Cumulative Risk Of Breast Cancer Research Articles

Breast cancer risk assessment for prescription of Menopausal Hormone Therapy in women who have a family history of breast cancer

Background Menopausal Hormone Therapy (MHT) can alleviate menopausal symptoms but is associated with increased risk of breast cancer (BC). MHT prescription should be preceded by individualised risk/benefit evaluation; however, data outlining the impact of family history alongside different MHT therapeutic approaches are lacking. Aim To quantify the risks associated with MHT use in women with varying BC family histories of i) developing and ii) dying from BC. Design and setting An epidemiological modelling study (UK women). Method We used i) background risks of BC by age and family history, ii) relative risks for BC associated with MHT use, and iii) 10-year BC-specific net mortality rates to model the risk of developing and dying from BC between the ages of 50 and 80 in women with four different BC family history profiles: ‘average’, ‘modest’, ‘intermediate’, and ‘strong’. Results For a woman of ‘average’ family history taking no MHT, the cumulative BC risk (age 50-80) is 9.8%, and the risk of dying from the BC is 1.7%. Five years’ exposure to combined-cyclical MHT (age 50-55) increases these risks to 11.0% and 1.8%, respectively. For a woman with a ‘strong’ family history taking no MHT, the cumulative BC risk is 19.6%, and the risk of dying is 3.2%. With 5 years of MHT (age 50-55), this increases to 22.4% and 3.5%. Conclusion Both family history and MHT are associated with increased risk of BC. Estimates of the risks associated with MHT for women with different family histories can support decision-making around MHT prescription.

Abstract PO5-18-02: A Population-Based Analysis of the Impact of Omission of Anthracyclines in the Neoadjuvant Setting on the Risk of Mortality

Abstract Background Most patients with high-risk non-metastatic breast cancer are treated with neoadjuvant chemotherapy (NAC), which includes the administration of anthracyclines. The omission of anthracyclines was shown to be associated with excellent outcomes in selected patients. However, the extent to which anthracyclines are omitted among a population of women treated with NAC and its impact on mortality remain unclear. Objective To investigate the extent to which anthracyclines are omitted among a population of patients with invasive breast cancer treated with NAC and to examine the impact of non-anthracycline NAC on risks of breast cancer-specific and all-cause mortality. Methods We performed a retrospective population-based cohort analysis using patient-level health administrative data. The cohort includes women aged ≥18 years with stage I – III invasive breast cancer diagnosed between January 2012 and December 2020, treated with NAC and surgery. Patients were excluded if they received < 50% of the planned chemotherapy regimen, had bilateral breast cancer and/or a previous malignancy. The exposure of interest was anthracycline versus non-anthracycline NAC regimen. The primary and secondary endpoints were breast cancer-specific mortality and overall (all-cause) mortality. Multivariable Cox proportional hazards models adjusted by propensity score, and clinical/pathologic variables including a measure of comorbidity was performed to examine impact of omission of anthracyclines on outcomes. Cumulative incidence curves were generated to calculate the 5-year cumulative incidence of breast cancer and all-cause mortality for the whole cohort and in subset analyses, stratified by stage and receptor subtype. Results The cohort includes 4,180 women. Median follow was 62 months (IQR 44-85) and median age was 51 years (IQR 43-60). Most patients had low co-morbidities (96.0%), Stage II (44.1%) or Stage III (47.7%) disease, underwent mastectomy (72.6%), had axillary node dissection (64.4%) and received post-operative radiotherapy (88.8%). 279 (6.7%) individuals were treated with a non-anthracycline NAC and 3,901 (93.3 %) received an anthracycline NAC. Women who received non-anthracycline NAC were older (median 62 years vs. 50 years; p< 0.001), more likely to have stage I-II disease (77.0% vs. 51.3%; p< 0.001), and more likely to have triple-negative breast cancer (TNBC) (14.0% vs. 24.4%; p< 0.001) than those who received anthracyclines.On propensity adjusted multivariable analysis, factors associated with an increased risk of BC mortality include Stage III (HR 9.3, 95%CI 4.5 - 19.2, p< 0.0001) or stage II at presentation (HR 2.57 95% CI 1.24, 5.34, p=.01) (ref: stage I) or triple negative subtype (HR 3.7 95% CI 3.03, 4.51, p< .0001) (ref: hormone positive/HER2-). There was no significant difference in the relative risks of BC death (HR 0.8, 95% CI 0.5-1.27) or all-cause mortality (HR 0.85, 95% CI 0.60-1.21) for patients selected for treatment without anthracyclines compared to those treated with anthracyclines.Overall, among individuals selected for treatment without or with anthracycline NAC there was no significant difference in the 5-year cumulative incidence of BC (15.4% vs 10.5%, P=.05) or all-cause mortality (16.4% vs 11.9%, P=.07). However, the 5-year cumulative incidence of BC specific death (31.8% vs 16.5%, p=.03) and 5-year cumulative incidence of all-cause death (31.8% vs. 18.2%, p=.06) was higher among 420 women with HER2+ Stage III breast cancer who received non-anthracycline versus anthracycline-based chemotherapy. No difference was observed for other subgroups. Conclusions The omission of anthracyclines in NAC for individuals with stage III HER2+ breast cancer was associated with higher cumulative risks of breast cancer and all-cause mortality but no difference was observed for other subgroups. Further research is warranted to better understand in whom anthracyclines can be safely omitted. Citation Format: Danilo Giffoni M. M. Mata, Rinku Sutradhar, Matthew Castelo, Lena Nguyen, Danielle Rodin, Ezra Hahn, Omolara Fatiregun, Cindy Fong, Sabina Trebinjac, Andrea Eisen, Lawrence Paszat, Katarzyna Jerzak, Eileen Rakovitch. A Population-Based Analysis of the Impact of Omission of Anthracyclines in the Neoadjuvant Setting on the Risk of Mortality [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-18-02.

Invasive breast cancer and breast cancer death after non-screen detected ductal carcinoma in situ from 1990 to 2018 in England: population based cohort study

ObjectivesTo evaluate the long term risks of invasive breast cancer and death related to breast cancer after non-screen detected ductal carcinoma in situ. Risks for women in the general population...

THU504 Is Carney Complex A Predisposing Syndrome For Breast Cancer? Prospective Study Of 50 Women

Abstract Disclosure: P. Vaduva: None. F. Violon: None. A. Jouinot: None. L. Bouys: None. S. Espiard: None. F. Bonnet-Serrano: None. N. Marie Odile: None. C. Cardot-bauters: None. G. Raverot: None. S. Hieronimus: None. H. Lefebvre: None. M.L. Nunes: None. A. Tabarin: None. L. Groussin Rouiller: None. G. Assié: None. M. Sibony: None. M. Vantyghem: None. P. Eric: None. J. Bertherat: None. Objective: Carney Complex (CNC) is a rare hereditary genetic syndrome, mostly due to inactivating pathogenic variants of the tumor suppressor gene PRKAR1A. It has a wide spectrum of manifestations with frequent pigmented skin lesions, cardiac myxomas, primary pigmented nodular adrenocortical dysplasia (PPNAD) causing Cushing syndrome, acromegaly and thyroid cancers. Breast benign tumors (fibroadenomas, ductal adenomas and myxoid lesions) have been associated with CNC, but so far, association with malignancy has not been investigated. Methods: The present study was designed to describe the characteristics of breast tumors diagnosed in CNC patients and their association with other manifestations of CNC and PRKAR1A genotype. Since breast cancer is the most frequent cancer in women and the leading cause of death from cancer worldwide, malignant breast lesions were carefully analyzed. This cohort comes from a 3 years’ follow-up multicenter French prospective study of CNC patients (Espiard, JCEM 2020). The 50 included women were investigated for CNC manifestations and particularly breast tumors, with breast imaging (echography+/-mammography), genetic and hormonal investigations, in order to characterize them and assess the frequency and average age of breast cancer. Results: Among the 38 women with breast imaging, 14 (28%) had breast tumors, half of them being bilateral. Ten women (20%) presented with benign tumors. Six women presented (12%) with breast carcinomas: five had invasive cancer under 50 years of age (10%) with one contralateral recurrence (4 ductal adenocarcinomas and one solid intracystic papillary carcinoma) and one had ductal carcinoma in situ. The occurrence of breast cancer was more frequent in the CNC women with PRKAR1A pathogenic variants than in the general population (OR=6.2[1.6-17.3]; p=0.006). The mean age at breast cancer diagnosis was 44.7 years old, 17 years younger than in the general population. Cumulative risk of breast cancer for women under 40 years of age was much higher in CNC women, compared to women worldwide (OR=592.1[79.7-3817.4]; p=9.58). Breast cancer had good prognosis factors: 5 out of 6 tumors were T1N0M0, so stage I. One woman had metastatic breast cancer, still alive after 15 years follow up. All breast cancers were negative for HER2, with 100% positivity for estrogen receptor and 50% for progesterone receptor. They all occurred in individuals with familial CNC and PRKAR1A pathogenic variants. Loss of heterozygosity at the PRKAR1A locus observed in 2 investigated breast carcinomas tumor tissue suggests that PRKAR1A bi-allelic inactivation could promote breast cancer development. Conclusions: Breast carcinoma occurs frequently and at an early age in women with CNC, suggesting that CNC predisposes to breast carcinoma. This suggests that adequate screening strategy (starting around 40 years old) and follow up should be discussed in CNC women. Presentation: Thursday, June 15, 2023

Use of Breast Cancer Risk Factors to Identify Risk-Adapted Starting Age of Screening in China

Although current guidelines highlight the need for earlier screening in women at increased risk of breast cancer in China, data on risk-adapted starting ages of screening are limited. To explore the risk-adapted starting age of breast cancer screening in China, with comprehensive consideration of breast cancer risk factors. A multicenter community-based cohort study was conducted under the framework of the Cancer Screening Program in Urban China. Data were collected from January 1, 2013, to December 31, 2018, for unscreened community-dwelling women aged 40 to 74 years without a history of cancer, kidney dysfunction, or severe heart, brain, or lung disease. Data analysis was performed from October 1, 2021, to August 16, 2022. Baseline characteristics associated with breast cancer, including first-degree family history of breast cancer, benign breast disease, breastfeeding, age at menarche, and body mass index. Outcomes included breast cancer diagnosis and age at diagnosis. Risk-adapted starting age of screening was defined as the age at which women with different levels of breast cancer risk attained a 10-year cumulative risk level similar to women aged 50 years in the general population. Of the 1 549 988 women enrolled in this study, 3895 had breast cancer (median follow-up, 4.47 [IQR, 3.16-6.35] years). Participants were divided into different risk groups according to breast cancer risk scores (driven by risk factors including first-degree family history of breast cancer, benign breast disease, breastfeeding, age at menarche, and body mass index). Using the 10-year cumulative risk of breast cancer at age 50 years in the general population as a benchmark (2.65% [95% CI, 2.50%-2.76%]), the optimal starting age of screening for women with high, medium, or low risk of breast cancer was identified as 43, 48, or after 55 years, respectively. An online calculator was developed to calculate an individual's optimal starting age of screening. This study identifies the risk-adapted starting age of breast cancer screening based on the principle of equal management of equal risks, which may inform updates of current screening guidelines.

The prevention of hereditary breast cancer in Italy: towards the implementation of the national prevention plan in the Italian regions

Breast cancer is the malignant cancer with highest incidence in females, representing 29% of all cancers, followed by colorectal cancer (13%), lung cancer (6%), thyroid cancer (5%), and uterine body cancer (5%). It has been estimated that in Italy almost 48,000 women were be affected in 2015 [1]. The majority of breast cancers shows a multifactorial pathogenesis, however 5-7% shows a strong hereditary component, namely genetic factors that follow mendelian inheritance mechanisms. In fact, among affected woman, almost 2% of breast cancers is determined by genetic variants of BRCA1 and BRCA2 (“BRCA genes”), that show an high penetrance pattern of hereditary predisposition. Nevertheless, when considering only affected women younger than 40 years, the percentage of carriers of pathogenic variants BRCA genes rises up to 10%. The prevalence of pathogenic variants of BRCA genes in the Caucasians is around 1/400 [2]. When applying this frequency to the whole Italian resident population in 2015, it can be estimated that in our country almost 152,000 people are carriers of these variants, and can therefore be at higher risk to develop breast cancer. In fact, the median estimate of cumulative risk of breast cancer in 70 years-old women is 57% for carriers of BRCA1 variants and 49% for BRCA2 [1]. Moreover, carriers of pathogenic variants show a tendency to develop breast cancer at earlier age, and are also at increased risk of ovarian cancer (lifetime risk is 40% and 18% for carriers of BRCA1 and BRCA2 variants, respectively [1]).

Population-based estimates of age-specific cumulative risk of breast cancer for pathogenic variants in ATM

BackgroundMultigene panel tests for breast cancer predisposition routinely include ATM as it is now a well-established breast cancer predisposition gene.MethodsWe included ATM in a multigene panel test applied to the Australian Breast Cancer Family Registry (ABCFR), a population-based case–control–family study of breast cancer, with the purpose of estimating the prevalence and penetrance of heterozygous ATM pathogenic variants from the family data, using segregation analysis.ResultsThe estimated breast cancer hazard ratio for carriers of pathogenic ATM variants in the ABCFR was 1.32 (95% confidence interval 0.45–3.87; P = 0.6). The estimated cumulative risk of breast cancer to age 80 years for heterozygous ATM pathogenic variant carriers was estimated to be 13% (95% CI 4.6–30).ConclusionsAlthough ATM has been definitively identified as a breast cancer predisposition gene, further evidence, such as variant-specific penetrance estimates, are needed to inform risk management strategies for carriers of pathogenic variants to increase the clinical utility of population testing of this gene.

The risks of breast and ovarian cancer associated with the Ashkenazi Jewish founder allele BRCA2 6174delT.

Approximately 1% of the Ashkenazi Jewish population carries the BRCA2 6174delT (c.5946del) pathogenic variant. It is important to have accurate knowledge of the risks of breast and ovarian cancer associated with this specific variant so that women may be counseled accordingly. In this prospective study, we estimated the risks of breast and ovarian cancer associated with the 6174delT variant compared with the risks for other pathogenic variants in the BRCA2 gene. The annual risk for developing breast cancer was significantly lower in 246 women who carried the 6174delT variant compared with 721 non-Jewish women who carried a variant at any other locus in BRCA2 (1.2% per year vs. 2.4% per year, p=0.003). We estimated the cumulative risk of breast cancer from age 30 to 70 to be 39% for carriers of the BRCA2 6174delT variant and 61% for carriers of other BRCA2 variants. The annual risk for ovarian or fallopian tube cancer was 0.51% per year for the 233 women who carried the 6174delT variant compared to 0.22% per year for the 1128 carriers of other BRCA2 variants; the difference was not significant. Lower risks for breast cancer associated with 6174delT may not impact screening and prevention choices, however, the discussion should be based on accurate risk assessment.

Population-based estimates of the age-specific cumulative risk of breast cancer for pathogenic variants in CHEK2: Findings from the Australian Breast Cancer Family Registry.

551 Background: Case-control studies of breast cancer have consistently shown that pathogenic variants in CHEK2 are associated with about a 3-fold increased risk of breast cancer. Information about the recurrent protein truncating variant CHEK2c.1100delC dominates this estimate. There have been no formal estimates of age-specific cumulative risk of breast cancer for all CHEK2 pathogenic (including likely pathogenic) variants combined. Methods: We conducted a genetic screen of CHEK2 in an Australian population-based case-control-family study of breast cancer. This study is focused on disease at an early age and participants were unselected for family history. The age-specific cumulative risk (penetrance) of breast cancer was estimated using segregation analysis. Results: The estimated hazard ratio for carriers of pathogenic CHEK2 variants (combined) was 4.9 (95% CI 2.5-9.5; p < 0.0001) relative to non-carriers. The HR for carriers of the CHEK2 c.1100delC variant was estimated to be 3.5 (95% CI 1.02-11.6) and the HR for carriers of all other CHEK2 variants combined was estimated to be 5.7 (95% CI 2.5-12.9). The age-specific cumulative risk of breast cancer was estimated to be 18% (95% CI 11-30%) and 33% (95% CI 21-48%) to age 60 and 80 years, respectively. Conclusions: These findings provide important information for the clinical management of breast cancer risk for women carrying pathogenic variants in CHEK2.

Population-Based Estimates of the Age-Specific Cumulative Risk of Breast Cancer for Pathogenic Variants in CHEK2: Findings from the Australian Breast Cancer Family Registry.

Simple SummaryIt is well established that women who carry pathogenic CHEK2 variants have about a 3-fold increased risk of developing breast cancer. CHEK2 is now commonly included in genetic tests for breast cancer predisposition and increasingly used to inform the clinical management of women who are identified to carry pathogenic variants. Important information for counselling these women includes knowing how breast cancer risk, due to having a pathogenic variant in CHEK2, changes over a woman’s lifetime. This information is currently not well established. By conducting a population-based case-control-family study of pathogenic CHEK2 variants we aimed to provide this information and estimated the penetrance (age-specific cumulative risk) of breast cancer to be 18% (95% CI 11–30%) to age 60 years and 33% (95% CI 21–48%) to age 80 years. These findings provide new and important information for the clinical management of breast cancer risk for women carrying pathogenic variants in CHEK2.Case-control studies of breast cancer have consistently shown that pathogenic variants in CHEK2 are associated with about a 3-fold increased risk of breast cancer. Information about the recurrent protein-truncating variant CHEK2 c.1100delC dominates this estimate. There have been no formal estimates of age-specific cumulative risk of breast cancer for all CHEK2 pathogenic (including likely pathogenic) variants combined. We conducted a population-based case-control-family study of pathogenic CHEK2 variants (26 families, 1071 relatives) and estimated the age-specific cumulative risk of breast cancer using segregation analysis. The estimated hazard ratio for carriers of pathogenic CHEK2 variants (combined) was 4.9 (95% CI 2.5–9.5) relative to non-carriers. The HR for carriers of the CHEK2 c.1100delC variant was estimated to be 3.5 (95% CI 1.02–11.6) and the HR for carriers of all other CHEK2 variants combined was estimated to be 5.7 (95% CI 2.5–12.9). The age-specific cumulative risk of breast cancer was estimated to be 18% (95% CI 11–30%) and 33% (95% CI 21–48%) to age 60 and 80 years, respectively. These findings provide important information for the clinical management of breast cancer risk for women carrying pathogenic variants in CHEK2.

Association of Risk-Reducing Salpingo-Oophorectomy With Breast Cancer Risk in Women With BRCA1 and BRCA2 Pathogenic Variants

Women with pathogenic variants in BRCA1 and BRCA2 are at high risk of developing breast and ovarian cancers. They usually undergo intensive cancer surveillance and may also consider surgical interventions, such as risk-reducing mastectomy or risk-reducing salpingo-oophorectomy (RRSO). Risk-reducing salpingo-oophorectomy has been shown to reduce ovarian cancer risk, but its association with breast cancer risk is less clear. To assess the association of RRSO with the risk of breast cancer in women with BRCA1 and BRCA2 pathogenic variants. This case series included families enrolled in the Breast Cancer Family Registry between 1996 and 2000 that carried an inherited pathogenic variant in BRCA1 (498 families) or BRCA2 (378 families). A survival analysis approach was used that was designed specifically to assess the time-varying association of RRSO with breast cancer risk and accounting for other potential biases. Data were analyzed from August 2019 to November 2020. Risk-reducing salpingo-oophorectomy. In all analyses, the primary end point was the time to a first primary breast cancer. A total of 876 families were evaluated, including 498 with BRCA1 (2650 individuals; mean [SD] event age, 55.8 [19.1] years; 437 White probands [87.8%]) and 378 with BRCA2 (1925 individuals; mean [SD] event age, 57.0 [18.6] years; 299 White probands [79.1%]). Risk-reducing salpingo-oophorectomy was associated with a reduced risk of breast cancer for BRCA1 and BRCA2 pathogenic variant carriers within 5 years after surgery (hazard ratios [HRs], 0.28 [95% CI, 0.10-0.63] and 0.19 [95% CI, 0.06-0.71], respectively), whereas the corresponding HRs were weaker after 5 years postsurgery (HRs, 0.64 [95% CI, 0.38-0.97] and 0.99 [95% CI; 0.84-1.00], respectively). For BRCA1 and BRCA2 pathogenic variant carriers who underwent RRSO at age 40 years, the cause-specific cumulative risk of breast cancer was 49.7% (95% CI, 40.0-60.3) and 52.7% (95% CI, 47.9-58.7) by age 70 years, respectively, compared with 61.0% (95% CI, 56.7-66.0) and 54.0% (95% CI, 49.3-60.1), respectively, for women without RRSO. Although the primary indication for RRSO is the prevention of ovarian cancer, it is also critical to assess its association with breast cancer risk in order to guide clinical decision-making about RRSO use and timing. The results of this case series suggest a reduced risk of breast cancer associated with RRSO in the immediate 5 years after surgery in women carrying BRCA1 and BRCA2 pathogenic variants, and a longer-term association with cumulative breast cancer risk in women carrying BRCA1 pathogenic variants.

Risk-tailored starting age of breast cancer screening based on women's reproductive profile: A nationwide cohort study

BackgroundAlthough reproductive history is recognised to affect the risk of breast cancer, current breast cancer screening guidelines do not consider risk differences by this important factor. As there is a need for an earlier screening in women at increased risk of breast cancer, we provided evidence-based risk-adapted starting age of screening based on different reproductive profiles. Material and methodsWe conducted a nationwide cohort study including 5,099,172 Swedish women born after 1931. Records of study participants in Swedish Cancer Registry, Multi-generation Register, Cause of Death Register, and national censuses (follow-up, 1958–2015) have been linked. We used 10-year cumulative risk of breast cancer curves to determine the age at which women with different reproductive factors attained the risk level at which breast screening is usually recommended. ResultsThe 10-year cumulative risk of breast cancer at age 40, 45 and 50 years in the general population, at which current screening guidelines recommend screening was calculated. We found that women with various reproductive factors (defined by parity and age at first birth) obtained this level of risk at different ages. The difference was between nine years later and three years earlier. ConclusionsThis study provides the age at which women with particular reproductive profile could start risk-adapted breast cancer screening. This supplies novel information for clinicians and women about when to start breast cancer screening and is an important step towards a personalised screening.

Recommendations for Preventive Care for Women with Rare Genetic Cause of Breast and Ovarian Cancer.

An inherited predisposition to breast cancer underlies 5-10% of breast tumors. High-risk BRCA1 and BRCA2 genes result in an 85% lifetime risk of breast cancer and a 20-60% lifetime risk of ovarian cancer. Next-generation sequencing or massive parallel sequencing are now established testing methods that enable screening for many genes that predispose to heterogeneous hereditary cancer syndromes (22 genes are required by the health insurance companies). In addition to BRCA1 and BRCA2, inherited mutations in other genes predispose to breast and/or ovarian cancer. High-risk breast cancer genes include TP53, STK11, CDH1, PTEN, PALB2, and NF1, while moderate-risk (2-4 times increased risk) breast cancer genes include ATM, CHEK2, and NBN. Moderate risk is also suggested for Lynch syndrome, MUTYH, BRIP1, RAD51C, RAD51D, BARD1, FANCA, FANCC, FANCM, BLM, WRN genes. In heterozygotes for other recessive syndromes the risk of developing breast cancer is subject to current research. Low-risk genes are (mostly) irrelevant from a clinical perspective. Other genes that increase the risk of ovarian cancer include the genes for Lynch syndrome, the BRIP1, RAD51C and RAD51D genes. Preventive care should be proposed based on assumed cumulative breast cancer risk (see http: //www.mamo.cz): a risk of >20% for BRCA1/2, TP53, PTEN, STK11, CDH1, PALB2, CHEK2, ATM, and NF1; and a risk of 10-20% for BRIP1, RAD51C, RAD51B, BARD1, FANCA, FANCC, FANCM, NBN, BLM, and WRN. The genetic risk should be assessed by a geneticist and be based on inherited mutations and empirical risk according to family history. Prophylactic mastectomy is considered for high-risk gene carriers but not for moderate-risk gene carriers; however, it may be considered if there is an underlying family history, a risk of parenchyma of the mammary gland, or other risk factors. Ovarian cancer risk increases significantly in carriers of the BRIP1, RAD51C, and RAD51D genes. For prevention of ovarian cancer, prophylactic salpingo-oophorectomy is an important component of preventive care. In ovarian cancer families with no identified risk germline mutation, preventive salpingo-oophorectomy is not routinely recommended but may be considered as the only efficient method of prevention due to the increased empirical risk (4 times) of ovarian cancer in first-degree relatives. Supported by the grant project MH CZ - RVO (MMCI, 00209805), AZV 15-27695A and AZV 16-29959A. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 17. 5. 2019 Accepted: 31. 5. 2019.

Prevalence and Penetrance of BRCA1 and BRCA2 Germline Mutations in Colombian Breast Cancer Patients

Pathogenic BRCA1/2 germline mutations confer high risks of breast and ovarian cancer to women of European ancestry. Characterization of BRCA1/2 mutations in other ethnic groups is also medically important. We comprehensively screened 68 Colombian breast/ovarian cancer families for small-range mutations, 221 families for large-genomic rearrangements, and 1,022 unselected breast cancer cases for Colombian founder mutations in BRCA1/2. The risk of cancer among relatives of mutation carriers and the mutation penetrance were estimated by survival analysis. Identified BRCA2 mutations included 6310delGA and the recurrent 1991del4 mutations. A novel large BRCA2 deletion was found in 0.9% of the screened families. Among unselected breast cancer cases, 3.3% tested positive for BRCA1/3450del4, 2.2% for BRCA1/A1708E, 1.1% for BRCA2/3034del4, and 0.4% for BRCA2/1991del4. Female relatives of carriers of BRCA1/2 founder mutations showed a 5.90 times higher risk of breast cancer, when the woman herself carried a BRCA1 mutation compared to a non-carrier (95% CI 2.01–17.3). The estimated cumulative risk of breast cancer by age 70 years for BRCA1 mutations carriers was 14% (95% CI 5–38) compared to 3% for the general Colombian population (relative risk of breast cancer 4.05). Together with known founder mutations, reported novel variants may ease a cost-effective BRCA1/2 screening in women with Colombian ancestry.

Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers

The clinical management of BRCA1 and BRCA2 mutation carriers requires accurate, prospective cancer risk estimates. To estimate age-specific risks of breast, ovarian, and contralateral breast cancer for mutation carriers and to evaluate risk modification by family cancer history and mutation location. Prospective cohort study of 6036 BRCA1 and 3820 BRCA2 female carriers (5046 unaffected and 4810 with breast or ovarian cancer or both at baseline) recruited in 1997-2011 through the International BRCA1/2 Carrier Cohort Study, the Breast Cancer Family Registry and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, with ascertainment through family clinics (94%) and population-based studies (6%). The majority were from large national studies in the United Kingdom (EMBRACE), the Netherlands (HEBON), and France (GENEPSO). Follow-up ended December 2013; median follow-up was 5 years. BRCA1/2 mutations, family cancer history, and mutation location. Annual incidences, standardized incidence ratios, and cumulative risks of breast, ovarian, and contralateral breast cancer. Among 3886 women (median age, 38 years; interquartile range [IQR], 30-46 years) eligible for the breast cancer analysis, 5066 women (median age, 38 years; IQR, 31-47 years) eligible for the ovarian cancer analysis, and 2213 women (median age, 47 years; IQR, 40-55 years) eligible for the contralateral breast cancer analysis, 426 were diagnosed with breast cancer, 109 with ovarian cancer, and 245 with contralateral breast cancer during follow-up. The cumulative breast cancer risk to age 80 years was 72% (95% CI, 65%-79%) for BRCA1 and 69% (95% CI, 61%-77%) for BRCA2 carriers. Breast cancer incidences increased rapidly in early adulthood until ages 30 to 40 years for BRCA1 and until ages 40 to 50 years for BRCA2 carriers, then remained at a similar, constant incidence (20-30 per 1000 person-years) until age 80 years. The cumulative ovarian cancer risk to age 80 years was 44% (95% CI, 36%-53%) for BRCA1 and 17% (95% CI, 11%-25%) for BRCA2 carriers. For contralateral breast cancer, the cumulative risk 20 years after breast cancer diagnosis was 40% (95% CI, 35%-45%) for BRCA1 and 26% (95% CI, 20%-33%) for BRCA2 carriers (hazard ratio [HR] for comparing BRCA2 vs BRCA1, 0.62; 95% CI, 0.47-0.82; P=.001 for difference). Breast cancer risk increased with increasing number of first- and second-degree relatives diagnosed as having breast cancer for both BRCA1 (HR for ≥2 vs 0 affected relatives, 1.99; 95% CI, 1.41-2.82; P<.001 for trend) and BRCA2 carriers (HR, 1.91; 95% CI, 1.08-3.37; P=.02 for trend). Breast cancer risk was higher if mutations were located outside vs within the regions bounded by positions c.2282-c.4071 in BRCA1 (HR, 1.46; 95% CI, 1.11-1.93; P=.007) and c.2831-c.6401 in BRCA2 (HR, 1.93; 95% CI, 1.36-2.74; P<.001). These findings provide estimates of cancer risk based on BRCA1 and BRCA2 mutation carrier status using prospective data collection and demonstrate the potential importance of family history and mutation location in risk assessment.

Cumulative risk of breast cancer screening outcomes according to the presence of previous benign breast disease and family history of breast cancer: supporting personalised screening

Background:Our aim was to assess the cumulative risk of false-positive screening results, screen-detected cancer, and interval breast cancer in mammography screening among women with and without a previous benign breast disease and a family history of breast cancer.Methods:The cohort included 42 928 women first screened at the age of 50–51 years at three areas of the Spanish Screening Programme (Girona, and two areas in Barcelona) between 1996 and 2011, and followed up until December 2012. We used discrete-time survival models to estimate the cumulative risk of each screening outcome over 10 biennial screening exams.Results:The cumulative risk of false-positive results, screen-detected breast cancer, and interval cancer was 36.6, 5.3, and 1.4 for women with a previous benign breast disease, 24.1, 6.8, and 1.6% for women with a family history of breast cancer, 37.9, 9.0, and 3.2%; for women with both a previous benign breast disease and a family history, and 23.1, 3.2, and 0.9% for women without either of these antecedents, respectively.Conclusions:Women with a benign breast disease or a family history of breast cancer had an increased cumulative risk of favourable and unfavourable screening outcomes than women without these characteristics. A family history of breast cancer did not increase the cumulative risk of false-positive results. Identifying different risk profiles among screening participants provides useful information to stratify women according to their individualised risk when personalised screening strategies are discussed.

Breast cancer risk in Chinese women with BRCA1 or BRCA2 mutations.

BRCA1/2 mutations represent approximately 5 % of unselected Chinese women with breast cancer. However, the breast cancer risk of Chinese women with BRCA1/2 mutations is unknown. Therefore, the aim of this study was to estimate the age-specific cumulative risk of breast cancer in Chinese women who carry a BRCA1 or BRCA2 mutation. Our study included 1816 unselected Chinese women with breast cancer and 5549 female first-degree relatives of these probands. All probands were screened for BRCA1/2 mutation. The age-specific cumulative risks of BRCA1/2 carriers were estimated using the kin-cohort study by comparing the history of breast cancer in first-degree female relatives of BRCA1/2 carriers and non-carriers. Among the 1816 probands, 125 BRCA1/2 pathogenic mutations were identified (70 in the BRCA1 gene and 55 in the BRCA2 gene). The incidence of breast cancer in the first-degree female relatives of BRCA1/2 mutation carriers was significantly higher (3.7-fold and 4.4-fold for BRCA1 and BRCA2 mutation carriers, respectively) than in non-carriers. The estimated cumulative risks of breast cancer by age 70 years were 37.9 % [95 % confidence interval (CI) 24.1-54.4 %] for BRCA1 mutation carriers and 36.5 % (95 % CI 26.7-51.8 %) for BRCA2 mutation carriers, respectively. Our study suggests that the breast cancer risk of Chinese women with BRCA1/2 mutations appears to be relatively high by the age of 70. Therefore, genetic counseling, enhanced surveillance, and individual preventive strategies should be provided for Chinese women who carry a BRCA1/2 mutation.

Breast Cancer Risk in Childhood Cancer Survivors Without a History of Chest Radiotherapy: A Report From the Childhood Cancer Survivor Study.

Little is known about the breast cancer risk among childhood cancer survivors who did not receive chest radiotherapy. We sought to determine the magnitude of risk and associated risk factors for breast cancer among these women. We evaluated cumulative breast cancer risk in 3,768 female childhood cancer survivors without a history of chest radiotherapy who were participants in the Childhood Cancer Survivor Study. With median follow up of 25.5 years (range, 8 to 39 years), 47 women developed breast cancer at a median age of 38.0 years (range, 22 to 47 years) and median of 24.0 years (range, 10 to 34 years) from primary cancer to breast cancer. A four-fold increased breast cancer risk (standardized incidence ratio [SIR] = 4.0; 95% CI, 3.0 to 5.3) was observed when compared with the general population. Risk was highest among sarcoma and leukemia survivors (SIR = 5.3; 95% CI, 3.6 to 7.8 and SIR = 4.1; 95% CI, 2.4 to 6.9, respectively). By the age of 45 years, the cumulative incidence of breast cancer in sarcoma and leukemia survivors was 5.8% (95% CI, 3.7 to 8.4) and 6.3% (95% CI, 3.0 to 11.3), respectively. No other primary cancer diagnosis was associated with an elevated risk. Alkylators and anthracyclines were associated with an increased breast cancer risk in a dose-dependent manner (P values from test for trend were both < .01). Women not exposed to chest radiotherapy who survive childhood sarcoma or leukemia have an increased risk of breast cancer at a young age. The data suggest high-dose alkylator and anthracycline chemotherapy increase the risk of breast cancer. This may suggest a possible underlying gene-environment interaction that warrants further study.

Towards personalized screening: Cumulative risk of breast cancer screening outcomes in women with and without a first-degree relative with a history of breast cancer.

Several reviews have estimated the balance of benefits and harms of mammographic screening in the general population. The balance may, however, differ between individuals with and without family history. Therefore, our aim is to assess the cumulative risk of screening outcomes; screen-detected breast cancer, interval cancer, and false-positive results, in women screenees aged 50-75 and 40-75, with and without a first-degree relative with a history of breast cancer at the start of screening. Data on screening attendance, recall and breast cancer detection were collected for each woman living in Nijmegen (The Netherlands) since 1975. We used a discrete time survival model to calculate the cumulative probability of each major screening outcome over 19 screening rounds. Women with a family history of breast cancer had a higher risk of all screening outcomes. For women screened from age 50-75, the cumulative risk of screen-detected breast cancer, interval cancer and false-positive results were 9.0, 4.4 and 11.1% for women with a family history and 6.3, 2.7 and 7.3% for women without a family history, respectively. The results for women 40-75 followed the same pattern for women screened 50-75 for cancer outcomes, but were almost doubled for false-positive results. To conclude, women with a first-degree relative with a history of breast cancer are more likely to experience benefits and harms of screening than women without a family history. To complete the balance and provide risk-based screening recommendations, the breast cancer mortality reduction and overdiagnosis should be estimated for family history subgroups.

Abstract 3702: Cumulative incidence rates of breast cancer for Filipinos and Chamorros in Guam and the United States

Abstract Background Breast cancer is the leading cause of cancer-related death among women on Guam. However incidence rates vary between Chamorros and Filipinos, the two predominant ethnic groups on Guam. Objective Our objective was to compare age-specific cumulative incidence rates among ethnic groups in Guam and US. Cumulative incidence rates are relatively stable and thus provide a good estimate of cumulative risk of breast cancer. Methods This study included all breast cancer cases (n = 576) reported to the Guam Cancer Registry from 2000 to 2009 and all breast cancer cases (n = 678,637) reported to the Surveillance, Epidemiology,and End Results (SEER) 18-Registry Database. Cumulative incidence rates were calculated for Filipinos and Chamorros for two time periods: 2000-2004 and 2005-2009. For comparison, cumulative incidence rates were also calculated for all women in Guam and the US, and for Filipino only in the US. Results Remarkable differences were seen in cumulative incidence rates by age and ethnicity. During the 2000-2004 time period, the cumulative incidence rates by age 40 in Filipinos on Guam were the highest (0.7%) and almost threefold higher than the rate in Chamorros (0.24%). But after age 40, the rates for Chamorros increased rapidly. The lifetime cumulative incidence rates (age 0-75) for Chamorros was highest in Guam (11.4%) and close to the US rate (12%). Interestingly, there was a marked difference in lifetime cumulative incidence rates between Filipino women in Guam and Filipinos in the US (7% and 10.9% respectively). Similar results were found for the 2005-2009 time period. Conclusions The observed disparity among ethnic groups suggests ethnic differences in exposure or response to certain risk factors. Further study is needed to examine possible differences in risk behaviors between Filipinos and Chamorros in Guam, as well as between Filipinos in Guam and Filipinos in the US. Citation Format: Grazyna Badowski, Rachael Leon Guerrero, Brayan Simsiman, Rachel Novotny, Lynne Wilkens. Cumulative incidence rates of breast cancer for Filipinos and Chamorros in Guam and the United States. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3702. doi:10.1158/1538-7445.AM2015-3702