Characterization of the HER2 status in BRCA-mutated breast cancer: a single institutional series and systematic review with pooled analysis.

BACKGROUND: Pathogenic variants (PVs) in BRCA1/2 genes account for ∼6% of breast and 20% of ovarian cancers. Most breast tumors developed by BRCA1 carriers are triple negative. BRCA2 tumors have similar rates of estrogen receptor positivity as sporadic controls but are less likely to be human epidermal growth factor receptor 2 (HER2)-positive. Prevalence of HER2 positivity among breast cancers (BCs) in BRCA1/2 mutation carriers is poorly and variably described, ranging from 0% to 10% and 0% to 13% in BRCA1 and BRCA2 carriers, respectively. PATIENTS AND METHODS: We assessed the prevalence of HER2 positivity among a single institutional cohort of 398 BCs developed in carriers of BRCA1/2 PVs (240 BRCA1, 158 BRCA2). Subsequently, a systematic review of the literature and pooled analysis was carried out. RESULTS: In our series we found a 7% HER2 positivity rate among all first BRCA1/2 BCs overall. In BRCA1 carriers, 5.4% of BCs were HER2-positive compared with 9.5% in BRCA2-mutated patients. Among bilateral BCs, HER2-positive cases were 15.2% in the BRCA1 group and 23.1% in the BRCA2 group. Notably, six BRCA1 and eight BRCA2 carriers showed discordant HER2 status between BC and bilateral BC (23.7%, 14/59). The systematic review included 21 083 BRCA1/2 patients from 73 eligible studies. The pooled rate of BRCAmut/HER2-positive BCs is 9.1% (95% confidence interval 7.3% to 11.2%). BRCA1 and BRCA2 when reported as separate data ranged from 0% to 33.3% (mean 8.3%) and from 0% to 86% (mean 10.3%), respectively. CONCLUSIONS: As compared with sporadic cases, BCs occurring in BRCA1 and/or BRCA2 PVs carriers are less frequently HER2-positive. Prevalence of HER2 positivity in our series was consistent with pooled analysis and did not exceed 10%. Although not common, co-existence of BRCA mutations and HER2 overexpression and/or gene amplification should be acknowledged. More research is needed to better characterize this subgroup of patients who should not be excluded a priori from clinical trials of targeted therapy for BRCA1/2-driven cancers.

Comparison of multistate model, survival regression, and matched case-control methods for estimating excess length of stay due to healthcare-associated infections.

BACKGROUND: A recent systematic review recommended time-varying methods for minimizing bias when estimating the excess length of stay (LOS) for healthcare-associated infections (HAIs); however, little evidence exists concerning which time-varying method is best used for HAI incidence studies. AIM: To undertake a retrospective analysis of data from a one-year prospective incidence study of HAIs, in one teaching hospital and one general hospital in NHS Scotland. METHODS: Three time-varying methods - multistate model, multivariable adjusted survival regression, and matched case-control approach - were applied to the data to estimate excess LOS and compared. FINDINGS: The unadjusted excess LOS estimated from the multistate model was 7.8 (95% confidence interval: 5.7-9.9) days, being shorter than the excess LOS estimated from survival regression adjusting for the admission characteristics (9.9; 8.4-11.7) days, and the adjusted estimates from matched case-control approach (10; 8.5-11.5) days. All estimates from the time-varying methods were much lower than the crude time-fixed estimates of 27 days. CONCLUSION: Studies examining LOS associated with HAI should consider a design which addresses time-dependent bias as a minimum. If there is an imbalance in patient characteristics between the HAI and non-HAI groups, then adjustment for patient characteristics is also important, where survival regression with time-dependent covariates is likely to provide the most flexible approach. Matched design is more likely to result in data loss, whereas a multistate model is limited by the challenge in adjusting for covariates. These findings have important implications for future cost-effectiveness studies of infection prevention and control programmes.

Epidemiology of healthcare-associated infection reported from a hospital-wide incidence study: considerations for infection prevention and control planning.

BACKGROUND: The measure of disease frequency most widely used to report healthcare-associated infection (HAI) is the point-prevalence survey. Incidence studies are rarely performed due to time and cost constraints; they show which patients are affected by HAI, when and where, and inform planning and design of infection prevention and control (IPC) measures. AIM: To determine the epidemiology of HAI within a general and a teaching hospital in Scotland. METHODS: A prospective observational incidence study was undertaken for one year from April 2018 using data collected as part of the Evaluation of Cost of Nosocomial Infection (ECONI) study. A novel, robust approach was undertaken, using record linkage to national administrative data to provide full admission and discharge information. Cases were recorded if they met international HAI definitions. FINDINGS: Incidence of HAI for the combined hospitals was 250 HAI cases per 100,000 acute occupied bed-days (AOBD). Highest frequency was in urinary tract (51.2 per 100,000 AOBD), bloodstream (44.7), and lower respiratory tract infection (42.2). The most frequently reported organisms were Escherichia coli, Staphylococcus aureus, and norovirus. Incidence of HAI was higher in older people and emergency cases. There was an increase in the rate of HAI in summer months (pneumonia, respiratory, surgical, and gastrointestinal infection) and in winter months norovirus gastrointestinal infection (P < 0.0001). The highest incidence specialties were intensive care, renal medicine, and cardiothoracic surgery. HAI occurred at a median of 9 days (interquartile range: 4-19) after admission. Incidence data were extrapolated to provide an annual national estimate of HAI in NHS Scotland of 7437 (95% confidence interval: 7021-7849) cases. CONCLUSION: This study provides a unique overview of incidence of HAI and identifies the burden of HAI at the national level for the first time. Understanding the incidence in different clinical settings, at different times, will allow targeting of IPC measures to those patients who would benefit the most.

Impact of healthcare-associated infection on length of stay.

BACKGROUND: Increased length of stay (LOS) for patients is an important measure of the burden of healthcare-associated infection (HAI). AIM: To estimate the excess LOS attributable to HAI. METHODS: This was a one-year prospective incidence study of HAI observed in one teaching hospital and one general hospital in NHS Scotland as part of the Evaluation of Cost of Nosocomial Infection (ECONI) study. All adult inpatients with an overnight stay were included. HAI was diagnosed using European Centres for Disease Prevention and Control definitions. A multi-state model was used to account for the time-varying nature of HAI and the competing risks of death and discharge. FINDINGS: The excess LOS attributable to HAI was 7.8 days (95% confidence interval (CI): 5.7-9.9). Median LOS for HAI patients was 30 days and for non-HAI patients was 3 days. Using a simple comparison of duration of hospital stay for HAI cases and non-cases would overestimate the excess LOS by 3.5 times (27 days compared with 7.8 days). The greatest impact on LOS was due to pneumonia (16.3 days; 95% CI: 7.5-25.2), bloodstream infections (11.4 days; 5.8-17.0) and surgical site infection (SSI) (9.8 days; 4.5-15.0). It is estimated that 58,000 bed-days are occupied due to HAI annually. CONCLUSION: A reduction of 10% in HAI incidence could make 5800 bed-days available. These could be used to treat 1706 elective patients in Scotland annually and help reduce the number of patients awaiting planned treatment. This study has important implications for investment decisions in infection prevention and control interventions locally, nationally, and internationally.

Personalized infection prevention and control: identifying patients at risk of healthcare-associated infection.

BACKGROUND: Few healthcare-associated infection (HAI) studies focus on risk of HAI at the point of admission. Understanding this will enable planning and management of care with infection prevention at the heart of the patient journey from the point of admission. AIM: To determine intrinsic characteristics of patients at hospital admission and extrinsic events, during the two years preceding admission, that increase risk of developing HAI. METHODS: An incidence survey of adults within two hospitals in NHS Scotland was undertaken for one year in 2018/19 as part of the Evaluation of Cost of Nosocomial Infection (ECONI) study. The primary outcome measure was developing any HAI using recognized case definitions. The cohort was derived from routine hospital episode data and linkage to community dispensed prescribing data. FINDINGS: The risk factors present on admission observed as being the most significant for the acquisition of HAI were: being treated in a teaching hospital, increasing age, comorbidities of cancer, cardiovascular disease, chronic renal failure and diabetes; and emergency admission. Relative risk of developing HAI increased with intensive care unit, high-dependency unit, and surgical specialties, and surgery <30 days before admission and a total length of stay of >30 days in the two years to admission. CONCLUSION: Targeting patients at risk of HAI from the point of admission maximizes the potential for prevention, especially when extrinsic risk factors are known and managed. This study proposes a new approach to infection prevention and control (IPC), identifying those patients at greatest risk of developing a particular type of HAI who might be potential candidates for personalized IPC interventions.

Bed-days and costs associated with the inpatient burden of healthcare-associated infection in the UK.

BACKGROUND: Healthcare-associated infection (HAI) is associated with increased morbidity and mortality resulting in excess costs. AIM: To investigate the impact of all types of HAI on the inpatient cost of HAI using different approaches. METHODS: The incidence, types of HAI, and excess length of stay were estimated using data collected as part of the Evaluation of Cost of Nosocomial Infection (ECONI) study. Scottish NHS reference costs were used to estimate unit costs for bed-days. Variable (cash) costs associated with infection prevention and control (IPC) measures and treatment were calculated for each HAI type and overall. The inpatient cost of HAI is presented in terms of bed-days lost, bed-day costs, and cash costs. FINDINGS: In Scotland 58,010 (95% confidence interval: 41,730-74,840) bed-days were estimated to be lost to HAI during 2018/19, costing £46.4 million (19m-129m). The total annual cost in the UK is estimated to be £774 million (328m-2,192m). Bloodstream infection and pneumonia were the most costly HAI types per case. Cash costs are a small proportion of the total cost of HAI, contributing 2.4% of total costs. CONCLUSION: Reliable estimates of the cost burden of HAI management are important for assessing the cost-effectiveness of IPC programmes. This unique study presents robust economic data, demonstrating that HAI remains a burden to the UK NHS and bed-days capture the majority of inpatient costs. These findings can be used to inform the economic evaluation and decision analytic modelling of competing IPC programmes at local and national level.

Evaluating the post-discharge cost of healthcare-associated infection in NHS Scotland.

BACKGROUND: Whereas the cost burden of healthcare-associated infection (HAI) extends beyond the inpatient stay into the post-discharge period, few studies have focused on post-discharge costs. AIM: To investigate the impact of all types of HAI on the magnitude and distribution of post-discharge costs observed in acute and community services for patients who developed HAI during their inpatient stay. METHODS: Using data from the Evaluation of Cost of Nosocomial Infection (ECONI) study and regression methods, this study identifies the marginal effect of HAI on the 90-daypost-discharge resource use and costs. To calculate monetary values, unit costs were applied to estimates of excess resource use per case of HAI. FINDINGS: Post-discharge costs increase inpatient HAI costs by 36%, with an annual national cost of £10,832,437. The total extra cost per patient with HAI was £1,457 (95% confidence interval: 1,004-4,244) in the 90 days post discharge. Patients with HAI had longer LOS if they were readmitted and were prescribed more antibiotics in the community. The results suggest that HAI did not have an impact on the number of readmissions or repeat surgeries within 90 days of discharge. The majority (95%) of the excess costs was on acute care services after readmission. Bloodstream infection, gastrointestinal infection, and pneumonia had the biggest impact on post-discharge cost. CONCLUSION: HAI increases costs and antibiotic consumption in the post-discharge period. Economic evaluations of IPC studies should incorporate post-discharge costs. These findings can be used nationally and internationally to support decision-making on the impact of IPC interventions.

The economic benefits of surgical site infection prevention in adults: a systematic review.

BACKGROUND: Surgical site infections (SSIs) present a significant burden to healthcare and patients in terms of excess length of stay, distress, disability and death. SSI risk and the associated economic burden may be reduced through adherence to prevention guidelines although the irreducible minimum is unclear. AIM: To evaluate the methods used to estimate the cost-effectiveness of prevention strategies for all SSIs. METHODS: PubMed, Medline, CINAHL, and UK National Health Service Economic Evaluation Database were searched from inception to January 2020 to identify English language economic evaluation studies, embedded economic evaluations, and studies with some analysis in relation to cost and benefit in adult patients receiving surgical care in any setting. Risk of bias was assessed using two published checklists. FINDINGS: Thirty-two studies involving 24,043 participants were included. Most studies evaluated SSI prevention in orthopaedic surgeries. Antibiotic prophylaxis, screening, treating, or decolonization of meticillin-resistant Staphylococcus aureus and surgical wound closure were the main methods evaluated. Methods ranged from cost-analyses to cost-effectiveness and cost-utility analyses. Synthesis of results was not possible due to heterogeneity. All studies reported some economic benefit associated with preventing SSI; however, measures of benefit were not reported consistently and the quality of studies was low to moderate. Limited evidence in relation to SSI impact on quality of life was identified. CONCLUSION: Current evidence in relation to the economic benefits of SSI prevention is limited. Further robust studies that utilize sound economic and epidemiological methods are required to inform future investment decisions in SSI prevention.

Estimating excess length of stay due to healthcare-associated infections: a systematic review and meta-analysis of statistical methodology.

BACKGROUND: Healthcare-associated infection (HCAI) affects millions of patients worldwide. HCAI is associated with increased healthcare costs, owing primarily to increased hospital length of stay (LOS) but calculating these costs is complicated due to time-dependent bias. Accurate estimation of excess LOS due to HCAI is essential to ensure that we invest in cost-effective infection prevention and control (IPC) measures. AIM: To identify and review the main statistical methods that have been employed to estimate differential LOS between patients with, and without, HCAI; to highlight and discuss potential biases of all statistical approaches. METHODS: A systematic review from 1997 to April 2017 was conducted in PubMed, CINAHL, ProQuest and EconLit databases. Studies were quality-assessed using an adapted Newcastle-Ottawa Scale (NOS). Methods were categorized as time-fixed or time-varying, with the former exhibiting time-dependent bias. Two examples of meta-analysis were used to illustrate how estimates of excess LOS differ between different studies. FINDINGS: Ninety-two studies with estimates on excess LOS were identified. The majority of articles employed time-fixed methods (75%). Studies using time-varying methods are of higher quality according to NOS. Studies using time-fixed methods overestimate additional LOS attributable to HCAI. Undertaking meta-analysis is challenging due to a variety of study designs and reporting styles. Study differences are further magnified by heterogeneous populations, case definitions, causative organisms, and susceptibilities. CONCLUSION: Methodologies have evolved over the last 20 years but there is still a significant body of evidence reliant upon time-fixed methods. Robust estimates are required to inform investment in cost-effective IPC interventions.

Association of SULT1A1 Arg²¹³His polymorphism with male breast cancer risk: results from a multicenter study in Italy.

Male breast cancer (MBC) is rare and poorly understood. Like female breast cancer (FBC), MBCs are highly sensitive to hormonal changes, and hyperestrogenism, specifically, represents a major risk factor for MBC. MBC is considered similar to late-onset, post-menopausal estrogen/progesteron receptors positive FBC (ER+/PR+). Sulfotransferase 1A1 (SULT1A1) is an enzyme involved in the metabolism of estrogens. Recently, SULT1A1 common functional polymorphism Arg(213)His (638G>A) variant has been found to be associated with increased breast cancer (BC) risk, particularly in post-menopausal women. For this reason, we decided to explore whether SULT1A1 Arg(213)His could exert an effect on MBC development. The primary aim of this study was to evaluate the influence of the SULT1A1 Arg(213)His polymorphism on MBC risk. The secondary aim was to investigate possible associations with relevant clinical-pathologic features of MBC. A total of 394 MBC cases and 786 healthy male controls were genotyped for SULT1A1 Arg(213)His polymorphism by PCR-RFLP and high-resolution melting analysis. All MBC cases were characterized for relevant clinical-pathologic features. A significant difference in the distribution of SULT1A1 Arg(213)His genotypes was found between MBC cases and controls (P < 0.0001). The analysis of genotype-specific risk showed a significant increased MBC risk in individuals with G/A (OR 1.97, 95% CI 1.50-2.59; P < 0.0001) and A/A (OR 3.09, 95% CI 1.83-5.23; P < 0.0001) genotypes in comparison to wild-type genotype, under co-dominant model. A significant association between SULT1A1 risk genotypes and HER2 status emerged. Results indicate that SULT1A1 Arg(213)His may act as a low-penetrance risk allele for developing MBC and could be associated with a specific tumor subtype associated with HER2 overexpression.

A randomized controlled trial of diet and physical activity in BRCA mutation carriers.

High serum levels of insulin-like growth factor I (IGF-I) are associated with an increased risk of sporadic breast cancer (BC). Furthermore, insulin and markers of insulin resistance, such as abdominal obesity, high blood glucose, high serum testosterone and metabolic syndrome, may affect both BC incidence and prognosis. We hypothesized that all these factors might be relevant also for hereditary BC, due to a deleterious mutation of BRCA genes. Epidemiological observation suggested that weight, energy intake (usually associated with higher bio-availability of growth factors) and physical activity may be relevant in BRCA mutation carriers. Mechanistic studies hypothesized a functional interaction between BRCA genes and the IGF-I system. We have provided some evidence that high serum levels of IGF-I are associated with a significantly increased penetrance. We are recruiting a larger cohort of BRCA mutation carriers in order to test potential modulators of penetrance and prognosis. Within this cohort, we have planned a randomized controlled trial to test whether moderate calorie and protein restriction, together with physical activity, decrease IGF-I. Eligible study subjects are women with or without BC, aged 18-70, with a proven deleterious BRCA mutation, and without metastases. All the women will receive recommendations for the dietary prevention of cancer. The women will be then randomized into an active life-style intervention group and into a control group that will receive only the baseline recommendations. We expect to significantly reduce IGF-I in the intervention group. This trial and the subsequent cohort follow-up might open up primary prevention options for genetic BC.

The psychological impact of breast and ovarian cancer preventive options in BRCA1 and BRCA2 mutation carriers.

This study was performed to describe the impact of preventive options on the psychological condition of BRCA1/BRCA2 carriers. A sample of 52 cancer-affected (C-A) and 27 cancer-unaffected (C-UN) women were enrolled after gene test disclosure (T0). Psychological evaluations were performed at T0 and 15 months later (T1). The surgical options were more likely to be chosen in C-A women (62%), although a consistent proportion of C-UN women (30%) also opt for these preventive measures. At the baseline, both samples had average anxiety and depression scores below the cut-off value, restrained average cancer worry scores and a risk perception consistent with the risk percentage provided during genetic counselling. The longitudinal results indicated no clinically meaningful variations in the anxiety and depression scores in either of the two samples. Statistically significant reductions in cancer-risk perception emerged in women who chose surgery in both C-A and C-UN women. In BRCA1/BRCA2 mutation carriers, surveillance does not influence their initial psychological condition, whereas prophylactic surgery has a significant impact in reducing the perceived risk and worry about getting sick. C-A and C-UN women have to be considered as two separate populations of BRCA mutation carriers requiring personalized approaches to risk management.

Association of low-penetrance alleles with male breast cancer risk and clinicopathological characteristics: results from a multicenter study in Italy.

It is well-known that male breast cancer (MBC) susceptibility is mainly due to high-penetrance BRCA1/2 mutations. Here, we investigated whether common low-penetrance breast cancer (BC) susceptibility alleles may influence MBC risk in Italian population and whether variant alleles may be associated with specific clinicopathological features of MBCs. In the frame of the Italian Multicenter Study on MBC, we genotyped 413 MBCs and 745 age-matched male controls at 9 SNPs annotating known BC susceptibility loci. By multivariate logistic regression models, we found a significant increased MBC risk for 3 SNPs, in particular, with codominant models, for rs2046210/ESR1 (OR = 1.71; 95 % CI: 1.43-2.05; p = 0.0001), rs3803662/TOX3 (OR = 1.59; 95 % CI: 1.32-1.92; p = 0.0001), and rs2981582/FGFR2 (OR = 1.26; 95 % CI: 1.05-1.50; p = 0.013). Furthermore, we showed that the prevalence of the risk genotypes of ESR1 tended to be higher in ER- tumors (p = 0.062). In a case-case multivariate analysis, a statistically significant association between ESR1 and ER- tumors was found (OR = 1.88; 95 % CI: 1.03-3.49; p = 0.039). Overall, our data, based on a large and well-characterized MBC series, support the hypothesis that common low-penetrance BC susceptibility alleles play a role in MBC susceptibility and, interestingly, indicate that ESR1 is associated with a distinct tumor subtype defined by ER-negative status.

Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA).

BACKGROUND: In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. METHODS: We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach. RESULTS: We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93-1.04, P = 0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89-1.06, P = 0.5) mutation carriers. CONCLUSION: This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out.

The TP53 Arg72Pro and MDM2 309G>T polymorphisms are not associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers.

BACKGROUND: The TP53 pathway, in which TP53 and its negative regulator MDM2 are the central elements, has an important role in carcinogenesis, particularly in BRCA1- and BRCA2-mediated carcinogenesis. A single nucleotide polymorphism (SNP) in the promoter region of MDM2 (309T>G, rs2279744) and a coding SNP of TP53 (Arg72Pro, rs1042522) have been shown to be of functional significance. METHODS: To investigate whether these SNPs modify breast cancer risk for BRCA1 and BRCA2 mutation carriers, we pooled genotype data on the TP53 Arg72Pro SNP in 7011 mutation carriers and on the MDM2 309T>G SNP in 2222 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analysed using a Cox proportional hazards model within a retrospective likelihood framework. RESULTS: No association was found between these SNPs and breast cancer risk for BRCA1 (TP53: per-allele hazard ratio (HR)=1.01, 95% confidence interval (CI): 0.93-1.10, P(trend)=0.77; MDM2: HR=0.96, 95%CI: 0.84-1.09, P(trend)=0.54) or for BRCA2 mutation carriers (TP53: HR=0.99, 95%CI: 0.87-1.12, P(trend)=0.83; MDM2: HR=0.98, 95%CI: 0.80-1.21, P(trend)=0.88). We also evaluated the potential combined effects of both SNPs on breast cancer risk, however, none of their combined genotypes showed any evidence of association. CONCLUSION: There was no evidence that TP53 Arg72Pro or MDM2 309T>G, either singly or in combination, influence breast cancer risk in BRCA1 or BRCA2 mutation carriers.

Indications for breast magnetic resonance imaging. Consensus document "Attualità in senologia", Florence 2007.

The clinical use of breast magnetic resonance (MR) imaging is increasing, especially for applications requiring paramagnetic contrast-agent injection. This document presents a synthetic list of acceptable indications with potential advantages for women according to evidence from the literature and the expert opinion of the panel that developed this statement. We generally recommend that breast MR imaging be performed in centres with experience in conventional breast imaging [mammography and ultrasonography (US)] and needle-biopsy procedures (under stereotactic or US guidance) as well as in breast MR imaging and second-look US for findings not revealed by conventional imaging performed before MR imaging. In our opinion, there is no evidence in favour of breast MR imaging as a diagnostic tool to characterise equivocal findings at conventional imaging when needle-biopsy procedures can be performed, nor for the study of asymptomatic, non-high-risk women with negative conventional imaging. After a description of technical and methodological requirements, we define the indications and limitations of breast MR imaging for surveillance of high-risk women, local staging before surgery, evaluation of the effect of neoadjuvant chemotherapy, breast previously treated for carcinoma, carcinoma of unknown primary syndrome, nipple discharge and breast implants.

The BOADICEA model of genetic susceptibility to breast and ovarian cancers: updates and extensions.

Multiple genetic loci confer susceptibility to breast and ovarian cancers. We have previously developed a model (BOADICEA) under which susceptibility to breast cancer is explained by mutations in BRCA1 and BRCA2, as well as by the joint multiplicative effects of many genes (polygenic component). We have now updated BOADICEA using additional family data from two UK population-based studies of breast cancer and family data from BRCA1 and BRCA2 carriers identified by 22 population-based studies of breast or ovarian cancer. The combined data set includes 2785 families (301 BRCA1 positive and 236 BRCA2 positive). Incidences were smoothed using locally weighted regression techniques to avoid large variations between adjacent intervals. A birth cohort effect on the cancer risks was implemented, whereby each individual was assumed to develop cancer according to calendar period-specific incidences. The fitted model predicts that the average breast cancer risks in carriers increase in more recent birth cohorts. For example, the average cumulative breast cancer risk to age 70 years among BRCA1 carriers is 50% for women born in 1920-1929 and 58% among women born after 1950. The model was further extended to take into account the risks of male breast, prostate and pancreatic cancer, and to allow for the risk of multiple cancers. BOADICEA can be used to predict carrier probabilities and cancer risks to individuals with any family history, and has been implemented in a user-friendly Web-based program (http://www.srl.cam.ac.uk/genepi/boadicea/boadicea_home.html).

Methyl group metabolism gene polymorphisms as modifier of breast cancer risk in Italian BRCA1/2 carriers.

BRCA1 and 2 are major cancer susceptibility genes but their penetrance is highly variable. The folate metabolism plays an important role in DNA methylation and its alterated metabolism is associated with cancer risk. The role of allele variants 677T and 1298C (MTHFR gene) and 2756G (MS gene) has been investigated as potentially modifying factors of BRCA gene penetrance, evaluated as age at first diagnosis of cancer, in 484 BRCA1/BRCA2 carriers and in 108 sporadic breast cancer cases as a control group. The genotype analysis has been performed by means of PCR/RFLP's. The analysis of association between a particular genotype and disease risk was performed using Cox Regression with time to breast or ovarian cancer onset as the end-point. The presence of 677T allele confers an increased risk of breast cancer in BRCA1 carriers (P = 0.007) and the presence of 1298C allele confers an increased risk of breast cancer in sporadic cases (P = 0.015).