Lifetime Risk Of Breast Cancer Research Articles

A Population-Based Analysis of BRCA1/2 Genes and Associated Breast and Ovarian Cancer Risk in Korean Patients: A Multicenter Cohort Study.

Simple SummaryAlthough it has been suggested that cancer risk and genetic variation vary by population, there is still a lack of research on non-European populations. In this study, we applied Korean patients as a model to find out the way to conduct BRCA1/2-related clinical studies in non-European populations who do not have as much clinical data as Europeans. The BRCA1/2 variants were classified following the 2015 ACMG standards/guidelines and using a multifactorial probability-based approach. To estimate the additional sample numbers needed to resolve BRCA1/2 unclassified status, we applied a simulation analysis considering population-specific clinical characteristics. In addition, we estimated the risks of breast or ovarian cancer for BRCA1/2 carriers by mutation regions. Data from this study reveal that BRCA1/2 variants in the non-European population are highly specific; therefore, population-specific study is essential for clinical application of treatment or prevention for breast or ovarian cancer.In this study, we performed a comprehensive analysis of BRCA1/2 variants and associated cancer risk in Korean patients considering two aspects: variants of uncertain significance (VUS) and pathogenic or likely pathogenic variants (PLPVs) in BRCA1 and BRCA2. This study included 5433 Korean participants who were tested for BRCA1/2 genes. The BRCA1/2 variants were classified following the standards/guidelines for interpretation of genetic variants and using a multifactorial probability-based approach. In Korea, 15.8% of participants had BRCA1 or BRCA2 PLPVs. To estimate the additional sample numbers needed to resolve unclassified status, we applied a simulation analysis. The simulation study for VUS showed that the smaller the number of samples, the more the posterior probability was affected by the prior probability; in addition, more samples for BRCA2 VUS than those of BRCA1 VUS were required to resolve the unclassified status, and the presence of clinical information associated with their VUS was an important factor. The cumulative lifetime breast cancer risk was 59.1% (95% CI: 44.1–73.6%) for BRCA1 and 58.3% (95% CI: 43.2–73.0%) for BRCA2 carriers. The cumulative lifetime ovarian cancer risk was estimated to be 36.9% (95% CI: 23.4–53.9%) for BRCA1 and 14.9% (95% CI: 7.4–28.5%) for BRCA2 carriers.

Cancer Progress and Priorities: Breast Cancer.

Breast cancer is the most commonly diagnosed invasive cancer among women both globally and within the United States and the number one cause of cancer-related deaths among women globally ([1, 2][1]). Less than 1% of diagnosed breast cancers occur in men ([2][2]) and, therefore, male breast cancer is

Gail model utilization in predicting breast cancer risk in Egyptian women: a cross-sectional study.

Herein, our purpose was to calculate the 5-year and lifetime risk of breast cancer and to assess new breast cancer potential contributors among Egyptian women utilizing the modified Gail model, while presenting a global comparison of risk assessment. This study included 7009 women from both urban and rural areas scattered across 40% of the Egyptian provinces. The 5-year risk categories were defined as low risk (≤ 1.66%) or high risk (> 1.66%), whereas the lifetime risk categories were defined as low risk (≤ 20%) or high risk (> 20%). Pearson's Chi-squared test was performed to determine the association between participants' characteristics and distinct risk categories. Binary logistic regression was carried out for correlation analysis. The mean estimated risk for developing invasive breast cancer over 5 years was 0.86 (± 0.67), whereas the mean lifetime breast cancer risk score was 11.26 (± 5.7). Accordingly, only 614 (8.75%) and 470 (6.7%) women were categorized as individuals with high risk of breast cancer incidence in 5-year and lifetime, respectively. Only 192 participants (2.7%) conferred both high 5-year and high lifetime risk scores. Marital status, method of feeding, physical activity behavior, contraceptive use, menopause and number of children were found to have a statistically significant association with both 5-year and lifetime breast cancer risk categories. We revealed that modified Gail model had a well-fitting and discrimination accuracy in Egyptian women when compared with other countries.

Mammography Screening Among Latinas: Does Gender and Ethnic Patient-Physician Concordance Matter?

Breast cancer is the most commonly diagnosed cancer among Latinas. Dominican women in particular have a higher lifetime risk of breast cancer than do other Latinas in the U.S. This study examines how gender, ethnic, and language concordance between providers and patients areassociated with recent mammography screening for Latina immigrant women from the Dominican Republic. We conducted structured interviews, in Spanish, with 419 Dominican women aged 40years or older living in New York City. Using bivariate analysis and logistic regressions, we tested whether patient-provider gender, ethnic, and language concordance was associated with recent mammography when controlling for demographic covariates, breast cancer screening knowledge, and self-rated health. Gender concordance predicted recent mammography after controlling for covariates (β = 0.13). Neither ethnic nor language concordance significantly predicted recent mammography. Our findings suggest that promotion of patient-provider gender concordance may help reduce health disparities among Latinos/as and other minority groups across the United States.

Time-Dependent Effects of Oral Contraceptive Use on Breast, Ovarian, and Endometrial Cancers.

Oral contraceptive use has been suggested to influence the risk of breast, ovarian, and endometrial cancer. The purpose of this study is to clarify the time-dependent effects between long-term oral contraceptive use and cancer risk. We performed an observational study in 256,661 women from UK Biobank, born between 1939 and 1970. Information on cancer diagnoses were collected from self-reported data and from national registers until March 2019. Cumulative risk of cancer over the timespan of the study, as measured by the OR, and instantaneous risk, as measured by the HR, were assessed using Logistic and Cox regression analyses, respectively. The odds were lower among ever users, compared with never users, for ovarian cancer [OR = 0.72; 95% confidence interval (CI), 0.65-0.81] and endometrial cancer (OR = 0.68; 95% CI, 0.62-0.75), an association that was stronger with longer use (P < 0.001). Increased odds were seen for breast cancer in women when limiting the follow-up to 55 years of age (OR = 1.10; 95% CI, 1.03-1.17), but not for the full timespan. We only found a higher HR for breast cancer in former users immediately (≤2 years) after discontinued oral contraceptive use (HR = 1.55; 95% CI, 1.06-2.28), whereas the protective association for ovarian and endometrial cancer remained significant up to 35 years after last use of oral contraceptives. Given the body of evidence presented in our study, we argue that oral contraceptives can dramatically reduce women's risk of ovarian and endometrial cancer, whereas their effect on lifetime risk of breast cancer is limited. SIGNIFICANCE: These results enable women and physicians to make more informed decisions considering oral contraceptive use, thus constituting an important step toward personalized medicine.

Abstract PD10-03: Triple-negative breast cancer (TNBC) risk with pathogenic variants (PV) in hereditary cancer predisposition genes

Abstract BACKGROUND: TNBC is among the most aggressive subtypes of invasive breast cancer (BC), and accounts for approximately 10-15% of incidental BC diagnoses. TNBC is associated with early age of onset (median age of diagnosis &amp;lt;50) and disproportionately affects African American women. Breast MRI is currently recommended to screen for BC in women with at least a moderate-to-high lifetime risk of BC (a 2-fold or higher increased risk), and may also be superior to mammogram to screen for TNBC. TNBC has been most closely associated with germline PVs in BRCA1. However, recent studies have suggested that PVs in other genes previously associated with invasive BC may specifically confer high risks of the TNBC subtype. METHODS: Results were analyzed from 627,219 women undergoing clinical multi-gene panel testing at a single US-based commercial laboratory between 5/2013 and 2/2020, including genes associated with hereditary BC and other cancers. Demographic and personal/family history data were collected on a test requisition form. Individuals who had single- or founder-site testing, or prior BRCA1 or BRCA2 testing, were excluded. Multivariable regression analysis was used to examine the association between PVs/suspected PVs and personal history (PHx) of TNBC. Models were adjusted for age, personal/family cancer history, and ancestry. Odds ratios (OR) with 95% confidence intervals (CI) excluding 1.0 were considered significant. RESULTS: In total, 22.4% (140,467/627,219) of women tested reported PHx of BC, of whom 12.8% (17,951/140,467) reported PHx of TNBC. Elevated risks of TNBC were identified in carriers of PVs in 10 genes (see Table). While the highest TNBC risk was associated with PVs in BRCA1 (OR 21.24, 95% CI 19.71-22.88), high risks were also seen for BARD1 (OR 7.05, 95% CI 5.71-8.71), TP53 (OR 5.64, 95% CI 3.08-10.33), PTEN (OR 5.52, 95% CI 2.35-13.00) and PALB2 (OR 5.27, 95% CI 4.55-6.10). Moderate-to-high risks (2-5-fold increased risk) of TNBC were also seen for carriers of PVs in RAD51C, RAD51D, BRCA2, and CDKN2A/P16. By contrast, PVs in NBN, ATM, and CHEK2 were all associated with an apparent decreased risk of TNBC. CONCLUSIONS: PVs in several hereditary cancer genes routinely tested on multi-gene panel tests are associated with high risks (OR&amp;gt;5.0) and moderate-to-high risks (OR 2.0-5.0) of TNBC. These findings can inform practice guidelines about which genes to test when evaluating breast cancer risk and which PV carriers may benefit from intensive breast screening with magnetic resonance imaging (MRI). Odds ratios for TNBC in germline carriers of PV in hereditary cancer risk genesRisk GenePV Positive with TNBCOR95% CIp-valueHigh RiskBRCA1119321.2419.71-22.88&amp;lt;0.001BARD11257.055.71-8.71&amp;lt;0.001TP53125.643.08-10.33&amp;lt;0.001PTEN65.522.35-13.00&amp;lt;0.001PALB22315.274.55-6.10&amp;lt;0.001Moderate-to-High RiskRAD51C864.923.86-6.26&amp;lt;0.001RAD51D454.643.34-6.45&amp;lt;0.001BRCA24884.434.02-4.89&amp;lt;0.001CDKN2A (p16)172.521.52-4.18&amp;lt;0.001Moderate-to-Low RiskBRIP1771.921.51-2.44&amp;lt;0.001Protective EffectNBN140.550.32-0.940.030ATM400.510.37-0.70&amp;lt;0.001CHEK2490.440.33-0.58&amp;lt;0.001HOXB1350.330.14-0.810.015 Citation Format: Michael J Hall, Eric Rosenthal, Susana San Roman, Ryan Bernhisel, John Kidd, Elisha Hughes, Thomas Slavin, Allison Kurian. Triple-negative breast cancer (TNBC) risk with pathogenic variants (PV) in hereditary cancer predisposition genes [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD10-03.

Abstract PS8-02: Influence of a breast cancer polygenic risk score on adherence to preventive endocrine therapy in high risk women at 1 and 2 year follow-up: The genetic risk estimate (GENRE) trial

Abstract Background: Preventive endocrine therapy (ET) has been proven extensively to decrease breast cancer (BC) risk by 50-65%. Despite this significant reduction, a small proportion of high risk women take ET, due to attitudes toward medications, inaccurate risk perception and drug side-effects. The addition of a polygenic risk score (PRS), comprised of 77 BC genetic susceptibility loci (Single Nucleotide Polymorphisms (SNP)), to the standard risk calculator estimates, can be used to improve BC risk estimation. We previously reported on the influence of the PRS-adjusted BC risk estimates on the intent to use ET (Abstract, SABCS, 2019). Here we report on the influence of PRS-adjusted BC risk estimates on ET adherence at 1 and 2 year follow –up. We also report on ET side effects over this same time period. Methods: Women older than age 35 were eligible if they were deemed at high risk for BC by either a 5 year Gail Model risk of ≥3% or 10 year Tyrer-Cuzick risk (IBIS) of ≥5%. We excluded women with a personal history of BC or hereditary BC syndromes. At baseline, participants were counseled on their BC risk using standard risk calculators: Gail and IBIS risk scores (5 yr, 10 yr, &amp; lifetime) and ET options were discussed, including benefits and risks. Blood samples were obtained and genotyped for 77 SNPs, and an updated BC -PRS risk report was shared with study participants that reflected the IBIS and Gail risk predictions for 5 yr, 10 yr, &amp; lifetime BC risk with and without the PRS. A baseline self-reported questionnaire assessed understanding of BC risk and decision to take ET. Follow-up questionnaires at 1 and 2 years assessed self-reported ET adherence and ET side effects (vasomotor symptoms, vaginal symptoms, sexual dysfunction, weight gain, GI symptoms, headaches, breast sensitivity, mood changes, and joint pain). Adherence to ET at 1 and 2 year follow-up was stratified by three categories of lifetime PRS-BC risk: 0-20%; 20-40%; 40-100%. Results: 151 women at Mayo Clinic Rochester and CancerCare Manitoba were enrolled in the study from 2016 to 2017. Of the 149 participants with evaluable data at 1 and 2 year follow-up, 57 (38%) started on ET therapy, all within 1 year of the baseline visit; 43 (29%) were taking ET at 1 year and 33 (22%) were taking ET at 2 year follow-up, representing a discontinuation rate of 26% at 1 year and 42% at 2 year follow-up. Adherence to ET use at 1 year and 2 year follow-ups correlated significantly with the category of PRS-BC risk estimation: at 1 year follow up, 17% of those in the lowest PRS-IBIS risk category, 23% in the middle risk category and 50% of those in the highest risk category were taking ET (p=0.001). At 2 year follow up, 12% of those in the lowest PRS-IBIS risk category, 18% in the middle risk category and 38% of those in the highest risk category were taking ET (p=0.008). At 1 year follow up, participants taking ET reported significantly more bothersome symptoms of vaginal itching (p=0.010), weight gain (p=0.015) and joint pain (p=0.044), compared with those not on ET. There was a trend towards increased irritability and mood swings on those taking ET (p=0.059). At year 2 there was no significant difference in side effects between those taking and not taking ET. Conclusion: Adherence to ET in a population of women at high risk for BC decreased overtime and strongly correlated with the level of risk, with 38% of those at highest risk of breast cancer taking ET at 2 year follow up. Side effects of vaginal itching, weight gain and body aches were more common on those taking ET versus not taking ET at the 1 year follow-up, but did not differ at 2 year follow-up, possibly due to the fact that those with the most bothersome symptoms have discontinued ET by the 2 year follow up. Citation Format: Daniela Stan, Julian Kim, Daniel Schaid, Erin Carlson, Andrew Cooke, Christina A. Kim, Benjamin Goldenberg, Jason Sinnwell, Debjani Grenier, Amy Degnim, Fergus Couch, Celine Vachon, Sandhya Pruthi. Influence of a breast cancer polygenic risk score on adherence to preventive endocrine therapy in high risk women at 1 and 2 year follow-up: The genetic risk estimate (GENRE) trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS8-02.

Uptake and efficacy of bilateral risk reducing surgery in unaffected female BRCA1 and BRCA2 carriers

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...

Abnormal screens among nonmutation carriers in the High Risk Ontario Breast Screening Program.

The Ontario Breast Screening Program was expanded in 2011 to offer annual MRI and mammography to women with high-risk genetic mutations (e.g., BRCA1/2) and women with strong family histories and ≥25% estimated lifetime risk of breast cancer. Data to support high-risk screening is less clear in the nonmutation carrier group, as MRI has lower specificity among this population. The potential unintended consequences may be considerable and need to be explored. We aimed to describe the frequency of abnormal screens and biopsies. Demographic surveys and chart review consent were sent to a sample of 441 individuals enrolled in a high-risk screening program at two tertiary care hospitals in Toronto, Ontario. Retrospective cross-sectional chart review was undertaken for clinicopathologic data. The frequencies of abnormal screens and biopsies were calculated. One hundred sixty-nine nonmutation carriers were included. The majority were white, employed, and highly educated. The median International Breast Cancer Intervention Study lifetime risk of breast cancer was 28.0% (range 24.5%-89.0%). 108 individuals (64%) experienced at least 1 abnormal screen and 13 (8%) had 3 or more over a median 3years of screening (range 1-6years). Of 55 biopsies, 3 (5.5%) were malignant. The cancer detection rate was 8.4/1000 screens (95% CI 3.2-22.4). An MRI-based screening program for nonmutation carriers was effective at diagnosing breast cancer. However, this population experienced a high rate of abnormal screens and intervention. Further research is needed to improve the performance of MRI-based screening in these women.

The Angelina Jolie effect: Contralateral risk-reducing mastectomy trends in patients at increased risk of breast cancer

Contralateral risk-reducing mastectomy (CRRM) rates have tripled over the last 2 decades. Reasons for this are multi-factorial, with those harbouring a pathogenic variant in the BRCA1/2 gene having the greatest survival benefit. On May 14th, 2013, Angelina Jolie shared the news of her bilateral risk-reducing mastectomy (BRRM), on the basis of her BRCA1 pathogenic variant status. We evaluated the impact of this news on rates of CRRM in women with increased risk for developing breast cancer after being diagnosed with unilateral breast cancer. The prospective cohort study included all women with at least a moderate lifetime risk of developing breast cancer who attended our family history clinic (1987–2019) and were subsequently diagnosed with unilateral breast cancer. Rates of CRRM were then compared between patients diagnosed with breast cancer before and after Angelina Jolie’s announcement (pre- vs. post-AJ). Of 386 breast cancer patients, with a mean age at diagnosis of 48 ± 8 years, 268 (69.4%) were diagnosed in the pre-AJ period, and 118 (30.6%) in the post-AJ period. Of these, 123 (31.9%) underwent CRRM, a median 42 (interquartile range: 11–54) days after the index cancer surgery. Rates of CRRM doubled following AJ’s news, from 23.9% pre-AJ to 50.0% post AJ (p < 0.001). Rates of CRRM were found to decrease with increasing age at breast cancer (p < 0.001) and tumour TNM stage (p = 0.040), and to increase with the estimated lifetime risk of breast cancer (p < 0.001) and tumour grade (p = 0.015) on univariable analysis. After adjusting for these factors, the step-change increase in CRRM rates post-AJ remained significant (odds ratio: 9.61, p < 0.001). The AJ effect appears to have been associated with higher rates of CRRM amongst breast cancer patients with increased cancer risk. CRRM rates were highest amongst younger women and those with the highest lifetime risk profile. Clinicians need to be aware of how media news can impact on the delivery of cancer related services. Communicating objective assessment of risk is important when counselling women on the merits of risk-reducing surgery.

FaMRIsc trial shows: MRI breast screening for women with ≥20% lifetime risk is also cost-effective in Europe

Background: The randomized trial FaMRIsc showed the huge stage shift caused by screening women with ≥20% lifetime breast cancer risk with MRI compared to mammography at every breast density1. Yearly MRI, as advised in the USA is too costly for the European NICE threshold. Possible affordable strategies have just been published. 2 Here we discuss different strategies, womens preferences and future possibilities .

Breast Cancer Chemoprevention: Use and Views of Australian Women and Their Clinicians.

Guidelines endorse the use of chemoprevention for breast cancer risk reduction. This study examined the barriers and facilitators to chemoprevention use for Australian women at increased risk of breast cancer, and their clinicians. Surveys, based on the Theoretical Domains Framework, were mailed to 1,113 women at ≥16% lifetime risk of breast cancer who were enrolled in the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer cohort study (kConFab), and their 524 treating clinicians. Seven hundred twenty-five women (65%) and 221 (42%) clinicians responded. Only 10 (1.4%) kConFab women had ever taken chemoprevention. Three hundred seventy-eight (52%) kConFab women, two (3%) breast surgeons, and 51 (35%) family physicians were not aware of chemoprevention. For women, the strongest barriers to chemoprevention were side effects (31%) and inadequate information (23%), which operate in the Theoretical Domains Framework domains of "beliefs about consequences" and "knowledge," respectively. Strongest facilitators related to tamoxifen's long-term efficacy (35%, "knowledge," "beliefs about consequences," and "goals" domains), staying healthy for family (13%, "social role" and "goals" domains), and abnormal breast biopsy (13%, "environmental context" domain). The strongest barrier for family physicians was insufficient knowledge (45%, "knowledge" domain) and for breast surgeons was medication side effects (40%, "beliefs about consequences" domain). The strongest facilitators for both clinician groups related to clear guidelines, strong family history, and better tools to select patients ("environmental context and resources" domain). Clinician knowledge and resources, and beliefs about the side-effect consequences of chemoprevention, are key domains that could be targeted to potentially enhance uptake. PREVENTION RELEVANCE: Despite its efficacy in reducing breast cancer incidence, chemoprevention is underutilised. This survey study of Australian women and their clinicians used behavioural change theory to identify modifiable barriers to chemoprevention uptake, and to suggest interventions such as policy change, educational resources and public campaigns, that may increase awareness and use.See related Spotlight by Vogel, p. 1.

Challenges and Perspectives on Breast Cancer Survivorship: The Journey Continues

Women have a 1-in-8 lifetime risk of breast cancer. Earlier diagnosis and treatment advances have improved 15- and 20-year survival rates. Increased survival can mean coping with the effects of cancer and its treatment over an extended period of time, while experiencing age-related changes in functioning and the emergence of other health issues. To explore breast cancer survivors’ perspectives on their issues and concerns across the life-course, focus groups were conducted with a culturally diverse sample (N=18) of survivors (72% white, 28% Black, 11% Hispanic). Participants were 44-82 years old. Most, 83% were 50 and older, 56% were 60 and older. The majority (83%) were diagnosed in their 40’s and 50’s. Two were diagnosed in their early 30’s and one at age 68. Participants reaffirmed the necessity, as a breast cancer survivor, of being a life-long health advocate on their own behalf, and the importance of being self-informed. As one woman commented: “Knowledge is power”. Survivors shared that their emergent health issues were complicated by their cancer history, and, that, as a cancer survivor, “I never stop worrying”. A widespread concern was not knowing if the health issues and co-morbidities they experienced (such as joint pain, neuropathy, tendinitis, heart disease), were age-related, a consequence of their cancer, or a late treatment effect. An overriding sentiment expressed was that clinicians have not recognized the importance of quality of life in cancer survival. As a survivor succinctly stated: “We are living longer, but we need to live long with quality of life.”

Comparing 5-Year and Lifetime Risks of Breast Cancerusing the Prospective Family Study Cohort.

Clinical guidelines often use predicted lifetime risk from birth to define criteria for making decisions regarding breast cancer screening rather than thresholds based on absolute 5-year risk from current age. We used the Prospective Family Cohort Study of 14657 women without breast cancer at baseline in which, during a median follow-up of 10 years, 482 women were diagnosed with invasive breast cancer. We examined the performances of the International Breast Cancer Intervention Study (IBIS) and Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) risk models when using the alternative thresholds by comparing predictions based on 5-year risk with those based on lifetime risk from birth and remaining lifetime risk. All statistical tests were 2-sided. Using IBIS, the areas under the receiver-operating characteristic curves were 0.66 (95% confidence interval = 0.63 to 0.68) and 0.56 (95% confidence interval = 0.54 to 0.59) for 5-year and lifetime risks, respectively (Pdiff < .001). For equivalent sensitivities, the 5-year incidence almost always had higher specificities than lifetime risk from birth. For women aged 20-39 years, 5-year risk performed better than lifetime risk from birth. For women aged 40 years or older, receiver-operating characteristic curves were similar for 5-year and lifetime IBIS risk from birth. Classifications based on remaining lifetime risk were inferior to 5-year risk estimates. Results were similar using BOADICEA. Our analysis shows that risk stratification using clinical models will likely be more accurate when based on predicted 5-year risk compared with risks based on predicted lifetime and remaining lifetime, particularly for women aged 20-39 years.

Long-Term Evaluation of Women Referred to a Breast Cancer Family History Clinic (Manchester UK 1987–2020)

Simple SummaryThis study reports the management of women at high risk for breast cancer over a 33 years period. The aim was to summarize the numbers seen and to report the results of our studies on gene testing, the outcomes of screening and the success of preventive methods including lifestyle change, chemoprevention and risk-reducing mastectomy. We also discuss how the clinical Family History Service may be improved in the future.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 1987–2020, 14,311 women were referred, of whom 6.4% were from known gene families, 38.2% were at high risk (≥30% lifetime risk), 37.7% at moderate risk (17–29%), 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 14–27% entered various lifestyle studies. From 1992–2003, 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 2013–2020. Since 1994, 7164 eligible women at ≥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.

Osteoporosis in Postmenopausal Women with Breast Cancer

Breast cancer and osteoporosis are both diseases of aging. The "one in eight" lifetime risks of breast cancer occur primarily in the sixth, seventh, eighth, and ninth decades of life. One-third of postmenopausal women will experience an osteoporotic fracture. It is the coalescence of osteoporosis, breast cancer, and breast cancer treatments that, in some cases, increases the risks of osteoporotic fracture. That makes it imperative to assess risk factors, screen, and prevent or treat osteoporosis in postmenopausal women with breast cancer. Osteoporosis is primarily a genetic disease with a few modifiable risk factors. These risk factors include greater than two to three alcoholic drinks per day, current smoking, and decreased physical activity. The standard screening tool for osteoporosis is dual-energy x-ray absorptiometry (DXA) that gives a readout of T-scores of the lumbar spine, total hip, and femoral neck. The T-score is the number of standard deviations (SD) above or below the mean bone mineral density (BMD) of an average young adult of the same sex. For every SD below the mean BMD, the fracture risks double. Osteoporosis prevention and treatment do not differ in women with or without breast cancer. The difference is in breast cancer treatments, such as aromatase inhibitors (AI), which cause two to three-fold higher bone loss than average postmenopausal bone loss. Two classes of drugs for osteoporosis are oral and intravenous (iv) bisphosphonates and the receptor activator of nuclear factor kappa B ligand (RANKL) ligand inhibitor, subcutaneous (sc) denosumab. All three prevent bone loss and reduce the likelihood of fragility fractures. The treatment choice depends upon patient and provider preferences, specific contraindications (e.g., renal insufficiency), compliance, and costs. Despite guidelines and algorithms for AI-induced bone loss, the screening and treatment of osteoporosis remain suboptimal in postmenopausal women with breast cancer.

Osteoporosis in Postmenopausal Women with Breast Cancer

Breast cancer and osteoporosis are both diseases of aging. The "one in eight" lifetime risks of breast cancer occur primarily in the sixth, seventh, eighth, and ninth decades of life. One-third of postmenopausal women will experience an osteoporotic fracture. It is the coalescence of osteoporosis, breast cancer, and breast cancer treatments that, in some cases, increases the risks of osteoporotic fracture. That makes it imperative to assess risk factors, screen, and prevent or treat osteoporosis in postmenopausal women with breast cancer. Osteoporosis is primarily a genetic disease with a few modifiable risk factors. These risk factors include greater than two to three alcoholic drinks per day, current smoking, and decreased physical activity. The standard screening tool for osteoporosis is dual-energy x-ray absorptiometry (DXA) that gives a readout of T-scores of the lumbar spine, total hip, and femoral neck. The T-score is the number of standard deviations (SD) above or below the mean bone mineral density (BMD) of an average young adult of the same sex. For every SD below the mean BMD, the fracture risks double. Osteoporosis prevention and treatment do not differ in women with or without breast cancer. The difference is in breast cancer treatments, such as aromatase inhibitors (AI), which cause two to three-fold higher bone loss than average postmenopausal bone loss. Two classes of drugs for osteoporosis are oral and intravenous (iv) bisphosphonates and the receptor activator of nuclear factor kappa B ligand (RANKL) ligand inhibitor, subcutaneous (sc) denosumab. All three prevent bone loss and reduce the likelihood of fragility fractures. The treatment choice depends upon patient and provider preferences, specific contraindications (e.g., renal insufficiency), compliance, and costs. Despite guidelines and algorithms for AI-induced bone loss, the screening and treatment of osteoporosis remain suboptimal in postmenopausal women with breast cancer.

Lobular intraepithelial neoplasia: Outcomes and optimal management.

Lobular neoplasia is a term encompassing both atypical lobular hyperplasia and lobular carcinoma in situ. These pathological findings are of uncertain malignant potential and predispose to a higher lifetime risk of breast cancer. Debate surrounds the management of such lesions, with the rationale for diagnostic excision based on the possibility of upgrading to malignancy. In this study, we report the upgrade rate of these lesions and risk of subsequent development of breast cancer. This is a retrospective review of a prospectively maintained data base of all biopsies of breast screening-detected abnormalities in a single Irish breast-screening unit. We included all patients with lobular neoplasia on core needle biopsy who underwent diagnostic excision from 2005 to 2012. We excluded those who had concurrent high-risk lesions on biopsy. End points included upgrade rate and subsequent diagnosis of malignancy on follow-up. During the study period, 66 patients met criteria for inclusion, with a mean age of 53.74years. Upgrade rate following excision was 13.64% (n=9/66). Of those not upgraded, 7.02% (n=4/57) were subsequently diagnosed with malignancy. Median time to diagnosis was 59.61months (range=10.5-124.4). There is a significant rate of upgrade following diagnostic excision of lobular neoplasia, supporting the practice of diagnostic excision. There is an increased lifetime risk of breast cancer for women with a diagnosis of lobular neoplasia, with many of these cancers occurring outside the standard five-year monitoring period, suggesting a potential benefit in extending surveillance.

The role of polygenic risk and susceptibility genes in breast cancer over the course of life

Polygenic risk scores (PRS) for breast cancer have potential to improve risk prediction, but there is limited information on their utility in various clinical situations. Here we show that among 122,978 women in the FinnGen study with 8401 breast cancer cases, the PRS modifies the breast cancer risk of two high-impact frameshift risk variants. Similarly, we show that after the breast cancer diagnosis, individuals with elevated PRS have an elevated risk of developing contralateral breast cancer, and that the PRS can considerably improve risk assessment among their female first-degree relatives. In more detail, women with the c.1592delT variant in PALB2 (242-fold enrichment in Finland, 336 carriers) and an average PRS (10–90th percentile) have a lifetime risk of breast cancer at 55% (95% CI 49–61%), which increases to 84% (71–97%) with a high PRS ( > 90th percentile), and decreases to 49% (30–68%) with a low PRS ( < 10th percentile). Similarly, for c.1100delC in CHEK2 (3.7–fold enrichment; 1648 carriers), the respective lifetime risks are 29% (27–32%), 59% (52–66%), and 9% (5–14%). The PRS also refines the risk assessment of women with first-degree relatives diagnosed with breast cancer, particularly among women with positive family history of early-onset breast cancer. Here we demonstrate the opportunities for a comprehensive way of assessing genetic risk in the general population, in breast cancer patients, and in unaffected family members.

Breast Cancer Mortality among Women with a BRCA1 or BRCA2 Mutation in a Magnetic Resonance Imaging Plus Mammography Screening Program.

Simple SummaryWomen with a BRCA1 or BRCA2 gene mutation have up to an 80% lifetime risk of breast cancer unless their breasts are surgically removed, but many decline or defer surgery and choose screening, hoping that if cancer occurs, it will be detected at a curable stage. In this study 489 women with a BRCA1 or BRCA2 mutation aged from 25 to 65 years, who had never had breast or ovarian cancer, were screened annually with breast magnetic resonance imaging (MRI) in addition to mammography and were followed for an average of 13 years (range: 9 to 23 years). Ninety-five of the 489 women enrolled in the study had a bilateral preventive mastectomy in the follow-up period. Of the 91 women diagnosed with breast cancer, four died of breast cancer. The most common cause of death was ovarian cancer. For women with BRCA mutations who choose annual screening with MRI and mammography, the probability of dying of breast cancer within 20 years is 2%.Annual breast magnetic resonance imaging (MRI) plus mammography is the standard of care for screening women with inherited BRCA1/2 mutations. However, long-term breast cancer-related mortality with screening is unknown. Between 1997 and June 2011, 489 previously unaffected BRCA1/2 mutation carriers aged 25 to 65 years were screened with annual MRI plus mammography on our study. Thereafter, participants were eligible to continue MRI screening through the high-risk Ontario Breast Screening Program. In 2019, our data were linked to the Ontario Cancer Registry of Cancer Care Ontario to identify all incident cancers, vital status and causes of death. Observed breast cancer mortality was compared to expected mortality for age-matched women in the general population. There were 91 women diagnosed with breast cancer (72 invasive and 19 ductal carcinoma in situ (DCIS)) with median follow-up 7.4 (range: 0.1 to 19.2) years. Four deaths from breast cancer were observed, compared to 2.0 deaths expected (standardized mortality ratio (SMR) 2.0, p = 0.14). For the 489 women in the study, the probability of not dying of breast cancer at 20 years from the date of the first MRI was 98.2%. Annual screening with MRI plus mammography is a reasonable option for women who decline or defer risk-reducing mastectomy.