Retrospective studies provide conflicting interpretations of the effect of inherited genetic factors on the prognosis of patients with breast cancer. The primary aim of this study was to determine ...the effect of a germline BRCA1 or BRCA2 mutation on breast cancer outcomes in patients with young-onset breast cancer.
We did a prospective cohort study of female patients recruited from 127 hospitals in the UK aged 40 years or younger at first diagnosis (by histological confirmation) of invasive breast cancer. Patients with a previous invasive malignancy (except non-melanomatous skin cancer) were excluded. Patients were identified within 12 months of initial diagnosis. BRCA1 and BRCA2 mutations were identified using blood DNA collected at recruitment. Clinicopathological data, and data regarding treatment and long-term outcomes, including date and site of disease recurrence, were collected from routine medical records at 6 months, 12 months, and then annually until death or loss to follow-up. The primary outcome was overall survival for all BRCA1 or BRCA2 mutation carriers (BRCA-positive) versus all non-carriers (BRCA-negative) at 2 years, 5 years, and 10 years after diagnosis. A prespecified subgroup analysis of overall survival was done in patients with triple-negative breast cancer. Recruitment was completed in 2008, and long-term follow-up is continuing.
Between Jan 24, 2000, and Jan 24, 2008, we recruited 2733 women. Genotyping detected a pathogenic BRCA mutation in 338 (12%) patients (201 with BRCA1, 137 with BRCA2). After a median follow-up of 8·2 years (IQR 6·0–9·9), 651 (96%) of 678 deaths were due to breast cancer. There was no significant difference in overall survival between BRCA-positive and BRCA-negative patients in multivariable analyses at any timepoint (at 2 years: 97·0% 95% CI 94·5–98·4 vs 96·6% 95·8–97·3; at 5 years: 83·8% 79·3–87·5 vs 85·0% 83·5–86·4; at 10 years: 73·4% 67·4–78·5 vs 70·1% 67·7–72·3; hazard ratio HR 0·96 95% CI 0·76–1·22; p=0·76). Of 558 patients with triple-negative breast cancer, BRCA mutation carriers had better overall survival than non-carriers at 2 years (95% 95% CI 89–97 vs 91% 88–94; HR 0·59 95% CI 0·35–0·99; p=0·047) but not 5 years (81% 73–87 vs 74% 70–78; HR 1·13 0·70–1·84; p=0·62) or 10 years (72% 62–80 vs 69% 63–74; HR 2·12 0·82–5·49; p= 0·12).
Patients with young-onset breast cancer who carry a BRCA mutation have similar survival as non-carriers. However, BRCA mutation carriers with triple-negative breast cancer might have a survival advantage during the first few years after diagnosis compared with non-carriers. Decisions about timing of additional surgery aimed at reducing future second primary-cancer risks should take into account patient prognosis associated with the first malignancy and patient preferences.
Cancer Research UK, the UK National Cancer Research Network, the Wessex Cancer Trust, Breast Cancer Now, and the PPP Healthcare Medical Trust Grant.
Breast cancer (BC) risk prediction allows systematic identification of individuals at highest and lowest risk. We extend the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation ...Algorithm (BOADICEA) risk model to incorporate the effects of polygenic risk scores (PRS) and other risk factors (RFs).
BOADICEA incorporates the effects of truncating variants in BRCA1, BRCA2, PALB2, CHEK2, and ATM; a PRS based on 313 single-nucleotide polymorphisms (SNPs) explaining 20% of BC polygenic variance; a residual polygenic component accounting for other genetic/familial effects; known lifestyle/hormonal/reproductive RFs; and mammographic density, while allowing for missing information.
Among all factors considered, the predicted UK BC risk distribution is widest for the PRS, followed by mammographic density. The highest BC risk stratification is achieved when all genetic and lifestyle/hormonal/reproductive/anthropomorphic factors are considered jointly. With all factors, the predicted lifetime risks for women in the UK population vary from 2.8% for the 1st percentile to 30.6% for the 99th percentile, with 14.7% of women predicted to have a lifetime risk of ≥17-<30% (moderate risk according to National Institute for Health and Care Excellence NICE guidelines) and 1.1% a lifetime risk of ≥30% (high risk).
This comprehensive model should enable high levels of BC risk stratification in the general population and women with family history, and facilitate individualized, informed decision-making on prevention therapies and screening.
The principle of risk-stratified screening, beyond age and sex, is already incorporated into guidelines by the National Institute for Health and Care Excellence (NICE)1 and others, for example ...through offering enhanced breast cancer screening to women with a family history of breast cancer. In this regard, PRS tools have shown promise in providing personalised risk prediction and informing cancer screening strategies.2,3 Combining PRS with age and other risk factors would allow for improved risk stratification for risk-targeted and risk-tailored cancer screening.4 In The Lancet Oncology, Catherine Huntley and colleagues5 model the outcome of hypothetical screening programmes in terms of cancer detection and cancer deaths averted, by initiating or extending screening for several cancers, including breast (for women aged 40–49 years), colorectal (for individuals aged 50–59 years), and prostate cancers (for men aged 60–69 years) to individuals with a high PRS. In practice, stratification can also be considerably improved by combining PRS with other risk factors (notably, family history and, for breast cancer, breast imaging markers).4 Huntley and colleagues focused on providing additional screening to the PRS-defined high-risk group, but there are several other ways in which risk-stratified screening might be used—most importantly, by providing less intensive screening to low-risk individuals (to reduce the unnecessary harms and costs of overscreening) and tailoring screening age range, frequency, and method to each risk group.
The CanRisk Tool (https://canrisk.org) is the next-generation web interface for the latest version of the BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) ...state-of-the-art risk model and a forthcoming ovarian cancer risk model.
The tool captures information on family history, rare pathogenic variants in cancer susceptibility genes, polygenic risk scores, lifestyle/hormonal/clinical features, and imaging risk factors to predict breast and ovarian cancer risks and estimate the probabilities of carrying pathogenic variants in certain genes. It was implemented using modern web frameworks, technologies, and web services to make it extensible and increase accessibility to researchers and third-party applications. The design of the graphical user interface was informed by feedback from health care professionals and a formal evaluation.
This freely accessible tool was designed to be user friendly for clinicians and to boost acceptability in clinical settings. The tool incorporates a novel graphical pedigree builder to facilitate collection of the family history data required by risk calculations.
The CanRisk Tool provides health care professionals and researchers with a user-friendly interface to carry out multifactorial breast and ovarian cancer risk predictions. It is the first freely accessible cancer risk prediction program to carry the CE marking.
There have been over 3,100 account registrations, and 98,000 breast and ovarian cancer risk calculations have been run within the first 9 months of the CanRisk Tool launch.
Testosterone supplementation is commonly used for its effects on sexual function, bone health and body composition, yet its effects on disease outcomes are unknown. To better understand this, we ...identified genetic determinants of testosterone levels and related sex hormone traits in 425,097 UK Biobank study participants. Using 2,571 genome-wide significant associations, we demonstrate that the genetic determinants of testosterone levels are substantially different between sexes and that genetically higher testosterone is harmful for metabolic diseases in women but beneficial in men. For example, a genetically determined 1 s.d. higher testosterone increases the risks of type 2 diabetes (odds ratio (OR) = 1.37 (95% confidence interval (95% CI): 1.22-1.53)) and polycystic ovary syndrome (OR = 1.51 (95% CI: 1.33-1.72)) in women, but reduces type 2 diabetes risk in men (OR = 0.86 (95% CI: 0.76-0.98)). We also show adverse effects of higher testosterone on breast and endometrial cancers in women and prostate cancer in men. Our findings provide insights into the disease impacts of testosterone and highlight the importance of sex-specific genetic analyses.
Genome-wide association studies (GWAS) have revolutionized the field of cancer genetics, but the causal links between increased genetic risk and onset/progression of disease processes remain to be ...identified. Here we report the first step in such an endeavor for prostate cancer. We provide a comprehensive annotation of the 77 known risk loci, based upon highly correlated variants in biologically relevant chromatin annotations--we identified 727 such potentially functional SNPs. We also provide a detailed account of possible protein disruption, microRNA target sequence disruption and regulatory response element disruption of all correlated SNPs at r(2) ≥ 0.88%. 88% of the 727 SNPs fall within putative enhancers, and many alter critical residues in the response elements of transcription factors known to be involved in prostate biology. We define as risk enhancers those regions with enhancer chromatin biofeatures in prostate-derived cell lines with prostate-cancer correlated SNPs. To aid the identification of these enhancers, we performed genomewide ChIP-seq for H3K27-acetylation, a mark of actively engaged enhancers, as well as the transcription factor TCF7L2. We analyzed in depth three variants in risk enhancers, two of which show significantly altered androgen sensitivity in LNCaP cells. This includes rs4907792, that is in linkage disequilibrium (r(2) = 0.91) with an eQTL for NUDT11 (on the X chromosome) in prostate tissue, and rs10486567, the index SNP in intron 3 of the JAZF1 gene on chromosome 7. Rs4907792 is within a critical residue of a strong consensus androgen response element that is interrupted in the protective allele, resulting in a 56% decrease in its androgen sensitivity, whereas rs10486567 affects both NKX3-1 and FOXA-AR motifs where the risk allele results in a 39% increase in basal activity and a 28% fold-increase in androgen stimulated enhancer activity. Identification of such enhancer variants and their potential target genes represents a preliminary step in connecting risk to disease process.
There is a growing focus on the development of multi-factorial cancer risk prediction algorithms alongside tools that operationalise them for clinical use. BOADICEA is a breast and ovarian cancer ...risk prediction model incorporating genetic and other risk factors. A new user-friendly Web-based tool (CanRisk.org) has been developed to apply BOADICEA. This study aimed to explore the acceptability of the prototype CanRisk tool among two healthcare professional groups to inform further development, evaluation and implementation.
A multi-methods approach was used. Clinicians from primary care and specialist genetics clinics in England, France and Germany were invited to use the CanRisk prototype with two test cases (either face-to-face with a simulated patient or via a written vignette). Their views about the tool were examined via a semi-structured interview or equivalent open-ended questionnaire. Qualitative data were subjected to thematic analysis and organised around Sekhon's Theoretical Framework of Acceptability.
Seventy-five clinicians participated, 21 from primary care and 54 from specialist genetics clinics. Participants were from England (n = 37), France (n = 23) and Germany (n = 15). The prototype CanRisk tool was generally acceptable to most participants due to its intuitive design. Primary care clinicians were concerned about the amount of time needed to complete, interpret and communicate risk information. Clinicians from both settings were apprehensive about the impact of the CanRisk tool on their consultations and lack of opportunities to interpret risk scores before sharing them with their patients.
The findings highlight the challenges associated with developing a complex tool for use in different clinical settings; they also helped refine the tool. This prototype may not have been versatile enough for clinical use in both primary care and specialist genetics clinics where the needs of clinicians are different, emphasising the importance of understanding the clinical context when developing cancer risk assessment tools.
The European Collaborative on Personalized Early Detection and Prevention of Breast Cancer (ENVISION) brings together several international research consortia working on different aspects of the ...personalized early detection and prevention of breast cancer. In a consensus conference held in 2019, the members of this network identified research areas requiring development to enable evidence-based personalized interventions that might improve the benefits and reduce the harms of existing breast cancer screening and prevention programmes. The priority areas identified were: 1) breast cancer subtype-specific risk assessment tools applicable to women of all ancestries; 2) intermediate surrogate markers of response to preventive measures; 3) novel non-surgical preventive measures to reduce the incidence of breast cancer of poor prognosis; and 4) hybrid effectiveness-implementation research combined with modelling studies to evaluate the long-term population outcomes of risk-based early detection strategies. The implementation of such programmes would require health-care systems to be open to learning and adapting, the engagement of a diverse range of stakeholders and tailoring to societal norms and values, while also addressing the ethical and legal issues. In this Consensus Statement, we discuss the current state of breast cancer risk prediction, risk-stratified prevention and early detection strategies, and their implementation. Throughout, we highlight priorities for advancing each of these areas.
Reliable estimates of cancer risk are critical for guiding management of BRCA1 and BRCA2 mutation carriers. The aims of this study were to derive penetrance estimates for breast cancer, ovarian ...cancer, and contralateral breast cancer in a prospective series of mutation carriers and to assess how these risks are modified by common breast cancer susceptibility alleles.
Prospective cancer risks were estimated using a cohort of 978 BRCA1 and 909 BRCA2 carriers from the United Kingdom. Nine hundred eighty-eight women had no breast or ovarian cancer diagnosis at baseline, 1509 women were unaffected by ovarian cancer, and 651 had been diagnosed with unilateral breast cancer. Cumulative risks were obtained using Kaplan-Meier estimates. Associations between cancer risk and covariables of interest were evaluated using Cox regression. All statistical tests were two-sided.
The average cumulative risks by age 70 years for BRCA1 carriers were estimated to be 60% (95% confidence interval CI = 44% to 75%) for breast cancer, 59% (95% CI = 43% to 76%) for ovarian cancer, and 83% (95% CI = 69% to 94%) for contralateral breast cancer. For BRCA2 carriers, the corresponding risks were 55% (95% CI = 41% to 70%) for breast cancer, 16.5% (95% CI = 7.5% to 34%) for ovarian cancer, and 62% (95% CI = 44% to 79.5%) for contralateral breast cancer. BRCA2 carriers in the highest tertile of risk, defined by the joint genotype distribution of seven single nucleotide polymorphisms associated with breast cancer risk, were at statistically significantly higher risk of developing breast cancer than those in the lowest tertile (hazard ratio = 4.1, 95% CI = 1.2 to 14.5; P = .02).
Prospective risk estimates confirm that BRCA1 and BRCA2 carriers are at high risk of developing breast, ovarian, and contralateral breast cancer. Our results confirm findings from retrospective studies that common breast cancer susceptibility alleles in combination are predictive of breast cancer risk for BRCA2 carriers.
Genetic susceptibility to breast cancer Mavaddat, Nasim; Antoniou, Antonis C.; Easton, Douglas F. ...
Molecular oncology,
June 2010, Letnik:
4, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Genetic and lifestyle/environmental factors are implicated in the aetiology of breast cancer. This review summarizes the current state of knowledge on rare high penetrance mutations, as well as ...moderate and low-penetrance genetic variants implicated in breast cancer aetiology. We summarize recent discoveries from large collaborative efforts to combine data from candidate gene studies, and to conduct genome-wide association studies (GWAS), primarily in breast cancers in the general population. These findings are compared with results from collaborative efforts aiming to identify genetic modifiers in
BRCA1 and
BRCA2 carriers. Breast cancer is a heterogeneous disease, and tumours from
BRCA1 and
BRCA2 carriers display distinct pathological characteristics when compared with tumours unselected for family history. The relationship between genetic variants and pathological subtypes of breast cancer, and the implication of discoveries of novel genetic variants to risk prediction in
BRCA1/2 mutation carriers and in populations unselected for mutation carrier status, are discussed.
PDF
