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IntroductionBCG vaccination modulates immune responses to unrelated pathogens. This off-target effect could reduce the impact of emerging pathogens. As a readily available, inexpensive intervention that has a well-established safety profile, BCG is a good candidate for protecting healthcare workers (HCWs) and other vulnerable groups against COVID-19.Methods and analysisThis international multicentre phase III randomised controlled trial aims to determine if BCG vaccination reduces the incidence of symptomatic and severe COVID-19 at 6 months (co-primary outcomes) compared with no BCG vaccination. We plan to randomise 10 078 HCWs from Australia, The Netherlands, Spain, the UK and Brazil in a 1:1 ratio to BCG vaccination or no BCG (control group). The participants will be followed for 1 year with questionnaires and collection of blood samples. For any episode of illness, clinical details will be collected daily, and the participant will be tested for SARS-CoV-2 infection. The secondary objectives are to determine if BCG vaccination reduces the rate, incidence, and severity of any febrile or respiratory illness (including SARS-CoV-2), as well as work absenteeism. The safety of BCG vaccination in HCWs will also be evaluated. Immunological analyses will assess changes in the immune system following vaccination, and identify factors associated with susceptibility to or protection against SARS-CoV-2 and other infections.Ethics and disseminationEthical and governance approval will be obtained from participating sites. Results will be published in peer-reviewed open-access journals. The final cleaned and locked database will be deposited in a data sharing repository archiving system.Trial registrationClinicalTrials.gov NCT04327206

Background A decrease in breast density due to tamoxifen preventive therapy might indicate greater benefit from the drug. It is not known whether mammographic density continues to decline after 1 year of therapy, or whether measures of breast density change are sufficiently stable for personalised recommendations. Methods Mammographic density was measured annually over up to 5 years in premenopausal women with no previous diagnosis of breast cancer but at increased risk of breast cancer attending a family-history clinic in Manchester, UK (baseline 2010-2013). Tamoxifen (20 mg/day) for prevention was prescribed for up to 5 years in one group; the other group did not receive tamoxifen and were matched by age. Fully automatic methods were used on mammograms over the 5-year follow-up: three area-based measures (NN-VAS, Stratus, Densitas) and one volumetric (Volpara). Additionally, percentage breast density at baseline and first follow-up mammograms was measured visually. The size of density declines at the first follow-up mammogram and thereafter was estimated using a linear mixed model adjusted for age and body mass index. The stability of density change at 1 year was assessed by evaluating mean squared error loss from predictions based on individual or mean density change at 1 year. Results Analysis used mammograms from 126 healthy premenopausal women before and as they received tamoxifen for prevention (median age 42 years) and 172 matched controls (median age 41 years), with median 3 years follow-up. There was a strong correlation between percentage density measures used on the same mammogram in both the tamoxifen and no tamoxifen groups (all correlation coeficients > 0.8). Tamoxifen reduced mean breast density in year 1 by approximately 17–25% of the inter-quartile range of four automated percentage density measures at baseline, and from year 2, it decreased further by approximately 2–7% per year. Predicting change at 2 years using individual change at 1 year was approximately 60–300% worse than using mean change at 1year. Conclusions All measures showed a consistent and large average tamoxifen-induced change in density over the first year, and a continued decline thereafter. However, these measures of density change at 1 year were not stable on an individual basis.

Purpose Precision oncology develops and implements evidence-based personalized therapies that are based on specific genetic targets within each tumor. However, a major challenge that remains is the provision of a standardized, up-to-date, and evidenced-based precision medicine initiative across a geographic region. Materials and Methods We developed a statewide molecular tumor board that integrates academic and community oncology practices. The Precision Medicine Molecular Tumor Board (PMMTB) has three components: a biweekly Web-based teleconference tumor board meeting provided as a free clinical service, an observational research registry, and a monthly journal club to establish and revise evidence-based guidelines for off-label therapies. The PMMTB allows for flexible and rapid implementation of treatment, uniformity in practice, and the ability to track outcomes. Results We describe the implementation of the PMMTB and its first year of activity. Seventy-seven patient cases were presented, 48 were enrolled in a registry, and 38 had recommendations and clinical follow-up. The 38 subjects had diverse solid tumors (lung, 45%; GI, 21%; breast, 13%; other, 21%). Of these subjects, targeted therapy was recommended for 32 (84%). Clinical trials were identified for 24 subjects (63%), and nontrial targeted medicines for 16 (42%). Nine subjects (28%) received recommended therapy with a response rate of 17% (one of six) and a clinical benefit rate (partial response + stable disease) of 38% (three of eight). Although clinical trials often were identified, patients rarely enrolled. Conclusion The PMMTB provides a model for a regional molecular tumor board with clinical utility. This work highlights the need for outcome registries and improved access to clinical trials to pragmatically implement precision oncology.

Background High mammographic density is associated with both risk of cancers being missed at mammography, and increased risk of developing breast cancer. Stratification of breast cancer prevention and screening requires mammographic density measures predictive of cancer. This study compares five mammographic density measures to determine the association with subsequent diagnosis of breast cancer and the presence of breast cancer at screening. Methods Women participating in the “Predicting Risk Of Cancer At Screening” (PROCAS) study, a study of cancer risk, completed questionnaires to provide personal information to enable computation of the Tyrer-Cuzick risk score. Mammographic density was assessed by visual analogue scale (VAS), thresholding (Cumulus) and fully-automated methods (Densitas, Quantra, Volpara) in contralateral breasts of 366 women with unilateral breast cancer (cases) detected at screening on entry to the study (Cumulus 311/366) and in 338 women with cancer detected subsequently. Three controls per case were matched using age, body mass index category, hormone replacement therapy use and menopausal status. Odds ratios (OR) between the highest and lowest quintile, based on the density distribution in controls, for each density measure were estimated by conditional logistic regression, adjusting for classic risk factors. Results The strongest predictor of screen-detected cancer at study entry was VAS, OR 4.37 (95% CI 2.72–7.03) in the highest vs lowest quintile of percent density after adjustment for classical risk factors. Volpara, Densitas and Cumulus gave ORs for the highest vs lowest quintile of 2.42 (95% CI 1.56–3.78), 2.17 (95% CI 1.41–3.33) and 2.12 (95% CI 1.30–3.45), respectively. Quantra was not significantly associated with breast cancer (OR 1.02, 95% CI 0.67–1.54). Similar results were found for subsequent cancers, with ORs of 4.48 (95% CI 2.79–7.18), 2.87 (95% CI 1.77–4.64) and 2.34 (95% CI 1.50–3.68) in highest vs lowest quintiles of VAS, Volpara and Densitas, respectively. Quantra gave an OR in the highest vs lowest quintile of 1.32 (95% CI 0.85–2.05). Conclusions Visual density assessment demonstrated a strong relationship with cancer, despite known inter-observer variability; however, it is impractical for population-based screening. Percentage density measured by Volpara and Densitas also had a strong association with breast cancer risk, amongst the automated measures evaluated, providing practical automated methods for risk stratification. Electronic supplementary material The online version of this article (10.1186/s13058-018-0932-z) contains supplementary material, which is available to authorized users.

Body: Introduction In the IBIS I Prevention Trial we demonstrated that tamoxifen prevented breast cancer in women with greater than 9 % absolute reduction in visually assessed mammographic density over a 12-18 month period as assessed by an expert radiologist, RW (1). In this study we investigated: whether RW obtained similar results in a different group of women treated with tamoxifen; how other expert mammographic film readers with experience of density assessment (radiologists, advanced practitioner radiographers and a breast physician) estimated mammographic change; how visual change relates to change in automated measures of volumetric density; and whether we can predict change by serum markers or SNPs. Methods 105 women aged 33 to 46 at greater than 1 in 6 lifetime breast cancer risk completed one year’s treatment with tamoxifen. RW assessed mammographic percentage density in increments of 5% for baseline and one year mammograms. Two or three of a pool of eight readers estimated % density using a visual analogue scale (VAS). Percent change was also estimated using a computer-assisted thresholding technique (Cumulus). Change in volume of dense tissue (Quantra™ & Volpara™) was measured. Changes in lipids, IGF1, insulin and relevant SNPs were measured to determine whether they predicted density change. Results. Estimates of change obtained by RW were broadly consistent with those from our previous study, as were those from Cumulus, but could not be replicated using estimates from the pooled results of VAS readers. Tamoxifen was associated with marked reductions of dense volume of the breast (Table 1) However the different methods were at best only moderately correlated with RW (r less than 0.6). Change in serum triglycerides significantly predicted density change as measured by RW but none of the other serum measures or SNPs did. Table 1 Numbers of women and percentage change in density measures after one year of tamoxifen% Density changeRW %changeOther radiologists %changeCumulus %change_____% Dense volume change^Quantra %changeVolpara %change40+001 40+15930+503 30+141020+12013 20+202010+35630 10+17260+498143 0+16190-4188 0-1615Number10510598 9899RW = Ruth Warren. CUMULUS was measured by JS, a trained operator of the software. * Percentage point change eg if density changed from 40% to 30% this was regarded as a 10% change.^ Reduction in dense volume expressed as a percentage of baseline dense volume. We used Quantra version 2.0 and Volpara version 1.4.5 Conclusions Whilst RW remained consistent with previous density estimation it was not possible to use a pool of other expert readers to predict change. Cumulus gave similar results to RW but is difficult to use in practice. There was good agreement between the two objective volumetric measures used (r=0.5) and since these are automated they may be suitable for clinical practice. However their relationship to the long term breast cancer preventative effect of tamoxifen needs to be established. Reference 1 Tamoxifen-induced reduction in mammographic density and breast cancer risk reduction: a nested case-control study. Cuzick J, Warwick J, Pinney E, Duffy JW, Cawthorn S, Howell A, Forbes JF, Warren RM. J Natl Cancer Inst. 2011 May 4; 103 (9): 744-52. Citation Format: Anthony Howell, Sue Astley, Elaine Harkness, Julia Wiseman, Jill Fox, Paula Stavrinos, Mary Wilson, Yit Lim, Valerie Reece, Ursula Beetles, Anil Jain, Jamie Sergeant, Jack Cuzick, Ruth Warren, Gareth Evans. Predicting the effect of tamoxifen on the breast: Change in measures of breast density, serum markers and SNPs [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-12-01.

Mammographic density is a strong risk factor for breast cancer, but its potential application in risk management is not clear, partly due to uncertainties about its interaction with other breast cancer risk factors. We aimed to quantify the impact of mammographic density on breast cancer risk in women aged 40-49 at intermediate familial risk of breast cancer (average lifetime risk of 23%), in particular in premenopausal women, and to investigate its relationship with other breast cancer risk factors in this population. We present the results from a case-control study nested with the FH01 cohort study of 6,710 women mostly aged 40-49 at intermediate familial risk of breast cancer. One hundred and three cases of breast cancer were age-matched to one or two controls. Density was measured by semiautomated interactive thresholding. Absolute density, but not percent density, was a significant risk factor for breast cancer in this population after adjusting for area of nondense tissue (OR per 10 cm(2) = 1.07, 95% CI 1.00-1.15, p = 0.04). The effect was stronger in premenopausal women, who made up the majority of the study population. Absolute density remained a significant predictor of breast cancer risk after adjusting for age at menarche, age at first live birth, parity, past or present hormone replacement therapy, and the Tyrer-Cuzick 10-year relative risk estimate of breast cancer. Absolute density can improve breast cancer risk stratification and delineation of high-risk groups alongside the Tyrer-Cuzick 10-year relative risk estimate.

Background Observational studies indicate that weight gain or loss alters breast cancer risk. Hormonal prevention with tamoxifen or ovarian suppression reduces mammographic breast density, but has no impact on breast adipose tissue.1 The aim of this study was to assess whether change in weight is associated with change in breast density, breast fat or both. Methods 74 premenopausal women aged between 35 and 45 years, with a family history of breast cancer, were recruited from our Family History Clinic. 36 were allocated to a 25% calorie-restricted Mediterranean diet and exercise intervention; a further 38 women were separately recruited into a control group and given written diet and exercise advice only. At baseline and 12 months breast dense and non-dense (largely adipose) components of the breast were measured: area using Cumulus2 and volume using the Manchester ‘stepwedge’ method.3 Visual assessment of percentage density was reported to the nearest 5%.4 We used correlations to relate percentage change in absolute dense and non-dense (area and volume) to percentage change in: weight, total body fat (DXA), intra-abdominal and subcutaneous abdominal fat (MRI), as well as serum total IGF-I. Results At 12 months, 40 (54%) women lost >1.5% body weight, 14 (19%) gained >1.5% and 21 (28%) remained weight stable, Conclusions These data indicate that dense area and volume remain stable irrespective of change in weight. Non-dense area changes significantly in response to weight change in parallel with total and abdominal fat stores. These observations were performed on relatively small numbers of women and require confirmation in larger series. 1. Cuzick et al J Natl Cancer Inst. 103(9): 744–52, 2011. 2. Boyd NF et al J Natl Cancer Inst. 87(9) 670–675 1995. 3. Diffy et al IWIDM 2006, LNCS 4046 p1-9. In Astley et al (Eds) Springer-Verlag Berlin Heidelberg 2006 4. Brisson J et al. Cancer Epidemiol Biomarkers Prev 2003;12:7288–32. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-13-09.

Background: Mammographic breast density and endogenous sex-hormone levels are both strong risk factors for breast cancer. This study investigated whether there is evidence for a shared genetic basis between these risk factors. Methods: Using data on 1,286 women from 617 families, we estimated the heritabilities of serum estradiol, testosterone, and sex-hormone binding globulin (SHBG) levels and of three measures of breast density (dense area, nondense area, and percentage density). We tested for associations between hormone levels and density measures and estimated the genetic and environmental correlations between pairs of traits using variance and covariance components models and pedigree-based maximum likelihood methods. Results: We found no significant associations between estradiol, testosterone, or SHBG levels and any of the three density measures, after adjusting for body mass index (BMI). The estimated heritabilities were 63%, 66%, and 65% for square root–transformed adjusted percentage density, dense area, and nondense area, respectively, and 40%, 25%, and 58% for log-transformed–adjusted estradiol, testosterone, and SHBG. We found no evidence of a shared genetic basis between any hormone levels and any measure of density, after adjusting for BMI. The negative genetic correlation between dense and nondense areas remained significant even after adjustment for BMI and other covariates (ρ = −0.34; SE = 0.08; P = 0.0005). Conclusions: Breast density and sex hormones can be considered as independent sets of traits. Impact: Breast density and sex hormones can be used as intermediate phenotypes in the search for breast cancer susceptibility loci. Cancer Epidemiol Biomarkers Prev; 21(12); 2167–75. ©2012 AACR.

Breast density is a well-known breast cancer risk factor. Most current methods of measuring breast density are area based and subjective. Standard mammogram form (SMF) is a computer program using a volumetric approach to estimate the percent density in the breast. The aim of this study is to evaluate the current implementation of SMF as a predictor of breast cancer risk by comparing it with other widely used density measurement methods. The case-control study comprised 634 cancers with 1,880 age-matched controls combined from the Cambridge and Norwich Breast Screening Programs. Data collection involved assessing the films based both on Wolfe's parenchymal patterns and on visual estimation of percent density and then digitizing the films for computer analysis (interactive threshold technique and SMF). Logistic regression was used to produce odds ratios associated with increasing categories of breast density. Density measures from all four methods were strongly associated with breast cancer risk in the overall population. The stepwise rises in risk associated with increasing density as measured by the threshold method were 1.37 [95% confidence interval (95% CI), 1.03-1.82], 1.80 (95% CI, 1.36-2.37), and 2.45 (95% CI, 1.86-3.23). For each increasing quartile of SMF density measures, the risks were 1.11 (95% CI, 0.85-1.46), 1.31 (95% CI, 1.00-1.71), and 1.92 (95% CI, 1.47-2.51). After the model was adjusted for SMF results, the threshold readings maintained the same strong stepwise increase in density-risk relationship. On the contrary, once the model was adjusted for threshold readings, SMF outcome was no longer related to cancer risk. The available implementation of SMF is not a better cancer risk predictor compared with the thresholding method. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1074–81)

Introduction. Currently, there is a lack of data on the role of combined positron emission tomography–computed tomography (PET–CT) in the staging of early invasive primary breast cancer. We therefore evaluated the role of 18F-fluorodeoxyglucose (18F-FDG)-PET–CT in this patient population. Methods. We prospectively recruited 70 consecutive patients (69 women, one man; mean age, 61.9 ± 8.1 years) with early primary breast cancer for staging with 18F-FDG-PET–CT. All PET–CT images were interpreted by two readers (independently of each other). A third reader adjudicated any discrepancies. All readers had ≥5 years of specific experience. Ethics board approval and informed consent were obtained. Results. The mean clinical follow-up was 22.7 ± 12.6 months. The primary tumor was identified with PET–CT in 64 of 70 patients. Of the unidentified lesions, surgical pathology revealed two intraductal carcinomas, one invasive tubular carcinoma, and three invasive lobular carcinomas. Undiagnosed multifocal breast disease was shown in seven of 70 patients. PET–CT identified avid axillary lymph nodes in 19 of 70 patients, compared with 24 of 70 confirmed during surgery. There were four patients who were axillary node positive on PET but had no axillary disease at surgery. Five patients were reported with avid metastases. Two of those patients were treated for metastatic disease (nodal, lung, and liver in one and bone metastases in the other) following further imaging and clinical assessment. In the other three patients, lesions (lung, n = 1; pleural, n = 1; paratrachael node, n = 1) were subsequently diagnosed as benign lesions. Conclusion. Integrated 18F-FDG-PET–CT may have a role in staging patients presenting with early breast cancer.

Percent mammographic breast density (PMD) is a strong heritable risk factor for breast cancer. However, the pathways through which this risk is mediated are still unclear. To explore whether PMD and breast cancer have a shared genetic basis, we identified genetic variants most strongly associated with PMD in a published meta-analysis of five genome-wide association studies (GWAS) and used these to construct risk scores for 3,628 breast cancer cases and 5,190 controls from the UK2 GWAS of breast cancer. The signed per-allele effect estimates of single-nucleotide polymorphisms (SNP) were multiplied with the respective allele counts in the individual and summed over all SNPs to derive the risk score for an individual. These scores were included as the exposure variable in a logistic regression model with breast cancer case–control status as the outcome. This analysis was repeated using 10 different cutoff points for the most significant density SNPs (1%–10% representing 5,222–50,899 SNPs). Permutation analysis was also conducted across all 10 cutoff points. The association between risk score and breast cancer was significant for all cutoff points from 3% to 10% of top density SNPs, being most significant for the 6% (2-sided P = 0.002) to 10% (P = 0.001) cutoff points (overall permutation P = 0.003). Women in the top 10% of the risk score distribution had a 31% increased risk of breast cancer [OR = 1.31; 95% confidence interval (CI), 1.08–1.59] compared with women in the bottom 10%. Together, our results show that PMD and breast cancer have a shared genetic basis that is mediated through a large number of common variants. Cancer Res; 72(6); 1478–84. ©2012 AACR.

Mammographic breast density is a strong risk factor for breast cancer. Tamoxifen, which reduces the risk of breast cancer in women at high risk, also reduces mammographic breast density. However, it is not known if tamoxifen-induced reductions in breast density can be used to identify women who will benefit the most from prophylactic treatment with this drug.We conducted a nested case-control study within the first International Breast Cancer Intervention Study, a randomized prevention trial of tamoxifen vs placebo. Mammographic breast density was assessed visually and expressed as a percentage of the total breast area in 5% increments. Case subjects were 123 women diagnosed with breast cancer at or after their first follow-up mammogram, which took place 12-18 months after trial entry, and control subjects were 942 women without breast cancer. Multivariable logistic regression was used to adjust for other risk factors. All statistical tests were two-sided.In the tamoxifen arm, 46% of women had a 10% or greater reduction in breast density at their 12- to 18-month mammogram. Compared with all women in the placebo group, women in the tamoxifen group who experienced a 10% or greater reduction in breast density had 63% reduction in breast cancer risk (odds ratio = 0.37, 95% confidence interval = 0.20 to 0.69, P = .002), whereas those who took tamoxifen but experienced less than a 10% reduction in breast density had no risk reduction (odds ratio = 1.13, 95% confidence interval = 0.72 to 1.77, P = .60). In the placebo arm, there was no statistically significant difference in breast cancer risk between subjects who experienced less than a 10% reduction in mammographic density and subjects who experienced a greater reduction.The 12- to 18-month change in mammographic breast density is an excellent predictor of response to tamoxifen in the preventive setting.

n Abstract: The aim of this study was to examine the relationship between mammographic density and histological characteristics of breast tumors within a case–control study population. This study was an expansion of a large size case– control study examining the relationship between breast density and breast cancer risk. Percent and area of breast density was assessed in 370 invasive breast cancer cases and 1904 age-matched controls, using a computer-assisted method. Associations between breast density and estrogen receptor (ER) status, histological grade, histological size, lymph node status, vascular invasion, disease extent, and Nottingham Prognostic Index were evaluated, using logistic regression. Women with 50% or greater mammographic density have a 2.63-fold risk (95% confidence interval [95% CI] = 1.78–3.87; p < 0.001) of developing breast cancer compared to women with less than 10% density. Increase in every category of percentage of breast density is also associated with a 1.45-fold risk in developing ER positive tumors relative to ER negative tumors (odds ratio [OR] = 1.02; 95% CI = 1.00–1.04; p = 0.048), and increase in every quartile of absolute area of density is associated with a 1.48-fold ER positive breast cancer risk [95% CI = 1.06–2.07; p = 0.020]. Furthermore, breast density was found to be associated with specifically ER positivity, invasion as well as invasion with in situ, histological grades 1 and 2, tumor size larger than 1.1 cm, lack of vascular invasion, lymph node positivity and negativity, and NPI less than 4.0. After stratifying the data according to mode of diagnosis, the relationship became slightly stronger in the interval cancer group. Similar results were in observed using percent density and absolute density readings. Mammographic density was a stronger risk factor for ER positive [OR = 2.94; 95% CI = 1.94–4.43; p < 0.001] than ER negative cancers when comparing breasts with greater than 50% dense region to those with less than 10% density. No other tumor characteristic had a significant correlation with breast density. These results suggest that mammographic percent density may be more strongly related to ER positive than ER negative breast cancer, but otherwise is a risk factor for breast cancer independent of other tumor characteristics. n

Introduction: A UK multicenter study compared the performance of contrast enhanced-magnetic resonance imaging with X-Ray Mammography in women at high-risk of breast cancer commencing in 1997. Selection criteria were used to identify women with at least 0.9% annual risk of breast cancer. Methods: Women at high breast cancer risk, with a strong family history and/or high probability of a BRCA1/BRCA2/TP53 mutation, were recruited from 22 centers. Those not known as gene carriers were asked to give a blood sample, which was tested anonymously for mutations. Women ages 35 to 49 years were offered annual screening for 2 to 7 years. Study eligibility at entry was assessed retrospectively by detailed examination of pedigrees and overall eligibility accounting for computer risk assessment and mutation results. Results: Seventy-eight of 837 (9%) women entered for screening were ineligible using the strict entry criteria. Thirty-nine cancers were detected in 1,869 women-years in study (incidence 21 per 1,000). Including 3,561 further years follow-up, 28 more breast cancers were identified (12 of 1,000). Incidence rates for 759 eligible women were 22 of 1,000 in study and 13 of 1,000 in total follow-up, compared with 9 of 1,000 and 4 of 1,000, respectively, in 78 ineligible women. Breast cancer rates were higher for BRCA2 than BRCA1 after testing anonymized samples in this selected population at 65 of 1,000 in study and 36 of 1,000 in total follow-up for BRCA2 compared with 44 of 1,000 and 27 of 1,000 for BRCA1. Conclusions: Strict enforcement of study criteria would have minimally improved the power of the study, whereas testing for BRCA1/2 in advance would have substantially increased the detection rates. (Cancer Epidemiol Biomarkers Prev 2009;18(7):2123–31)

Background: Mammographic breast density (MBD) has a strong genetic component. Investigating the genetic models for mammographic density may provide further insights into the genetic factors affecting breast cancer risk. Purpose: To evaluate the familial aggregation of MBD and investigate the genetic models of susceptibility. Methods: We used data on 746 women from 305 families participating in the Sisters in Breast Screening study. Retrieved mammograms were digitized, and percent mammographic density was determined using the Cumulus software. Linear regression analysis was done to identify the factors that are associated with mammographic density and a multivariate regression model was constructed. Familial correlations between relative pairs were calculated using the residuals from these models. Genetic models of susceptibility were investigated using segregation analysis. Results: After adjusting for covariates, the intraclass correlation coefficient among the residuals was 0.26 (95% confidence interval, 0.16-0.36) in sister-sister pairs and 0.67 (0.27-1.00) among the monozygotic twin pairs. The most parsimonious model was a Mendelian single major gene model in which an allele with population frequency 0.39 (95% confidence interval, 0.33-0.46) influenced mammographic density in an additive fashion. This model explained 66% of the residual variance. Conclusion: These results confirm that MBD has a strong heritable basis, and suggest that major genes may explain some of the familial aggregation. These results may have implications for the search of genes that control mammographic density. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1277–84)

In a systematic review of breast MRI for assessing ipsilateral breast cancer to detect additional lesions, technical details were extracted from publications to assess their effect on diagnostic performance. Where technical parameters were complete, we examined their effect on summary ROC models, and the TP:FP ratio and PPV, using random-effects logistic regression. A total of 2,801 breasts in 19 publications underwent statistical analysis for year of study, slice thickness, and repetitions after contrast-medium injection. None were associated with TP/FP ratio. Summary ROC analysis provided weak evidence (P = 0.09) of an association between diagnostic performance and time period, however no trend over time. Tesla strength was reported in 2,801 cases. Other key information was omitted including whether both breasts were examined for 1683 (60%), position of the patient in 1,375 (49%), and imaging planes used in 688 (25%). Contrast agent and dose were reported for 2,646 (95%) breasts. Reporting technique was inconsistently reported. Single radiology reports were found in 1,637 (58%) cases, double in 347 (12.4%), and in 960 (34%) knowledge of mammography or ultrasound findings was not stated. Slice thickness, number of sequences after contrast medium, and year of study did not show significant performance differences. Other technical information was deficient. There is an urgent need to improve the quality of reporting of breast MRI studies.

Overexpression of the endothelin A (ET(A)) receptor has been found in a number of human cancer cell lines. Activation of the ET(A) receptor by endothelin-1 (ET-1) promotes cell proliferation and survival in these tumors, whereas activation of the endothelin B (ET(B)) receptor results in an opposing effect. Therefore, blockade of ET(A) may have antitumor effects, while sparing ET(B)-mediated effects such as induction of apoptosis and clearance of ET-1.ZD4054 is an orally bioavailable, specific ET(A) antagonist currently being investigated in prostate cancer. In receptor-binding studies, ZD4054 only bound to ET(A), with no binding detected towards ET(B). Prostate cancer cell lines are known to produce ET-1 and there is a relative increase in expression of ET(A) to ET(B) in these cancers. There is also an association of greater ET(A) expression in higher grade versus lower grade tumors, suggesting that ET(A) may be involved in the malignant transformation process. As ET-1 may also mediate nociceptive effects and osteoblastic effects, there is much interest in clinically assessing ZD4054 in prostate cancer.The data describing the endothelin axis, the role of ET(A) and ET(B) in malignancy, and the effects of ET(A) antagonist ZD4054 in prostate cancer, as demonstrated in preclinical and clinical studies, are reviewed.Further investigation of ZD4054 in prostate cancer is warranted, and Phase III trials are already planned in patients with non-metastatic castrate-resistant prostate cancer (CRPC) with rising prostate specific antigen values, metastatic (asymptomatic) CRPC, and in metastatic CRPC in combination with docetaxel, assessing either differences in progression-free survival and overall survival or overall survival alone.

Background: Hormone replacement therapy (HRT) is known to increase breast density, thus decreasing the sensitivity of cancer screening by mammography. Some authors recommend short cessation of HRT before mammography, but evidence showing the effect of such short cessation is limited. The purpose of this study is to examine whether a short cessation of HRT changes mammographic density. Methods: Forty-eight women taking HRT agreed to have mammograms taken before and after stopping HRT for 4 weeks. Mammographic density was measured by Wolfe’s four-point classification, six-categorical visual scale and two different computer methods (interactive-thresholding and SMF). Density values of mammography before and after the cessation of HRT were compared using Wilcoxon signed-rank test for categorical variables and paired t-test for continuous variables. Changes in breast pain and tenderness during mammography, radiation dose, compression force, and breast thickness were also recorded. Results: No significant changes in mammographic density were observed by either visual or computer methods. There were no significant changes in breast pain or in tenderness on mammograms before and after the month’s cessation of HRT. Radiographic measurements were not significantly altered by the 4-week cessation of HRT. Conclusion: In this screening population, a 4-week cessation of HRT before mammograms did not significantly alter mammographic density. © 2008 Elsevier Ireland Ltd. All rights reserved.

We conducted a cross-sectional study nested within a prospective cohort of breast cancer risk factors and two novel measures of breast density volume among 590 women who had attended Glasgow University (1948-1968), replied to a postal questionnaire (2001) and attended breast screening in Scotland (1989-2002). Volumetric breast density was estimated using a fully automated computer programme applied to digitised film-screen mammograms, from medio-lateral oblique mammograms at the first-screening visit. This measured the proportion of the breast volume composed of dense (non-fatty) tissue (Standard Mammogram Form (SMF)%) and the absolute volume of this tissue (SMF volume, cm3). Median age at first screening was 54.1 years (range: 40.0-71.5), median SMF volume 70.25 cm3 (interquartile range: 51.0-103.0) and mean SMF% 26.3%, s.d.=8.0% (range: 12.7-58.8%). Age-adjusted logistic regression models showed a positive relationship between age at last menstrual period and SMF%, odds ratio (OR) per year later: 1.05 (95% confidence interval: 1.01-1.08, P=0.004). Number of pregnancies was inversely related to SMF volume, OR per extra pregnancy: 0.78 (0.70-0.86, P0.001). There was a suggestion of a quadratic relationship between birthweight and SMF%, with lowest risks in women born under 2.5 and over 4 kg. Body mass index (BMI) at university (median age 19) and in 2001 (median age 62) were positively related to SMF volume, OR per extra kg m(-2) 1.21 (1.15-1.28) and 1.17 (1.09-1.26), respectively, and inversely related to SMF%, OR per extra kg m(-2) 0.83 (0.79-0.88) and 0.82 (0.76-0.88), respectively, P0.001. Standard Mammogram Form% and absolute SMF volume are related to several, but not all, breast cancer risk factors. In particular, the positive relationship between BMI and SMF volume suggests that volume of dense breast tissue will be a useful marker in breast cancer studies.

Purpose: Magnetic resonance imaging (MRI) screening enables early detection of breast cancers in women with an inherited predisposition. Interval cancers occurred in women with a BRCA1 mutation, possibly due to fast tumor growth. We investigated the effect of a BRCA1 or BRCA2 mutation and age on the growth rate of breast cancers, as this may influence the optimal screening frequency. Experimental Design: We reviewed the invasive cancers from the United Kingdom, Dutch, and Canadian MRI screening trials for women at hereditary risk, measuring tumor size at diagnosis and on preceding MRI and/or mammography. We could assess tumor volume doubling time (DT) in 100 cancers. Results: Tumor DT was estimated for 43 women with a BRCA1 mutation, 16 women with a BRCA2 mutation, and 41 women at high risk without an identified mutation. Growth rate slowed continuously with increasing age (P = 0.004). Growth was twice as fast in BRCA1 (P = 0.003) or BRCA2 (P = 0.03) patients as in high-risk patients of the same age. The mean DT for women with BRCA1/2 mutations diagnosed at ages ≤40, 41 to 50, and >50 years was 28, 68, and 81 days, respectively, and 83, 121, and 173 days, respectively, in the high-risk group. Pathologic tumor size decreased with increasing age (P = 0.001). Median size was 15 mm for patients ages ≤40 years compared with 9 mm in older patients (P = 0.003); tumors were largest in young women with BRCA1 mutations. Conclusion: Tumors grow quickly in women with BRCA1 mutations and in young women. Age and risk group should be taken into account in screening protocols.

Although breast cancer screening has been shown to work in randomised trials, there is a need to evaluate service screening programmes to ensure that they are delivering the benefit indicated by the trials. We carried out a case–control study to investigate the effect of mammography service screening, in the NHS breast screening programme, on breast cancer mortality in the East Anglian region of the UK. Cases were deaths from breast cancer in women diagnosed between the ages of 50 and 70 years, following the instigation of the East Anglia Breast Screening Programme in 1989. The controls were women (two per case) who had not died of breast cancer, from the same area, matched by date of birth to the cases. Each control was known to be alive at the time of death of her matched case. All women were known to the breast screening programme and were invited, at least once, to be screened. There were 284 cases and 568 controls. The odds ratio (OR) for risk of death from breast cancer in women who attended at least one routine screen compared to those who did not attend was 0.35 (CI: 0.24, 0.50). Adjusting for self-selection bias gave an estimate of the breast cancer mortality reduction associated with invitation to screening of 35% (OR=0.65, 95% CI: 0.48, 0.88). The effect of actually being screened was a 48% breast cancer mortality reduction (OR=0.52, 95% CI: 0.32, 0.84). The results suggest that the National Breast Screening Programme in East Anglia is achieving a reduction in breast cancer deaths, which is at least consistent with the results from the randomised controlled trials of mammographic screening.

Breast cancer risk is grouped into high risk, moderate risk and woman at or near population risk. Who are moderate-risk women? How is their risk assessed? What is the evidence and best practice for screening moderate-risk women?

Breast density measurements can be made from mammograms using either area-based methods, such as the six category classification (SCC), or volumetric based methods, such as the standard mammogram form (SMF). Previously, we have shown how both types of methods generate breast density estimates which are generally close. In this paper, we switch our attention to the question of why, for certain cases, they provide widely differing estimates. First, we show how the underlying physical models of the breast employed in the methods need to be consistent, and how area-based methods are susceptible to projection effects. We then analyse a set of patients whose mammograms show large differences between their SCC and SMF assessments. More precisely, 12% of 657 patients were found to fall into this category. Of these, 2.7% were attributable to errors either in the SMF segmentation algorithms, human error in SCC categorization or poor image exposure. More importantly, 9.3% of the cases appear to be due to fundamental differences between the area- and volume-based techniques. We conclude by suggesting how we might remove half of those discrepancies by introducing a new categorization of the SMF estimates based on the breast thickness. We note however, that this still leaves 6% of patients with large differences between SMF and SCC estimates. We discuss why it might not be appropriate to assume SMF (or any volume measure) has a similar breast cancer risk prediction capability to SCC.

Mammographic density measures adjusted for age and body mass index (BMI) are heritable predictors of breast cancer risk, but few mammographic density-associated genetic variants have been identified. Using data for 10,727 women from two international consortia, we estimated associations between 77 common breast cancer susceptibility variants and absolute dense area, percent dense area and absolute nondense area adjusted for study, age, and BMI using mixed linear modeling. We found strong support for established associations between rs10995190 (in the region of ZNF365), rs2046210 (ESR1), and rs3817198 (LSP1) and adjusted absolute and percent dense areas (all P < 10−5). Of 41 recently discovered breast cancer susceptibility variants, associations were found between rs1432679 (EBF1), rs17817449 (MIR1972-2: FTO), rs12710696 (2p24.1), and rs3757318 (ESR1) and adjusted absolute and percent dense areas, respectively. There were associations between rs6001930 (MKL1) and both adjusted absolute dense and nondense areas, and between rs17356907 (NTN4) and adjusted absolute nondense area. Trends in all but two associations were consistent with those for breast cancer risk. Results suggested that 18% of breast cancer susceptibility variants were associated with at least one mammographic density measure. Genetic variants at multiple loci were associated with both breast cancer risk and the mammographic density measures. Further understanding of the underlying mechanisms at these loci could help identify etiologic pathways implicated in how mammographic density predicts breast cancer risk. Cancer Res; 75(12); 2457–67. ©2015 AACR.

Contrast enhanced magnetic resonance imaging (CE MRI) is the most sensitive tool for screening women who are at high familial risk of breast cancer. Our aim in this study was to assess the cost-effectiveness of X-ray mammography (XRM), CE MRI or both strategies combined. In total, 649 women were enrolled in the MARIBS study and screened with both CE MRI and mammography resulting in 1881 screens and 1-7 individual annual screening events. Women aged 35-49 years at high risk of breast cancer, either because they have a strong family history of breast cancer or are tested carriers of a BRCA1, BRCA2 or TP53 mutation or are at a 50% risk of having inherited such a mutation, were recruited from 22 centres and offered annual MRI and XRM for between 2 and 7 years. Information on the number and type of further investigations was collected and specifically calculated unit costs were used to calculate the incremental cost per cancer detected. The numbers of cancer detected was 13 for mammography, 27 for CE MRI and 33 for mammography and CE MRI combined. In the subgroup of BRCA1 (BRCA2) mutation carriers or of women having a first degree relative with a mutation in BRCA1 (BRCA2) corresponding numbers were 3 (6), 12 (7) and 12 (11), respectively. For all women, the incremental cost per cancer detected with CE MRI and mammography combined was pound28 284 compared to mammography. When only BRCA1 or the BRCA2 groups were considered, this cost would be reduced to pound11 731 (CE MRI vs mammography) and pound15 302 (CE MRI and mammography vs mammography). Results were most sensitive to the unit cost estimate for a CE MRI screening test. Contrast-enhanced MRI might be a cost-effective screening modality for women at high risk, particularly for the BRCA1 and BRCA2 subgroups. Further work is needed to assess the impact of screening on mortality and health-related quality of life.

The purpose of this study was to examine the relationship between breast arterial calcification (BAC), commonly found on mammography, and cardiovascular disease and its risk factors.The study population, nested within the European Prospective Investigation of Cancer-Norfolk (EPIC-Norfolk) cohort study, consisted of 1,590 women older than 55 years, not taking hormone replacement therapy, and with available screening mammograms. Mammograms were coded by three radiologists for presence or absence of BAC. History of coronary heart disease (CHD), stroke, and diabetes and risk factors for cardiovascular disease (including smoking status, body mass index [BMI], blood pressure, diabetes, and glycosylated hemoglobin [HbA1c]) were independently measured from health examinations in the EPIC study.The prevalence of BAC was 16.0%. Women with BAC were significantly older than those without it. BAC was associated with prevalent CHD, but not stroke. The odds ratio of having CHD was 2.54 (95% confidence interval, 1.03-6.30). The sensitivity and specificity were 32.4% and 85.5%, respectively. Except for smoking, which showed an inverse association, there was no consistent significant association of BAC with cardiovascular disease risk factors including BMI, diabetes, HbA1c, or lipids.BAC found on mammograms was associated with prevalent CHD after adjustment for age, but with low sensitivity. BAC may provide additional information toward identifying cardiovascular disease risk among otherwise healthy women.

High breast density as measured on mammograms is a strong risk factor for breast cancer in the general population, but its effect in carriers of germline BRCA1 and BRCA2 mutations is unclear. We obtained mammograms from 206 female carriers of BRCA1 or BRCA2 mutations, 96 of whom were subsequently diagnosed with breast cancer and 136 relatives of carriers who were themselves noncarriers. We compared the mammographic densities of affected carriers (cases) and unaffected carriers (controls), and of mutation carriers and noncarriers, using a computer-assisted method of measurement and visual assessment by two observers. Analyses were adjusted for age, parity, body mass index, menopausal status, and hormone replacement therapy use. There was no difference in the mean percent density between noncarriers and carriers. Among carriers, increasing mammographic density was associated with an increased risk of breast cancer (Ptrend = 0.024). The odds ratio (OR; 95% confidence interval) for breast cancer associated with a density of ≥50% was 2.29 (1.23-4.26; P = 0.009). The OR did not differ between BRCA1 and BRCA2 carriers or between premenopausal and postmenopausal carriers. The results suggest that the distribution of breast density in BRCA1 and BRCA2 carriers is similar to that in non-carriers. High breast density in carriers is associated with an increased risk of breast cancer, with the relative risk being similar to that observed in the general population. Use of mammographic density could improve individual risk prediction in carriers. (Cancer Res 2006; 66(3): 1866-72)

Background Women genetically predisposed to breast cancer often develop the disease at a young age when dense breast tissue reduces the sensitivity of X-ray mammography. Our aim was, therefore, to compare contrast enhanced magnetic resonance imaging (CE MRI) with mammography for screening. Methods We did a prospective multicentre cohort study in 649 women aged 35-49 years with a strong family history of breast cancer or a high probability of a BRCA1, BRCA2, or TP53 mutation. We recruited participants from 22 centres in the UK, and offered the women annual screening with CE MRI and mammography for 2-7 years. Findings We diagnosed 35 cancers in the 649 women screened with both mammography and CE MRI (1881 screens): 19 by CE MRI only, six by mammography only, and eight by both, with two interval cases. Sensitivity was significantly higher for CE MRI (77%, 95% CI 60-90) than for mammography (40%, 24-58; p=0.01), and was 94% (81-99) when both methods were used. Specificity was 93% (92-95) for mammography, 81% (80-83) for CE MRI (p

Contrast-enhanced (CE) MRI was used to monitor breast cancer response to neoadjuvant chemotherapy. Patients underwent CE MRI before and after therapy, together with conventional assessment methods (CAM). CE MRI was carried out at 1.5 T in the coronal plain with 3D sequences before and after bolus injection. An expert panel determined chemotherapy response using both CE MRI and CAM. Histopathological response in the surgical specimen was then used to determine the sensitivity and specificity of CE MRI and CAM. In total, 67 patients with 69 breast cancers were studied (mean age of 46 years). Tumour characteristics showed a high-risk tumour population: median size 49 mm: histopathological grade 3 (55%): oestrogen receptor (ER) negative (48%). Histopathological response was as follows: – complete pathological response (pCR) 17%; partial response (pPR) 68%; no response (NR) 15%. Sensitivity of CAM for pCR or pPR was 98% (CI 91–100%) and specificity was 50% (CI 19–81%). CE MRI sensitivity was 100% (CI 94–100%), and specificity was 80% (CI 44–97%). The absolute agreement between assessment methods and histopathology was marginally higher for CE MRI than CAM (81 vs 68%; P=0.09). In 71%, CE MRI increased diagnostic knowledge, although in 20% it was judged confusing or incorrect. The 2nd MRI study significantly increased diagnostic confidence, and in 19% could have changed the treatment plan. CE MRI persistently underestimated minimal residual disease. In conclusion, CE MRI of breast cancer proved more reliable for predicting histopathological response to neoadjuvant chemotherapy than conventional assessment methods.

OBJECTIVE: To establish the diagnostic impact of breast magnetic resonance imaging (MRI), on the management of cases in our mammographic screening programme. METHODS AND MATERIALS: We analysed the cases examined from July 1997 to December 2000 during which time 44,000 population screening mammograms and 85 MRI studies were undertaken on women identified by computer overlap. The studies were reviewed to find the reason for the MRI study and its diagnostic impact. RESULTS: Of 83 studies analysed, 31 were for recurrence of tumour, 33 in newly diagnosed cancer, 22 to assess extent, 11 to monitor primary chemotherapy. In a small diagnostic subset of 19 cases MRI was used to find or characterize a lesion. The 11 cases in which MRI results caused a measurable beneficial change in management were from the query recurrence and diagnostic groups. In 52 cases from all groups, MR increased diagnostic confidence. In 11 cases MRI results were indeterminate, and in six of these stimulated more studies. CONCLUSION: MRI is an expensive investigation and its use must be justified. There is a limited, but valuable role for breast MRI in selected cases from screening assessment. Misinterpretation of enhancing lesions may generate additional procedures. Diagnostic impact was greatest for the detection of tumour recurrence. Warren R. M. L. and Crawley A. (2002). Clinical Radiology, 57, 1090–1097.

Dense mammographic patterns are a risk factor for breast cancer. In a recent case–control study, dense patterns were observed to be associated with a higher relative risk estimate for the more aggressive grade 3 tumors than for grade 1 or 2 tumors. The present study was designed to ascertain, by reference to odds ratio estimates of relative risk by tumor size and histologic grade, whether this was more likely to be due to increased innate predisposition of dense parenchymal patterns to grade 3 tumors, or to dedifferentiation of cases missed at screening due to dense patterns. If the observation were due entirely to dedifferentiation, then for a given size the relative risk of grade 3 tumors would be the same as for grades 1–2. Size-specific relative risks of grade 3 tumors were higher than those of grade 1–2 tumors. It is concluded that the majority of the enhanced risk of grade 3 tumors is due to enhanced innate predisposition to grade 3 tumors in dense breasts.

Geneticists are able to identify the risk of breast cancer. Strategies on offer include prevention, early diagnosis by screening, and prophylactic surgery. This paper analyses the evidence for offering screening. The radiation dose of mammography has been measured, but the risk is not fully known. Mammography screening of women of 40-50 years in the normal population has known effect. Little evidence is available for women under 40 years or for women with genetic susceptibility to breast cancer. Dense parenchymal pattern is associated with high grade cancers, and is both a risk factor and a reason for impaired screening sensitivity. Whether this applies to younger women or women at high risk is speculative. The pathological features of the cancers in gene carriers show differences from those occurring in normal women. This work should be correlated with imaging features. There is no literature to support the use of newer imaging methods in these women. Ultrasound and MRI avoid radiation and may be useful in dense breasts. SestaMIBI and PET scanning are not yet mature enough for screening, and may never have such a role. Any newer modality must be subjected to a formal randomised trial before being offered to screen women at high risk.

Objective To determine whether association between classification of interval cancers (false negative, minimal sign, true interval, occult) and tumour characteristics can indicate areas for improvement in effectiveness of screening . Setting East Anglian regional Breast Screening Programme. Method The consensus classification of interval cases, obtained through peer review, was compared with tumour characteristics: size; grade; and nodal status, and with radiological signs. A set of 923 cancers with known tumour characteristics, presenting in unscreened women, was available for comparison. Result In total, 385 interval cases were analysed. Prognosis of interval cancers was at least as good as that of cancers in unscreened women, with fewer node positive cases. No significant relation was found between classification of cases and age of patients. True intervals tended to present later after a negative screen, although false negatives commonly presented earlier. Occult cancers were significantly smaller than false negatives. Analysis of histological type yielded little of relevance, and mammographic appearance was similar in all classifications. At diagnosis, cancers in the low risk group were more likely to be seen as spiculate masses, whereas high risk cases more often appeared as opacities. A higher proportion of interval cases had been assessed than in the normal screened population. Conclusion Sensitivity may be improved by reducing false negative and minimal sign cases (21% of interval cancers in East Anglia). These will include tumours in all risk groups, and with all radiological features, thus no particular age group or radiological feature may be targeted for improvement. Misdiagnosis at assessment reduces sensitivity and therefore merits particular study.

Objective To perform a pilot study to compare ultrasound and mammographic screening with particular respect to specificity, in a cohort of women at moderate family history risk of breast cancer. Material and methods High resolution ultrasound of both breasts was undertaken in 149 women at moderate risk of breast cancer who were referred for mammographic screening. The two tests were read blind to the other. Core biopsy was undertaken for solid lesions found on ultrasound. Results 149 Patients, mean age 42.15 years, were screened with bilateral ultrasound. 90 Examinations were normal. 46 Women had cysts, two had lesions previously biopsied and found to be benign, and one had a lymph node. 10 Focal solid lesions were biopsied on account of their ultrasound findings, 6.7% (95% confidence intervals (95% CIs) 2.7% to 10.7%). All but one of the 149 mammograms were normal. In this case both mammography and ultrasound showed a focal solid lesion that at core biopsy was found to be a fibroadenoma. Histology showed seven fibroadenomata, two areas of fibrocystic change, and one adenoid cystic carcinoma. Positive predictive value for biopsy was 10%. Mean follow up was 13.7 months. There was one interval cancer. Conclusion Screening with breast ultrasound, in a cohort of women at moderate risk of breast cancer due to family history, has an acceptable biopsy rate. Screening with ultrasound and mammography in patients with an increased risk of breast cancer may be beneficial and a randomised study to examine issues of acceptability, reproducibility, and cost effectiveness is apt.

BACKGROUND Estimations of mean sojourn time (MST) and sensitivity (S) in disease screening have been previously calculated from case-control data, using simple models which did not include covariates. Many studies have shown an effect of mammographic parenchymal pattern (MPP) on breast-cancer risk and tumour histology. We have expanded previous models on these to estimate MST and S with the effects of MPP as a covariate. METHODS Data were from a nested case-control study within the East Anglian screening programme, with 875 cases and 2,601 controls. Estimates of disease progression and screening parameters were based on conditional likelihood calculation, using a Markov process model. Ninety-five per cent confidence intervals (CI) were calculated using the profile likelihood wherever possible and using a numerical estimate of the information matrix or the area under the likelihood curve where necessary. RESULTS We obtained estimates of the incidence of preclinical disease, rate of transition from preclinical to clinical and screening sensitivity, and evaluated the association of these parameters with mammographic parenchymal pattern. A higher incidence of preclinical disease was found for high-risk MPP [relative incidence = 1.62 (95% CI: 0.89; 2.73)]. However, no difference in progression rate from preclinical to clinical disease between different MPP was found. Dense MPPs were associated with decreased sensitivity [relative sensitivity = 0.24 (95% CI: 0.06; 15)]. Wide CIs were found, probably being a consequence of the relative sparsity of interval cancer data. DISCUSSION It is possible to estimate multiple parameters of disease progression and screening quality from case-control data. The reduction in sensitivity of the screening process associated with high-risk patterns presented here, could be of paramount interest for proposing new screening strategies, such as possible additional screening tools.

The imaging and analysis protocol of the UK multicentre study of magnetic resonance imaging (MRI) as a method of screening for breast cancer in women at genetic risk is described. The study will compare the sensitivity and specificity of contrast-enhanced MRI with two-view x-ray mammography. Approximately 500 women below the age of 50 at high genetic risk of breast cancer will be recruited per year for three years, with annual MRI and x-ray mammography continuing for up to 5 years. A symptomatic cohort will be measured in the first year to ensure consistent reporting between centres. The MRI examination comprises a high-sensitivity three-dimensional contrast-enhanced assessment, followed by a high-specificity contrast-enhanced study in equivocal cases. Multiparametric analysis will encompass morphological assessment, the kinetics of contrast agent uptake and determination of quantitative pharmacokinetic parameters. Retrospective analysis will identify the most specific indicators of malignancy. Sensitivity and specificity, together with diagnostic performance, diagnostic impact and therapeutic impact will be assessed with reference to pathology, follow-up and changes in diagnostic certainty and therapeutic decisions. Mammography, lesion localisation, pathology and cytology will be performed in accordance with the UK NHS Breast Screening Programme quality assurance standards. Similar standards of quality assurance will be applied for MR measurements and evaluation.

The protocol of the national multicentre study of Magnetic Resonance Imaging (MRI) as a method of screening for breast cancer in women at genetic risk is described. The sensitivity and specificity of contrast-enhanced MRI will be compared with two-view X-ray mammography in a comparative trial. Approximately 500 women below the age of 50 at high genetic risk of breast cancer will be recruited per year for 3 years, with annual MRI and X-ray examination continuing for up to 5 years. A symptomatic cohort will be measured in the initial phase of the study to ensure consistent reporting between centres. The MRI examination will comprise an initial high-sensitivity screening measurement, followed by a high-specificity measurement in equivocal cases. Retrospective analysis will identify the most specific indicators of malignancy. Sensitivity and specificity, together with diagnostic performance, diagnostic impact and therapeutic impact will be assessed with reference to pathology, follow-up and changes in diagnostic certainty and therapeutic decisions. The psychological impact of screening in this high-risk group will be ascertained.

Background: The literature shows that breast screening performance varies between centers. Those who monitor the performance of screening programs must use appropriate methods to demonstrate quality. Analysis of interval cancer rates provides one such measure. This study analyses interval cancers over a ten-year period in a single center of the UK National Breast Screening Program, offering screening to a population of 45 000 women. Methods: 108 948 screening examinations were undertaken between 1987 and 1996. Sequential interval cancer rates were studied and compared with the results of the Swedish Two-County trial. More detailed analysis of the first prevalence round was undertaken. Results: Improvement in rates occurred after three years. Two-year time bands show some fluctuation in rates, indicating variation in performance. For one time period, rates equivalent to the Two County Trial were achieved, but this was not consistently maintained. Overall rates equate to performance reported elsewhere in the UK (25% in the first year after screening, 48% in the second year after screening and 48% in the third year after screening, equivalent Two County rates are 17%, 32% and 57%). The prevalence round analysis shows that undiagnosed cancers arose after the film reading stage in 88% of interval cases. The team was able to distinguish minor signs from significant lesions effectively. Assessment procedures were effective once the patient hod been recalled. Conclusion: Interval cancer rates fell initially but reached a plateau. Recall procedures were effective in making the diagnosis, and cases were missed at the film reading stage. Consistency of performance may be important in achieving low rates. Breast Cancer 7:9-18, 2000.

Mammographic parenchymal patterns are related to breast cancer risk and are also affected by anthropometric measure. We carried out a case–control study comprising 200 cases with high-risk (P2 and DY) mammographic parenchymal pattern and 200 controls with low-risk (N1 and P1) patterns in order to investigate the effect of body size and shape and breast size on mammographic patterns. Women in the highest quartile of body mass index (BMI) distribution were significantly less likely to have a high-risk pattern (odds ratio (OR) = 0.21, 95% confidence interval (CI) 0.08–0.52, P-value for trend = 0.001) compared to those in the lowest quartile. Relative to women with a waist to hip ratio (WHR) of less than 0.75, the OR of having a high-risk pattern in women with a WHR greater than 0.80 was 0.30 (95% CI 0.14–0.63). Breast size as measured by cup size was significantly and negatively related to high-risk pattern. Our study indicates that both BMI and WHR are negatively associated with high-risk patterns. However, both phenomena are associated with increased risk of breast cancer in post-menopausal women. This negative confounding of two positive risk factors means that the effect of parenchymal patterns on risk will tend to be underestimated when not adjusted for BMI and WHR and vice versa. Thus we may have underestimated the importance of BMI and mammographic parenchymal patterns in the past. Further studies are needed to determine a measure of parenchymal density that is independent of anthropometric measures and breast size. © 1999 Cancer Research Campaign

Objectives To assess the effects of mammographic parenchymal patterns on the risk of breast cancer detected at first screen, second screen, and in the interval between these two screens. Settings A nested case-control study within a screening cohort in East Anglia was designed. The study group comprised 502 patients with cancer at the prevalence screening round, 198 patients with interval cancer, and 175 with cancer at the first incidence screen. These patients were matched with 2601 controls. Methods The mammographic parenchymal patterns of breast tissue were assessed according to Wolfe's classification. Statistical analysis was by conditional logistic regression. Results Overall, 67% of patients and 59% of controls were considered to have high risk pattern (P2+DY) mammogram. The risk associated with P2 or DY mammographic patterns compared with N1 was higher for interval cancers (odds ratios (ORs) 2.2 and 2.4 respectively) than for screen detected cancers (ORs 1.7 and 1.1 respectively). For interval cancers in the first 18 months after the last negative mammogram, the risk was particularly high (ORs 3.8 for P2 and 4.1 for DY compared with N1). The high risk associated with P2 and DY patterns was concentrated on invasive ductal grade III cancers (ORs 2.7 and 3.8) rather than grade I or II cancers (ORs 1.6 and 1.2). Conclusions The study strongly suggests that screening effectiveness is reduced for high risk parenchymal patterns which are associated with high grade cancers. Changes should aim at improving screening sensitivity for dense parenchymal patterns, and the diagnosis of high grade tumours.

We recently changed from using fine needle aspiration cytology to using core biopsy exclusively in the assessment of screen detected abnormalities. Two hundred and two biopsies (1% of women screened) were performed. Surgical histological confirmation was obtained in 111 patients (101 malignant and 10 benign). The remaining patients were either returned to standard 3-yearly screening or early repeat screening after 1 year. Analysis of the results was performed in accordance with the standards specified in the National Health Service Breast Screening Programme (NHSBSP) Publication Number 22. Absolute sensitivity was 89.3%, complete sensitivity was 93.2%, specificity (including patients undergoing both surgical excision and follow-up) was 88.7%. The predictive value of a positive (malignant) core biopsy result was 100%. The false negative rate was 3.9%. Twelve (5.9%) biopsies were classified inadequate for diagnosis. Core biopsy is a safe and accurate way of assessing screen detected abnormalities and can be used as a substitute for fine needle aspiration cytology with results that exceed the National Health Service Breast Screening Programme target standards, even in the learning phase.

The purpose of this study was to compare the clinical effectiveness of breast screening using a mammographic technique of 25 kV without a grid, with one of 28 kV with a grid. Effectiveness is judged by cancer detection, interval cancer rates, sensitivity and specificity calculations and tumour characteristics. The doses on standard physics tests given by the three machines when these exposure factors are selected were compared to see whether there is any scientific basis for recommendations on which is the more effective technique. The experiment was undertaken in the prevalence round of a screening programme set up in the UK in 1987. The main comparison is on 25,078 women randomized to one or other technique after March 1989. Comparison can also be made with the preceding 8482 women, who were examined by the 25 kV method, but not randomized and in whom there were a variety of other differences. In the randomized group there was no statistically significant difference in cancer detection. A minor difference in overall numbers without statistical significance was seen in favour of the 28 kV grid technique, but is offset by a greater interval cancer rate in this group. Small cancer detection was equal in the two groups. By contrast, the first 8482 women showed significantly worse screening performance, both in lower overall and small cancer detection rate, and in increased number of interval cancers, for which the explanation is likely to be complex. The dose measurements show that the use of a higher tube potential with the grid mitigates the dose increase that may have been expected. The choice between these two techniques is therefore neither automatically made by greater cancer detection nor made on grounds of dose. There was a minor dose penalty in using the 28 kV technique with grid.

BACKGROUND: Women with a significant family history of breast cancer are often offered more intensive and earlier surveillance than is offered to the general population in the National Breast Screening Programme. Up to now, this strategy has not been fully evaluated. OBJECTIVE: To evaluate the benefit of mammographic surveillance for women aged 40-49 years at moderate risk of breast cancer due to family history. The study is referred to as FH01. DESIGN: This was a single-arm cohort study with recruitment taking place between January 2003 and February 2007. Recruits were women aged < 50 years with a family history of breast or ovarian cancer conferring at least a 3% risk of breast cancer between ages 40 and 49 years. The women were offered annual mammography for at least 5 years and observed for the occurrence of breast cancer during the surveillance period. The age group 40-44 years was targeted so that they would still be aged < 50 years after 5 years of surveillance. SETTING: Seventy-four surveillance centres in England, Wales, Scotland and Northern Ireland. PARTICIPANTS: A total of 6710 women, 94% of whom were aged < 45 years at recruitment, with a family history of breast cancer estimated to imply at least a 3% risk of the disease between the ages of 40 and 50 years. INTERVENTIONS: Annual mammography for at least 5 years. MAIN OUTCOME MEASURES: The primary study end point was the predicted risk of death from breast cancer as estimated from the size, lymph node status and grade of the tumours diagnosed. This was compared with the control group from the UK Breast Screening Age Trial (Age Trial), adjusting for the different underlying incidence in the two populations. RESULTS: As of December 2010, there were 165 breast cancers diagnosed in 37,025 person-years of observation and 30,556 mammographic screening episodes. Of these, 122 (74%) were diagnosed at screening. The cancers included 44 (27%) cases of ductal carcinoma in situ. There were 19 predicted deaths in 37,025 person-years in FH01, with an estimated incidence of 6.3 per 1000 per year. The corresponding figures for the Age Trial control group were 204 predicted deaths in 622,127 person-years and an incidence of 2.4 per 1000 per year. This gave an estimated 40% reduction in breast cancer mortality (relative risk = 0.60; 95% confidence interval 0.37 to 0.98; p = 0.04). CONCLUSIONS: Annual mammography in women aged 40-49 years with a significant family history of breast or ovarian cancer is both clinically effective in reducing breast cancer mortality and cost-effective. There is a need to further standardise familial risk assessment, to research the impact of digital mammography and to clarify the role of breast density in this population. TRIAL REGISTRATION: National Research Register N0484114809. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 17, No. 11. See the HTA programme website for further project information.

In the prevalence round of screening for breast cancer at a single centre, the benefit of the second radiological report has been assessed using data from 33,734 women, their screening results and knowledge of the interval cancers. The service was set up under the UK National Breast Screening Programme, and the data show evidence of learning by both individuals and the team as a whole. Of the 269 cancers detected by screening, 33 would not have been diagnosed if the only report available had been the first. The recall recommendation rate associated with the first report was 6.9% and 236 cancers were detected. The recall recommendation rate associated with all queries of all the reports was 10% (3354 queries). Had these 3354 queries all been investigated (instead of the 1423 actually recalled) only a further three cancers would have been detected. Sensitivity of the programme as a whole was substantially better than that of individual radiologists, while the specificity was maintained. The decision pathway by which recalls were agreed between the two radiologists resulted in a low recall rate (4.2%) for the programme as a whole, and is a critical factor in gaining the benefit of the improved sensitivity without a concomitant deterioration in the specificity. With the passage through the prevalent round, recall rates steadily fell, the malignant to benign biopsy ratio improved and sensitivity increased. The second radiological report yielded 14% additional cancers diagnosed and contributed very significantly to good sensitivity and so to the effectiveness of screening. Economic analysis of the results will be reported in a further paper.

STUDY OBJECTIVE--To compare the costs and effects of routine mammography screening by a single mediolateral-oblique view and two views (mediolateral-oblique plus craniocaudal) of each breast. DESIGN--A cost effectiveness analysis of a prospective non-randomised trial comparing one and two view mammography screening was carried out at St Margaret's Hospital, Epping. All women in the study had two view mammography. The mediolateral-oblique view was always the first image read by the radiologist. After reading the films for a clinic session, the same radiologist then went back and read both the mediolateral-oblique and craniocaudal views together. Each set of films was read by two radiologists. The main outcome measures were recall rates, number of cancers detected, screening and assessment costs, and cost effectiveness ratios. SUBJECTS--A total of 26,430 women who attended for breast screening using both one and two view mammography participated. A sample of 132 women attending for assessment provided data on the private costs incurred in attending for assessment. RESULTS--There was a reduction in the recall rate from 9.1% (2404 of 26,430) after one view screening to 6.7% (1760 of 26,430) after two view screening. The results also suggest that for every 10,000 women screened an additional five cancers would be detected earlier with two view screening. The additional health service screening cost associated with two view screening was estimated to be 3.63 pounds: the costs associated with one and two view screening policies were estimated to be 41.49 pounds and 32.99 pounds respectively. Private costs incurred were estimated to be 0.35 pounds per woman screened and 32.75 pounds per woman assessed. Two cost effectiveness ratios were calculated: an incremental health service cost per additional cancer detected of 4129 pounds and an incremental health service plus private cost per additional cancer detected of 2742 pounds. The sensitivity analysis suggested that the results were sensitive to relatively large changes in a number of parameters. These included screening costs, assessment costs, equipment life, and recall rates. CONCLUSIONS--Use of two view screening increased early cancer detection and also costs. The reduction in the recall rate with two views was not sufficiently large to make the cost of two view screening neutral. While these results are not completely generalisable, a framework is provided to allow other centres to estimate the cost effectiveness of two view screening in their locality.

BACKGROUND: Mammographic density adjusted for age and body mass index (BMI) is a heritable marker of breast cancer susceptibility. Little is known about the biologic mechanisms underlying the association between mammographic density and breast cancer risk. We examined whether common low-penetrance breast cancer susceptibility variants contribute to interindividual differences in mammographic density measures. METHODS: We established an international consortium (DENSNP) of 19 studies from 10 countries, comprising 16,895 Caucasian women, to conduct a pooled cross-sectional analysis of common breast cancer susceptibility variants in 14 independent loci and mammographic density measures. Dense and nondense areas, and percent density, were measured using interactive-thresholding techniques. Mixed linear models were used to assess the association between genetic variants and the square roots of mammographic density measures adjusted for study, age, case status, BMI, and menopausal status. RESULTS: Consistent with their breast cancer associations, the C-allele of rs3817198 in LSP1 was positively associated with both adjusted dense area (P = 0.00005) and adjusted percent density (P = 0.001), whereas the A-allele of rs10483813 in RAD51L1 was inversely associated with adjusted percent density (P = 0.003), but not with adjusted dense area (P = 0.07). CONCLUSION: We identified two common breast cancer susceptibility variants associated with mammographic measures of radiodense tissue in the breast gland. IMPACT: We examined the association of 14 established breast cancer susceptibility loci with mammographic density phenotypes within a large genetic consortium and identified two breast cancer susceptibility variants, LSP1-rs3817198 and RAD51L1-rs10483813, associated with mammographic measures and in the same direction as the breast cancer association. This study was supported by Research Grant FIS PI060386 from Spain’s Health Research Fund (Fondo de Investigación Sanitaria); the EPY 1306/06 Collaboration Agreement between Astra-Zeneca and the Instituto de Salud Carlos III; and a grant from the Spanish Federation of Breast Cancer (FECMA). Sí

The aim of this study is to determine breast cancer risk at mammographic screening episodes and integrate standard risk factors with mammographic density and genetic data to assess changing the screening interval based on risk and offer women at high risk preventive strategies. We report our experience of assessing breast cancer risk within the U.K. National Health Service Breast Screening Program using results from the first 10,000 women entered into the "Predicting Risk Of breast Cancer At Screening" study. Of the first 28,849 women attending for screening at fifteen sites in Manchester 10,000 (35%) consented to study entry and completed the questionnaire. The median 10-year Tyrer–Cuzick breast cancer risk was 2.65% (interquartile range, 2.10–3.45). A total of 107 women (1.07%) had 10-year risks 8% or higher (high breast cancer risk), with a further 8.20% having moderately increased risk (5%–8%). Mammographic density (percent dense area) was 60% or more in 8.3% of women. We collected saliva samples from 478 women for genetic analysis and will extend this to 18% of participants. At time of consent to the study, 95.0% of women indicated they wished to know their risk. Women with a 10-year risk of 8% or more or 5% to 8% and mammographic density of 60% or higher were invited to attend or be telephoned to receive risk counseling; 81.9% of those wishing to know their risk have received risk counseling and 85.7% of these were found to be eligible for a risk-reducing intervention. These results confirm the feasibility of determining breast cancer risk and acting on the information in the context of population-based mammographic screening. Cancer Prev Res; 5(7); 943–51. ©2012 AACR.

Background: It is recommended that BRCA1/2 mutation carriers undergo breast cancer screening using MRI because of their very high cancer risk and the high sensitivity of MRI in detecting invasive cancers. Clinical observations suggest important differences in the natural history between breast cancers due to mutations in BRCA1 and BRCA2, potentially requiring different screening guidelines. Methods: Three studies of mutation carriers using annual MRI and mammography were analyzed. Separate natural history models for BRCA1 and BRCA2 were calibrated to the results of these studies and used to predict the impact of various screening protocols on detection characteristics and mortality. Results: BRCA1/2 mutation carriers (N = 1,275) participated in the studies and 124 cancers (99 invasive) were diagnosed. Cancers detected in BRCA2 mutation carriers were smaller [80% ductal carcinoma in situ (DCIS) or ≤10 mm vs. 49% for BRCA1, P < 0.001]. Below the age of 40, one (invasive) cancer of the 25 screen-detected cancers in BRCA1 mutation carriers was detected by mammography alone, compared with seven (three invasive) of 11 screen-detected cancers in BRCA2 (P < 0.0001). In the model, the preclinical period during which cancer is screen-detectable was 1 to 4 years for BRCA1 and 2 to 7 years for BRCA2. The model predicted breast cancer mortality reductions of 42% to 47% for mammography, 48% to 61% for MRI, and 50% to 62% for combined screening. Conclusions: Our studies suggest substantial mortality benefits in using MRI to screen BRCA1/2 mutation carriers aged 25 to 60 years but show important clinical differences in natural history. Impact: BRCA1 and BRCA2 mutation carriers may benefit from different screening protocols, for example, below the age of 40. Cancer Epidemiol Biomarkers Prev; 21(9); 1458–68. ©2012 AACR.

Objectives: To validate the use of “Imagebox”- a web-based image review system for large scale multicentre trials. Patients and Methods: As part of the multicentre trial ‘Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) study’ mammograms were collected and digitised. Software was created allowing digitised mammograms to be viewed from any location with internet access. Two validation studies were performed. Firstly phantom studies using line-pairs (1–20 lpmm -1 ) to assess spatial resolution and the CDMAM 3.4 phantom were used to assess the visibility of gold discs for contrast detail .Secondly a comparison was made between the scoring of 77 patients’ original diagnostic analogue mammograms from 29 hospitals and the corresponding web images. Films and web images were scored by one experienced breast radiologist according to the BIRADS classification. At least 8 weeks elapsed between scoring images from the same patient. Results: The original analogue spatial resolution was 20 lpmm -1 and web resolution of the same image reduced at 8.9 lpmm -1 . Contrast detail assessment demonstrated analogue and web images with near concordance and the image quality factor, IQF inv for the web was reduced but within the 95% confidence interval of the original mammograms. BIRADS final assessment showed good agreement between the analogue and the identical web images (Kappa 0.82). Conclusion: The overall reduction in spatial resolution did not adversely affect the quality of the diagnostic image on “Imagebox”. This may be due to its functionality, specifically the high magnification zoom which enhances diagnostic interpretation. Imagebox is a promising solution to address the logistical challenges for large breast imaging reviews and has further potential for education and self assessment.