Randomised controlled trial of breast cancer and multiple disease prevention weight loss programmes vs written advice amongst women attending a breast cancer family history clinic.

BACKGROUND: Overweight and obesity are common amongst women attending breast cancer Family History, Risk and Prevention Clinics (FHRPCs). Overweight increases risk of breast cancer (BC) and conditions including1 cardiovascular disease (CVD) and type-2 diabetes (T2D). Clinics provide written health behaviour advice with is likely to have minimal effects. We assessed efficacy of two remotely delivered weight loss programmes vs. written advice. METHOD: 210 women with overweight or obesity attending three UK FHRPCs were randomised to either a BC prevention programme (BCPP) framed to reduce risk of BC (n = 86), a multiple disease prevention programme (MDPP) framed to reduce risk of BC, CVD and T2D (n = 87), or written advice (n = 37). Change in weight and health behaviours were assessed at 12-months. RESULTS: Weight loss at 12 months was -6.3% (-8.2, -4.5) in BCPP, -6.0% (-7.9, -4.2) in MDPP and -3.3% (-6.2, -0.5) in the written group (p = 0.451 across groups). The percentage losing ≥10% weight in these groups were respectively 34%, 23% and 14% (p = 0.038 across groups). DISCUSSION: BCPP and MDPP programmes resulted in more women achieving ≥10% weight loss, but no evidence of additional benefits of MDPP. A multicentre RCT to test the BCPP across UK FHRPCs is warranted. Clinical Trial Registration ISRCTN16431108.

Quantifying the effects of risk-stratified breast cancer screening when delivered in real time as routine practice versus usual screening: the BC-Predict non-randomised controlled study (NCT04359420).

BACKGROUND: Risk stratification as a routine part of the NHS Breast Screening Programme (NHSBSP) could provide a better balance of benefits and harms. We developed BC-Predict, to offer women when invited to the NHSBSP, which collects standard risk factor information; mammographic density; and in a sub-sample, a Polygenic Risk Score (PRS). METHODS: Risk prediction was estimated primarily from self-reported questionnaires and mammographic density using the Tyrer-Cuzick risk model. Women eligible for NHSBSP were recruited. BC-Predict produced risk feedback letters, inviting women at high risk (≥8% 10-year) or moderate risk (≥5-<8% 10-year) to have appointments to discuss prevention and additional screening. RESULTS: Overall uptake of BC-Predict in screening attendees was 16.9% with 2472 consenting to the study; 76.8% of those received risk feedback within the 8-week timeframe. Recruitment was 63.2% with an onsite recruiter and paper questionnaire compared to <10% with BC-Predict only (P < 0.0001). Risk appointment attendance was highest for those at high risk (40.6%); 77.5% of those opted for preventive medication. DISCUSSION: We have shown that a real-time offer of breast cancer risk information (including both mammographic density and PRS) is feasible and can be delivered in reasonable time, although uptake requires personal contact. Preventive medication uptake in women newly identified at high risk is high and could improve the cost-effectiveness of risk stratification. TRIAL REGISTRATION: Retrospectively registered with clinicaltrials.gov (NCT04359420).

How do women who are informed that they are at increased risk of breast cancer appraise their risk? A systematic review of qualitative research.

This review aimed to synthesise qualitative research on how women notified that they are at increased risk of breast cancer view their risk. Five electronic databases were systematically reviewed for qualitative research investigating how women who have received an increased breast cancer risk estimate appraise their risk status. Fourteen records reporting 12 studies were included and critically appraised. Data were thematically synthesised. Four analytical themes were generated. Women appraise their risk of breast cancer through comparison with their risk of other familial diseases. Clinically derived risk estimates were understood in relation to pre-conceived risk appraisals, with incongruences met with surprise. Family history is relied upon strongly, with women exploring similarities and differences in attributes between themselves and affected relatives to gauge the likelihood of diagnosis. Women at increased risk reported living under a cloud of inevitability or uncertainty regarding diagnosis, resulting in concerns about risk management. Women hold stable appraisals of their breast cancer risk which appear to be mainly formed through their experiences of breast cancer in the family. Healthcare professionals should explore women's personal risk appraisals prior to providing clinically derived risk estimates in order to address misconceptions, reduce concerns about inevitability and increase perceived control over risk reduction.

Clinical utility of testing for PALB2 and CHEK2 c.1100delC in breast and ovarian cancer.

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 < 0.0001). PALB2_PGV likelihood increased with increasing Manchester score (MS) (MS < 15 = 17/1,763, MS 20-39 = 11/520, P = 0.04) but not for CHEK2_1100delC (MS < 15 = 29/1,762, MS 20-39 = 4/520). PALB2 PGVs showed perfect segregation in 20/20 first-degree relatives with breast cancer, compared with 7/13 for CHEK2_1100delC (P = 0.002). CONCLUSION: PALB2 PGVs and CHEK2_1100delC together account for ~2.5% of familial breast/ovarian cancer risk. PALB2 PGVs are associated with grade 3, TN, and grade 3 ER-positive HER2-negative breast tumors.

Suggested application of HER2+ breast tumor phenotype for germline TP53 variant classification within ACMG/AMP guidelines.

Early onset breast cancer is the most common malignancy in women with Li-Fraumeni syndrome, caused by germline TP53 pathogenic variants. It has repeatedly been suggested that breast tumors from TP53 carriers are more likely to be HER2+ than those of noncarriers, but this information has not been incorporated into variant interpretation models for TP53. Breast tumor pathology is already being used quantitatively for assessing pathogenicity of germline variants in other genes, and it has been suggested that this type of evidence can be incorporated into current American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for germline variant classification. Here, by reviewing published data and using internal datasets separated by different age groups, we investigated if breast tumor HER2+ status has utility as a predictor of TP53 germline variant pathogenicity, considering age at diagnosis. Overall, our results showed that the identification of HER2+ breast tumors diagnosed before the age of 40 can be conservatively incorporated into the current TP53-specific ACMG/AMP PP4 criterion, following a point system detailed in this manuscript. Further larger studies will be needed to reassess the value of HER2+ breast tumors diagnosed at a later age.

Young adulthood body mass index, adult weight gain and breast cancer risk: the PROCAS Study (United Kingdom).

BACKGROUND: We tested the hypothesis that body mass index (BMI) aged 20 years modifies the association of adult weight gain and breast cancer risk. METHODS: We recruited women (aged 47-73 years) into the PROCAS (Predicting Risk Of Cancer At Screening; Manchester, UK: 2009-2013) Study. In 47,042 women, we determined BMI at baseline and (by recall) at age 20 years, and derived weight changes. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for new breast cancer using Cox models and explored relationships between BMI aged 20 years, subsequent weight changes and breast cancer risk. RESULTS: With median follow-up of 5.6 years, 1142 breast cancers (post-menopausal at entry: 829) occurred. Among post-menopausal women at entry, BMI aged 20 years was inversely associated [HR per SD: 0.87 (95% CI: 0.79-0.95)], while absolute weight gain was associated with breast cancer [HR per SD:1.23 (95% CI: 1.14-1.32)]. For post-menopausal women who had a recall BMI aged 20 years <23.4 kg/m2 (75th percentile), absolute weight gain was associated with breast cancer [HR per SD: 1.31 (95% CIs: 1.21-1.42)], but there were no associations for women with a recall BMI aged 20 years of >23.4 kg/m2 (Pinteraction values <0.05). CONCLUSIONS: Adult weight gain increased post-menopausal breast cancer risk only among women who were <23.4 kg/m2 aged 20 years.

Development of Breast Cancer Choices: a decision support tool for young women with breast cancer deciding whether to have genetic testing for BRCA1/2 mutations.

PURPOSE: To develop a decision support tool for young women with breast cancer considering genetic testing for BRCA1/2 mutations soon after cancer diagnosis. METHODS: A four-stage iterative development process was employed; stage 1, literature review exploring the availability and efficacy of empirically tested decision support tools; stage 2, in-depth interviews with 29 young women (< 50 years) recently diagnosed with breast cancer, exploring information requirements and experiences of genetic testing decision making; stage 3, three focus groups (N = 21) exploring preferences for information presentation and prioritisation of content; stage 4, think-aloud interviews to refine the prototype (N = 16). RESULTS: Participants wanted information regarding the pros and cons of testing, the testing process and implications for their family, presented in a way that allowed them to choose the level of detail they required. They preferred the term 'altered gene', valued a medical word definition function and warnings before accessing sensitive information. CONCLUSION: Participants valued the decision support tool, the accessibility of the information and its clinical endorsement. The decision support tool has considerable clinical utility as an adjunct to genetic counselling or for use in busy oncology clinics where formal genetic counselling may be unavailable.

Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database.

BACKGROUND: Most patients with path_MMR gene variants (Lynch syndrome (LS)) now survive both their first and subsequent cancers, resulting in a growing number of older patients with LS for whom limited information exists with respect to cancer risk and survival. OBJECTIVE AND DESIGN: This observational, international, multicentre study aimed to determine prospectively observed incidences of cancers and survival in path_MMR carriers up to 75 years of age. RESULTS: 3119 patients were followed for a total of 24 475 years. Cumulative incidences at 75 years (risks) for colorectal cancer were 46%, 43% and 15% in path_MLH1, path_MSH2 and path_MSH6 carriers; for endometrial cancer 43%, 57% and 46%; for ovarian cancer 10%, 17% and 13%; for upper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancers 21%, 10% and 7%; for urinary tract cancers 8%, 25% and 11%; for prostate cancer 17%, 32% and 18%; and for brain tumours 1%, 5% and 1%, respectively. Ovarian cancer occurred mainly premenopausally. By contrast, upper gastrointestinal, urinary tract and prostate cancers occurred predominantly at older ages. Overall 5-year survival for prostate cancer was 100%, urinary bladder 93%, ureter 85%, duodenum 67%, stomach 61%, bile duct 29%, brain 22% and pancreas 0%. Path_PMS2 carriers had lower risk for cancer. CONCLUSION: Carriers of different path_MMR variants exhibit distinct patterns of cancer risk and survival as they age. Risk estimates for counselling and planning of surveillance and treatment should be tailored to each patient's age, gender and path_MMR variant. We have updated our open-access website www.lscarisk.org to facilitate this.

Fanconi anemia with sun-sensitivity caused by a Xeroderma pigmentosum-associated missense mutation in XPF.

BACKGROUND: Fanconi anemia (FA) is an inherited genomic instability disorder with congenital and developmental abnormalities, bone marrow failure and predisposition to cancer early in life, and cellular sensitivity to DNA interstrand crosslinks. CASE PRESENTATION: A fifty-one-year old female patient, initially diagnosed with FA in childhood on the basis of classic features and increased chromosomal breakage, and remarkable sun-sensitivity is described. She only ever had mild haematological abnormalities and no history of malignancy. To identify and characterise the genetic defect in this lady, who is one of the oldest reported FA patients, we used whole-exome sequencing for identification of causative mutations, and functionally characterized the cellular phenotype. Detection of the novel splice site mutation c.793-2A > G and the previously described missense mutation c.1765C > T (p.Arg589Trp) in XPF/ERCC4/FANCQ assign her as the third individual of complementation group FA-Q. Ectopic expression of wildtype, but not mutant, XPF/ERCC4/FANCQ, in patient-derived fibroblasts rescued cellular resistance to DNA interstrand-crosslinking agents. Patient derived FA-Q cells showed impaired nuclear excision repair capacity. However, mutated XPF/ERCC4/FANCQ protein in our patient's cells, as in the two other patients with FA-Q, was detectable on chromatin, in contrast to XP-F cells, where missense-mutant protein failed to properly translocate to the nucleus. CONCLUSIONS: Patients with FA characteristics and UV sensitivity should be tested for mutations in XPF/ERCC4/FANCQ. The missense mutation p.Arg589Trp was previously detected in patients diagnosed with Xeroderma pigmentosum or Cockayne syndrome. Hence, phenotypic manifestations associated with this XPF/ERCC4/ FANCQ mutation are highly variable.

Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3.

PURPOSE: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways. METHODS: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2. RESULTS: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10-6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance. CONCLUSION: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.

Progress of hearing loss in neurofibromatosis type 2: implications for future management.

The objective of this study was to describe changes in hearing over time in patients with neurofibromatosis type 2 (NF2) treated conservatively. A retrospective case review was conducted in a tertiary referral centre. Pure tone audiometry, speech discrimination scores, serviceable hearing (American Academy of Otolaryngology class A or B) and measurement of vestibular schwannoma (VS) size on magnetic resonance imaging were evaluated in 56 patients (89 ears) with NF2 with at least one conservatively managed VS. Over a mean follow-up period of 7 years (range 0.8-21 years) pure tone average thresholds increased gradually with a mean annual rate of 1.3 dB for the right ear (p = 0.0003) and 2 dB for the left ear (p = 0.0009). Speech discrimination scores dropped with an average annual rate of 1.3 and 0.34% in the right and left ear, respectively. Patients maintained serviceable hearing for an average of 7.6 years (range 2.7-19.3 years). The average annual VS growth was 0.4 mm without any correlation with hearing loss. There was a correlation between patients' age and pure tone threshold increase (p < 0.05 for both ears). In this selected population of patients with NF2, hearing threshold increases were very slow. In NF2 patients with indolently behaving tumours, serviceable hearing can be maintained for a significant length of time, making conservative management an attractive option.

MRI breast screening in high-risk women: cancer detection and survival analysis.

Women with a genetic predisposition to breast cancer tend to develop the disease at a younger age with denser breasts making mammography screening less effective. The introduction of magnetic resonance imaging (MRI) for familial breast cancer screening programs in recent years was intended to improve outcomes in these women. We aimed to assess whether introduction of MRI surveillance improves 5- and 10-year survival of high-risk women and determine the accuracy of MRI breast cancer detection compared with mammography-only or no enhanced surveillance and compare size and pathology of cancers detected in women screened with MRI + mammography and mammography only. We used data from two prospective studies where asymptomatic women with a very high breast cancer risk were screened by either mammography alone or with MRI also compared with BRCA1/2 carriers with no intensive surveillance. 63 cancers were detected in women receiving MRI + mammography and 76 in women receiving mammography only. Sensitivity of MRI + mammography was 93 % with 63 % specificity. Fewer cancers detected on MRI were lymph node positive compared to mammography/no additional screening. There were no differences in 10-year survival between the MRI + mammography and mammography-only groups, but survival was significantly higher in the MRI-screened group (95.3 %) compared to no intensive screening (73.7 %; p = 0.002). There were no deaths among the 21 BRCA2 carriers receiving MRI. There appears to be benefit from screening with MRI, particularly in BRCA2 carriers. Extended follow-up of larger numbers of high-risk women is required to assess long-term survival.

Body composition changes during breast cancer preventive treatment with anastrozole: Findings from the IBIS-II trial.

Background: Uptake to anastrozole for breast cancer prevention is low, partly due to women's concerns about side effects including gains in weight and specifically gains in body fat. Previous evidence does not link anastrozole with gains in weight, but there is a lack of data on any effects on body composition i.e. changes in fat and fat free mass. Here we assess association of anastrozole with body composition changes in a prospective sub-study from the second international breast intervention trial (IBIS-II). Methods: Participants had DXA scans at baseline and for five years of anastrozole/placebo and beyond (between March 2004 and September 2017. Primary outcomes were changes in body weight, body fat and fat free mass at 9-18 months. A linear model was used to estimate the size of a differential effect in these outcomes by randomised treatment allocation adjusted for baseline value and time since last scan, age, 10-year breast cancer risk, smoking and HRT status. Results: 203 postmenopausal women were recruited (n = 95 anastrozole, n = 108 placebo), mean age 58 years (SD = 5.4), BMI 28.0 kg/m2 (SD = 5.5). There was no evidence of a strong association between anastrozole or placebo and endpoints at 9-18 months; effect size (95 %CI) for anastrozole minus placebo for body weight (per/kg) -0.11 (-1.29-1.08); body fat 0.11 (-0.75-0.96) and fat free mass -0.30 (-0.79-0.19). Conclusions: There is unlikely to be a clinically significant change to body composition with anastrozole for breast cancer prevention.

Risk perception and disease knowledge in attendees of a community-based lung cancer screening programme.

OBJECTIVES: In England, a risk-based approach is used to determine eligibility for lung cancer screening. Ensuring effective communication and counselling of risk is therefore increasingly important. In this study, we explore the perception of lung cancer risk in attendees of a community-based screening service, located in socio-economically deprived areas of Manchester. We analyse responses based on demographic variables, calculated risk score and screening eligibility. MATERIALS AND METHODS: The Manchester Lung Health Check (LHC) programme invited ever smokers, age 55-80, to a lung cancer risk assessment in which their 6-year risk was calculated (using the PLCOM2012 model). Those at high risk (PLCOM2012 score ≥ 1.51%) were eligible for low dose CT (LDCT) screening. Prior to their assessment, attendees were invited to complete the study questionnaire, which assessed absolute and comparative risk perception, disease knowledge (incidence, survival, and risk factors), lung cancer specific worry, and mental health. RESULTS: 371 participants completed the questionnaire; 66% (n = 243) had linked clinical data. Perceived absolute risk was markedly higher than calculated risk (median: 20% vs. 1%; p < 0.001) and higher in women than men (25% vs. 15%; p = 0.001). There was no correlation between perceived absolute and calculated risk. Overall, 30% classified themselves at higher, and 21% at lower, lung cancer risk compared to others their age. Median PLCOM2012 score increased with perceived comparative risk (p = 0.004). Those eligible for screening were more likely to: classify themselves at higher comparative risk (41% vs. 21%; p < 0.0001), report lung cancer-specific worry (27% vs. 10%; p = 0.001) and have indications of depression (20% vs. 10%; p = 0.05). Family history of lung cancer was significantly associated with higher comparative risk (adjOR 4.03, 95%CI 1.74-9.3; p = 0.001). CONCLUSION: Employing comparative rather than absolute risk may assist risk counselling. Further research is required to determine the optimal approach to risk communication in this setting.

Back to the future: proceedings from the 2010 NF Conference.

The neurofibromatoses (NF) encompass the rare diseases NF1, NF2, and schwannomatosis. The NFs affect 100,000 Americans; over 2 million persons worldwide; and are caused by mutation of tumor suppressor genes. Individuals with NF1 in particular may develop tumors anywhere in the nervous system; additional manifestations can include learning disabilities, bone dysplasia, cardiovascular defects, unmanageable pain, and physical disfigurement. Ultimately, the NFs can cause blindness, deafness, severe morbidity, and increased mortality and NF1 includes a risk of malignant cancer. Today there is no treatment for the NFs (other than symptomatic); however, research efforts to understand these genetic conditions have made tremendous strides in the past few years. Progress is being made on all fronts, from discovery studies-understanding the molecular signaling deficits that cause the manifestations of NF-to the growth of preclinical drug screening initiatives and the emergence of a number of clinical trials. An important element in fuelling this progress is the sharing of knowledge, and to this end, for over 20 years the Children's Tumor Foundation has convened an annual NF Conference, bringing together NF professionals to share ideas and build collaborations. The 2010 NF Conference held in Baltimore, MD June 5-8, 2010 hosted over 300 NF researchers and clinicians. This paper provides a synthesis of the highlights presented at the Conference and as such, is a "state-of-the-field" for NF research in 2010.

Mutation and association analysis of GEN1 in breast cancer susceptibility.

GEN1 was recently identified as a key Holliday junction resolvase involved in homologous recombination. Somatic truncating GEN1 mutations have been reported in two breast cancers. Together these data led to the proposition that GEN1 is a breast cancer predisposition gene. In this article we have formally investigated this hypothesis. We performed full-gene mutational analysis of GEN1 in 176 BRCA1/2-negative familial breast cancer samples and 159 controls. We genotyped six SNPs tagging the 30 common variants in the transcribed region of GEN1 in 3,750 breast cancer cases and 4,907 controls. Mutation analysis revealed one truncating variant, c.2515_2519delAAGTT, which was present in 4% of cases and 4% of controls. We identified control individuals homozygous for the deletion, demonstrating that the last 69 amino acids of GEN1 are dispensable for its function. We identified 17 other variants, but their frequency did not significantly differ between cases and controls. Analysis of 3,750 breast cancer cases and 4,907 controls demonstrated no evidence of significant association with breast cancer for six SNPs tagging the 30 common GEN1 variants. These data indicate that although it also plays a key role in double-strand DNA break repair, GEN1 does not make an appreciable contribution to breast cancer susceptibility by acting as a high- or intermediate-penetrance breast cancer predisposition gene like BRCA1, BRCA2, CHEK2, ATM, BRIP1 and PALB2 and that common GEN1 variants do not act as low-penetrance susceptibility alleles analogous to SNPs in FGFR2. Furthermore, our analyses demonstrate the importance of undertaking appropriate genetic investigations, typically full gene screening in cases and controls together with large-scale case-control association analyses, to evaluate the contribution of genes to cancer susceptibility.

Screening Strategy Modification Based on Personalized Breast Cancer Risk Stratification and its Implementation in the National Guidelines - Pilot Study.

BACKGROUND: One of the most consistent models for estimating personalized breast cancer (BC) risk is the Tyrer-Cuzick algorithm that is incorporated into the International Breast Cancer Intervention Study (IBIS) software. Our main objective was to provide criteria for the classification of the Slovenian population, which has BC incidence below the European average, into risk groups, and to evaluate the integration of the criteria in Slovenian guidelines. Our main focus was on women age <50 with higher BC risk, since no organized BC screening is available for these women. METHODS: Slovenian age-specific BC risks were incorporated into IBIS software and threshold values of risk categories were determined. Risk categories were assigned according to the individual's ten-year risk for women aged 40 and older, and lifetime risk for women between 20 and 39. To test the software, we compared screening strategies with the use vs. no use of IBIS. RESULTS: Of the 197 women included in the study IBIS assigned 75.1% to the BC risk group, and the rest to the moderately increased risk. Without IBIS 80 women were offered mammographic and 33 ultrasound screening. In contrast, 28 instead of 80 would have been offered mammographic screening and there would have been no referrals for ultrasound if IBIS had been used. CONCLUSIONS: The Slovenian IBIS has been developed, tested and suggested for personalized breast cancer risk assessment. The implementation of the software with the consideration of Slovenian risk thresholds enables a more accurate and nationally unified assessment.