Incidence of cancer in 161 families affected by ataxia-telangiectasia

BACKGROUND. Ataxia-telangiectasia is an autosomal recessive syndrome in which cancers develop in affected homozygotes at a rate approximately 100 times higher than in unaffected age-matched subjects. Retrospective studies have shown that persons heterozygous for the ataxia-telangiectasia gene, who make up about 1 percent of the general population, also have an excess risk of cancer, particularly breast cancer in women. Patients with ataxia-telangiectasia and cells derived from homozygotes and heterozygotes are unusually sensitive to ionizing radiation. METHODS. Cancer incidence and mortality, mortality from ischemic heart disease, and mortality from all causes were compared prospectively for a mean of 6.4 years in 1599 adult blood relatives of patients with ataxia-telangiectasia and 821 of their spouses, who served as controls, in 161 families affected by ataxia-telangiectasia. In a case-control substudy, we compared documented occupational and fluoroscopic diagnostic exposures to radiation in the 19 female blood relatives in whom breast cancer was first diagnosed during the period of prospective observation with the exposures in 57 matched blood relatives who did not have breast cancer. RESULTS. Cancer rates were significantly higher in the group of blood relatives than in their spouses, specifically in the subgroup of 294 blood relatives who were known to be heterozygous for the ataxia-telangiectasia gene. The estimated risk of cancer of all types among heterozygotes as compared with noncarriers was 3.8 in men and 3.5 in women, and that for breast cancer in women was 5.1. Among the blood relatives, women with breast cancer were more likely to have been exposed to selected sources of ionizing radiation than controls without cancer (odds ratio = 5.8, P = 0.005). Male and female blood relatives also had 3-fold and 2.6-fold excess mortality from all causes, respectively, from the ages of 20 through 59 years. CONCLUSIONS. The ataxia-telangiectasia gene predisposes heterozygotes to cancer, particularly breast cancer in women. There is also excess mortality from all causes in adults under the age of 60. Diagnostic or occupational exposure to ionizing radiation probably increases the risk of breast cancer in women heterozygous for ataxia-telangiectasia.     

Screening and genetic counselling for relatives of patients with breast cancer in a family cancer clinic.

Family history is the major risk factor in the aetiology of breast cancer. Breast screening is currently available to women from the age of 50 to 64 through the National Breast Screening Programme. There is, however, an equivalent risk of developing breast cancer below 50 for first degree relatives of women diagnosed with breast cancer premenopausally. We have estimated the risk of breast cancer for relatives of women affected at different ages and used these to establish a family cancer clinic offering breast screening based on individual risk. In three years we have seen 851 patients. Compliance for annual radiology was in excess of 83% over this period and of five cancers detected one had a lump at presentation, two developed interval breast lumps, and two were asymptomatic.     

Impact of patient age on family cancer history.

PURPOSE: Younger individuals with relatives diagnosed with cancer are at greater risk for developing certain cancer when compared with older individuals with affected relatives. The purpose of this study was to calculate the age-specific proportion of individuals reporting positive family histories for colon, breast, and prostate cancer. METHODS: Family cancer history information was reviewed on 32,374 adults interviewed for the 2000 National Health Interview Survey. Family histories were categorized as high risk, with a relative diagnosed before 50 years of age or with multiple affected relatives, or moderate risk, with a single relative diagnosed at age 50 years or older. RESULTS: For individuals with a family history of colorectal cancer, the odds of having a high-risk pedigree decreased by 1% (95% confidence interval 0%-2%) for every year of age increase. For women reporting a family breast cancer history, the odds of reporting a pedigree with high-risk features decreased by 3% (95% confidence interval 2%-4%) for each year of age increase. Age was not associated with reporting a high-risk pedigree for prostate cancer. CONCLUSION: For colorectal and breast cancers, younger individuals reporting a family history of these cancers were more likely to report a pedigree with high-risk features than older individuals.     

Prophylactic mastectomy: pathologic findings in high-risk patients

BACKGROUND: According to recently published data, prophylactic mastectomy (PM) appears to prevent about 90% of the expected malignant neoplasms in women with a family history of breast cancer. OBJECTIVES: To identify the frequency of high-risk lesions in PM specimens and to determine occurrence of any new primary breast cancer following PM. DESIGN: We performed a retrospective study of women undergoing unilateral or bilateral PM. Medical charts and pathologic findings of 35 patients who underwent bilateral mastectomies at University Hospital, Syracuse, NY, from 1989 to 1996 were reviewed. Patients with biopsy-proven bilateral breast cancer were excluded. Patients were divided into 3 groups: (A) positive family history and no known breast cancer (n = 9), (B) positive family history and contralateral neoplasia (n = 13), and (C) negative family history and contralateral neoplasia (n = 13). These findings were compared with those found in reduction mammoplasty specimens from 10 women at standard risk of breast cancer. RESULTS: The mean age of the control group of women undergoing reduction mammoplasty was 38 years. The pathologic specimens demonstrated no significant pathologic findings in 9 and fibrocystic change in 1. In group A, the mean number of affected relatives was 3.1, and the mean age was 38 years. Two of these 9 women had atypical duct hyperplasia and 1 had atypical lobular hyperplasia in their breasts (ie, 33% with high-risk pathologic findings). Of the 13 group B women (mean age, 46.6 years; mean of 2.5 affected relatives and unilateral breast cancer), the contralateral PM specimen contained duct carcinoma in situ in one and invasive ductal cancer in a second (15% with occult malignant neoplasms). In 13 group C patients (mean age, 47.1 years), 3 (23.1%) of the contralateral PM specimens displayed atypical duct hyperplasia or atypical lobular hyperplasia. At a mean follow-up of 4.8 years, there have been no new breast malignant neoplasms in these 45 women. CONCLUSIONS: The occurrence of unilateral cancer in patients with family history of breast cancer is associated with a 15.4% probability of simultaneous occult malignant neoplasms in the contralateral breast. Patients with a strong family history but no evidence of breast cancer have a substantially similar rate of proliferative disease in their PM specimens as those women who have unilateral cancer but no significant family history.     

Breast and other cancers in families with ataxia-telangiectasia

Patients who are homozygous for ataxia-telangiectasia have an exceptionally high incidence of cancer. In a group of families expected to have a high proportion of heterozygotes for ataxia-telangiectasia, we tested the hypothesis that such heterozygotes, estimated to make up 0.68 to 7.7 percent of the U.S. white population, also have an excess cancer risk. Retrospective cancer incidence rates in adult blood relatives of patients with ataxia-telangiectasia in 110 white non-Amish families were significantly elevated over the incidence rates in spouse controls (rate ratios, 1.6 for men [P = 0.032]; 2.0 for women [P = 0.013]). For persons who are heterozygous for ataxia-telangiectasia, the relative risk of cancer was estimated to be 2.3 for men (P = 0.014) and 3.1 for women (P = 0.004). Breast cancer in women was the cancer most clearly associated with heterozygosity for ataxia-telangiectasia (rate ratio, 3.0 [P = 0.028]; heterozygote relative risk, 6.8 [P = 0.006]). On the basis of this estimated relative risk of 6.8 and an estimated heterozygote frequency in the general population of 1.4 percent, 8.8 percent of patients with breast cancer in the U.S. white population would be heterozygous for ataxia-telangiectasia. We conclude that heterozygous carriers of the gene for ataxia-telangiectasia have an excess risk of cancer, particularly breast cancer in women.     

Identification of women at high genetic risk of breast cancer through the National Health Service Breast Screening Programme (NHSBSP).

Breast cancer is a multifactorial disease with an inherited predisposition being implicated in around 5% of all cases. Using previous epidemiological data assessing risks for the relatives of women with breast cancer, we have identified 154 women (from a screened population of 35,505) and 289 of their relatives between 50 and 64 years who have more than twice the age related risk of developing breast cancer. This constitutes 1.24% of the breast screening population attending the North East Scotland NHSBSP. For each woman identified to be at high risk, we have found 1.87 female relatives between 50 and 64 years and 1.85 relatives under 50 years also to be at high risk. Around 78% of the women identified with a significant family history of breast or other cancer have attended for counselling about their risks. The breast screening programme can be used to identify women at high risk of breast cancer in order to offer them (and their relatives) access to genetic counselling and appropriate screening.     

Population-based screening for hereditary breast cancer in a region of North-Central Italy

Assessment of family history is an important element in the identification of individuals and families likely to be at risk of hereditary cancers. It is based on the recognition of important features in the natural history of cancer syndromes. These include the occurrence of the same type of cancer in two or more close relatives, bilateral cancer in paired organs, multiple primaries in the same individual, early age at onset, a specific constellation of cancers or other physical findings associated with a known syndrome, and a mendelian pattern of inheritance. We set up a population-based screening program to identify women at increased risk of breast or ovarian cancer in a region of North-Central Italy. As a preliminary screening, 159 women with a family history of breast and ovarian cancer were recruited at the Cancer Prevention Unit of Pierantoni Hospital in Forli. Information on the number of affected individuals and the age at onset of breast or ovarian cancer in each woman's family was recorded. Thirty-nine women reported two or more first- or second-degree relatives with breast cancer under the age of 50 (25%) and 95 a single first- or second-degree relative with breast cancer under the age of 50 (60%) with or without other late onset breast cancers in the family. The remaining 25 women reported first- and second-degree relatives with breast cancer over the age of 50 (15%). There were five families with a history of ovarian cancer (3%), one of which comprised 3 affected members. Twenty-three families showed multiple cancers associated with breast cancer cases. Associated prostate and colorectal cancers were found in 5 and 4 families with a history of breast cancer, respectively. On the basis of these preliminary data, we aimed to extend the population-based screening to the whole of the Emilia-Romagna population, involving the Cancer Prevention Units of neighboring towns and adopting homogeneous family history evaluation and risk assessment criteria.     

Cancer risks in first degree relatives of BRCA1 mutation carriers: effects of mutation and proband disease status

Background

Mutations in the BRCA1 (MIM 113705) gene are found in many families with multiple cases of breast and ovarian cancer, and women with a BRCA1 mutation are at significantly higher risk of developing breast and ovarian cancer than are the general public.

Methods

We obtained blood samples and pedigree information from 3568 unselected cases of early‐onset breast cancer and 609 unselected patients with ovarian cancer from hospitals throughout Poland. Genetic testing was performed for three founder BRCA1 mutations. We also calculated the risk of breast and ovarian cancer to age 75 in the first degree relatives of carriers using Kaplan‐Meier methods.

Results

The three founder BRCA1 mutations were identified in 273 samples (187 with 5382insC, 22 with 4153delA, and 64 with C61G). A mutation was present in 4.3% of patients with breast cancer and 12.3% of patients with ovarian cancer. The overall risk of breast cancer to age 75 in relatives was 33% and the risk of ovarian cancer was 15%. The risk for breast cancer was 42% higher among first degree relatives of carriers of the C61G missense mutation compared to other mutations (HR = 1.42; p = 0.10) and the risk for ovarian cancer was lower than average (OR = 0.26; p = 0.03). Relatives of women diagnosed with breast cancer had a higher risk of breast cancer than relatives of women diagnosed with ovarian cancer (OR = 1.7; p = 0.03).

Conclusions

The risk of breast cancer in female relatives of women with a BRCA1 mutation depends on whether the proband was diagnosed with breast or ovarian cancer.     

Rare germline mutations in PALB2 and breast cancer risk: a population-based study

Germline mutations in the PALB2 gene are associated with an increased risk of developing breast cancer but little is known about the frequencies of rare variants in PALB2 and the nature of the variants that influence risk. We selected participants recruited to the Women's Environment, Cancer, and Radiation Epidemiology (WECARE) Study and screened lymphocyte DNA from cases with contralateral breast cancer (n = 559) and matched controls with unilateral breast cancer (n = 565) for PALB2 mutations. Five pathogenic PALB2 mutations were identified among the cases (0.9%) versus none among the controls (P = 0.04). The first-degree female relatives of these five carriers demonstrated significantly higher incidence of breast cancer than relatives of noncarrier cases, indicating that pathogenic PALB2 mutations confer an estimated 5.3-fold increase in risk (95% CI: 1.8-13.2). The frequency of rare (<1% MAF) missense mutations was similar in both groups (23 vs. 21). Our findings confirm in a population-based study setting of women with breast cancer the strong risk associated with truncating mutations in PALB2 that has been reported in family studies. Conversely, there is no evidence from this study that rare PALB2 missense mutations strongly influence breast cancer risk.     

Attitudes about genetic testing and genetic testing intentions in African American women at increased risk for hereditary breast cancer.

PURPOSE: To evaluate attitudes about the benefits, limitations, and risks of genetic testing for BRCA1 and BRCA2 (BRCA1/2) mutations and explore testing intentions in African American women at increased risk for hereditary breast cancer. METHODS: Attitudes and intentions were evaluated by telephone in African American women (n = 74) at moderate and high risk for having a BRCA1/2 mutation. RESULTS: Attitudes about the benefits of genetic testing were endorsed at a higher rate relative to limitations and risks; however, only 30% of respondents indicated that they would definitely have testing. In regression analysis, women most likely to be considering testing were those with fatalistic beliefs about cancer and those who believed they had a BRCA1/2 mutation. Women who had two or more affected relatives were also most likely to be considering testing. Women who had a personal history of cancer and those who believed they were at high risk for developing breast cancer were most likely to report greater limitations and risks. Pros scores were higher among women older than age 50 and those who were unemployed. CONCLUSION: Although African American women at moderate and high risk for BRCA1/2 mutations report favorable attitudes about genetic testing, interest in testing may be limited. Women affected with cancer and those who believe they are at a higher risk for developing breast cancer may be most concerned about the negative consequences of testing. Increased attention may need to be given to beliefs about genetic testing and testing motivations during genetic counseling with African American women.     

Epidemiology of breast cancer in families in Iceland.

The Icelandic Cancer Registry has collected 989 pedigrees of breast cancer patients since 1972. In addition to the probands, the families also include 401 other women with breast cancer, so family information exists for 1390 women with breast cancer out of a total of 2748 diagnosed with the disease from 1910 to 1988. Most of the probands have been selected with care to avoid the bias of selecting families with a known history of breast cancer. After excluding all those who did not conform to the strict selection criteria, 947 pedigrees remained for this analysis. First, second, and third degree relatives all had a significantly increased risk of breast cancer: 2.26, 1.43, and 1.49, respectively. Male relatives also had a significantly increased risk, whereas females related by marriage had not. Of the first degree relatives, sisters had the largest increase in risk. When pedigrees were classified by the age at diagnosis of breast cancer of the proband, the risk was highest in the relatives of probands who were young at diagnosis. Bilaterality of breast cancer increased the risk in relatives and the highest risk (9.04) was found in sisters of probands with bilateral disease and an age at diagnosis of first cancer of less than 45 years (95% confidence limits 4.14, 17.18). Sisters consistently have the highest risk, significantly higher than other first degree relatives. This points to an important role of shared environmental aetiological factors acting after birth and it can not yet be excluded that most of the increase in risk can be explained by this.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cancer in the contralateral breast after radiotherapy for breast cancer.

BACKGROUND. Patients with breast cancer have a threefold increase in the risk that a second breast cancer will develop. Radiation treatment for the initial cancer can result in moderately high doses to the contralateral breast, possibly contributing to this heightened risk. METHODS. We conducted a case-control study in a cohort of 41,109 women diagnosed with breast cancer between 1935 and 1982 in Connecticut. We reviewed the medical records of 655 women in whom a second breast cancer developed five or more years after the initial tumor and compared their radiation exposure with that of 1189 matched controls from the cohort who did not have a second cancer. The dose of radiation to the contralateral breast was estimated from the original radiotherapy records. Among the exposed women, the average radiation dose to the contralateral breast was 2.82 Gy (maximum, 7.10). RESULTS. Overall, 23 percent of the women who had a second breast cancer and 20 percent of the controls had received radiotherapy (relative risk of a second breast cancer associated with radiotherapy, 1.19). Among women who survived for at least 10 years, radiation treatment was associated with a small but marginally significant elevation in the risk of a second breast cancer (relative risk, 1.33); the risk increased significantly with the dose of radiation. An increase in risk in association with radiotherapy was evident only among women who were under 45 years of age when they were treated (relative risk, 1.59) and not among older women (relative risk, 1.01). CONCLUSIONS. Radiotherapy for breast cancer contributes little to the already high risk of a second cancer in the opposite breast. Fewer than 3 percent of all second breast cancers in this study could be attributed to previous radiation treatment; the risk, however, was significantly increased among women who underwent irradiation at a relatively young age (less than 45 years). Radiation exposure after the age of 45 entails little, if any, risk of radiation-induced breast cancer.     

The credibility of the Breast Cancer Risk Assessment (BCRA) tool for Asians

This paper presents an overview of the Breast Cancer Risk Assessment (BCRA) Tool, assessing the credibility of the BCRA tool in estimating the risk of developing breast cancer for Asians and the carrying out of tests to identify the changes in the risks that follow with changes in one or more risk factors of the tool. It is essential to increase the awareness of women of their risk of developing breast cancer, as it is not surprising that some women may not even be conscious of the individual factors that might contribute to the increase of their risk of developing breast cancer. On the other hand, relatively accurate means of determining increases in relative risks of developing breast cancer due to changes in some of the risk factors are also important. This is done so that unnecessary worry due to an overestimation of an individual's risk of developing breast cancer can be avoided. Due to the origin of the BCRA tool which is used in this study, it is important to verify the validity of the tool on Asians and to identify, as far as possible, the effect that each risk factor has on individuals. The effect that a specific risk factor has on a white woman may not be exactly the same for that of an Asian woman. As the above-mentioned tool has been arrived at using the statistics and databases of white women, in this work, tests have been carried out to determine the suitability of the tool on Asian women. On top of that, various tests are also carried out to determine the effects of the change of certain risk factors on a woman's risk of developing breast cancer. These factors include age, number of breast biopsies and number of first-degree relatives with breast cancer. Five-year risks and lifetime risks are also looked into separately with the change of each of these factors.     

Risk factors for detecting germline BRCA1 and BRCA2 founder mutations in Ashkenazi Jewish women with breast or ovarian cancer

We ascertained 184 Ashkenazi Jewish women with breast/ovarian cancer (171 breast and 13 ovarian cancers, two of the former also had ovarian cancer) in a self-referral study. They were tested for germline founder mutations in BRCA1 (185delAG, 5382insC, 188del11) and BRCA2 (6174delT). Personal/family histories were correlated with mutation status. Logistic regression was used to develop a model to predict those breast cancer cases likely to be germline BRCA1/BRCA2 mutation carriers in this population. The most important factors were age at diagnosis, personal/family history of ovarian cancer, or breast cancer diagnosed before 60 years in a first degree relative. A total of 15.8% of breast cancer cases, one of 13 ovarian cancer cases (7.7%), and both cases with ovarian and breast cancer carried one of the founder mutations. Age at diagnosis in carriers (44.6 years) was significantly lower than in non-carriers (52.1 years) (p<0.001), and was slightly lower in BRCA1 than BRCA2 carriers. Thirty three percent of carriers had no family history of breast or ovarian cancer in first or second degree relatives. Conversely, 12% of non-mutation carriers had strong family histories, with both a first and a second degree relative diagnosed with breast or ovarian cancer. The predicted values from the logistic model can be used to define criteria for identifying Ashkenazi Jewish women with breast cancer who are at high risk of carrying BRCA1 and BRCA2 mutations. The following criteria would identify those at approximately 10% risk: (1) breast cancer <50 years, (2) breast cancer <60 years with a first degree relative with breast cancer <60 years, or (3) breast cancer <70 years and a first or second degree relative with ovarian cancer.     

Soft tissue nasal asymmetry as an indicator of orofacial cleft predisposition

The biological relatives of offspring with nonsyndromic orofacial clefts have been shown to exhibit distinctive facial features, including excess asymmetry, which are hypothesized to indicate the presence of genetic risk factors. The significance of excess soft tissue nasal asymmetry in at‐risk relatives is unclear and was examined in the present study. Our sample included 164 unaffected parents from families with a history of orofacial clefting and 243 adult controls. Geometric morphometric methods were used to analyze the coordinates of 15 nasal landmarks collected from three‐dimensional facial surface images. Following generalized Procrustes analysis, Procrustes ANOVA and MANOVA tests were applied to determine the type and magnitude of nasal asymmetry present in each group. Group differences in mean nasal asymmetry were also assessed via permutation testing. We found that nasal asymmetry in both parents and controls was directional in nature, although the magnitude of the asymmetry was greater in parents. This was confirmed with permutation testing, where the mean nasal asymmetry was significantly different (p < .0001) between parents and controls. The asymmetry was greatest for midline structures and the nostrils. When subsets of parents were subsequently analyzed and compared (parents with bilateral vs. unilateral offspring; parents with left vs. right unilateral offspring), each group showed a similar pattern of asymmetry and could not be distinguished statistically. Thus, the side of the unilateral cleft (right vs. left) in offspring was not associated with the direction of the nasal asymmetry in parents.     

Breast cancer incidence and familiality in Iceland during 75 years from 1921 to 1995

Information in the Icelandic Cancer Registry on breast cancer and its collection of breast cancer families has been used to elucidate changes in breast cancer incidence by time period and by age, and the effect of degree of relationship and age on the familial risk of breast cancer. Since 1921 the incidence rates have increased, but the increase is significantly greater (2.06% per year) for ages over 44 years than for ages 20-44 (1.20% per year). It has been shown before that when familial risk is computed, the age of the proband influences the risk for the relatives. However, this study shows that the age of the relative is also important and with increasing age the familial risk decreases.     

A protein-truncating mutation in CYP17A1 in three sisters with early-onset breast cancer

The hormonal etiology of breast cancer is well-established. Many studies have assessed whether polymorphisms in steroid hormone metabolism genes are associated with breast cancer risk. We measured the CYP17A1 -34T>C (c.-34T>C) promoter polymorphism in a population-based study of 1,404 Australian women with breast cancer diagnosed before age 60 years (case probands), 1,903 relatives, and 788 controls. Within-family analyses suggested the CC genotype was associated with, on average, a small increased risk. This finding appeared to be influenced by the families of three early-onset case probands with multiple affected sisters. CYP17A1 mutation screening revealed a case proband diagnosed at age 38 years who had a germline protein-truncating mutation (c.775C>T, p.Arg239X), which results in a nonfunctional enzyme and has been reported in a male compound heterozygote with 17 alpha-hydroxylase deficiency. This mutation was carried by both sisters diagnosed with breast cancer at ages 34 and 42 years, but not by a 57-year-old unaffected sister. It was not found in any of the other tested case probands (48 with multiple-affected relatives and 241 randomly selected) or controls. This study suggests there may be rare mutations in steroid hormone metabolism genes associated with a high dominantly-inherited breast cancer risk, and demonstrates how "high-risk susceptibility genes" might be discovered using population-based case-control-family studies.     

Genetic implications of double primary cancers of the colorectum and endometrium.

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant condition predisposing to cancers of the colorectum and endometrium. Endometrial cancer is the most commonly occurring extracolonic cancer in HNPCC. Estimates of the cumulative incidence of endometrial cancer in women with mutations in the HNPCC genes range from 22-43%. In order to determine how frequently double primary cancers of the colorectum and endometrium are the result of a hereditary factor, we conducted a registry based study in Ontario and Quebec, Canada. We obtained pedigrees on 80 women diagnosed with double primary cancers of the colorectum and endometrium at less than 70 years of age. Family histories of cancer were obtained for all first degree relatives of these women and cancer rates were compared with age standardised provincial incidence rates in order to estimate the relative risks. There was a total of 82 cancers observed in relatives below the age of 55, compared with 31.2 expected, giving a relative risk of 2.6 (95% confidence interval (CI) 2.1-3.3). The relative risk for colorectal cancer below 55 was 16.1 (95% CI 11.6-21.8). This risk decreased with increasing age of onset of cancers in probands. For probands with both colorectal and endometrial cancer diagnosed under the age of 55, the relative risk of colorectal cancer in relatives below the age of 55 was 30.5 (95% CI 18.8-46.6). Similar patterns were observed for endometrial and pancreatic cancer. There were non-significant increases in rates of cancer of the oesophagus, stomach, small intestine, and bladder. There was no increased risk of breast cancer. The risk of lung cancer was decreased, especially in older relatives. Our findings indicate the presence of a significant genetic component of cancer in women with double primary cancers of the colorectum and endometrium.     

Computerized Analysis of Mammographic Parenchymal Patterns on a Large Clinical Dataset of Full-Field Digital Mammograms: Robustness Study with Two High-Risk Datasets

The purpose of this study was to demonstrate the robustness of our prior computerized texture analysis method for breast cancer risk assessment, which was developed initially on a limited dataset of screen-film mammograms. This current study investigated the robustness by (1) evaluating on a large clinical dataset, (2) using full-field digital mammograms (FFDM) as opposed to screen-film mammography, and (3) incorporating analyses over two types of high-risk patient sets, as well as patients at low risk for breast cancer. The evaluation included the analyses on the parenchymal patterns of women at high risk of developing of breast cancer, including both BRCA1/2 gene mutation carriers and unilateral cancer patients, and of women at low risk of developing breast cancer. A total of 456 cases, including 53 women with BRCA1/2 gene mutations, 75 women with unilateral cancer, and 328 low-risk women, were retrospectively collected under an institutional review board approved protocol. Regions-of-interest (ROIs), were manually selected from the central breast region immediately behind the nipple. These ROIs were subsequently used in computerized feature extraction to characterize the mammographic parenchymal patterns in the images. Receiver operating characteristic analysis was used to assess the performance of the computerized texture features in the task of distinguishing between high-risk and low-risk subjects. In a round robin evaluation on the FFDM dataset with Bayesian artificial neural network analysis, AUC values of 0.82 (95% confidence interval [0.75, 0.88]) and 0.73 (95% confidence interval [0.67, 0.78]) were obtained between BRCA1/2 gene mutation carriers and low-risk women, and between unilateral cancer and low-risk women, respectively. These results from computerized texture analysis on digital mammograms demonstrated that high-risk and low-risk women have different mammographic parenchymal patterns. On this large clinical dataset, we validated our methods for quantitative analyses of mammographic patterns on FFDM, statistically demonstrating again that women at high risk tend to have dense breasts with coarse and low-contrast texture patterns.     

Attitudes and distress levels in women at risk to carry a BRCA1/BRCA2 gene mutation who decline genetic testing

Genetic testing enables women at risk for hereditary breast and/or ovarian cancer to find out whether they have inherited the gene mutation, and if so, to opt for undergoing frequent surveillance and/or prophylactic surgery. However, the option to know about one's genetic status is not always seen as a benefit by women at risk. Motives for declining genetic testing were explored in 13 women at 25% or 50% risk to be a BRCA1/BRCA2 mutation carrier, who participated in a surveillance program for breast/ovarian cancer (the non-tested group). We hypothesized that high anxiety might be an important motive to decline testing. In addition, we investigated whether the non-tested group differed from a reference group of women who did undergo the test (tested group; n = 85) with regard to biographical factors, experience with cancer in relatives, and personality traits. Most non-tested women (10/13) were satisfied with participating in the surveillance program. Four reported to feel emotionally unprepared to cope with the consequences of testing. Compared with the tested group, the non-tested women had similar mean distress levels (which were not high), but a higher education level, they were more often childless, showed more reluctance towards prophylactic surgery, were younger when first confronted with a relative affected with breast/ovarian cancer, and were longer aware of the genetic nature of the disease. This study showed that women were more likely to have thoroughly reflected on their decision not to undergo genetic testing, than to deny the whole issue due to high anxiety. Being confronted at a relatively young age with breast/ovarian cancer in a relative, and being aware of the genetic risk for a many years, may have resulted in the risk for cancer becoming an integrated part of their lives. However, generalization of these results to women who neither underwent the test nor participated in a surveillance program should be considered with caution.