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Background Bilateral-Risk-Reducing-Mastectomy-(BRRM) is well described in BRCA1/2 pathogenic variant carriers. However, little is known about the relative uptake, time trends or factors influencing uptake in those at increased breast cancer risk not known to be carriers. The aim of this study is to assess these factors in both groups. Methods BRRM uptake was assessed from entry to the Manchester Family History Clinic or from date of personal BRCA1/2 test. Follow up was censored at BRRM, breast cancer diagnosis, death or January 01, 2020. Cumulative incidence and cause specific and competing risk regression analyses were used to assess the significance of factors associated with BRRM. Results Of 7195 women at ≥25% lifetime breast cancer risk followed for up to 32 years, 451 (6.2%) underwent pre-symptomatic BRRM. Of those eligible in different risk groups the 20-year uptake of BRRM was 47.7%-(95%CI = 42.4–53.2%) in 479 BRCA1/2 carriers; 9.0% (95%CI = 7.26–11.24%) in 1261 women at ≥40% lifetime risk (non-BRCA), 4.8%-(95%CI = 3.98–5.73%) in 3561 women at 30–39% risk and 2.9%-(95%CI = 2.09–4.09%) in 1783 women at 25–29% lifetime risk. In cause-specific Cox regression analysis death of a sister with breast cancer50; OR = 0.26,95%CI = 0.17–0.41). Uptake continued to rise to 20 years from initial risk assessment. Conclusion We have identified several additional factors that correlate with BRRM uptake and demonstrate continued increases over time. These factors will help to tailor counselling and support for women., Highlights • BRRM continues even 20 years post original breast cancer risk assessment. • Potential triggers include death of mother/sister, children and a breast biopsy. • Uptake is clearly informed by lifetime risk of BC and higher in younger the women.

Polygenic risk scores (PRS) for disease risk stratification show great promise for application in general populations, but most are based on data from individuals of white European origin. We assessed two well validated PRS (SNP18, SNP143) in the Predicting-Risk-of-Cancer-At-Screening (PROCAS) study in North-West England for breast cancer prediction based on ethnicity. Overall, 9475 women without breast cancer at study entry, including 645 who subsequently developed invasive breast cancer or ductal carcinoma in situ provided DNA. All were genotyped for SNP18 and a subset of 1868 controls were genotyped for SNP143. For white Europeans both PRS discriminated well between individuals with and without cancer. For n=395 Black (n=112), Asian (n=119), mixed (n=44) or Jewish (n=120) women without cancer both PRS overestimated breast cancer risk, being most marked for women of Black and Jewish origin (p

PURPOSE To investigate the contribution of PALB2 pathogenic gene variants (PGVs, PALB2_PGV) and the CHEK2 c.1100delC (CHEK2_1100delC) PGV to familial breast and ovarian cancer, and PALB2_PGV associated breast cancer pathology. METHODS Outcomes of germline PALB2_PGV and CHEK2_1100delC testing were recorded in 3,127 women with histologically confirmed diagnoses of invasive breast cancer, carcinoma in situ, or epithelial nonmucinous ovarian cancer, and 1,567 female controls. Breast cancer pathology was recorded in PALB2_PGV cases from extended families. RESULTS Thirty-five PALB2 and 44 CHEK2_1100delC PGVs were detected in patients (odds ratio [OR] PALB2 breast-ovarian = 5.90 [95% CI: 1.92-18.36], CHEK2 breast-ovarian = 4.46 [95% CI: 1.86-10.46], PALB2 breast = 6.16 [95% CI: 1.98-19.21], CHEK2 breast = 4.89 [95% CI: 2.01-11.34]). Grade 3 ER-positive HER2-negative, grade 3 and triple negative (TN) tumors were enriched in cases with PALB2 PGVs compared with all breast cancers known to our service (respectively: 15/43, 254/1,843, P = 0.0005; 28/37, 562/1,381, P = 0.0001; 12/43, 204/1,639, P

Background Follicular lymphoma (FL) prognosis is influenced by the composition of the tumour microenvironment. We tested an automated approach to quantitatively assess the phenotypic and spatial immune infiltrate diversity as a prognostic biomarker for FL patients. Methods Diagnostic biopsies were collected from 127 FL patients initially treated with rituximab-based therapy (52%), radiotherapy (28%), or active surveillance (20%). Tissue microarrays were constructed and stained using multiplex immunofluorescence (CD4, CD8, FOXP3, CD21, PD-1, CD68, and DAPI). Subsequently, sections underwent automated cell scoring and analysis of spatial interactions, defined as cells co-occurring within 30 μm. Shannon’s entropy, a metric describing species biodiversity in ecological habitats, was applied to quantify immune infiltrate diversity of cell types and spatial interactions. Immune infiltrate diversity indices were tested in multivariable Cox regression and Kaplan–Meier analysis for overall (OS) and progression-free survival (PFS). Results Increased diversity of cell types (HR = 0.19 95% CI 0.06–0.65, p = 0.008) and cell spatial interactions (HR = 0.39, 95% CI 0.20–0.75, p = 0.005) was associated with favourable OS, independent of the Follicular Lymphoma International Prognostic Index. In the rituximab-treated subset, the favourable trend between diversity and PFS did not reach statistical significance. Conclusion Multiplex immunofluorescence and Shannon’s entropy can objectively quantify immune infiltrate diversity and generate prognostic information in FL. This automated approach warrants validation in additional FL cohorts, and its applicability as a pre-treatment biomarker to identify high-risk patients should be further explored. The multiplex image dataset generated by this study is shared publicly to encourage further research on the FL microenvironment.

BackgroundWhile the likelihood of identifying constitutional breast cancer-associated BRCA1, BRCA2 and TP53 pathogenic variants (PVs) increases with earlier diagnosis age, little is known about the correlation with age at diagnosis in other predisposition genes. Here, we assessed the contribution of known breast cancer-associated genes to very early onset disease.MethodsSequencing of BRCA1, BRCA2, TP53 and CHEK2 c.1100delC was undertaken in women with breast cancer diagnosed ≤30 years. Those testing negative were screened for PVs in a minimum of eight additional breast cancer-associated genes. Rates of PVs were compared with cases ≤30 years from the Prospective study of Outcomes in Sporadic vs Hereditary breast cancer (POSH) study.ResultsTesting 379 women with breast cancer aged ≤30 years identified 75 PVs (19.7%) in BRCA1, 35 (9.2%) in BRCA2, 22 (5.8%) in TP53 and 2 (0.5%) CHEK2 c.1100delC. Extended screening of 184 PV negative women only identified eight additional actionable PVs. BRCA1/2 PVs were more common in women aged 26–30 years than in younger women (p=0.0083) although the younger age group had rates more similar to those in the POSH cohort. Out of 26 women with ductal carcinoma in situ (DCIS) alone, most were high-grade and 11/26 (42.3%) had a PV (TP53=6, BRCA2=2, BRCA1=2, PALB2=1). This PV yield is similar to the 61 (48.8%) BRCA1/2 PVs identified in 125 women with triple-negative breast cancer. The POSH cohort specifically excluded pure DCIS which may explain lower TP53 PV rates in this group (1.7%).ConclusionThe rates of BRCA1, BRCA2 and TP53 PVs are high in very early onset breast cancer, with limited benefit from testing of additional breast cancer-associated genes.

BackgroundWomen testing positive for BRCA1/2 pathogenic variants have high lifetime risks of breast cancer (BC) and ovarian cancer. The effectiveness of risk reducing surgery (RRS) has been demonstrated in numerous previous studies. We evaluated long-term uptake, timing and effectiveness of risk reducing mastectomy (RRM) and bilateral salpingo-oophorectomy (RRSO) in healthy BRCA1/2 carriers.MethodsWomen were prospectively followed up from positive genetic test (GT) result to censor date. χ² testing compared categorical variables; Cox regression model estimated HRs and 95% CI for BC/ovarian cancer cases associated with RRS, and impact on all-cause mortality; Kaplan-Meier curves estimated cumulative RRS uptake. The annual cancer incidence was estimated by women-years at risk.ResultsIn total, 887 women were included in this analysis. Mean follow-up was 6.26 years (range=0.01–24.3; total=4685.4 women-years). RRS was performed in 512 women, 73 before GT. Overall RRM uptake was 57.9% and RRSO uptake was 78.6%. The median time from GT to RRM was 18.4 months, and from GT to RRSO–10.0 months. Annual BC incidence in the study population was 1.28%. Relative BC risk reduction (RRM versus non-RRM) was 94%. Risk reduction of ovarian cancer (RRSO versus non-RRSO) was 100%.ConclusionOver a 24-year period, we observed an increasing number of women opting for RRS. We showed that the timing of RRS remains suboptimal, especially in women undergoing RRSO. Both RRM and RRSO showed a significant effect on relevant cancer risk reduction. However, there was no statistically significant RRSO protective effect on BC.

Poly(ADP-ribose) polymerase (PARP) inhibitors improve survival in BRCA-mutant high-grade serous ovarian carcinoma. As a result, germline and somatic BRCA1/2 testing has become standard practice in women diagnosed with ovarian cancer. We outline changes in testing and detection rates of germline BRCA1/2 pathogenic variants (PVs) in cases of non-mucinous epithelial ovarian cancer diagnosed during three eras, spanning 12 years, within the North West of England, and compare the uptake of cascade testing in families identified by oncology-led mainstreaming versus regional genetics clinics. Eras included: Period 1 (20% risk threshold for testing): between January 2007 and May 2013; Period 2 (10% risk threshold for testing): between June 2013 and October 2017 and; Period 3 (mainstream testing): between November 2017 and November 2019. A total of 1081 women underwent germline BRCA1/2 testing between January 2007 and November 2019 and 222 (20.5%) were found to have a PV. The monthly testing rate increased by 3.3-fold and 2.5-fold between Periods 1–2 and Periods 2–3, respectively. A similar incidence of germline BRCA1/2 PVs were detected in Period 2 (17.2%) and Period 3 (18.5%). Uptake of cascade testing from first-degree relatives was significantly lower in those women undergoing mainstream testing compared with those tested in regional genetics clinics (31.6% versus 47.3%, P = 0.038). Mainstream testing allows timely detection of germline BRCA1/2 status to select patients for PARP inhibitors, but shortfalls in the uptake of cascade testing in first-degree relatives requires optimisation to broaden benefits within families.

The incidence of breast cancer continues to increase worldwide. Population-based screening is available in many countries but may not be the most efficient use of resources, thus interest in risk-based/stratified screening has grown significantly in recent years. An important part of risk-based screening is the incorporation of mammographic density (MD) and single nucleotide polymorphisms (SNPs) into risk prediction models to be combined with classical risk factors. In this article, we discuss different measures of MD and risk prediction models that are available. Risk-stratified screening options including supplemental or alternative screening modalities including digital breast tomosynthesis (DBT), automated ultrasound (ABUS) and magnetic resonance imaging (MRI) are discussed, as well as potential risk-based interventions (diet and lifestyle, chemoprevention and risk-reducing surgery). Furthermore, we look at risk feedback in practice and the cost-effectiveness and acceptability of risk-based screening, highlighting some of the current challenges.

BackgroundGenetic testing for BRCA1 and BRCA2 pathogenic variants (PVs) has been available in North West England since 1995. We assessed uptake of pre-symptomatic testing in 1564 families with PVs over a 24.5year follow-up (FU) period.MethodsFirst-degree relatives (FDRs) in families with BRCA1 or BRCA2 PVs were eligible from date of index family report if unaffected by a relevant cancer and alive at report date. FDRs were censored as not having undergone a pre-symptomatic test at diagnosis of a relevant cancer, date of death, age 93 or 30/03/2019. Time to uptake of pre-symptomatic testing was assessed by Kaplan–Meier curves, by gender and children.Results2554 male and 3115 female FDRs were eligible. Overall uptake was 775 (30.3%) in men and 1935 (62.1%) in women. This increased at 15 years to 33.6% and 67.9%, and continued to rise until 24 years (p80% by 15 years. Uptake was higher in parous women (pConclusionUptake of BRCA1/2 pre-symptomatic testing is age, gender and time-dependent, and higher in women with children and men with daughters.

Genome-wide analysis identifies 32 loci associated with breast cancer susceptibility, accounting for estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype(1-3). To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 x 10(-8)), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.

PURPOSE: To evaluate the incidence of mosaicism in de novo neurofibromatosis 2 (NF2).METHODS: Patients fulfilling NF2 criteria, but with no known affected family member from a previous generation (n = 1055), were tested for NF2 variants in lymphocyte DNA and where available tumor DNA. The proportion of individuals with a proven or presumed mosaic NF2 variant was assessed and allele frequencies of identified variants evaluated using next-generation sequencing.RESULTS: The rate of proven/presumed mosaicism was 232/1055 (22.0%). However, nonmosaic heterozygous pathogenic variants were only identified in 387/1055 (36.7%). When variant detection rates in second generation nonmosaics were applied to de novo cases, we assessed the overall probable mosaicism rate to be 59.7%. This rate differed by age from 21.7% in those presenting with bilateral vestibular schwannoma CONCLUSION: This study has identified a very high probable mosaicism rate in de novo NF2, probably making NF2 the condition with the highest expressed rate of mosaicism in de novo dominant disease that is nonlethal in heterozygote form. Risks to offspring are small and probably correlate with variant allele frequency detected in blood.

We compared accuracy for breast cancer (BC) risk stratification of a new fully automated system (DenSeeMammo—DSM) for breast density (BD) assessment to a non-inferiority threshold based on radiologists’ visual assessment. Pooled analysis was performed on 14,267 2D mammograms collected from women aged 48–55 years who underwent BC screening within three studies: RETomo, Florence study and PROCAS. BD was expressed through clinical Breast Imaging Reporting and Data System (BI-RADS) density classification. Women in BI-RADS D category had a 2.6 (95% CI 1.5–4.4) and a 3.6 (95% CI 1.4–9.3) times higher risk of incident and interval cancer, respectively, than women in the two lowest BD categories. The ability of DSM to predict risk of incident cancer was non-inferior to radiologists’ visual assessment as both point estimate and lower bound of 95% CI (AUC 0.589; 95% CI 0.580–0.597) were above the predefined visual assessment threshold (AUC 0.571). AUC for interval (AUC 0.631; 95% CI 0.623–0.639) cancers was even higher. BD assessed with new fully automated method is positively associated with BC risk and is not inferior to radiologists’ visual assessment. It is an even stronger marker of interval cancer, confirming an appreciable masking effect of BD that reduces mammography sensitivity., SCOPUS: ar.j, info:eu-repo/semantics/published

BACKGROUNDProtein truncating variants in ATM, BRCA1, BRCA2, CHEK2 and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain.METHODSCombining 59,639 breast cancer cases and 53,165 controls, we sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1,146 training variants), BRCA1 (644), BRCA2 (1,425), CHEK2 (325) and PALB2 (472). We evaluated breast cancer risks according to five in-silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated.RESULTSThe most predictive in-silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1 and BRCA2, data were compatible with small subsets (approximately 7%, 2% and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47-2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set.CONCLUSIONSThese results will inform risk prediction models and the selection of candidate variants for functional assays, and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility.

Whilst panel testing of an extended group of genes including BRCA1/2 is commonplace, these studies have not been subdivided by histiotype or by a priori BRCA1/2 probability. Patients with a breast cancer diagnosis undergoing extended panel testing were assessed for frequency of actionable variants in breast cancer genes other than BRCA1/2 by histiotype and Manchester score (MS) to reflect a priori BRCA1/2 likelihood. Rates were adjusted by prior testing for BRCA1/2 in an extended series. 95/1398 (6.3%) who underwent panel testing were found to be positive for actionable non-BRCA1/2 breast/ovarian cancer genes (ATM, BARD1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, TP53). As expected, PALB2, CHEK2 and ATM were predominant with 80-(5.3%). The highest rate occurred in Grade-3 ER+/HER2− breast cancers-(9.6%). Rates of non-BRCA actionable genes was fairly constant over all likelihoods of BRCA1/2 but adjusted rates were three times higher with MS &lt, 9 (BRCA1/2 = 1.5%, other = 4.7%), but was only 1.6% compared to 79.3% with MS ≥ 40. Although rates of detection of non-BRCA actionable genes are relatively constant across BRCA1/2 likelihoods this disguises an overall adjusted low frequency in high-likelihood families which have been heavily pre-tested for BRCA1/2. Any loss of detection sensitivity for BRCA1/2 actionable variants in breast cancer panels should lead to bespoke BRCA1/2 testing being conducted first.

Menopausal hormone therapy (MHT) has an attenuated effect on breast cancer (BC) risk amongst heavier women, but there are few data on a potential interaction with early adulthood body mass index (at age 20 years) and age of first pregnancy. We studied 56,489 women recruited to the PROCAS (Predicting Risk of Cancer at Screening) study in Manchester UK, 2009-15. Cox regression models estimated the effect of reported MHT use at entry on breast cancer (BC) risk, and potential interactions with a. self-reported current body mass index (BMI), b. BMI aged 20 and c. First pregnancy &gt, 30 years or nulliparity compared with first pregnancy &lt, 30 years. Analysis was adjusted for age, height, family history, age of menarche and menopause, menopausal status, oophorectomy, ethnicity, self-reported exercise and alcohol. With median follow up of 8 years, 1663 breast cancers occurred. BC risk was elevated amongst current users of combined MHT compared to never users (Hazard ratioHR 1.64, 95% CI 1.32–2.03), risk was higher than for oestrogen only users (HR 1.03, 95% CI 0.79–1.34). Risk of current MHT was attenuated by current BMI (interaction HR 0.80, 95% CI 0.65–0.99) per 5 unit increase in BMI. There was little evidence of an interaction between MHT use, breast cancer risk and early and current BMI or with age of first pregnancy.

Purpose: We have evaluated deficiencies in existing diagnostic criteria for neurofibromatosis 2 (NF2). Methods: Two large databases of individuals fulfilling NF2 criteria (n=1361) and those tested for NF2 variants with criteria short of diagnosis (n=1416) were interrogated. We assessed the proportions meeting each diagnostic criterion with constitutional or mosaic NF2 variants and the Positive Predictive Value (PPV) with regard to definite diagnosis.Results: There was no evidence for usefulness of old criteria ‘glioma’ or ‘neurofibroma’. ‘Ependymoma’ had 100% PPV and high levels of confirmed NF2 diagnosis (67.7%). Those with bilateral vestibular schwannoma (VS) alone aged ≥60 years had the lowest confirmation rate (6.6%) and reduced PPV(80%). Siblings as a first-degree-relative, without an affected parent, had 0% PPV. All three individuals with unilateral VS and an affected sibling were proven not to have NF2. The biggest overlap was with LZTR1-associated schwannomatosis. In this category, seven individuals with unilateral VS plus ≥2 non-dermal schwannomas reduced PPV to 67%.Conclusion: The present study has confirmed important deficiencies in NF2 diagnostic criteria. The term ‘glioma’ should be dropped and replaced by ‘ependymoma’. Similarly ‘neurofibroma’ should be removed. Dropping ‘sibling’ from first-degree-relatives should be considered and testing of LZTR1 should be recommended for unilateral VS.

Purpose Women at increased familial breast cancer risk have been offered screening starting at an earlier age and increased frequency than national Screening Programmes for over 30 years. There are limited data on longer-term largescale implementation of this approach on cancer diagnosis. Methods Women at our institution at ≥ 17% lifetime breast cancer risk have been offered enhanced screening with annual mammography starting at age 35 or 5-years younger than youngest affected relative, with upper age limit 50 for moderate and 60 for high-risk. Breast cancer pathology, stage and receptor status were assessed as well as survival from cancer diagnosis by Kaplan–Meier analysis. Results Overall 14,311 women were seen and assessed for breast cancer risk, with 649 breast cancers occurring in 129,119 years follow up (post-prevalent annual incidence = 4.55/1000). Of 323/394 invasive breast cancers occurring whilst on enhanced screening, most were lymph-node negative (72.9%), T1 (≤ 20 mm, 73.2%) and stage-1 (61.4%), 126/394 stage2–4 (32%). 10-year breast cancer specific survival was 91.3% (95% CI 87.4–94.0) better than the 75.9% (95% CI 74.9–77.0) published for England in 2013–2017. As expected, survival was significantly better for women with screen detected cancers (p n = 75; 95% CI 84.2–97.6). Women with lobular breast cancers had worse 10-year survival at 85.9% (95% CI 66.7–94.5). Breast cancer specific survival was good for 119 BRCA1/2 carriers with 20-year survival in BRCA1:91.2% (95% CI 77.8–96.6) and 83.8% (62.6–93.5) for BRCA2. Conclusions Targeted breast screening in women aged 30–60 years at increased familial risk is associated with good long-term survival that is substantially better than expected from population data.

Purpose: Lobular breast cancer (LBC) accounts for ~ 15% of breast cancer. Here, we studied the frequency of pathogenic germline variants (PGVs) in an extended panel of genes in women affected with LBC. Methods: 302 women with LBC and 1567 without breast cancer were tested for BRCA1/2 PGVs. A subset of 134 LBC affected women who tested negative for BRCA1/2 PGVs underwent extended screening, including: ATM, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50, RAD51D, and TP53.Results: 35 PGVs were identified in the group with LBC, of which 22 were in BRCA1/2. Ten actionable PGVs were identified in additional genes (ATM(4), CDH1(1), CHEK2(1), PALB2(2) and TP53(2)). Overall, PGVs in three genes conferred a significant increased risk for LBC. Odds ratios (ORs) were: BRCA1: OR = 13.17 (95%CI 2.83–66.38; P = 0.0017), BRCA2: OR = 10.33 (95%CI 4.58–23.95; P ATM: OR = 8.01 (95%CI 2.52–29.92; P = 0.0053). We did not detect an increased risk of LBC for PALB2, CDH1 or CHEK2. Conclusion: The overall PGV detection rate was 11.59%, with similar rates of BRCA1/2 (7.28%) PGVs as for other actionable PGVs (7.46%), indicating a benefit for extended panel genetic testing in LBC. We also report a previously unrecognised association of pathogenic variants in ATM with LBC.

Background Limited data exist on the disease course of neurofibromatosis type 2 (NF2) to guide clinical trial design. Methods A prospective database of patients meeting NF2 diagnostic criteria, reviewed between 1990 and 2020, was evaluated. Follow-up to first vestibular schwannoma (VS) intervention and death was assessed by univariate analysis and stratified by age at onset, era referred, and inheritance type. Interventions for NF2-related tumors were assessed. Cox regression was performed to determine the relationship between individual factors from time of diagnosis to NF2-related death. Results Three hundred and fifty-three patients were evaluated. During 4643.1 follow-up years from diagnosis to censoring, 60 patients (17.0%) died. The annual mean number of patients undergoing VS surgery or radiotherapy declined, from 4.66 and 1.65, respectively, per 100 NF2 patients in 1990-1999 to 2.11 and 1.01 in 2010-2020, as the number receiving bevacizumab increased (2.51 per 100 NF2 patients in 2010-2020). Five patients stopped bevacizumab to remove growing meningioma or spinal schwannoma. 153/353 (43.3%) had at least one neurosurgical intervention/radiation treatment within 5 years of diagnosis. Patients asymptomatic at diagnosis had longer time to intervention and better survival compared to those presenting with symptoms. Those symptomatically presenting 40 years had poorer overall survival than those presenting at 26-39 years (P = .03 and P = .02, respectively) but those presenting between 16 and 39 had shorter time to VS intervention. Individuals with de novo constitutional variants had worse survival than those with de novo mosaic or inherited disease (P = .004). Conclusion Understanding disease course improves prognostication, allowing for better-informed decisions about care.

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.

Estimation of breast density for cancer risk prediction is generally achieved by analysis of full-field digital mammograms. Conventional digital mammography should be avoided if possible in young women because of concerns about potential cancer induction, particularly in those with dense breasts who receive higher doses. This precludes repeated examinations over a short timescale to assess density change. We assess whether density can be accurately estimated in low dose mammograms with one-tenth of the standard dose, with the aim of providing a safe and effective method for use in younger women which is suitable for serial density measurement. We present analysis of data from an on-going clinical trial in which both standard and low dose mammograms are acquired under the same compression. We used both an existing convolutional neural network model designed to estimate breast density and a new model developed using a transfer learning approach. We then applied three methods to estimate density on the low dose mammograms: training on a different mammogram dataset; using simulated low dose data; and training directly on low dose mammograms using cross-validation. Pearson correlation coefficients between measurements on full dose and low dose mammograms ranged from 0.92 to 0.98 with the root mean squared error ranging between 3.37 and 7.27. Our results indicate that accurate density measurements can be made using low dose mammograms.

Breast density is an important risk factor for breast cancer and has a substantial effect on the sensitivity of mammography screening. This study aimed to evaluate intra and inter reader variability of visual breast density assessment in Saudi Arabia, using the American College of Radiology (ACR) Breast Imaging Reporting and Data System (BI-RADS) breast density categories (5th edition) and Visual Analogue Scales (VAS). A random sample of 102 screening mammograms from the Saudi National Breast Cancer Screening Programme (SNBCSP) was assessed twice by two breast screening consultant radiologists for intra reader variability. Inter reader variability was assessed using screening mammograms from 1132 women. Each mammogram was assessed by two readers from a pool of 11 radiologists. Inter reader variability for two mammography technologists using a sample of 75 mammograms is also reported. Intra reader variability showed radiologist A had excellent agreement for VAS [Intraclass Correlation Coefficient (ICC) = 0.95] and BI-RADS [weighted kappa (κ) = 0.88], radiologist B had lower but still excellent agreement for VAS [ICC= 0.88] and substantial agreement for BI-RADS [κ = 0.71]. Inter reader variability between radiologists showed overall moderate agreement for BI-RADS [κ =0.61] while VAS had excellent agreement [ICC=0.89]. Results of inter reader agreement between two mammography technologists was fair using BI-RADS [κ= 0.35] and moderate using VAS [ICC=0.41]. In conclusion, agreement in breast density assessment by radiologists in the Saudi breast screening programme is acceptable. Mammography technologists showed lower agreement for both methods. Training is essential to increase reader agreement, double reading is also important in such population based breast cancer screening programmes.

Early age at diagnosis of breast cancer is a known risk factor for hereditary predisposition and some studies show a high risk of contralateral breast cancer in BRCA1 carriers diagnosed at very young ages. However, little is published on the risk of TP53 carriers. 397 women with breast cancer diagnosed BRCA1, BRCA2, and TP53 genes was carried out alongside tests for copy number for PV on all referred women. Rates of contralateral breast cancer were censored at death, last assessment, or risk-reducing mastectomy. In total, 47 TP53, 218 BRCA1, and 132 BRCA2 PV carriers were identified with breast cancer diagnosed aged 35 years and under, as well as a representative sample of 261 not known to carry a PV in BRCA1, BRCA2, and TP53. Annual rates of contralateral breast cancer (and percentage of synchronous breast cancers) were TP53: 7.03% (4.3%), BRCA1: 3.57% (1.8%), and BRCA2: 2.63% (1.5%). In non-PV carriers, contralateral rates in isolated presumed/tested non-carrier cases with no family history were 0.56%, and for those with a family history, 0.69%. Contralateral breast cancer rates are substantial in TP53, BRCA1, and BRCA2 PV carriers diagnosed with breast cancer aged 35 and under. Women need to be advised to help make informed decisions on contralateral mastectomy, guided by life expectancy from their index tumor.

PURPOSERisk-stratified breast cancer prevention requires accurate identification of women at sufficiently different levels of risk. We conducted a comprehensive evaluation of a model integrating classical risk factors and a recently developed 313-variant polygenic risk score (PRS) to predict breast cancer risk.METHODSFifteen prospective cohorts from six countries with 237,632 women (7,529 incident breast cancer patients) of European ancestry aged 19-75 years at baseline were included. Calibration of five-year risk was assessed by comparing predicted and observed proportions of cases overall and within risk categories. Risk stratification for women of European ancestry aged 50-70 years in those countries was evaluated by the proportion of women and future breast cancer cases crossing clinically-relevant risk thresholds.RESULTSThe model integrating classical risk factors and PRS accurately predicted five-year risk. For women younger than 50 years, median (range) expected-to-observed ratio across the cohorts was 0.94 (0.72 to 1.01) overall and 0.9 (0.7 to 1.4) at the highest risk decile. For women 50 years or older, these ratios were 1.04 (0.73 to 1.31) and 1.2 (0.7 to 1.6), respectively. The proportion of women in the general population identified above the 3% five-year risk threshold (used for recommending risk-reducing medications in the US) ranged from 7.0% in Germany (∼841,000 of 12 million) to 17.7% in the US (∼5.3 of 30 million). At this threshold, 14.7% of US women were re-classified by the addition of PRS to classical risk factors, identifying 12.2% additional future breast cancer cases.CONCLUSIONEvaluation across multiple prospective cohorts demonstrates that integrating a 313-SNP PRS into a risk model substantially improves its ability to stratify women of European ancestry for applying current breast cancer prevention guidelines.

ObjectivesSchwannomatosis is a dominantly inherited condition predisposing to schwannomas of mainly spinal and peripheral nerves with some diagnostic overlap with neurofibromatosis-2 (NF2), but the underlying epidemiology is poorly understood. We present the birth incidence and prevalence allowing for overlap with NF2.MethodsSchwannomatosis and NF2 cases were ascertained from the Manchester region of England (population=4.8 million) and from across the UK. Point prevalence and birth incidence were calculated from regional birth statistics. Genetic analysis was also performed on NF2, LZTR1 and SMARCB1 on blood and tumour DNA samples when available.ResultsRegional prevalence for schwannomatosis and NF2 were 1 in 126 315 and 50 500, respectively, with calculated birth incidences of 1 in 68 956 and 1 in 27 956. Mosaic NF2 causes a substantial overlap with schwannomatosis resulting in the misdiagnosis of at least 9% of schwannomatosis cases. LZTR1-associated schwannomatosis also causes a small number of cases that are misdiagnosed with NF2 (1%–2%), due to the occurrence of a unilateral vestibular schwannoma. Patients with schwannomatosis had lower numbers of non-vestibular cranial schwannomas, but more peripheral and spinal nerve schwannomas with pain as a predominant presenting symptom. Life expectancy was significantly better in schwannomatosis (mean age at death 76.9) compared with NF2 (mean age at death 66.2; p=0.004).ConclusionsWithin the highly ascertained North-West England population, schwannomatosis has less than half the birth incidence and prevalence of NF2.

Purpose Previous research assessing the impact of pregnancy and age at first pregnancy on breast cancer risk in BRCA1 and BRCA2 mutation carriers has produced conflicting results, with some studies showing an increased risk following early first pregnancy in contrast to the reduced risk in the general population of women. The present study addresses these inconsistencies. Methods Female BRCA1 and BRCA2 carriers from North West England were assessed for breast cancer incidence prior to 50 years of age comparing those with an early first full-term pregnancy (

Background: Whilst the requirement for thresholds for testing for mutations in BRCA1/2 is being questioned, they are likely to remain for individuals unaffected by a relevant cancer. It is still useful to provide pre-testing likelihoods, but models need to take into account tumour pathology.Methods: The Manchester scoring system (MSS) is a well utilised, simple, paper based model for assessing carrier probability that already incorporates pathology data. We have used mutation testing data from 4115 unrelated samples from affected non-Jewish individuals alongside tumour pathology to further refine the scoring system.Results: Adding additional points for high grade serous ovarian cancer

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype. To identify novel loci, we performed a genome-wide association study (GWAS) including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status and tumor grade. We identified 32 novel susceptibility loci (P-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate PIn-silico analyses showed these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 37.6% for triple-negative and 54.2% for luminal A-like disease. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.

Background: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. Methods: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). Results: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10 −8 . For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10 −7 , hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84–0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10 −7 , HR = 1.27, 95% CI = 1.16–1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. Conclusions: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.

Purpose To improve breast cancer risk stratification to enable more targeted early detection/prevention strategies that will better balance risks and benefits of population screening programmes. Methods 9362 of 57,902 women in the Predicting-Risk-Of-Cancer-At-Screening (PROCAS) study who were unaffected by breast cancer at study entry and provided DNA for a polygenic risk score (PRS). The PRS was analysed alongside mammographic density (density-residual-DR) and standard risk factors (Tyrer-Cuzick-model) to assess future risk of breast cancer based on tumour stage receptor expression and pathology. Results 195 prospective incident breast cancers had a prediction based on TC/DR/PRS which was informative for subsequent breast cancer overall [IQ-OR 2.25 (95% CI 1.89–2.68)] with excellent calibration-(0.99). The model performed particularly well in predicting higher stage stage 2+ IQ-OR 2.69 (95% CI 2.02–3.60) and ER + BCs (IQ-OR 2.36 (95% CI 1.93–2.89)). DR was most predictive for HER2+ and stage 2+ cancers but did not discriminate as well between poor and extremely good prognosis BC as either Tyrer-Cuzick or PRS. In contrast, PRS gave the highest OR for incident stage 2+ cancers, [IQR-OR 1.79 (95% CI 1.30–2.46)]. Conclusions A combined approach using Tyrer-Cuzick/DR/PRS provides accurate risk stratification, particularly for poor prognosis cancers. This provides support for reducing the screening interval in high-risk women and increasing the screening interval in low-risk women defined by this model. Electronic supplementary material The online version of this article (10.1007/s10549-019-05210-2) contains supplementary material, which is available to authorized users.

Panels of single nucleotide polymorphisms (SNPs) stratify risk for breast cancer in women from the general population, but studies are needed assess their use in a fully comprehensive model including classical risk factors, mammographic density and more than 100 SNPs associated with breast cancer. A case–control study was designed (1,668 controls, 405 cases) in women aged 47–73 years attending routine screening in Manchester UK, and enrolled in a wider study to assess methods for risk assessment. Risk from classical questionnaire risk factors was assessed using the Tyrer–Cuzick model; mean percentage visual mammographic density was scored by two independent readers. DNA extracted from saliva was genotyped at selected SNPs using the OncoArray. A predefined polygenic risk score based on 143 SNPs was calculated (SNP143). The odds ratio (OR, and 95% confidence interval, CI) per interquartile range (IQ‐OR) of SNP143 was estimated unadjusted and adjusted for Tyrer–Cuzick and breast density. Secondary analysis assessed risk by oestrogen receptor (ER) status. The primary polygenic risk score was well calibrated (O/E OR 1.10, 95% CI 0.86–1.34) and accuracy was retained after adjustment for Tyrer–Cuzick risk and mammographic density (IQ‐OR unadjusted 2.12, 95% CI% 1.75–2.42; adjusted 2.06, 95% CI 1.75–2.42). SNP143 was a risk factor for ER+ and ER− breast cancer (adjusted IQ‐OR, ER+ 2.11, 95% CI 1.78–2.51; ER− 1.81, 95% CI 1.16–2.84). In conclusion, polygenic risk scores based on a large number of SNPs improve risk stratification in combination with classical risk factors and mammographic density, and SNP143 was similarly predictive for ER‐positive and ER‐negative disease., What's new? Panels of single nucleotide polymorphisms (SNPs) stratify risk for breast cancer in women from the general population, but studies are needed to assess their use in a fully‐comprehensive model including classical questionnaire risk factors, mammographic density, and more than 100 SNPs associated with breast cancer. In this study, the predictive ability of a predefined panel of 143 SNPs was assessed after adjustment for questionnaire risk factors and mammography density using women from a U.K. cohort. The panel showed substantial improvement in risk stratification in combination with classical risk factors and mammographic density, for both oestrogen receptor‐positive and negative breast cancer.

Clinics for women concerned about their family history of breast cancer are widely established. A Family History Clinic was set-up in Manchester, UK, in 1987 in a Breast Unit serving a population of 1.8 million. In this review, we report the outcome of risk assessment, screening and prevention strategies in the clinic and propose future approaches. Between 1987&ndash, 2020, 14,311 women were referred, of whom 6.4% were from known gene families, 38.2% were at high risk (&ge, 30% lifetime risk), 37.7% at moderate risk (17&ndash, 29%), and 17.7% at an average/population risk who were discharged. A total of 4168 (29.1%) women were eligible for genetic testing and 736 carried pathogenic variants, predominantly in BRCA1 and BRCA2 but also other genes (5.1% of direct referrals). All women at high or moderate risk were offered annual mammographic screening between ages 30 and 40 years old: 646 cancers were detected in women at high and moderate risk (5.5%) with a detection rate of 5 per 1000 screens. Incident breast cancers were largely of good prognosis and resulted in a predicted survival advantage. All high/moderate-risk women were offered lifestyle prevention advice and 14&ndash, 27% entered various lifestyle studies. From 1992&ndash, 2003, women were offered entry into IBIS-I (tamoxifen) and IBIS-II (anastrozole) trials (12.5% of invitees joined). The NICE guidelines ratified the use of tamoxifen and raloxifene (2013) and subsequently anastrozole (2017) for prevention, 10.8% women took up the offer of such treatment between 2013&ndash, 2020. Since 1994, 7164 eligible women at &ge, 25% lifetime risk of breast cancer were offered a discussion of risk-reducing breast surgery and 451 (6.2%) had surgery. New approaches in all aspects of the service are needed to build on these results.

Background : Mammographic density is an important risk factor for breast cancer. Recent research demonstrated that percentage density assessed visually using Visual Analogue Scales (VAS) showed stronger risk prediction than existing automated density measures, suggesting readers may recognise relevant image features not yet captured by automated methods. Method : We have built convolutional neural networks (CNN) to predict VAS scores from full-field digital mammograms. The CNNs are trained using whole-image mammograms, each labelled with the average VAS score of two independent readers. They learn a mapping between mammographic appearance and VAS score so that at test time, they can predict VAS score for an unseen image. Networks were trained using 67520 mammographic images from 16968 women, and tested on a large dataset of 73128 images and case-control sets of contralateral mammograms of screen detected cancers and prior images of women with cancers detected subsequently, matched to controls on age, menopausal status, parity, HRT and BMI. Results : Pearson's correlation coefficient between readers' and predicted VAS in the large dataset was 0.79 per mammogram and 0.83 per woman (averaging over all views). In the case-control sets, odds ratios of cancer in the highest vs lowest quintile of percentage density were 3.07 (95%CI: 1.97 - 4.77) for the screen detected cancers and 3.52 (2.22 - 5.58) for the priors, with matched concordance indices of 0.59 (0.55 - 0.64) and 0.61 (0.58 - 0.65) respectively. Conclusion : Our fully automated method demonstrated encouraging results which compare well with existing methods, including VAS.

PurposeThe identification of BRCA1, BRCA2 or mismatch repair (MMR) pathogenic gene variants in familial breast/ovarian/colorectal cancer families facilitates predictive genetic testing of at-risk relatives. However, controversy still exists regarding overall lifetime risks of cancer in individuals testing positive.MethodsWe assessed the penetrance of BRCA1, BRCA2, MLH1 and MSH2 mutations in men and women using Bayesian calculations based on ratios of positive to negative presymptomatic testing by 10-year age cohorts. Mutation position was also assessed for BRCA1/BRCA2.ResultsUsing results from 2264 presymptomatic tests in first-degree relatives (FDRs) of mutation carriers in BRCA1 and BRCA2 and 646 FDRs of patients with MMR mutations, we assessed overall associated cancer penetrance to age of 68 years as 73% (95% CI 61% to 82%) for BRCA1, 60% (95% CI 49% to 71%) for BRCA2, 95% (95% CI 76% to 99%) for MLH1% and 61% (95% CI 49% to 76%) for MSH2. There was no evidence for significant penetrance for males in BRCA1 or BRCA2 families and males had equivalent penetrance to females with Lynch syndrome. Mutation position and degree of family history influenced penetrance in BRCA2 but not BRCA1.ConclusionWe describe a new method for assessing penetrance in cancer-prone syndromes. Results are in keeping with published prospective series and present modern-day estimates for overall disease penetrance that bypasses retrospective series biases.

Computer aided detection (CAD) systems assist medical experts during image interpretation. In mammography, CAD systems prompt suspicious regions which help medical experts to detect early signs of cancer. This is a challenging task and prompts may appear in regions that are actually normal, whilst genuine cancers may be missed. The effect prompting has on readers performance is not fully known. In order to explore the effects of prompting errors, we have created an online game (Bat Hunt), designed for non-experts, that mirrors mammographic CAD. This allows us to explore a wider parameter space. Users are required to detect bats in images of flocks of birds, with image difficulty matched to the proportions of screening mammograms in different BI-RADS density categories. Twelve prompted conditions were investigated, along with unprompted detection. On average, players achieved a sensitivity of 0.33 for unprompted detection, and sensitivities of 0.75, 0.83, and 0.92 respectively for 70%, 80%, and 90% of targets prompted, regardless of CAD specificity. False prompts distract players from finding unprompted targets if they appear in the same image. Player performance decreases when the number of false prompts increases, and increases proportionally with prompting sensitivity. Median lowest d' was for unprompted condition (1.08) and the highest for sensitivity 90% and 0.5 false prompts per image (d'=4.48).

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.

Background The differences between breast cancer risk factors in white British/Irish and Asian women attending screening in the UK are not well documented. Methods Between 2009-15 ethnicity and traditional breast cancer risk factors were self-identified by a screening cohort from Greater Manchester, with follow up to 2016. Risk factors and incidence rates were compared using age-standardised statistics (European standard population). Results Eight hundred and seventy-nine Asian women and 51,779 unaffected white British/Irish women aged 46-73 years were recruited. Asian women were at lower predicted breast cancer risk from hormonal and reproductive risk factors than white British/Irish women (mean 10 year risk 2.6% vs 3.1%, difference 0.4%, 95%CI 0.3-0.5%). White British/Irish women were more likely to have had a younger age at menarche, be overweight or obese, taller, used hormone replacement therapy and not to have had children.. However, despite being less overweight Asian women had gained more weight from age 20 years and were less likely to undertake moderate physical activity. Asian women also had a slightly higher mammographic density. Asian age-standardised incidence was 3.2 (95%CI 1.6-5.2, 18 cancers) per thousand women/year vs 4.5 (95%CI 4.2-4.8, 1076 cancers) for white British/Irish women. Conclusions Asian women attending screening in Greater Manchester are likely to have a lower risk of breast cancer than white British/Irish women, but they undertake less physical activity and have more adult weight gain. Electronic supplementary material The online version of this article (10.1186/s12889-018-5090-9) contains supplementary material, which is available to authorized users.

Background The percentage of mammographic dense tissue (PD) is an important risk factor for breast cancer, and there is some evidence that texture features may further improve predictive ability. However, relatively little work has assessed or validated textural feature algorithms using raw full field digital mammograms (FFDM). Method A case-control study nested within a screening cohort (age 46–73 years) from Manchester UK was used to develop a texture feature risk score (264 cases diagnosed at the same time as mammogram of the contralateral breast, 787 controls) using the least absolute shrinkage and selection operator (LASSO) method for 112 features, and validated in a second case-control study from the same cohort but with cases diagnosed after the index mammogram (317 cases, 931 controls). Predictive ability was assessed using deviance and matched concordance index (mC). The ability to improve risk estimation beyond percent volumetric density (Volpara) was evaluated using conditional logistic regression. Results The strongest features identified in the training set were “sum average” based on the grey-level co-occurrence matrix at low image resolutions (original resolution 10.628 pixels per mm; downsized by factors of 16, 32 and 64), which had a better deviance and mC than volumetric PD. In the validation study, the risk score combining the three sum average features achieved a better deviance than volumetric PD (Δχ2 = 10.55 or 6.95 if logarithm PD) and a similar mC to volumetric PD (0.58 and 0.57, respectively). The risk score added independent information to volumetric PD (Δχ2 = 14.38, p = 0.0008). Conclusion Textural features based on digital mammograms improve risk assessment beyond volumetric percentage density. The features and risk score developed need further investigation in other settings. Electronic supplementary material The online version of this article (doi:10.1186/s13058-017-0906-6) contains supplementary material, which is available to authorized users.

Background Despite classification of the BRCA2 c.9976A>T, p.(Lys3326Ter) variant as a polymorphism, it has been associated with increased risks of pancreatic, lung, oesophageal and breast cancer. Methods We have noticed multiple co-occurrences of the BRCA2 c.9976A>T variant with the pathogenic BRCA2 c.6275_6276delTT frameshift mutation p.(Leu2092ProfsTer7) and using a cohort study have assessed if this might account for these tumour risk associations. Results We identified 52 families with BRCA2 c.6275_6276delTT, all of which occur in cis with the BRCA2 c.9976A>T variant allele as demonstrated by co-segregation in all family members tested. Of 3245 breast/ovarian cancer samples sequenced for BRCA2 , only 43/3245 (1.3%) carried BRCA2 c.9976A>T alone, after excluding individuals with BRCA2 c.6275_6276delTT (n=22) or other BRCA1 (n=3) or BRCA2 (n=2) pathogenic mutations. The resultant frequency (1.3%) after removal of co-occurring mutations is lower than the 1.7% and 1.67% frequencies from two control populations for BRCA2 c.9976A>T, but similar to the 1.39% seen in the Exome Aggregation Consortium database. We did not identify increased frequencies of oesophageal, pancreatic or lung cancer in families with just BRCA2 c.9976A>T using person-years at risk analysis. Conclusions It is likely that the previous associations of increased cancer risks due to BRCA2 c.9976A>T represent reporting bias and are contributed to because the variant is in LD with BRCA2 c.6275_6276delTT.

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.

Breast density is a strong risk factor for breast cancer and has potential use in breast cancer risk prediction, with subjective methods of density assessment providing a strong relationship with the development of breast cancer. This study aims to assess intra- and inter-observer variability in visual density assessment recorded on Visual Analogue Scales (VAS) among trained readers, and examine whether reader age, gender and experience are associated with assessed density. Eleven readers estimated the breast density of 120 mammograms on two occasions 3 years apart using VAS. Intra- and inter-observer agreement was assessed with Intraclass Correlation Coefficient (ICC) and variation between readers visualised on Bland-Altman plots. The mean scores of all mammograms per reader were used to analyse the effect of reader attributes on assessed density. Excellent intra-observer agreement (ICC>0.80) was found in the majority of the readers. All but one reader had a mean difference of

High mammographic density is associated with an increased risk of breast cancer, however whether the association is stronger when there is agreement across measures is unclear. This study investigates whether a combination of density measures is a better predictor of breast cancer risk than individual methods alone. Women recruited to the Predicting Risk of Cancer At Screening (PROCAS) study and with mammographic density assessed using three different methods were included (n=33,304). Density was assessed visually using Visual Analogue Scales (VAS) and by two fully automated methods, Quantra and Volpara. Percentage breast density was divided into (high, medium and low) and combinations of measures were used to further categorise individuals (e.g. ‘all high’). A total of 667 breast cancers were identified and logistic regression was used to determine the relationship between breast density and breast cancer risk. In total, 44% of individuals were in the same tertile for all three measures, 8.6% were in non-adjacent (high and low) or mixed categories (high, medium and low). For individual methods the strongest association with breast cancer risk was for medium and high tertiles of VAS with odds ratios (OR) adjusted for age and BMI of 1.63 (95% CI 1.31-2.03) and 2.33 (1.87-2.90) respectively. For the combination of density methods the strongest association was for ‘all high’ (OR 2.42, 1.77-3.31) followed by “two high” (OR 1.90, 1.35-3.31) and “two medium” (OR 1.88, 1.40-2.52). Combining density measures did not affect the magnitude of risk compared to using individual methods.

BackgroundIn the UK, women are invited for 3-yearly mammography screening, through the NHS Breast Screening Programme (NHSBSP), from the ages of 47–50 years to the ages of 69–73 years. Women with family histories of breast cancer can, from the age of 40 years, obtain enhanced surveillance and, in exceptionally high-risk cases, magnetic resonance imaging. However, no NHSBSP risk assessment is undertaken. Risk prediction models are able to categorise women by risk using known risk factors, although accurate individual risk prediction remains elusive. The identification of mammographic breast density (MD) and common genetic risk variants [single nucleotide polymorphisms (SNPs)] has presaged the improved precision of risk models.ObjectivesTo (1) identify the best performing model to assess breast cancer risk in family history clinic (FHC) and population settings; (2) use information from MD/SNPs to improve risk prediction; (3) assess the acceptability and feasibility of offering risk assessment in the NHSBSP; and (4) identify the incremental costs and benefits of risk stratified screening in a preliminary cost-effectiveness analysis.DesignTwo cohort studies assessing breast cancer incidence.SettingHigh-risk FHC and the NHSBSP Greater Manchester, UK.ParticipantsA total of 10,000 women aged 20–79 years [Family History Risk Study (FH-Risk); UK Clinical Research Network identification number (UKCRN-ID) 8611] and 53,000 women from the NHSBSP [aged 46–73 years; Predicting the Risk of Cancer At Screening (PROCAS) study; UKCRN-ID 8080].InterventionsQuestionnaires collected standard risk information, and mammograms were assessed for breast density by a number of techniques. All FH-Risk and 10,000 PROCAS participants participated in deoxyribonucleic acid (DNA) studies. The risk prediction models Manual method, Tyrer–Cuzick (TC), BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) and Gail were used to assess risk, with modelling based on MD and SNPs. A preliminary model-based cost-effectiveness analysis of risk stratified screening was conducted.Main outcome measuresBreast cancer incidence.Data sourcesThe NHSBSP; cancer registration.ResultsA total of 446 women developed incident breast cancers in FH-Risk in 97,958 years of follow-up. All risk models accurately stratified women into risk categories. TC had better risk precision than Gail, and BOADICEA accurately predicted risk in the 6268 single probands. The Manual model was also accurate in the whole cohort. In PROCAS, TC had better risk precision than Gail [area under the curve (AUC) 0.58 vs. 0.54], identifying 547 prospective breast cancers. The addition of SNPs in the FH-Risk case–control study improved risk precision but was not useful inBRCA1(breast cancer 1 gene) families. Risk modelling of SNPs in PROCAS showed an incremental improvement from using SNP18 used in PROCAS to SNP67. MD measured by visual assessment score provided better risk stratification than automatic measures, despite wide intra- and inter-reader variability. Using a MD-adjusted TC model in PROCAS improved risk stratification (AUC = 0.6) and identified significantly higher rates (4.7 per 10,000 vs. 1.3 per 10,000;p ConclusionsRisk precision can be improved by using DNA and MD, and can potentially be used to stratify NHSBSP screening. It may also identify those at greater risk of high-stage cancers for enhanced screening. The cost-effectiveness of risk stratified screening is currently associated with extensive uncertainty. Additional research is needed to identify data needed for key inputs into model-based cost-effectiveness analyses to identify the impact on health-care resource use and patient benefits.Future workA pilot of real-time NHSBSP risk prediction to identify women for chemoprevention and enhanced screening is required.FundingThe National Institute for Health Research Programme Grants for Applied Research programme. The DNA saliva collection for SNP analysis for PROCAS was funded by the Genesis Breast Cancer Prevention Appeal.

Background Breast cancer familial risk clinics offer screening and preventive strategies. While BRCA1 / BRCA2 genetic testing provides important risk information for some women, panels of more common breast cancer risk genetic variants may have relevance to greater numbers of women with familial risk. Methods Three polygenic risk scores (PRS) based on 18 SNPs were investigated in a case–control study of women attending a familial risk clinic. PRS were derived from published general European population allele ORs and frequencies (18-SNPs (SNP18)). In women with BRCA1 / BRCA2 mutations, 3 SNPs/13 SNPs, respectively, generated the PRS estimates. In total, 364 incident breast cancer cases (112 with BRCA1/2 mutations) were matched with 1605 controls (691 BRCA1/2 ) by age last mammogram and BRCA1/2 genetic test result. 87 women with cancer before attendance were also considered. Logistic regression was used to measure PRS performance through ORs per IQR and calibration of the observed to expected (O/E) logarithm relative risk when unadjusted and adjusted for phenotypic risk factors assessed by the Tyrer-Cuzick (TC) model. Results SNP18 was predictive for non-carriers of BRCA1/2 mutations (IQR OR 1.55, 95% CI 1.29 to 1.87, O/E 96%). Findings were unaffected by adjustment from TC (IQR OR 1.56, 95% CI 1.29 to 1.89) or when prior cancers were included (IQR OR 1.55, 95% CI 1.30 to 1.87). There was some evidence to support polygenic scores with weights for individuals with BRCA1/2 mutations ( BRCA1 IQR OR 1.44, 95% CI 1.17 to 1.76; BRCA2 IQ OR 1.44, 95% CI 0.90 to 2.31). Conclusions PRS may be used to refine risk assessment for women at increased familial risk who test negative/have low likelihood of BRCA 1 /2 mutations. They may alter the recommended prevention strategy for many women attending family history clinics.

To assess the risks of induction of breast tumours from frequent screening mammography in younger females.A study group of 853 females was identified who had at least 5 mammograms starting before 37 years of age, with 4 or more before the age of 40 years. These were followed up from their 40th birthday or 8 years from their first mammogram, and their cancer incidence was compared with that of a control group of 1103 females who had an average of 5 mammograms between the ages of 40 and 46 years. All females in the study were previously assessed to be at moderate familial risk or higher.There were 43 incident breast cancers in the study group after the 8-year start point, whereas 38.3 were expected from life-table calculations (RR 1.12; 95% CI: 0.83 to 1.51). In the control group, 50 incident breast cancers developed some time after their first mammogram in follow up to age 60 years. The observed, expected ratio from life tables in this group was 0.94 (95% CI: 0.71-1.24), similar to that in the study group.There was no trend to greater cancer incidence in those receiving mammograms earlier.This study shows that there is no substantial effect on the induction of additional primary breast tumours from frequent mammography starting at37 years of age. Further work on larger numbers of females is necessary to assess longer term risks and determine whether a small excess cancer effect may be present.

This study investigates variations in mammographic density by ethnic group in women attending the NHS breast screening programme in Greater Manchester. Density was estimated using VolparaTM and QuantraTM. Data was analysed for 651 Asian/Asian British, 416 Black/Black British, 394 Jewish origin, 181 'Mixed', 700 'Other' and a random sample of 10,000 women who declared their ethnic origin as White British or Irish. Age ranged from 46---84 years and mean BMI was 27.4i¾?kg/m2. Fibroglandular volume VolparaTM was highest in women of Black/Black British origin 59.4i¾?cm3 and lowest in Asian/Asian British women 47.9i¾?cm3. After adjusting for a number of hormonal and other factors the magnitude of the difference between groups decreased, however, there were still a number of statistical differences between groups. Ethnic differences in mammographic density and personal factors may subsequently contribute to differences in breast cancer incidence.

This study compared mammographic density over time between women who developed breast cancer cases and women who did not controls. Cases had an initial negative mammographic screen and another three years later when cancer was diagnosed. Cases were matched to three controls with two successive negative screens by age, year of mammogram, BMI, parity, menopausal status and HRT use. Mammographic density was measured by VolparaTM. There was a significant reduction in percentage density in the affected breast for cases 5.2 to 4.8i?ź%, pi?ź

This study aimed to determine whether correcting for observer variability alters estimations of breast cancer risk associated with mammographic density. A case control design examined the relationship between mammographic density, measured by visual analogue scales VAS, and the risk of breast cancer after correcting for observer variability. Mammographic density was assessed by two observers and average scores V2 were adjusted to correct for observer variability V2ad. Two case-control sets were identified: i breast cancer detected during screening at entry and ii breast cancer detected subsequently. Cases were matched to three controls. In the first case-control set the odds ratio for breast cancer was 4.6 95i?ź%CI 2.8---7.5 for the highest compared to the lowest quintile of V2, and was attenuated for V2ad OR 3.1, 95i?ź%CI 1.9---4.8. Similar findings were observed for the second case-control set. Not adjusting for observer variability may lead to an overestimate of the risk of breast cancer.

Objective Patients accessing the chronic disease self-management programme (CDSMP) often report multiple long-term conditions (multimorbidity). Although multimorbidity often predicts poor outcomes, CDSMP effectiveness may be enhanced in multimorbidity via synergies between self-management for different conditions. This study assessed whether CDSMP benefits varied by patterns of multimorbidity. Methods The study was based on a secondary analysis of an RCT. Patients with long-term conditions (n = 629) were randomised to CDSMP or wait-list and completed baseline and 6 month assessments. We identified four multimorbidity groups: (1) single physical condition; (2) multiple physical conditions; (3) single physical condition plus ‘probable depression’; (4) multiple physical conditions plus ‘probable depression’. Results Multimorbidity group significantly moderated the effect of CDSMP on vitality, health-related quality of life, and mental well-being, with the greatest benefit found for patients with multiple physical conditions plus ‘probable depression’. Conclusion The coexistence of depression and multiple physical conditions is associated with increased illness burden, but such patients benefit more from the CDSMP. The mechanisms underlying this effect are unclear, but it does not appear to be through self-management or self-efficacy. Practice implications The presence of multimorbidity in combination with depression may be a useful criteria for referral to the CDSMP.

There is little evidence regarding the optimum interval between mammograms in a population breast cancer screening programme. The UK NHS Breast Screening Programme employs a 3-year interval, unlike other countries which screen more frequently. This study uses variations in the screening interval within a single large UK screening service to examine possible relationships between screening interval and screen-detected cancer characteristics.