Subsequent Development Of Breast Cancer Research Articles

Adherence to recommendations for clinical follow-up after benign breast biopsy.

Women who undergo a benign breast biopsy are at elevated risk for the subsequent development of breast cancer (BC). Therefore, appropriate clinical follow-up of a benign breast biopsy is important. The present study examines the extent and correlates of nonadherence with follow-up recommendations after a benign breast biopsy. Women (n = 114) who had undergone a benign breast biopsy completed an initial telephone interview within 50 days of their biopsy (mean = 21 days). Additional telephone interviews were completed at 4 and 8 months post-biopsy. Measures of BC risk perception, general and BC-specific distress, BC-related attitudes and beliefs, social support, optimism, and informational coping style were completed. Specific recommendations for clinical follow-up and evidence of actual follow-up were obtained from medical records. Of 103 women given a specific recommendation for clinical follow-up, 34% were classified as nonadherent with follow-up recommendations. Logistic regression analyses indicated that nonadherent women were characterized by younger age, recommendations for follow-up by clinical breast examination alone, greater confidence in their ability to perform breast self-examination properly, higher perceived personal risk for BC, and greater BC-specific distress. Despite the importance of appropriate clinical follow-up of a benign breast biopsy, about one-third of women did not adhere to recommended follow-up. Risk factors for nonadherence suggest potential avenues for interventions to enhance participation in appropriate clinical follow-up.

Cyclin D1 protein overexpression and gene amplification in benign breast tissue and breast cancer risk.

Cyclin D1 amplification and/or protein overexpression have been observed not only in breast cancer but also in the putative early stages of breast neoplasia. In a case-control study nested within a cohort of 4888 women, we investigated whether the occurrence of cyclin D1 gene amplification and/or protein overexpression in benign breast tissue might identify women at increased risk of subsequent breast cancer development. Cases were 92 women with a histological diagnosis of benign breast disease who subsequently developed breast cancer. Five controls (women with benign breast disease who had not developed breast cancer by the date of diagnosis of the corresponding case) were selected randomly for each case from those non-cases available within strata defined by screening centre, National Breast Screening Study (NBSS) study arm, year of birth and age at diagnosis of benign breast disease. Paraffin blocks of benign tissue were suitable for immunostaining for 71 cases and 293 controls. Sufficient DNA for analysis was obtained from a total of 356 subjects (69 cases, 287 controls). The benign breast tissues and breast cancers were immunostained for cyclin D1 and also analysed for the presence of cyclin D1 gene amplification by differential polymerase chain reaction (PCR). Fifteen cases and 60 controls showed evidence of cyclin D1 immunostaining, and 12 cases and 29 controls showed cyclin DL gene amplification. There was essentially no association between cyclin D1 protein overexpression in benign breast tissue and risk of subsequent breast cancer (adjusted odds ratio (OR) 1.06; 95% confidence interval (CI) 0.56-2.02). After adjustment for potential confounding, there was a statistically non-significant 40% increase in risk of breast cancer in association with cyclin D1 gene amplification (adjusted OR 1.41; 95% CI 0.62-3.22). As multiple genetic changes are required to develop breast cancer, it may not be until the cascade of molecular alterations leading to breast cancer development is understood that identification of biomarkers of breast cancer risk will be possible.

Prognostic value of morphometry in patients with normal breast tissue or usual ductal hyperplasia of the breast.

Women with usual ductal hyperplasia have a relative risk of 1.6-1.9 of subsequent breast cancer development. This slightly increased risk is generally not considered sufficiently high to justify (chemo)preventive therapy. It is therefore important to identify high-risk ductal hyperplastic lesions that would benefit from such a treatment. Nuclear morphometric features have been shown in previous work to be useful for objectively describing morphologic features associated with high risk in (pre)invasive breast lesions. The aim of this study was to evaluate whether such morphometric features can also predict subsequent invasive cancer development in patients with the common pattern of usual ductal hyperplasia or a normal breast biopsy. The present case-control study included 423 women with normal breast biopsies (n = 89) or biopsies containing usual ductal hyperplasia (n = 334). Of these 423 women, 132 developed invasive breast cancer during follow-up (mean 16.7 +/- 7.0 years). On the original hematoxylin and eosin-stained sections, nuclear morphometry was performed with a digitizing video overlay system, and mitotic and apoptotic indices were assessed. Patients with mean nuclear feature values for area, perimeter, diameter or longest axis above the 75th percentile had 1.6-1.7 times the breast cancer risk of women with mean nuclear feature values below this value. Pairwise combinations of these features yielded slightly higher cancer risks for the fourth quartile patients, with the highest risk (1.9) for patients with SD of nuclear area and perimeter values above the 75th percentile. The number of apoptotic or mitotic cells had no prognostic value for patients with apparently normal tissue or usual ductal hyperplasia. Our results give a first indication that normal breast tissue or usual ductal hyperplasia harbor nuclear morphologic changes that, when assessed by morphometry, may be used to predict breast cancer development. It is worthwhile studying this further in independent groups of patients with long-term follow-up.

In situ breast cancer.

The clinical expression of in situ cancer varies widely but is usually occult. Diagnosis can be made by a variety of minimally invasive techniques. Treatment of lobular carcinoma in situ (LCIS) is patient-directed but generally requires only close follow-up. Mastectomy is the gold standard for ductal carcinoma in situ (DCIS) and is associated with low recurrence rates. Breast conservation therapy (BCT) has become an acceptable alternative. This choice of definitive therapy for DCIS depends largely on the ability to obtain negative margins. Any attempt at BCT should be coupled with the caveat of close postoperative long-term follow-up. Patients diagnosed with LCIS or who have a history of DCIS should be given the options for the use of tamoxifen for the reduction of subsequent development of invasive breast cancer. Risk versus benefits should be clearly defined.

Breast cancer chemoprevention trials using the fine-needle aspiration model

Selection of surrogate endpoint biomarkers (SEBs) and appropriate study design are two of the main challenges in evaluating potential chemopreventive agents. In a prospective random fine-needle aspiration (FNA) study of women at high risk of development of breast cancer, we previously demonstrated that cytologic evidence of epithelial hyperplasia with or without atypia, as well as abnormalities of several cellular biomarkers (DNA ploidy; immunocytochemical expression of p53, EGFR, ER, and/or Her-2/neu), were more prevalent in high-risk women than in low-risk controls. We also demonstrated that the subsequent development of breast cancer was best predicted by an initial presentation of hyperplasia with atypia, as well as by multiple biomarker abnormalities. These findings indicate that FNA cytology and biomarkers can be used to identify women who are appropriate subjects for chemoprevention trials, and can then be used as surrogate endpoint biomarkers to monitor efficacy of potential agents. An example of this use in an ongoing single-agent phase II trial is provided. Several options for study design of possible multi-agent breast cancer chemoprevention trials are discussed, depending upon the existing preclinical and clinical data, the questions being asked, and the number of eligible subjects available.

Breast cancer: Genetic predisposition and exposure to radiation

The identification of breast cancer susceptibility genes, such as BRCA1, BRCA2, ATM, and p53, has been accompanied by the examination of the effects of radiation in combination with genetic mutations at these loci. Women at high risk for developing breast cancer may respond differently than the general population to low- and high-dose radiation exposures associated with screening and treatment. Epidemiologic studies are being performed to investigate the effects of radiation on subsequent breast cancer development in genetically predisposed individuals. Mouse strains with specific genetic modifications are being created to study the consequence of both inherited mutations and radiation on mammary gland carcinogenesis. Finally, studies investigating DNA damage-response pathways after radiation exposure are being performed. Recent work on the effects of several known or suspected breast cancer susceptibility genes, alone or in combination with radiation, is presented here, and directions for future research are considered.

Hormone replacement therapy and breast cancer risk in a nationally representative cohort

Background: The relative risk of breast cancer associated with the use of postmenopausal hormone replacement therapy (HRT) continues to be debated. We used a nationally representative cohort to study the issue. Methods: This analysis utilized data from the NHANES I Epidemiologic Follow-up Study. Subjects were interviewed in 1971 through 1974 and four waves of follow-up interviews were conducted through 1992. Survival analysis of 5761 postmenopausal women provided estimates of the relative risk of breast cancer in users of HRT when compared with non-users, controlling for potential confounders. Results: There were 219 incident cases of breast cancer in 73,253 person-years of follow-up. The incidence rate was 326 per 100,000 person-years in women who had never used HRT and 255 per 100,000 in women who had ever used HRT. There was no statistically significant association between the HRT use and subsequent development of breast cancer: relative risk (RR) = 0.8, 95% confidence interval 0.6, 1.1. There was no trend in RR by length of HRT use: less than 3 years HRT use, RR = 0.9; 3 to 9 years , RR = 0.5; 10 or more years, RR = 0.8. Conclusions: This study, based on a nationally representative cohort followed for up to 22 years, failed to find an increased risk of breast cancer associated with the use of HRT. It provides further evidence that if there is an increased risk of breast cancer associated with HRT use, this risk is small.

Loss of Heterozygosity at 3p in Benign Lesions Preceding Invasive Breast Cancer

Background.Loss of heterozygosity (LOH) at chromosome 3p is one of the most common genetic abnormalities identified in human cancers and has occasionally been noted in benign proliferative lesions predisposing to breast cancer. If the frequency of LOH at 3p in benign proliferative lesions correlates with the subsequent development of breast cancer, it may be possible to develop powerful tools for molecular risk assessment based on this technology.Materials and methods.Archival paraffin-embedded tissues from benign breast biopsies in five women who have developed breast cancer and three women who have not developed breast cancer were microdissected and allelotyped at 3p using six microsatellite markers.Results.No LOH was detected in the biopsies from women who have not developed breast cancer. For women developing breast cancer, the proportion of informative loci showing LOH in the benign proliferative lesions was 0.47 as compared to 0.57 for the associated breast cancers. There was no LOH detected in epithelial DNA from a fibroadenoma. Of 15 informative loci, 4 (27%) showed LOH in both the benign proliferative lesion and the associated cancer; however, the actual parental allele lost was different in three of these four cases.Conclusions.These results suggest that there are specific patterns of genetic instability common to preneoplastic lesions and the breast cancers that subsequently develop even when the paired lesions are not clonally related. LOH analysis of benign breast epithelium may provide a tool for molecular risk assessment and a surrogate endpoint for breast cancer chemoprevention trials.

Prospective assessment of breastfeeding and breast cancer incidence among 89 887 women

SummaryBackground The relation between breastfeeding and breast-cancer risk has been examined in many studies; some have reported no association, and others a reduced risk, particularly among premenopausal women. In the only prospective cohort study, no association was found. We have assessed prospectively the association between breastfeeding and incidence of breast cancer among 89887 women in the US Nurses' Health Study.Methods In 1986, participants were asked about the number of months they breastfed for all their children combined. Parous women with no history of cancer were included in this analysis. During 6 years of follow-up (513015 person-years), 1459 invasive breast cancer cases were diagnosed.Findings Relative to women who had never breastfed, no significant overall association was found—after adjusting for established risk factors for breast cancer—between a history of having breastfed and subsequent development of breast cancer (relative risk [RR] 0·93, 95% Cl 0·83-1·03). No inverse trend was observed with duration of breastfeeding; women who breastfed for 2 years or longer had a RR of 1·11 (0·90-1·38). Among women who had given birth only once, women who had breastfed their child experienced a lower incidence of breast cancer (RR 0·68, 0·46-1·00). Among premenopausal women, who tended to be near menopause due to the age structure of the cohort, the RR of breast cancer for those who had lactated was 1·16 (0·89-1·50). Premenopausal women who had lactated for 1 year or more had a RR of 1·10 (0·78-1·57).Interpretation These data suggest that there is no important overall association between breast-feeding and the occurrence of breast cancer.

MICROVESSEL QUANTIFICATION AS A MEASURE OF ANGIOGENIC ACTIVITY IN BENIGN BREAST-TISSUE LESIONS - A MARKER FOR PRECANCEROUS DISEASE

Neovascularization is a key step in the transformation of normal breast tissue into a cancerous phenotype. We investigated the angiogenic activity of 58 cases of histologically confirmed benign breast lesions quantitating angiogenic activity by factor VIII highlighting of endothelial cells. The mean microvessel count (MVC) for all patients was 51 per 0.19 mm(2) in the area of highest angiogenic activity at x400 magnification (range 21-113 per mm(2)). MVC in benign tissues were similar to those found previously in cancer tissues. These data suggest that the 'angiogenic switch' occurs early in breast transformation and that a role may exist for the use of MVC in the identification of persons at heightened risk for subsequent development of breast cancer.

Multiple births and risk of breast cancer

Data from a large, multicenter, population-based case-control study were analyzed to investigate the relation between multiple birth pregnancies and subsequent breast-cancer risk in the gravidas. Women less than 75 years old who had breast cancer were identified from statewide tumor registries in Wisconsin, western Massachusetts, Maine and New Hampshire. Controls aged less than 65 years were selected randomly from lists of licensed drivers, and controls aged between 65 and 74 were selected randomly from lists of Medicare beneficiaries. Information on reproductive history and other factors was obtained by means of telephone interviews. After excluding nulliparous women, 5,880 case subjects and 8,217 controls remained for analysis. Multiple birth pregnancies occurred in 146 cases and 218 controls. Adjusted for the number of full-term pregnancies and other confounders, the odds ratio (OR) for any multiple birth pregnancy was 0.94 (95% confidence interval, 0.75 to 1.17). The null association between multiple birth pregnancies and breast cancer remained if the mother's first pregnancy or last pregnancy resulted in a multiple birth. In addition, no trend in risk emerged for age at first multiple birth or time since last multiple birth. While other investigators have suggested biological mechanisms to explain both protective and detrimental effects of multiple births and subsequent development of breast cancer, this study does not support either assertion.

Cytomorphology of Fibrocystic Change, High-Risk, and Premalignant Breast Lesions

: Fine-needle aspiration biopsy has proven to be an accurate and well-tolerated procedure with a reported specificity of 99% and sensitivity of 70–99%. Similarly, nonpalpable breast lesions can be effectively sampled by needle biopsies under radiologic guidance. Breast aspirates have also been extensively utilized for assessment of nuclear grade, hormone receptor status, ploidy status, and proliferation rate, and have proven to be an attractive alternative to surgical biopsy. Using strict cytologic criteria, it may also be possible to recognize the cytomorphologic changes in breast lesions that are associated with increased risk for subsequent development of breast cancer. Presence of myoepithelial cells within the clusters of atypical epithelial cells recognized morphologically and/or detected by immunostaining for muscle specific actin is an important diagnostic feature of proliferative breast disease with atypia (atypical hyperplasia). This recognition has significant clinical implications and is important in the design of chemoprevention trials. The cytologic distinction between carcinoma in situ and invasive breast cancer remains difficult.

Epidemiologic and genetic follo‐up study of 544 Minnesota breast cancer families: Design and methods

AbstractIn 1944, a case‐control family study was initiated at the Dight Institute for Human Genetics at the University of Minnesota to study the influences of childbearing, breastfeeding, and hereditary susceptibility on the occurrence and age‐of‐onset of breast cancer. Index cases (probands) were women ascertained at the Tumor Clinic of the University of Minnesota Hospital. Medical history and life style information were obtained on probands and relatives, and all cancers were histologically verified. A total of 544 families were studied, with probands diagnosed between 1931 and 1952. All of the records and pathology slides have been maintained from the original study; for most probands this includes the original tissue blocks.We are conducting a historical cohort study of selected first‐ and second‐degree female relatives (sisters, daughters, nieces, granddaughters) of the probands and a group of control women identified as the spouses of all male first‐ and second‐degree relatives (brothers, sons, grandsons, and nephews). The subsequent development of breast cancer is being determined to quantify the absolute risk associated with a positive family history. Current disease status is ascertained with mammography, and stromal density is measured using digital imaging. Segregation analysis will be applied to examine how non‐genetic factors such as diet, exogenous hormone use, and body fat distribution influence risk in women at high risk because of family history. A subset of families are being selected for molecular analysis of the BRCA1 gene or for linkage analyses to identify putative susceptibility loci other than BRCA1. Documented cancer histories were known for at least three generations, and the current study extends the pedigrees up to four or five generations for every family, allowing a detailed description of familial risk.This cohort study of breast cancer families is likely to be important in both quantity and quality of data and will serve as a major genetic epidemiologic resource, being free of selection bias and having relevant non‐genetic exposure determined in at least four generations. ©1995 Wiley‐Liss, Inc.

CLONAL CHROMOSOME-ABERRATIONS IN FIBROCYSTIC BREAST DISEASE-ASSOCIATED WITH INCREASED RISK OF CANCER

Short-term cultures of 29 samples of fibrocystic breast disease were cytogenetically analyzed. Clonal chromosome aberrations were found in six specimens, whereas the remaining 23 had a normal karyotype. Three of the abnormal samples displayed karyotypic anomalies previously associated with breast cancer, i.e., gain of Iq, trisomy 18 and cytogenetic multiclonality. Furthermore, all cytogenetically aberrant specimens had either proliferative disease without atypia or atypical hyperplasia, features of fibrocystic disease considered risk factors for subsequent breast cancer development. The cytogenetic similarities between breast carcinomas and proliferative fibrocystic breast disease add further support for classifying certain types of fibrocystic disease as a premalignant condition. Whether cytogenetically abnormal fibrocystic lesions are the ones that subsequently progress to cancer remains to be elucidated.

MICROVESSEL QUANTIFICATION AS A MEASURE OF ANGIOGENIC ACTIVITY IN BENIGN BREAST TISSUES LESIONS - A MARKER FOR PRECANCEROUS DISEASE

Neovascularization is a key step in the transformation of normal breast tissue into a cancerous phenotype. We investigated the angiogenic activity of 58 cases of histologically confirmed benign breast lesions quantitating angiogenic activity by factor VIII highlighting of endothelial cells. The mean microvessel count (MVC) for all patients was 51 per 0.19 mm2 in the area of highest angiogenic activity at 400X magnification (range 21-113 per 0.19 mm). MVC in benign tissues were similar to those found previously in cancer tissues. These data suggest that the 'angiogenic switch' occurs early in breast transformation and that a role may exist for the use of MVC in the identification of persons at heightened risk for subsequent development of breast cancer.

Can patients with benign breast disease who are at high risk for breast cancer be identified using bombesin estimation?

ABSTRACT Clinical follow-up studies of women with breast cystic disease indicate an increased risk of subsequent development of breast cancer, but the absolute risk marker has not yet been identified. It has been shown that bombesin/gastrin-releasing peptide can stimulate the proliferation of breast cancer cells in culture. In order to address the question of whether biological measurements might identify women with benign breast disease (BBD) at particular risk for breast cancer, analyses of bombesin and dehydroepiandrosterone sulfate (DHEAS) levels in tumor tissue from patients with breast cancer and BBD were carried out. The groups of patients comprised 13 women with breast cancer (mean age 52.3 years), 12 women with fibroadenoma (mean age 47.5 years), 6 with microcystic breast disease (mean age 43.5 years) and 6 with gross cystic breast disease (mean age 47.2 years). Malignant and benign tumor tissues were collected after mastectomy or tumorectomy. Bombesin and DHEA-S levels was measured by RIA after homogenization and extraction of tissues. Bombesin concentrations were higher in women with breast cancer (83.67±21.07 ng/g) than in other groups, except women with gross cystic disease (79.6±10.9 ng/g). In contrast, tissue concentrations of DHEAS in women with breast cancer (130.5±34.5 μg/g) were lower with comparison to the others, except women with fibroadenoma (177.7±84.9 μg/g). Bombesin and DHEAS tissue concentrations showed significant negative correlation only in women with fibroadenoma. All values are means±S.D. The significantly higher bombesin levels in tissues from women with breast cancer and in breast benign gross cystic disease (high risk of cancer) suggests the possible role of bombesin in the malignant process. Further studies are necessary to confirm these initial results.

Radiation-induced breast cancer: long-term follow-up of radiation therapy for benign breast disease.

From the 1920s through the 1950s, radiation therapy was used in Sweden as a treatment for benign breast diseases. It is now known that exposure of the breast to ionizing radiation increases the relative risk of subsequent breast cancer, especially for younger women. However, the degree to which the patient's age contributes to the elevation of risk for subsequent development of breast cancer is not yet completely understood. The purpose was to study the risk of breast cancer after irradiation of the female breast and, in particular, to analyze the duration of the effect and the risk for women older than 40 years at first exposure. In this cohort study, data were obtained through population-based registers. The exposed group consisted of 1216 women (median age, 40 years) who, during the period spanning 1925 through 1954, received radiation therapy for benign breast disease. The reference group consisted of 1874 women (median age, 36 years) who had the same diagnosis during that time period but did not receive radiation therapy. The radiation doses were determined from the original medical records (mean dose, 5.8 Gy; range, 0.003-50.1 Gy). The follow-up lasted up to 60 years after first exposure. The incidence rate ratio was analyzed with Poisson regression models. The total number of breast cancers in the exposed cohort was 198 versus 101 in the unexposed cohort. Overall, the radiation-associated incidence rate ratio was 3.58 (95% confidence interval = 2.77-4.63). The dose-response gradient was statistically significant (P < .001) but leveled off at higher doses. The incidence rate ratios decreased starting about 25 years after first exposure but were at increased levels throughout the entire follow-up period. The incidence rate ratio decreased with age at first exposure but was significantly increased (P < .001) even when the age at time of first exposure was greater than 40 years. Total dose, age at first exposure, and time since first exposure were all determinants of the incidence rate ratio of breast cancer after exposure of the breast to ionizing radiation. A statistically significant increase in the incidence of breast cancer following radiation treatment of various benign breast diseases was observed even among women older than 40 years at the time of first treatment. These findings need to be considered when weighing the relative benefits versus risks of generalized screening of younger women for breast cancer by mammography.

Clinical, radiographic, and pathologic correlation of atypical hyperplasia, ductal carcinoma in situ, and ductal carcinoma in situ with micro-invasion

Atypical hyperplasia (AH) is a lesion known to be associated with a marked elevation of risk for subsequent development of breast cancer. Like ductal carcinoma in situ (DCIS), it is more commonly found by mammography. We studied all cases designated as AH, DCIS and ductal carcinoma in situ with microinvasion (DCISM) at the University of Alabama at Birmingham USA from 1984–1988. Clinical records, mammograms, and pathologic material were reviewed on 22 cases of AH (21 patients), 41 cases of DCIS (40 patients) and 14 cases of DCISM. Women with AH had a lower average age than those with either DCIS or DCISM. A family history of breast cancer in a first degree relative was present in 38% of women with AH, 25% of women with DCISM. These pathologic lesions were found in association with mammographically dense tissue in 50% or more of cases. Distinctive calcifications were present in 24% of DCIS lesions and 70% of patients with DCISM. While mammographic microcalcification was the indication for biopsy in 59% of cases of AH, the calcifications were most often in benign proliferative disease elsewhere in the specimen rather than in the atypical focus itself. In 82% of AH, the lesion extent was less than 5 mm in size, while 83% of DCIS lesions and 93% of DCISM lesions were larger than 5 mm. Atypical hyperplasia, unlike many cases of DCIS and DCISM, has no direct mammographic correlate in contrast to DCIS and DCISM, which often have distinctive features on mammography. Careful correlation of the relative size, extent, and morphology of these lesions is essential to appropriate management and counselling of these patients.

Are Patients with Solitary or Multiple Intraductal Papillomas at a Higher Risk of Developing Breast Cancer?

Solitary and multiple intraductal papillomas are proliferative lesions. As such, these lesions could be presumed to put the patient at increased risk for the development of breast cancer. This review summarizes several selected series of patients with papillomas, and discusses some of the difficulties in determining the exact risk for these patients. Conflicting data exist with regard to solitary papilloma, but the most recent series do find an elevated risk associated with this lesion. Multiple papillomas are associated with both coexisting cancer and with the subsequent development of breast cancer.

Psychosocial Stress as a Risk for Breast Cancer

Life events, important emotional losses, difficult life situations, and psychological characteristics were investigated in a case-control study of 87 breast cancer patients and their controls. In a second part, the effect of stressful life events preceding cancer diagnosis on survival was studied in an 8-year follow-up of the breast cancer group. The control group was selected from the general female population and matched for sex, age, number of child-births, and language. The findings showed that breast cancer patients had significantly more life events, important losses, and difficult life situations prior to the discovery of the breast tumor than controls. The analysis indicated that important losses during a 6-year prodromal period and life event scores prior to examination on both the 12-month and modified 6-year Social Readjustment Rating Scale were associated with subsequent development of breast cancer. The association persisted after adjustment for marital status, education, and social class. The findings of the survival analyses indicated that life events in the 12 months preceding the onset of breast cancer and lower social class were associated with a smaller chance of disease-free and overall survival after controlling for clinical factors.