesity is associated with atypia in breast ductal lavage of women with proliferative breast disease

Background: Benign proliferative breast disease without atypia slightly increases breast cancer risk but there are currently few clinical options for breast cancer prevention in this group of women. Methods: We conducted a pilot study of women with a past diagnosis of proliferative breast disease with a goal to determine if the characteristics of cells obtained by breast ductal lavage were related to nutritional factors. Results: There were 57 women who enrolled. A total of 39 women yielded nipple aspirate fluid (NAF) samples and 36 underwent breast ductal lavage. Five of the lavage samples were acellular and 28 had at least 200 cells. Surprisingly, atypia was present in 11 women. Presence of atypia was associated with slight changes in morphometric features of the epithelial cells such as measures of circularity as obtained by image analysis, but the only variable significantly different in women with atypia (versus no atypia) was a higher mean body mass index. Body mass index was also significantly correlated with C-reactive protein (CRP) levels in the nipple aspirate fluid, indicating that obesity might have a pro-inflammatory effect on the breast that can contribute to increased rates of atypia. Conclusions: Although the clinical significance of atypia in breast ductal lavage is uncertain, these results support further work on prevention of obesity as a strategy for reducing breast cancer risk.     

Parity and breast cancer.

Data from the 1961 and 1971 Censuses in England and Wales were used to estimate the age distribution of women of various parities in 1976. Applying the age-specific incidences of breast cancer for women in England and Wales in 1975 gave the expected number of cases of that disease in 1976 and permitted an estimate of the mean age at diagnosis of breast cancer at each parity. This showed that the highest average age for breast cancer occurred in nulliparous women (65.9 years) and that the lowest age for the disease occurred in women who had borne two children (60.4 years). The figures obtained were similar to those reported in a separate study of women treated in Birmingham. The results of that study, however, may have been due to the age distribution in the population of women by parity, rather than any direct influence of parity on the speed of growth of breast cancer.     

Stressful life experiences and risk of relapse of breast cancer: observational cohort study

ObjectiveTo confirm, using an observational cohort design, the relation between severely stressful life experiences and relapse of breast cancer found in a previous case-control study.DesignProspective follow up for five years of a cohort of women newly diagnosed as having breast cancer, collecting data on stressful life experiences, depression, and biological prognostic factors.SettingNHS breast clinic, London; 1991-9.ParticipantsA consecutive series of women aged under 60 newly diagnosed as having a primary operable breast tumour. 202/222 (91%) eligible women participated in the first life experiences interview. 170 (77%) provided complete interview data either up to 5 years after diagnosis or to recurrence.ResultsWe controlled for biological prognostic factors (lymph node infiltration and tumour histology), and found no increased risk of recurrence in women who had had one or more severely stressful life experiences in the year before diagnosis compared with women who did not (hazard ratio 1.01, 95% confidence interval 0.58 to 1.74, P=0.99). Women who had had one or more severely stressful life experiences in the 5 years after diagnosis had a lower risk of recurrence (0.52, 0.29 to 0.95, P=0.03) than those who did not.ConclusionThese data do not confirm an earlier finding from a case-control study that severely stressful life experiences increase the risk of recurrence of breast cancer. Differences in case control and prospective methods may explain the contradictory results. We took the prospective study as the more robust, and the results suggest that women with breast cancer need not fear that stressful experiences will precipitate the return of their disease.

What is already known on this topic

Women with apparently similar tumours at the time of presentation with breast cancer differ considerably in their disease-free survival and overall survivalSuch differences in outcome may well be explained by host and environmental factors, which could include psychological and social variablesData on the relation between severely stressful life experiences and cancer progression have been contradictory

What this study adds

Women who have a severely stressful life experience in the year before being diagnosed with breast cancer, or in the five years afterwards, do not seem to be at increased risk of developing a recurrence of the diseaseWomen with breast cancer need not fear that stressful experiences will precipitate the return of their disease.     

Breast cancer risk and the interaction between adolescent body size and weight gain in later life: A case-control study

BackgroundWhile the breast cancer risk associated with increasing adult BMI in postmenopausal women can be explained by increases in concentrations of endogenous estrogens the biologic mechanisms behind the inverse association between adolescent BMI and breast cancer risk are still a subject of controversial debate.MethodsWe investigated the association of breast cancer with body size and changes in body size across life time estimated by age-specific BMI Z scores and changes in BMI Z scores from teenage years to middle age in an age-matched population-based case-control study of 2994 Australian women. Logistic regression adjusted for the matching factor age and further potential confounders was used.ResultsAdolescent body leanness in postmenopausal women and excess adult weight gain in all study participants were associated with an increased breast cancer risk with an odds ratio [95% confidence interval] of 1.29 [1.08,1.54] and 1.31 [1.09,1.59], respectively. Interaction analyses restricted to postmenopausal women revealed an increased risk of breast cancer in those who were lean during adolescence and gained excess weight during adulthood (odds ratio [95% confidence interval]: 1.52 [1.19,1.95]) but not in women who were lean during adolescence and did not gain excess weight during adulthood (1.20 [0.97,1.48]) and not in women who were not lean during adolescence and but gained excess weight during adulthood (1.10 [0.95,1.27]) compared to postmenopausal women who were neither lean during adolescence nor gained excess weight.ConclusionIn postmenopausal women adolescent leanness was only associated with increased breast cancer risk when excess weight was gained during adulthood.     

Management of women at increased risk for breast cancer: preliminary results from a new program

OBJECTIVE: To examine the characteristics of malignant tumours that develop in women undergoing surveillance for increased risk for breast cancer and to identify presentation patterns in order to determine the respective roles of mammography, clinical breast examination (CBE) and breast self-examination (BSE). SETTING: Breast Diagnostic Clinic and Familial Breast Cancer Clinic at Toronto-Sunnybrook Regional Cancer Centre. PARTICIPANTS: A total of 1044 women evaluated for breast cancer risk from Oct. 1, 1990, to Dec. 31, 1996, of whom 381 were categorized as being at high risk, 204 as being at moderate risk, 401 as being at slightly increased risk and 58 as being at no appreciably increased risk. PROGRAM COMPONENTS: Comprehensive review and discussion of risk factors, clinical assessment, surveillance recommendations that include mammography, CBE and BSE, genetics consultation (Familial Breast Cancer Clinic) and psychosocial support. Data are captured prospectively, updated at each visit and audited every 3 to 6 months. PROGRAM OUTCOMES: During the study period breast cancer was diagnosed in 24 patients, 12 in the high-risk group, 4 in the moderate-risk group and 8 in the group at slightly increased risk. The mean age at diagnosis was 47 (range 32 to 82) years. Ten cases of cancer were diagnosed during surveillance (incident cancer), 5 in women under age 50. The mean length of time from initial assessment to diagnosis was 28.6 (range 12 to 51) months. Of the 24 women, 17 reported a family history of breast cancer. The mean age at diagnosis in this cohort was 45.5 years, and the diagnosis was made under age 50 in 10 patients (59%). The mean earliest age at which breast cancer was diagnosed in a family member was 42.5 years. CONCLUSIONS: These preliminary results suggest that surveillance of women at increased risk for breast cancer may be useful in detecting disease at an early stage. The regular performance of mammography, CBE and BSE appears necessary to achieve these results.     

Quantitative analysis of promoter methylation in exfoliated epithelial cells isolated from breast milk of healthy women

Promoter methylation analysis of genes frequently silenced in breast cancer is a promising indicator of breast cancer risk, as these methylation events are thought to occur long before presentation of disease. The numerous exfoliated epithelial cells present in breast milk may provide the breast epithelial DNA needed for detailed methylation analysis and assessment of breast cancer risk. Fresh breast milk samples and health, lifestyle and reproductive history questionnaires were collected from 111 women. Pyrosequencing analysis was conducted on DNA isolated from the exfoliated epithelial cells immunomagnetically separated from the total cell population in the breast milk of 102 women. A total of 65 CpG sites were examined in six tumor suppressor genes: PYCARD (also known as ASC or TMS1), CDH1, GSTP1, RBP1 (also known as CRBP1), SFRP1 and RASSF1. A sufficient quantity of DNA was obtained for meaningful analysis of promoter methylation; women donated an average of 86 ml of milk with a mean yield of 32,700 epithelial cells per ml. Methylation scores were in general low as expected of benign tissue, but analysis of outlier methylation scores revealed a significant relationship between breast cancer risk, as indicated by previous biopsy and methylation score, for several CpG sites in CDH1, GSTP1, SFRP1 and RBP1. Methylation of RASS F1 was positively correlated with women''s age irrespective of her reproductive history. Promoter methylation patterns in DNA from breast milk epithelial cells can likely be used to assess breast cancer risk. Additional studies of women at high breast cancer risk are warranted.Key words: biomarker, pyrosequencing, promoter methylation, breast epithelial cells, breast milk, breast cancer risk, parity, age-related promoter methylation, pregnancy-associated protection from breast cancer     

Breast cancer found at the time of breast reduction.

In a recent study involving 27,500 women who had breast reduction surgery in Ontario, Canada, 17 women who were diagnosed as having breast cancer at the time of their breast reduction surgery were identified. The aims of this study were to (1) describe a population-based series of patients who had breast cancer diagnosed at the time of breast reduction, (2) describe the treatment of these cancers, and (3) compare their survival rate with survival in patients in the general population who had breast cancer. Information about these women, their treatment, and outcome was extracted from hospital records, pathology reports, and reports from regional cancer centers. The chance of finding an invasive breast cancer at the time of breast reduction was 0.06 percent, which is lower than what has been reported previously. Sixty-seven percent of these women were treated with total mastectomy. In the remaining 33 percent, who were treated with partial mastectomy, the entire tumor was removed at the time of breast reduction. Fifty percent of the women were treated with radiation, and 25 percent were treated with chemotherapy or hormonal therapy. Compared with women in the general population of Ontario who have breast cancer, women whose breast cancer is discovered during breast reduction surgery are more likely to be treated with complete mastectomy and less likely to be treated with radiotherapy or chemotherapy. Seventy-one percent of the breast reduction group were axillary node-negative at diagnosis, compared with 58 percent in the general population of women with breast cancer. Survival from breast cancer in women diagnosed at the time of breast reduction (88 percent, 5-year survival) was better than survival from breast cancer in the general population (77 percent). These findings suggest that cancers found in women at the time of breast reduction are less advanced, possibly because they are diagnosed at an earlier stage.