Genetic Breast Cancer Risk Research Articles

Living with genetic risk of breast cancer: what have we learned?

Since genetic testing became a possibility for breast cancer predisposition in the mid-1990s, research attention has focused on the impact of predictive genetic testing for people who are told they are at significantly increased risk of developing breast cancer. The present study will review research evidence for the impact of testing in terms of distress experienced and risk management strategies adopted to manage risk of developing breast cancer [1,2]. In addition to the psychosocial implications and impact on risk management behaviour, research has uncovered dilemmas that people face in talking to their family members. This presentation will highlight some of the dilemmas that genetic testing and associated research has raised for families who are living with a family history of breast cancer [3,4]. With the evidence base that now exists, the challenge for the future is to develop interventions to support people undergoing genetic testing. In Southampton we are developing an intervention to support discussions within families about genetic testing and associated risks.

Complementary and alternative medicine use among women at increased genetic risk of breast and ovarian cancer.

BackgroundComplementary and alternative medicine (CAM) use is well documented among breast cancer patients and survivors, but little evidence is available to describe rates and patterns of use among women at increased genetic risk of breast cancer.MethodsA pre-visit telephone interview was conducted to ascertain CAM use among the BRCA mutation carriers enrolled in a high-risk breast cancer screening study. Participants were asked to report on their use of thirteen therapies within the year prior to enrollment into the study. Logistic regression was used to evaluate the association between various factors and CAM use in this population.ResultsAmong the 164 BRCA1 or BRCA2 mutation-positive (BRCA+) women in this analysis, 78% reported CAM use, with prayer and lifestyle diet being the two most commonly reported modalities. Many subjects used multiple CAM therapies, with 34% reporting use of three or more modalities. The most commonly used modalities were mind-body therapies and biologically-based practices, 61.6% and 51.8%, respectively. High-risk women were more likely to use CAM if they were older, more educated, more worried about ovarian cancer risk, or had a previous cancer diagnosis.ConclusionThis study suggests that the prevalence of CAM use is high among BRCA mutation carriers, with frequency of use comparable to that of breast cancer patients and survivors. Given the high prevalence of CAM use in our subjects, especially biologically-based therapies including herbal supplements, whose safety and efficacy in relation to cancer risk are unknown, our study suggests that future research is necessary to clarify these risks, and that it is important for providers to inquire about and to discuss the pros and cons of CAM use with their BRCA+ patients.

Peroxisome proliferator-activated receptor-alpha (PPARA) genetic polymorphisms and breast cancer risk: a Long Island ancillary study

Peroxisome proliferator-activated receptor-alpha (PPARA) has been shown to increase fatty acid oxidation and decrease cytokine levels and has been implicated in insulin production. Genetic variants of PPARA have been associated with cardiovascular disease, obesity and type II diabetes mellitus. Although no research to date has investigated the possible link between PPARA and breast cancer, the function of this gene suggests that it could play a role in breast cancer development. Six PPARA polymorphisms were evaluated in association with incident breast cancer in a population-based case-control study (n = 1073 cases and n = 1112 controls) using unconditional logistic and multilevel regression and haplotype-based analyses. The odds of breast cancer were doubled among women with PPARA polymorphism rs4253760 (odds ratio = 1.97 for rare versus common homozygote alleles; 95% confidence interval: 1.14, 3.43). This association remained constant with the inclusion of all interrogated polymorphisms studied in hierarchical models. No additive interactions with body mass index or weight gain were present, but there was some evidence of interaction between PPARA variants and aspirin use, defined as use at least once per week for 6 months or longer. Fourteen haplotypes were imputed with frequencies >1% among postmenopausal women, but no statistically significant differences in haplotype frequencies between cases and controls were evident. Our results are the first to evaluate the relationship between PPARA and breast cancer incidence and suggest that replication in an independent cohort is warranted.

Single nucleotide polymorphism D1853N of the ATM gene may alter the risk for breast cancer

Various ATM (ataxia telangiectasia-mutated) mutations and polymorphisms have been reported to be associated with an increased breast cancer risk. Recent studies have produced contradictory results regarding the association between ATM genetic variants and breast cancer risk. The common ATM polymorphism 5557G>A (p.D1853N) (rs1801516), previously suggested to be associated with bilateral breast cancer, was analyzed using real-time PCR in 514 unselected patients with breast cancer and 511 age-matched healthy control individuals. DNA was obtained from peripheral blood draw. The ATM genotype was weakly associated with the risk for breast cancer (P = 0.04 for the overall test). The odds ratio for women with a heterozygous genotype was 0.70 (95% CI, 0.52-0.94) and for the homozygous variant 0.63 (95% CI, 0.27-1.49). Disease-free survival and overall survival showed no significant association with specific genotypes. The results of this study might suggest a minor association between polymorphism 5557G>A and a reduced risk of breast cancer.

Peroxisome proliferator-activated receptor-alpha (PPARA) genetic polymorphisms and breast cancer risk: a Long Island ancillary study

Peroxisome proliferator-activated receptor-alpha (PPARA) genetic polymorphisms and breast cancer risk: a Long Island ancillary study

IGF-I and IGF-II Genetic Variation and Breast Cancer Risk in Chinese Women: Results from the Shanghai Breast Cancer Study

Insulin-like growth factor (IGF)-I and IGF-II have been implicated in breast tumorigenesis due to their ability to stimulate mitogenesis and promote differentiation and their key role in mammary gland cell proliferation and survival ([1][1]-[3][2]). It has been reported that genetic variations in

Mammographiescreening in Deutschland

Available data suggest that early detection of breast cancer by mammography screening can reduce mortality by about 25%. Intensified monitoring of women with a family history of breast cancer and regular general screening have recently been introduced in Germany. The screening program is expected to be fully established by 2008. Following its successful introduction (participation rates between 65 and 80%), the German screening program will be conducted and evaluated in accordance with the European guidelines. At least in the screening trials that were conducted prior to the now established screening program the quality criteria were more than fulfilled (e.g. cancer detection rate in Bremen 8.7, Wiesbaden 9.4, Weser-Ems region 8.3/1000). Additional parameters that can be taken into account for quality assurance are the overdiagnosis bias, lead time bias, length bias and selection bias. Moreover, there are some factors that are specific to the German program compared with the breast cancer screening programs already established in other countries. One of these is the intensified screening program for high-risk women (ca. 5% of all carcinomas) and as a result fewer women with an increased genetic risk of breast cancer will be represented in the general screening program. The German screening program involves only a few university centers and hospital-based physicians, which may have adverse effects on research and development as well as mammography training in the future. Therefore, the screening program should also provide for the investigation of new techniques or emerging techniques (e.g. CAD systems in screening mammography) in the future.

CYP17Genetic Variation and Risk of Breast and Prostate Cancer from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3)

CYP17 encodes cytochrome p450c17alpha, which mediates activities essential for the production of sex steroids. Common germ line variation in the CYP17 gene has been related to inconsistent results in breast and prostate cancer, with most studies focusing on the nonsynonymous single nucleotide polymorphism (SNP) T27C (rs743572). We comprehensively characterized variation in CYP17 by direct sequencing of exons followed by dense genotyping across the 58 kb region around CYP17 in five racial/ethnic populations. Two blocks of strong linkage disequilibrium were identified and nine haplotype-tagging SNPs, including T27C, were chosen to predict common haplotypes (R(h)(2) >or= 0.85). These haplotype-tagging SNPs were genotyped in 8,138 prostate cancer cases and 9,033 controls, and 5,333 breast cancer cases and 7,069 controls from the Breast and Prostate Cancer Cohort Consortium. We observed borderline significant associations with prostate cancer for rs2486758 [TC versus TT, odds ratios (OR), 1.07; 95% confidence intervals (95% CI), 1.00-1.14; CC versus TT, OR, 1.09; 95% CI, 0.95-1.26; P trend=0.04] and rs6892 (AG versus AA, OR, 1.08; 95% CI, 1.00-1.15; GG versus AA, OR, 1.11; 95% CI, 0.95-1.30; P trend=0.03). We also observed marginally significant associations with breast cancer for rs4919687 (GA versus GG, OR, 1.04; 95% CI, 0.97-1.12, AA versus GG, OR, 1.17; 95% CI, 1.03-1.34; P trend=0.03) and rs4919682 (CT versus CC, OR, 1.04; 95% CI, 0.97-1.12; TT versus CC, OR, 1.16; 95% CI, 1.01-1.33; P trend=0.04). Common variation at CYP17 was not associated with circulating sex steroid hormones in men or postmenopausal women. Our findings do not support the hypothesis that common germ line variation in CYP17 makes a substantial contribution to postmenopausal breast or prostate cancer susceptibility.

Rexinoids and Breast Cancer Prevention

In this issue of Clinical Cancer Research , Li et al. investigate the chemopreventive potential of the retinoid, LG100268 ([1][1]). The application of retinoids to cancer chemoprevention has a long history which predates the identification of retinoid receptors ([2][2], [3][3]). Early clinical

Genetic polymorphisms in the apoptosis-associated genes FAS and FASL and breast cancer risk

FAS and FAS ligand (FASL) play key roles in apoptotic signaling and down-regulation of this pathway may facilitate tumorigenesis. Alterations in apoptosis genes may affect cancer risk by influencing individual susceptibility to environmental carcinogens. Using a population-based breast cancer case-control study on Long Island, New York, we examined whether polymorphisms in FAS and FASL modified the association between breast cancer risk and a marker of environmental exposures, polycyclic aromatic hydrocarbon (PAH)-DNA adducts. We examined polymorphisms in FAS (5' UTR -1377G/A and 5' UTR -670G/A) and FASL (5' UTR -844C/T) in 1053 breast cancer cases and 1102 population-based controls. There was no significant association between these genetic polymorphisms and breast cancer risk. The presence of at least one variant allele (GA or AA) in FAS1377 was associated with a 36% increase in breast cancer risk among those with detectable PAH-DNA adduct levels [odds ratio (OR) = 1.36, 95% confidence interval (CI) = 1.01-1.83]. In addition, lactation history significantly modified the association between FAS1377 and FAS670 genetic variants and breast cancer risk (OR = 1.46, 95% CI = 1.04-2.06 and OR = 1.71, 95% CI = 1.13-1.58, respectively, in those who ever lactated compared with those who did not with the wild-type alleles). Overall, this study suggests that the risk of breast cancer may be elevated among women with polymorphisms in the FAS gene and detectable PAH-DNA adducts.

ERBB2 genetic polymorphism and breast cancer risk in Chinese women: a population-based case-control study

A polymorphism at codon 655 (ATC/isoleucine to GTC/valine [Ile655Val], rs1801200) in the transmembrane domain-coding region of human ERBB2 gene has been previously evaluated for its association with breast cancer risk with mixed results. We evaluated this polymorphism in association with breast cancer in a group of women who participated in a large-scale, population-based, case-control study of breast cancer in Shanghai, China, followed by an in vitro analysis of the function of this polymorphism. Genomic DNA from 3,012 patients with breast cancer and 3,004 healthy controls was examined for the Ile655Val polymorphism using a TaqMan genotyping method. Adjusted odds ratios (OR) were derived from multiple logistic regression. In vitro analyses were carried out to examine whether the Ile655Val polymorphism affect ERBB2 expression and the activity of its downstream targets. Approximately 2% of study subjects carry the Val/Val genotype. Compared with women with the Ile/Ile (76%) genotype, women who had the Ile/Val (22%) or Val/Val genotype did not have an elevated risk of breast cancer. Stratified analyses by age and menopausal status revealed no apparent association with this polymorphism in any subgroups of women. In a serious of biochemical analyses, we found that the Ile655Val substitution did not alter ErbB2 and its downstream signaling molecule activity. These study results suggest that Ile655Val polymorphism of the ERBB2 gene do not alter its activity and may not be associated with increased breast cancer risk among Chinese women.

Risk estimation for familial breast cancer: improving the system of counselling

Women with a family history of breast cancer dominate referrals for cancer genetic risk counselling across Europe. Given limited health care resources, managing this demand, while achieving good value for money for health services, is a major challenge. The paper reports the benefits and associated costs of moving from a traditional system of deriving family history of cancer during the patient's initial clinic attendance, to a protocol-driven system with pre-counselling assessment of family history. The evaluation was based on retrospective clinical data and a clinical audit. Changes in risk between referral and final risk assessment were ascertained and the cost difference between the two systems estimated. The study results showed that 14% of women assessed as 'low' genetic risk at referral were reassessed as 'moderate' or 'high' genetic risk for breast cancer following verification of family history. Sixteen per cent of those assessed as 'moderate' or 'high' genetic risk at referral were reassessed as 'low' genetic risk for breast cancer. Compared to the traditional system, the new protocol-driven system of risk assessment was more consistent, which reduced the number of return appointments and created time for clinicians to spend with other patients. The estimated cost of family history verification and genetic clinic appointment was calculated as 91.68 pounds (132.53 euro) per family history, compared to 104.00 pounds (150.34 euro) for the traditional system, representing a slight reduction in health service costs. Finally, the protocol-driven system can be used as part of ongoing audit for planning future genetics services in Scotland.

Modeling Genetic Risk of Breast Cancer

Modeling Genetic Risk of Breast Cancer

The Impact of Breast Cancer Genetic Risk Assessment on Intentions to Perform Cancer Surveillance Behaviors

One hundred and fifty-four women undergoing breast/ovarian cancer genetic risk assessment completed questionnaires at entry into the Cancer Genetic Service for Wales (CGSW) assessment program and following risk provision, mapping the strength of intentions to engage in a number of preventive/surveillance behaviors, including seeing specialists, breast self-examination, and involvement in screening programs, including mammography. A number of potential predictors of intentions were also assessed, including participants' mood and emotional response to receiving risk information, the perceived benefits (in terms of reassurance and early disease detection) of engaging in each preventive behavior, and the perceived desires of their family and General Practitioner. Intentions to self-examine did not change following risk provision, although strength of intentions to engage in some other preventive behaviors did lessen. Family and General Practitioners appeared to be strong social influences on behavioral intentions, as were the perceived benefits of gaining reassurance and/or early detection of disease.

Analysis of Morbidity with Unilateral vs. Bilateral Microvascular TRAM Breast Reconstruction

A greater understanding of the associated familial relationship and genetic risk of breast cancer has led oncologic surgeons to recommend prophylactic mastectomies more frequently. This places a greater demand on the reconstructive surgeon and potentially poses a greater risk to the patient. The microvascular transverse abdominis myocutaneous (TRAM) flap is frequently used in both bilateral and unilateral breast reconstruction. The purpose of this study was to compare the morbidity of unilateral vs. bilateral microvascular TRAM procedures, with the hypothesis that there is no significant difference in morbidity between the two procedures.

MRI in the Early Detection of Breast Cancer in Women with High Genetic Risk

Women with BRCA1 or BRCA2 germline mutations have an elevated risk of developing breast and/or ovarian cancer. Because of the early onset of the disease, screening of this group of women should start at an earlier age than in the general population. The association of breast magnetic resonance imaging (BMRI) and ultrasonography (US) with mammography (MX) and clinical breast examination (CBE) in the regular surveillance of these individuals has been proposed and seems to improve the early detection of breast cancer. Within a multicenter study started by the Istituto Superiore di Sanità (Rome), at the Istituto Nazionale Tumori of Milan (INT) we enrolled 116 women at high genetic risk for breast cancer; they were either BRCA1 or BRCA2 mutation carriers or had a strong family history of breast cancer. They underwent CBE, MX, US and BMRI once a year. Between June 2000 and April 2005, at INT 12 cancers were detected among the 116 screened individuals (10%). In this subgroup, 1 patient refused BMRI and in 2 cases US was not performed. With BMRI we found 11 cancers and 6 of them were detectable only by this technique. In these 6 cases, the size of the disease was less than 1 cm and MX was false negative due to irregularly nodular parenchyma in 4 cases and scar tissue or prosthesis in the other 2. US was not performed in 2 cases and was false negative in 4 cases. Three false positive results were found with BMRI: 1 case was considered suspect but related to hormonal influences; 1 case with the same pattern was sent for second-look US, which gave a negative result and BMRI review after 6 months showed normalization of the parenchyma; in the third case histology revealed the presence of adenosis. No false positive results were registered for MX. The aim of secondary prevention is the detection of cancer at its earliest stage. BMRI screening in women with BRCA1 or BRCA2 mutations or at high familiar risk appears to be highly sensitive and may detect mammographically occult disease. The accuracy of MR imaging is higher than that of conventional imaging but the technique is flawed by a lower specificity. In order to avoid unnecessary biopsies we believe that the combination of BMRI and conventional imaging can be very useful in screening women with a high genetic risk of breast cancer, especially with second-look evaluation by means of US when BMRI yields the only positive diagnostic result. Second-look US has been demonstrated to be of critical importance both in recognizing false positive BMRI results and in guiding biopsies, when necessary.

CYP1A1 and CYP1B1 genetic polymorphisms, smoking and breast cancer risk in a Finnish Caucasian population

We investigated the associations between two CYP1A1 polymorphisms (Ile462Val and Thr461Asn) and one CYP1B1 polymorphism (Leu432Val) and breast cancer risk. The study population consisted of 483 breast cancer patients and 482 healthy population controls, all of homogenous Finnish origin. No statistically significant overall associations were found between the CYP1A1 and CYP1B1 genotypes and breast cancer risk. However, a significant increase in the breast cancer risk was seen for women who had smoked 1-9 cigarettes/day and carried the CYP1B1 432Val allele; the OR was 2.6 (95% CI 1.07-6.46) for women carrying the Leu/Val genotype and 5.1 (95% CI 1.30-19.89, P for trend 0.005) for women with the Val/Val genotype compared to similarly smoking women homozygous for the 432Leu allele. Furthermore, when CYP1B1 genotypes were combined with the previously analyzed N-acetyl transferase (NAT2) genotypes, a significant increase in breast cancer risk was found among women who had at least one CYP1B1 432Val allele together with the NAT2 slow acetylator genotype (OR 1.52; 95% CI 1.03-2.24) compared to women carrying a combination of CYP1B1 Leu/Leu and NAT2 rapid acetylator genotypes. This risk was seen to be confined to ever smokers; the OR was 2.46 (95% CI 1.11-5.45) for ever smokers carrying at least one CYP1B1 432Val allele together with the NAT2 slow acetylator genotype compared to ever smokers with the CYP1B1 Leu/Leu and NAT2 rapid acetylator genotype combination. Our results suggest that the CYP1B1 polymorphism may be an important modifier of breast cancer risk in Finnish Caucasian women who have been exposed to tobacco smoke and/or carry the NAT2 slow acetylator genotype.

Hypoxia-inducible factor-1 in human breast and prostate cancer

The tumor microenvironment is best characterized as a fluctuation of hypoxia and nutrient deprivation, which leads to epigenetic and genetic adaptation of clones and increased invasiveness and metastasis. In turn, these hypoxic adaptations make the tumors more difficult to treat and confer increased resistance to current therapies. Part of this adaptation is the regulation of gene products in response to hypoxia. Many of these hypoxia-regulated genes are mediated by the hypoxia-inducible factor 1 (HIF-1) complex, which is composed of a heterodimer pair of HIF-1alpha and HIF-1beta. This heterodimer binds to the promoter of hypoxia-responsive genes, while interacting with other transcription factors, such as p300, signal and transducer of transcription 3, and Redox effector factor 1/apurinic/apyrimidinic endonuclease. HIF-1alpha levels itself can be regulated by hypoxia transcriptionally and post-translationally through ubiquitination; but the magnitude of the response is modulated by several other pathways, including free radicals that affect crosstalk with HIF-1alpha/HIF-1beta transcriptional activities. HIF-1alpha has emerged as an important transcription factor in breast cancer and prostate cancer biology, and is expressed in the early stages of mammary and prostate carcinogenesis. Its expression is correlated with diagnostic and prognostic indicators for early relapse and metastatic disease, thus making HIF-1alpha a potential prognostic biomarker in proteomic assessments of breast and prostate cancers. The importance of HIF-1alpha in tumor progression makes it a logical target for chemoprevention strategies in patients at higher genetic risk of breast and prostate cancer with Cox 2 inhibitors or 2-methoxyestradiol, as well as a target for new approaches to inhibiting angiogenesis. The crosstalk between estrogen signaling pathways and HIF-1alpha is still not fully defined in breast cancer, but downstream estrogen receptor signaling may be a candidate for estrogen modulation of HIF-1alpha levels. In prostate cancer, androgens upregulate HIF-1alpha through androgen-regulated autocrine receptor tyrosine kinase receptor signaling. This review will put into perspective the role of HIF-1alpha in endocrine oncology and present new data on HIF-1alpha signaling and the potential for targeted therapies, including combinatory hormonal therapies.

Breast Cancer Diagnosis in Women ≤ 40 versus 50 to 60 Years: Increasing Size and Stage Disparity Compared With Older Women Over Time

Women < or = 40 years account for 5% of new breast cancer diagnoses. Although there is increased awareness of genetic and other breast cancer risk factors, it is not clear whether this has resulted in earlier diagnosis in young women. A database review identified 8892 women treated for breast cancer from 1980 to 2002. We compared 925 women aged < or = 40 years with 2362 women aged 50 to 60 years. The mean and median tumor size and lymph node status were determined for each group. There were significant differences in tumor size and lymph node status in younger versus older women. From 1980 to the mid 1990s, tumor size and nodal status did not differ. Since the mid 1990s, tumor size has decreased more rapidly for women aged 50 to 60 years than for those < or = 40 years. In 1998 to 2002, the mean tumor size reached a plateau of 1.8 cm in women 50 to 60 years, compared with a plateau of 2.4 cm in women < or = 40 years (P < .001). The median tumor size in 1998 to 2002 was 1.4 cm in women 50 to 60 years compared with 1.9 cm in women < or = 40 years (P < .001). Lymph node status was also significantly different during 1998 to 2002: 23.9% positive in women 50 to 60 years versus 35.2% in women < or = 40 years (P < .001). Since the 1980s, women aged 50 to 60 years have enjoyed a greater decrease in tumor size and percentage with positive nodes. These data could be the result of ineffective screening of younger women or of more aggressive tumor biology. Further study is required to determine whether more effective identification and screening of young, high-risk women can result in earlier detection.

Genetic nurse counsellors can be an acceptable and cost-effective alternative to clinical geneticists for breast cancer risk genetic counselling. Evidence from two parallel randomised controlled equivalence trials

This study compared genetic nurse counsellors with standard services for breast cancer genetic risk counselling services in two regional genetics centres, in Grampian region, North East Scotland and in Cardiff, Wales. Women referred for genetic counselling were randomised to an initial genetic counselling appointment with either a genetic nurse counsellor (intervention) or a clinical geneticist (current service, control). Participants completed postal questionnaires before, immediately after the counselling episode and 6 months later to assess anxiety, general health status, perceived risk and satisfaction. A parallel economic evaluation explored factors influencing cost-effectiveness. The two concurrent randomised controlled equivalence trials were conducted and analysed separately. In the Grampian trial, 289 patients (193 intervention, 96 control) and in the Wales trial 297 patients (197 intervention and 100 control) returned a baseline questionnaire and attended their appointment. Analysis suggested at least likely equivalence in anxiety (the primary outcome) between the two arms of the trials. The cost per counselling episode was £11.54 less for nurse-based care in the Grampian trial and £12.50 more for nurse-based care in Cardiff. The costs were sensitive to the grade of doctor (notionally) replaced and the extent of consultant supervision required by the nurse. In conclusion, care based on genetic nurse counsellors was not significantly different from conventional cancer genetic services in both trial locations.