Management of familial breast cancer risk

Women who are members of breast cancer families are at increased risk for breast cancer. The cloning of BRCA1 and BRCA2 has made it possible to identify mutation carriers within some of these families. Management of breast cancer risk in these families, which presents enormous challenges to patients and clinicians, is addressed. Management should begin with a full evaluation of the patient, including construction of a three-generation pedigree, ascertainment of non-genetic factors that may impact on risk, information on previous and current breast health, practice of and attitudes toward screening, and the psychosocial impact of family history on the individual. Patient priorities in risk management should be explicitly reviewed; these may include survival, cancer prevention, breast preservation, optimization of quality of life or minimization of disruption of day-to-day activities. Approaches to risk management involve screening (usually considered the mainstay), anti-estrogens, prophylactic surgery and/or lifestyle modifications. Specific gene therapy may become available in the future. Management decisions should be individualized to reflect risk levels and patient priorities and goals, within bounds that are medically and scientifically reasonable. An explicit examination of different time-frames (1, 5, 10 years) is recommended given the rapid evolution of knowledge in this area.     

Prospective surveillance of women with a family history of breast cancer: auditing the risk threshold

To evaluate current guidelines criteria for inclusion of women in special 'breast cancer family history' surveillance programmes, records were reviewed of women referred to Scottish breast cancer family clinics between January 1994 and December 2003 but discharged as at 'less than 'moderate' familial risk'. The Scottish Cancer Registry was then interrogated to determine subsequent age-specific incidence of breast cancer in this cohort and corresponding Scottish population figures. Among 2074 women, with an average follow-up of 4.0 years, 28 invasive breast cancers were recorded up to December 2003, where 14.4 were expected, a relative risk (RR) of 1.94. Eleven further breast cancers were recorded between January 2004 and February 2006 (ascertainment incomplete for this period). The overall RR for women in the study cohort exceeded the accepted 'cutoff' level (RR=1.7) for provision of special counselling and surveillance. The highest RR was found for the age group 45-59 years and this group also generated the majority of breast cancers. The National Institute for Clinical Excellence ('NICE') guidelines appear to be more accurate than those of the Scottish Intercollegiate Guidelines Network ('SIGN') in defining 'moderate' familial risk, and longer follow-up of this cohort could generate an evidence base for further modification of familial breast cancer services.     

Effects of mammographic density and benign breast disease on breast cancer risk (United States)

Background: Having either a history of benign breast disease, particularly atypical hyperplasia or extensive mammographic breast density, is associated with increased breast cancer risk. Previous studies have described an association between benign breast disease histology and breast density. However, whether these features measure the same risk, or are independent risk factors, has not been addressed. Methods: This case–control study, nested within the prospective follow-up of the Breast Cancer Detection Demonstration Project, evaluated both benign histologic and mammographic density information from 347 women who later developed breast cancer and 410 age- and race-matched controls without breast cancer. Multivariate logistic regression analyses provided maximum-likelihood estimates of the odds ratios (OR) and 95% confidence intervals (CI) to evaluate the relative risk of breast cancer associated with each exposure. Results: Adjusting for mammographic density, the OR for atypical hyperplasia was 2.1 (95% CI: 1.3–3.6), and adjusting for benign breast histology, the OR for 75% density was 3.8 (95% CI: 2.0–7.2). Women with nonproliferative benign breast disease and 75% density had an OR of 5.8 (95% CI: 1.8–18.6), and women with <50% density and atypical hyperplasia had an OR of 4.1 (95% CI: 2.1–8.0). Conclusions: In this study, both benign breast disease histology and the percentage of the breast area with mammographic density were associated with breast cancer risk. However, women with both proliferative benign breast disease and 75% density were not at as high a risk of breast cancer due to the combination of effects (p = 0.002) as women with only one of these factors.     

Evaluation of a breast cancer risk prediction model expanded to include category of prior benign breast disease lesion

BACKGROUND:

Benign breast diseases (BBD) encompass several histologic subtypes with various risks of subsequent breast cancer. Information on previous benign breast disease biopsies has been incorporated into breast cancer risk prediction models; however, the type of histologic lesion has not been taken into account. Given the substantial heterogeneity in breast cancer risk dependent on the type of benign lesion, the authors evaluated whether incorporating this level of detail would improve the discriminatory power of risk classification models.

METHODS:

By using data from the Nurses' Health Study, a breast cancer nested case‐control study (240 cases; 1036 controls), the authors determined predictors of categories of BBD lesions and developed imputation models. The type of BBD, imputed for each cohort member who reported a diagnosis, was added to a modified version of the Rosner‐Colditz breast cancer risk prediction model.

RESULTS:

Compared with the model that included only previous BBD (yes/no), the model that included categories of BBD was significantly improved (P < .0001). Overall, including the category of BBD increased the concordance statistic from 0.628 to 0.635. By using risk reclassification, inclusion of the type of BBD resulted in a 17% increase in incidence per increase of 1 risk decile, holding the model without BBD type risk decile constant.

CONCLUSIONS:

Although the current data suggested that the inclusion of BBD category may improve breast cancer risk classification, the clinical utility of such a model will depend on the consistency of histologic classification of benign breast disease lesions. Cancer 2010. © 2010 American Cancer Society.     

Effects of screening for breast cancer on its age-incidence relationships and familial risk

Mammographic screening programs for breast cancer have been implemented in many countries and opportunistic mammographies are taken as a diagnostic method. The consequences of the wide application of this technology to age-incidence relationships in breast cancer have not been clarified nor is its effect on familial risk estimation. It was assumed that if screening and diagnostic methods bias familial risk, the highest risk should be noted for sisters diagnosed close in time. Age-specific incidence data were collected from the EUCAN database and from cancer registries of Finland, Norway and Sweden. The Swedish Family-Cancer Database was used to analyse risks for breast cancer among sisters, depending on the time since the first sister was diagnosed with breast cancer. Age-incidence patterns deviated between Germany, with low mammographic coverage, and Sweden, the Netherlands, the UK and France, with variable levels of coverage. The annual age-incidence patterns in Finland, Norway and Sweden changed in concert with the targeted mammographic service. The risk of breast cancer for women with an affected sister, diagnosed between ages 50 to 64 years, was significantly higher within the same or the subsequent year of the sister's diagnosis compared to 5+ years, accounting for 7.3% of all patients. The ordered increase in age-specific incidence of breast cancer in the women targeted by screening studied suggests that mammographic screening is one important factor responsible for the shift of the age of onset for breast cancer towards middle age. However, the effects on the estimation of familial risk are so far small.     

Family history of breast cancer,age and benign breast disease

A major risk factor for breast cancer is having a first-degree family history of the disease. Benign breast disease (BBD), particularly atypical hyperplasia, is also associated with an increased risk of breast cancer. However, the relationship between family history of breast cancer and BBD is unclear. From 1989 through 1997, 80,995 participants in the Nurses' Health Study II were followed; 16,849 reported a first diagnosis of BBD. Pathology slides were reviewed for 1,465 women who reported having a tissue biopsy, and these were classified as nonproliferative BBD, proliferative BBD without atypia or atypical hyperplasia. Women with a family history of breast cancer were more likely to report a physician diagnosis of BBD [rate ratio (RR) = 1.38, 95% confidence interval (CI) 1.29-1.46]. The magnitude of this association declined with age from RR = 1.96 (95% CI 1.55-2.47) at 25-29 years to RR = 1.20 (95% CI 0.95-1.52) at age 45-50 years. Among women with proliferative disease, those with a family history of breast cancer were almost 3 times as likely to have atypia (prevalence odds ratio = 2.72, 95% CI 1.23-5.89) than those with no family history. In conclusion, women with a family history of breast cancer appear to be at increased risk of being diagnosed with BBD, in particular the high-risk types of BBD associated with a greatly increased risk of breast cancer. This link adds weight to the belief that BBD with atypia is a precursor or marker lesion for breast cancer.     

Blood arsenic levels and the risk of familial breast cancer in Poland

Arsenic is recognized as a potent carcinogen at high concentrations, but the relationship between environmental arsenic and breast cancer risk has not well been studied. Most research has focused on the effect of arsenic in populations with high endemic exposure, and not in populations with arsenic levels within normal limits. We sought to determine if blood arsenic levels predict the risk of breast and other cancers risk among women in northern Poland. The cohort consisted of 1,702 healthy women, aged 40 and above, identified between 2010 and 2017. Blood arsenic level was determined by inductively coupled plasma mass spectrometry. After an average of 4.5 years of follow-up (range 0.7–7.3 years), there were 110 incident cases of cancer diagnosed in the cohort, including 68 cases of breast cancer. Women in the highest quartile of arsenic had a highly significant 13-fold increased risk of developing breast cancer, compared to women in the lowest quartile (hazard ratio [HR] = 13.2; 95% confidence interval [CI] 4.02–43.0). Results were similar for arsenic and all incident cancers (HR quartile 4 vs. quartile 1 = 13.3; 95% CI 4.78–37.0). If confirmed, our study suggests that the blood arsenic level may be a useful predictive marker of cancer risk in women.     

Age of onset in familial breast cancer as background data for medical surveillance

Background:

Familial breast cancers are known to be of early onset. This article provides differences in the age of onset of breast cancer and death by breast cancer between women with and without a family history.

Methods:

The Swedish Family-Cancer Database was used to estimate the cumulative risk of breast cancer and death by breast cancer according to family history with a stratified Cox model. Family history was defined separately for affected mother or sister considering their diagnostic ages.

Results:

The age to reach the same cumulative incidence as women without family history decreased with decreasing diagnostic age of the affected relative. Women with a maternal history reached the risk of women lacking a family history at the age of 50 years between 12.3 (mother affected <40 years) and 3.3 years (mother affected >82 years) earlier. The trend for breast cancer mortality was essentially similar.

Conclusions:

Women with mother or sister affected by breast cancer are diagnosed and die at earlier ages than do women without family history. The differences depend on the diagnostic age of the affected relative. The present data may provide a rationale to derive recommendations for the starting age of screening in women with affected family members.     

Benign breast lesions at risk of developing cancer—A challenging problem in breast cancer screening programs

BACKGROUND:

Cytology and core‐needle biopsies are not always sufficient to exclude malignancy in benign breast lesions (BBL) that are at risk of developing cancer, and open biopsy often is mandatory. In screening programs, open biopsies performed for lesions that are at risk of developing malignancy are considered benign. The authors of this report evaluated the impact of the screen‐detected BBL at risk of developing cancer that were counted in the quota of benign breast open biopsies in the Breast Cancer Screening Program of Verona.

METHODS:

Benign open biopsies were subdivided into 4 groups according to their risk of developing cancer: Histo1, normal histology; Histo2, ‘pure’ BBL (fibroadenoma, fibrocystic disease, mastitis, adenosis); Histo3, BBL with a low risk of developing cancer (radial scar, papilloma, papillomatosis, phyllodes tumor, mucocele‐like lesion); and Histo4, BBL with a high risk of developing cancer (atypical columnar cell hyperplasia, atypical ductal hyperplasia, atypical lobular hyperplasia).

RESULTS:

Of 510 open biopsies, 83 biopsies were benign, and the ratio of benign to malignant biopsies was 1:5. Histo1 was observed in 4.8% of all benign open biopsies, Histo2 was observed in 37.4%, Histo3 was observed in 31.3%, and Histo4 was observed 26.5%.

CONCLUSIONS:

BBL at risk of developing cancer may be numerous in screening programs. It is inappropriate to include BBL at risk of developing cancer in the overall benign open biopsy rate. The authors propose separating pure BBL from lesions at higher risk of developing cancer. To date, there is no evidence to support the premise that detecting high‐risk proliferative lesions leads to benefits in terms of reduced mortality; however, these lesions need to be counted separately for future evaluations. Cancer 2009. © 2008 American Cancer Society.     

Association of the ARLTS1 Cys148Arg variant with familial breast cancer risk

Recently, ARLTS1 (ADP-ribosylation factor-like tumor suppressor gene 1) has been identified as a tumor suppressor gene, playing a major role in apoptotic signaling. The ARLTS1 Trp149Stop mutation has been shown to predispose to general familial cancer and high-risk familial breast cancer (BC), provoking the attenuation of apoptotic function. We studied the impact of the ARLTS1 Pro131Leu and Cys148Arg variants on high-risk familial and familial BC risk, investigating 482 familial BC cases (including 305 high-risk cases) and 530 control individuals. Unlike ARLTS1 Pro131Leu, Cys148Arg revealed a significant association with an increased risk of high-risk familial BC (odds ratio (OR)=1.47, 95% confidence interval (95% CI)=1.04-2.06, p=0.03) in a dose-dependent manner (ptrend=0.007). The genotype distribution of Cys148Arg in familial cases was similar, indicating significance as well (OR=1.48, 95% CI=1.10-1.99, p=0.009; ptrend=0.003). On the basis of the small number of 46 cases, we additionally showed an association between the Trp149Stop mutation and an increased risk of bilateral BC (OR=4.11, 95% CI=1.27-13.31, p=0.011).     

A randomized trial of specialist genetic assessment: psychological impact on women at different levels of familial breast cancer risk

The aim was to compare the psychological impact of a multidisciplinary specialist genetics service with surgical provision in women at high risk and those at lower risk of familial breast cancer. Women (n=735) were randomized to a surgical consultation with (trial group) or without (control group) specialist genetic risk assessment and the possible offer of presymptomatic genetic testing. Participants completed questionnaires before and immediately after the consultation to assess anxiety, cancer worry, perceived risk, interest in genetic testing and satisfaction. Responses of subgroups of women stratified by clinicians as low, moderate, or high risk were analyzed. There were no significant main effects of study intervention on any outcome variable. Regardless of risk information, there was a statistically significant reduction in state anxiety (P<0.001). Reductions in cancer worry and perceived risk were significant for women at low or moderate risk (P<0.001) but not those at high risk, and satisfaction was significantly lower in the high risk group (P<0.001). In high risk women who received specialist genetic input, there was a marginally significant trend towards increased perceived risk. The effect of risk information on interest in genetic testing was not significant. Breast care specialists other than geneticists might provide assessments of breast cancer risk, reassuring women at reduced risk and targeting those at high risk for specialist genetic counselling and testing services. These findings are discussed in relation to the existing UK Calman-Hine model of service delivery in cancer genetics. DOI: 10.1038/sj/bjc/6600051 www.bjcancer.comCopyright 2002 The Cancer Research Campaign     

Lobule type and subsequent breast cancer risk: Results from the Nurses' Health Studies

BACKGROUND:

Lobules in normal breast tissue can be classified based on their degree of development, which may affect their susceptibility to carcinogenesis. However, few epidemiologic studies to date have addressed this.

METHODS:

The authors examined the association between lobule type and subsequent breast cancer risk in a nested case‐control study of benign breast disease (BBD) and breast cancer within the Nurses' Health Studies (200 cases, 915 controls). Benign breast biopsy slides were reviewed by pathologists, and normal terminal duct lobular units were classified as having no type 1 lobules, mixed lobule types, or predominant type 1 and no type 3 lobules. Logistic regression was used to compute odds ratios (ORs) and 95% confidence intervals (CIs) for the association between lobule type and breast cancer risk.

RESULTS:

Women with predominant type 1 and no type 3 lobules (54 cases, 321 controls) had a decreased risk of breast cancer compared with those with no type 1 lobules or mixed lobule types (OR=0.63; 95% CI, 0.44‐0.91), although this was attenuated after adjustment for histologic category of BBD (OR=0.71; 95% CI, 0.49‐1.02). Having predominant type 1 lobules and no type 3 lobules was associated with a similar risk reduction for all categories of BBD (nonproliferative: OR=0.73 [95% CI, 0.36‐1.50]; proliferative without atypia: OR=0.80 [95% CI, 0.47‐1.35]; and atypical hyperplasia: OR=0.61 [95% CI, 0.28‐1.35]).

CONCLUSIONS:

These results provided preliminary evidence that lobule type may be an important marker of breast cancer risk in women with BBD. Cancer 2009. © 2009 American Cancer Society.     

Attributable risks for familial breast cancer by proband status and morphology: a nationwide epidemiologic study from Sweden

Population attributable factions (PAFs) show the proportion of the disease that could be prevented if the cause could be removed. The PAF for familial breast cancer has not been precisely determined. We used the nationwide Swedish Family-Cancer Database on 10.2 million individuals and 190,000 mothers' and 26,000 daughters' breast cancers to calculate familial standardized incidence ratios (SIRs), proportion of cases with a family history and familial PAFs for all invasive and in situ and morphology-specific breast cancers in daughters who were 0-66 years old. The data were calculated by mother only, sister only or both as probands. More than 5,500 familial breast cancers were recorded. The familial SIRs for all invasive breast cancer were 1.79 by breast cancer in the mother only, 2.03 by breast cancer in a sister only and 2.82 by breast cancer in both a mother and sister. The familial PAFs were 3.61, 3.01 and 0.43%, respectively, giving a total PAF of 7.05%. Age-specific risks were shown for the mother and sister history of breast cancer. The PAF values decreased by age when the daughter had a mother history of breast cancer but not when she had a sister history. PAFs did not depend on the morphologic type of breast cancer. The data show that the familial PAF of breast cancer among a 0-66-year-old population of daughters was 7% and independent of the morphologic type. If contribution from the paternal side was allowed for, the PAF would be 11%.     

Prospective study of grapefruit intake and risk of breast cancer in postmenopausal women: the Multiethnic Cohort Study

In vitro and in vivo studies have shown that cytochrome P450 3A4 (CYP3A4) is involved in the metabolism of oestrogens. There is evidence that grapefruit, an inhibitor of CYP3A4, increases plasma oestrogen concentrations. Since it is well established that oestrogen is associated with breast cancer risk, it is plausible that regular intake of grapefruit would increase a woman's risk of breast cancer. We investigated the association of grapefruit intake with breast cancer risk in the Hawaii-Los Angeles Multiethnic Cohort Study, a prospective cohort that includes over 50 000 postmenopausal women from five racial/ethnic groups. A total of 1657 incident breast cancer cases were available for analysis. Grapefruit intake was significantly associated with an increased risk of breast cancer (relative risk=1.30, 95% confidence interval 1.06-1.58) for subjects in the highest category of intake, that is, one-quarter grapefruit or more per day, compared to non-consumers (P(trend)=0.015). An increased risk of similar magnitude was seen in users of oestrogen therapy, users of oestrogen+progestin therapy, and among never users of hormone therapy. Grapefruit intake may increase the risk of breast cancer among postmenopausal women.     

Association between meat consumption and risk of breast cancer: Findings from the Sister Study

Meat consumption has been postulated to increase the risk of breast cancer, but this association has not been consistently seen. We examined the association between consumption of different types of meat, meat mutagens and incident invasive breast cancer. Information on consumption of different meat categories and meat cooking practice behaviors was obtained from 42,012 Sister Study participants who completed a Block 1998 Food Frequency Questionnaire at enrollment (2003–2009) and satisfied eligibility criteria. Exposure to meat type and meat mutagens was calculated, and associations with invasive breast cancer risk were estimated using multivariable Cox proportional hazards regression. During follow-up (mean, 7.6 years), 1,536 invasive breast cancers were diagnosed at least 1 year after enrollment. Increasing consumption of red meat was associated with increased risk of invasive breast cancer (HR_{highest vs. lowest quartile}:1.23, 95% CI: 1.02–1.48, p_trend = 0.01). Conversely, increasing consumption of poultry was associated with decreased invasive breast cancer risk (HR _{highest vs. lowest quartile}: 0.85; 95% CI: 0.72–1.00; p_trend = 0.03). In a substitution model with combined red meat and poultry consumption held constant, substituting poultry for red meat was associated with decreased invasive breast cancer risk (HR _{highest vs. lowest quartile} of poultry consumption: 0.72, 95% CI: 0.58–0.89). No associations were observed for cooking practices, estimated heterocyclic amines or heme iron from red meat consumption with breast cancer risk. Red meat consumption may increase the risk of invasive breast cancer, whereas poultry consumption may be associated with reduced risk. Substituting poultry for red meat could reduce breast cancer risk.     

A randomised controlled trial of a psychoeducational intervention for women at increased risk of breast cancer

This study aimed to compare the impact of two versions of a psychoeducational written intervention on cancer worry and objective knowledge of breast cancer risk-related topics in women who had been living with an increased risk of familial breast cancer for several years. Participants were randomised to three conditions: scientific and psychosocial information pack (Group 1), scientific information pack only (Group 2) or standard care control (Group 3). They completed postal questionnaires at baseline (n=163) and 4 weeks (n=151). As predicted, there was a significant decrease in cancer worry for Group 1, but not Group 2. Objective knowledge significantly improved for both Group 1 and Group 2 as expected, but not Group 3. However, there was an unpredicted decline in cancer worry for Group 3. This study supports the value of a scientific and psychosocial information pack in providing up-to-date information related to familial risk of breast cancer for long-term attendees of a familial breast cancer clinic. Further research is warranted to determine how the information pack could be incorporated into the existing clinical service, thus providing these women with the type of ongoing psychosocial support that many familial breast cancer clinics are currently lacking.