First-degree Family History Of Breast Cancer Research Articles

Abstract PO4-09-01: Survival of patients harboring a germline ATM pathogenic/likely pathogenic variant and diagnosed with breast cancer: A case-control study

Abstract Introduction: Patients harboring a pathogenic/likely pathogenic variant (PV/LPV) in ATM present an increased lifetime risk of developing breast cancer (BC). The survival outcomes of these patients are not well-known. Methods: Retrospective, multicentric case-control study. Case group included patients with stage I-III breast cancer harboring a PV/LPV in ATM. Control group included patients with stage I-III breast cancer with a negative germline BC multigene panel testing including ATM gene analysis. Clinical outcomes defined as locoregional relapse-free survival (RFS), distant RFS and breast cancer specific survival were compared between cases and controls. Case group was obtained from five hereditary cancer units and control group was obtained from a sporadic clinic-based cohort. Cases and controls were matched 1:2 by stage, molecular subtype by immunohistochemistry, age at BC diagnosis and year of BC diagnosis. Baseline continuous variables were presented as mean and standard deviation and comparison was performed with Student´s t-test. Baseline categorical variables were presented with number and percentage and comparison were performed using chi-square test. Survival analyses were estimated by Kaplan-Meier curves, the comparison of survival was tested by stratified log-rank testing. Cox proportional hazards model was used to estimate the hazard ratio and confidence intervals. Results: We identified 64 patients (p) with an ATM PV/LPV and 120 controls. Median age at diagnosis was 47 years (28-84) and 46 years (25-88), respectively. The main tumoral characteristics in both groups were ductal (87.5% and 83.5%), luminal B-HER2 negative (37.5% and 45.8%) with histological grade II (54.7% and 58.5%) tumors. Majority of tumors in both groups were diagnosed at stage II (53.1% and 54.2%). Differences between groups were observed in first-degree BC family history (39p (61.9%) vs 51p (43.6%); p=0.02); frequency of multicentric/multifocal tumors (15p (25%) vs 13p (11.1%); p=0.018); contralateral breast cancer (16p (25%) vs 8p (6.7%); p=0.0004) and type of surgery (46.8% conservative surgery in cases and 69.2% in controls; p< 0.001). The result of the germline genetic study was not available for all patients before surgery. Baseline characteristics are summarized in Table 1. With a median follow-up of 6.7 years, we observed more locoregional recurrence and distant recurrence in the control group (ipsilateral local or lymphatic recurrence: 0p (0%) vs 15p (12.5%); p=0.078; metachronic contralateral breast cancer: 7p (12.7%) vs 3p (2.6%); p=0.02; distance recurrence 5p (7.8%) vs 24p (20%); p=0.03. No differences between groups were observed in BC-specific survival analysis, with a median BC-specific survival of 6.24y (4.67-12.1) in patients with ATM and 6.68y (6.12-7.94) in the control group (HR: 1.21 (0.88-1.65); p=0.24). Conclusions: Patients with BC harboring a germline ATM PV/LPV had more multifocal and multicentric disease at diagnosis; and more synchronous and metachronous contralateral BC compared to controls, with no differences in BC-specific survival. Further studies in a larger cohort are warranted to analyze sensitivity to systemic therapies. Table 1. Baseline characteristics of cases and control groups. ER (Estrogen Receptor) positive if > or equal to 1%; PR (Progesterone Receptor) positive if > or equal to 1%; HER2 (Human epidermal growth factor receptor-2); ChTh: Chemotherapy; SLNB: Sentinel Lymph Node Biopsy; AL: Axillar lymphadenectomy Citation Format: Mara Cruellas, Ariadna Roqué, Nuria Dueñas, Iris Teruel, Noemí Tuset Der-Abrain, Alejandra Rezqallah, Víctor Navarro, Laia Joval-Ramentol, Maite Torres, Cristina Saura, Joan Brunet, Judith Balmaña. Survival of patients harboring a germline ATM pathogenic/likely pathogenic variant and diagnosed with breast cancer: A case-control study [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 PO4-09-01.

Abstract PS10-01: Hormonal Contraception and Breast Cancer Risk for Carriers of Germline Pathogenic Variants in BRCA1 and BRCA2

Abstract BACKGROUND: Current use of hormonal contraception is associated with a 20-30% relative increase in the risk of breast cancer (BC) for women in the general population compared with never using. Longer duration of use is associated with higher risk, and the risk remains elevated above that of never users for at least 5 years after cessation. Most published data are for various formulations of the combined oral contraceptive pill, but associations are similar for progestogen-only contraceptives, including intrauterine devices. For women in the general population who use hormonal contraceptives in their 20s and 30s, when baseline BC risk for most women is low, these increased relative risks translate into only small increases in absolute risk. It is unclear whether use of hormonal contraceptives increases BC risk for women carrying a germline BRCA1 or BRCA2 pathogenic variant (PV). These women are at markedly higher risk of early-onset BC, so even slightly increased relative risks could translate to important increases in their absolute risk of BC. This study assessed the association between use of any hormonal contraception and BC risk for BRCA1 and BRCA2 PV carriers using individual participant data from four prospective cohorts. METHODS: Data from females born after 1920 with a PV in BRCA1 or BRCA2 and no history of cancer or bilateral mastectomy at cohort entry were analyzed. Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for BC (invasive disease or ductal carcinoma in situ) associated with use of hormonal contraceptives for at least 1 year, with age as the timescale, entry at cohort enrolment, and censoring at the earlier of bilateral mastectomy, death, diagnosis of another cancer or last follow-up. Analyses were adjusted for study, birth cohort, first-degree family history of BC, parity, premenopausal bilateral oophorectomy and menopausal status. Current use of hormonal contraceptives was defined as use within the previous year, to account for cessation of use due to BC symptoms or clinical investigation. RESULTS: Of 3,882 BRCA1 and 1,509 BRCA2 PV carriers, 53% and 71%, respectively had ever used hormonal contraceptives (for at least one year). The median cumulative duration of hormonal contraceptive use was 4.8 and 5.7 years, respectively. Overall, 488 BRCA1 and 191 BRCA2 PV carriers developed incident BC during a median of 5.9 and 5.6 years of follow-up, respectively. For BRCA1 PV carriers, use of hormonal contraceptives for at least 1 year was associated with increased BC risk (HR [95% CI]: 1.29 [1.04-1.60] p=0.019). BC risk increased with longer cumulative duration of hormonal contraceptive use (HR [95% CI]: 1.13 [0.88-1.45] p=0.35, 1.48 [1.11-1.96] p=0.007 and 1.56 [1.13-2.17] p=0.007 for 1-5, 6-10 and >10 years of use, respectively), with an estimated proportional increase in risk of 3% (1%-5%, p=0.002) for each additional year of use. For BRCA2 PV carriers, there was no evidence that current or past use, or cumulative duration of use, were associated with increased risk of BC, but confidence intervals on the HRs were wide. CONCLUSION: Hormonal contraceptive use is associated with an increased risk of BC for women carrying PVs in BRCA1 and risk increases with cumulative duration of use. Hormonal contraceptives are an important healthcare option for women; they provide excellent contraceptive efficacy and reduce risks of ovarian and endometrial cancer. Decisions about use of hormonal contraceptives in women at increased risk for BC due to BRCA1 PVs need to carefully weigh the risks and benefits; while shorter-term use may result in only small increases, prolonged cumulative use may result in larger increases in absolute BC risk that may not be acceptable to some women. Citation Format: Kelly-Anne Phillips, Joanne Kotsopoulos, Susan Domchek, James Chamberlain, Julie Bassett, Amber Aeilts, Irene Andrulis, Saundra Buys, Wanda Cui, Mary Daly, Andrea Eisen, William Foulkes, Michael Friedlander, Jacek Gronwald, John Hopper, Esther John, Beth Karlan, Raymond Kim, Jan Lubiński, Kelly Metcalfe, Katherine Nathanson, Christian F. Singer, Heather Symecko, Nadine Tung, Steven Narod, Mary Beth Terry, Roger Milne. Hormonal Contraception and Breast Cancer Risk for Carriers of Germline Pathogenic Variants in BRCA1 and BRCA2 [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 PS10-01.

Abstract 769: Incorporating a cross-ancestry polygenic risk score into a clinical model improved breast cancer risk prediction in women with pathogenic variants

Abstract Introduction. We previously developed and validated a cross-ancestry polygenic risk score (caPRS) to predict risk of developing breast cancer (BC) in women who do not carry pathogenic variants (PVs) in BC susceptibility genes. Here we aimed to expand upon that study by integrating the caPRS with the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) model to combine the effects of genetic and clinical factors in carriers of PVs in BRCA1, BRCA2, PALB2, CHEK2 and ATM. Methods. We explored the association of caPRS among 12,525 women from the UK Biobank and the Consortium of Investigators of Modifiers of BRCA1/2. The effect size of the caPRS was evaluated separately for individuals carrying PVs in BRCA1, BRCA2, CHEK2, ATM and PALB2. We used a logistic regression model adjusted for age, first-degree BC family history (FHx) and cohort for BRCA1 and BRCA2 to examine the association of the caPRS with BC. The effect sizes were expressed as standardized odds ratios (ORs) with 95% confidence intervals (CIs). The estimated absolute risks to age 80 of developing BC were calculated for unaffected women by combining the caPRS-based risk with gene-specific clinical risk estimates from the BOADICEA model based on U.S. incidences. Results. The caPRS was significantly associated with BC risk across all PV carrier groups. Using BOADICEA alone, the estimated absolute BC risk by age 80 for an average unaffected 20-year-old female in the U.S. with an unknown FHx ranged from 23.8% for CHEK2 carriers to 79.4% for BRCA2 carriers. Integration of caPRS into BOADICEA, yielded the distribution of risk for each gene. (Table) Gene N OR per SD (95% CI) Absolute risk by BOADICEA Median absolute risk by BOADICEA + caPRS (Range) ATM 2,037 1.46 (1.25 - 1.71) 24.9% 27.1% (0.1 - 70.5) BRCA1 5,794 1.24 (1.18 - 1.31) 76.1% 75.6% (55.6 - 87.7) BRCA2 4,018 1.40 (1.31 - 1.49) 79.4% 78.7% (45.2 - 92.1) CHEK2 372 1.88 (1.41 - 2.55) 23.8% 28.2% (0.0 - 78.4) PALB2 304 1.81 (1.37 - 2.43) 53.9% 56.3% (2.9 - 90.9) Conclusions. The caPRS significantly modified BC risk for carriers of PVs and could help tailor guidelines for women with PVs, particularly in moderate penetrance genes. More data is needed to increase the precision and reach of risk assessment in diverse populations. Citation Format: Placede Tshiaba, Monika Sun, Dariusz Ratman, Jeffrey N. Weitzel, Premal Shah, Matthew Rabinowitz, Akash Kumar, Kate Im. Incorporating a cross-ancestry polygenic risk score into a clinical model improved breast cancer risk prediction in women with pathogenic variants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 769.

Cross-ancestry polygenic risk score for breast cancer risk assessment.

10540 Background: Breast cancer (BC) risk is influenced by many common variants with small effects. Polygenic risk scores (PRS) weight these variants based on genome-wide association studies (GWAS) and aggregate them into a single measure. PRS has primarily shown benefit in Caucasian women. We established a cross-ancestry polygenic model (caPRS) which assesses risk of breast cancer across multiple ancestries. Methods: Performance of multiple BC polygenic models, both published and developed in-house, were evaluated for each of five ancestry groups: European, African, South Asian, East Asian, and Admixed American. To account for ancestry-specific mean and variance, we computed principal components (PCs) for all women by projecting their genotypes onto PCs calculated on individuals in the 1000 Genomes Project (1KGP). We next centered each ancestry-specific PRS by subtracting the PRS predicted from a linear regression of PRS against the first four PCs in unaffected individuals. Each centered PRS was then divided by the SD of the corresponding 1KGP population. We defined a cross-ancestry polygenic model as a linear combination of the best performing PRS model for each ancestry group weighted by fractional ancestry. Association of the caPRS with breast cancer risk was tested in a validation cohort of >130,000 women consisting of multiple independent cohorts (the Women’s Health Initiative, the Multiethnic Cohort, the ROOT cohort and the UK Biobank) using a multivariate logistic regression model that included caPRS, age, self-reported ancestry, personal history of ovarian cancer (when available) and first-degree family history of BC. Discrimination was assessed by the odds ratio (OR) per SD and the area under the receiver-operator curve (AUC). Results: This study included women with African/Black, East Asian, Caucasian/White, Hispanic/Latino, South Asian and ‘Other’ self-reported ancestry. The ancestry-specific models included in the caPRS ranged in size from 173 to >800,000 variants. The caPRS was associated with BC risk for women in each self-reported ancestry (Table). The caPRS offered a modest increase in performance over a commonly implemented 313-SNP PRS in non-European ancestries, most significantly in African/Black women where the OR per SD increased from 1.24 (1.08 - 1.43), p-value 2.3x10-3. Conclusions: The caPRS performed well for women of any ancestry and allows flexibility to update ancestry-specific models. These results suggest the caPRS has the potential to improve the clinical utility of existing clinical risk predictors. [Table: see text]

Abstract P3-07-01: Young women with breast cancer and high risk family history but no high penetrance germline mutations have a higher load of rare high functional impact germline variants in cancer relevant genes

Abstract Background: There is an incomplete understanding of why some women develop breast cancer 20-25 years earlier than the majority of women. Only 30-40% of women with high risk family history are found to have known cancer predisposing mutations. This phenomenon is referred to as “missing heredity”. We hypothesize that women with high-risk cancer family history but no known high penetrance cancer predisposing mutations who develop breast cancer at a young age have a higher deleterious load of germline high functional impact (gHFI) single nucleotide variants in cancer relevant genes. Methods: 94 women diagnosed with breast cancer age <50 with high risk cancer family history who tested negative for germline cancer predisposing mutations were identified at Yale Cancer Prevention Clinic (YCPC). 149 controls, healthy Caucasian individuals age > 65 with no cancer family history were identified from Yale Generations project. Whole-exome sequencing (WES) was performed on peripheral blood from 94 cases, 149 controls, and 42 matched tumors. WES data was analyzed from 1,112 female breast cancer cases with first-degree breast cancer family history and 50,887 healthy women without breast cancer family history from UKBiobank. Rare gHFI variants were defined as nonsynonymous variants predicted as deleterious in MetaSVM, or loss-of-function in gnormAD, or pathogenic in ClinVar database with mutation frequency <0.01. Hallmark genes were 1,558 genes involved in 21 cancer pathways and 83 cancer predisposition genes (CPGs). 468 somatic cancer genes were used. Rare gHFI in cases vs controls were compared using SNP-set (Sequence) Kernel Association Test (SKAT). Somatic mutations in YCPC vs 652 ER+ breast cancer TCGA cases were compared using 13/468 cancer genes mutated >5% of cases using Fisher’s exact test. FDRs were calculated using Benjamini & Hochberg. Results: The majority of YCPC patients were Caucasian (78.7%), median age (43.5), with invasive ductal carcinoma (85.1%), ER+PR+HER2- (67.0%). YCPC patients had a higher average burden of rare gHFI variants in cancer hallmark genes (excluding CPGs) compared to controls (p=0.0075, adjusted for race), but did not show a higher germline burden in CPGs. Similarly, UKBiobank breast cancer patients with a family history had a higher germline variant burden in hallmark genes (excluding CPGs) compared to controls (p=0.0368). The main pathways affected by gHFI in the YCPC cohort were adaptive immunity (p=1.61 x 10-8) and extracellular matrix (p=0.0034). Thirty six (87.8%) YCPC matched tumors carried somatic mutations in known cancer related genes. Compared to TCGA, YCPC samples had fewer TP53 mutations (5% vs 17%, FDR = 0.27), but more mutations in CHEK2, GNAQ, APC, and SDHA (FDR<0.028). Conclusions: Our cohort of young women with breast cancer and high risk family history with no known germline high penetrance cancer gene mutations showed a higher burden of germline high functional impact variants in hallmark cancer genes. This higher germline variant burden suggests that the totality of gHFI variants in cancer related genes could explain why these women develop breast cancer at a younger age. CohortRace (%)AgeCases (N)Control (N)GenesetAverage Case BurdenAverage Case BurdenSKAT testYaleCaucasian (78.7)439414983 CPGs0.27660.30200.56921508 Hallmark4.23404.18790.0075UK BiobankBritish (100)5611125088783 CPGs0.37410.28064.19x10-51508 Hallmark3.36423.33990.0368 Citation Format: Mariya Rozenblit, Tao Qing, Yixuan Ye, Hongyu Zhao, Erin Hofstatter, Vinit Singh, Emily Reisenbichler, Michael Murray, Lajos Pusztai. Young women with breast cancer and high risk family history but no high penetrance germline mutations have a higher load of rare high functional impact germline variants in cancer relevant genes [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-07-01.

Risk of Breast Cancer Among Carriers of Pathogenic Variants in Breast Cancer Predisposition Genes Varies by Polygenic Risk Score.

This study assessed the joint association of pathogenic variants (PVs) in breast cancer (BC) predisposition genes and polygenic risk scores (PRS) with BC in the general population. A total of 26,798 non-Hispanic white BC cases and 26,127 controls from predominately population-based studies in the Cancer Risk Estimates Related to Susceptibility consortium were evaluated for PVs in BRCA1, BRCA2, ATM, CHEK2, PALB2, BARD1, BRIP1, CDH1, and NF1. PRS based on 105 common variants were created using effect estimates from BC genome-wide association studies; the performance of an overall BC PRS and estrogen receptor-specific PRS were evaluated. The odds of BC based on the PVs and PRS were estimated using penalized logistic regression. The results were combined with age-specific incidence rates to estimate 5-year and lifetime absolute risks of BC across percentiles of PRS by PV status and first-degree family history of BC. The estimated lifetime risks of BC among general-population noncarriers, based on 10th and 90th percentiles of PRS, were 9.1%-23.9% and 6.7%-18.2% for women with or without first-degree relatives with BC, respectively. Taking PRS into account, more than 95% of BRCA1, BRCA2, and PALB2 carriers had > 20% lifetime risks of BC, whereas, respectively, 52.5% and 69.7% of ATM and CHEK2 carriers without first-degree relatives with BC, and 78.8% and 89.9% of those with a first-degree relative with BC had > 20% risk. PRS facilitates personalization of BC risk among carriers of PVs in predisposition genes. Incorporating PRS into BC risk estimation may help identify > 30% of CHEK2 and nearly half of ATM carriers below the 20% lifetime risk threshold, suggesting the addition of PRS may prevent overscreening and enable more personalized risk management approaches.

First- and second-degree family history of ovarian and breast cancer in relation to risk of invasive ovarian cancer in African American and white women.

Family history (FH) of ovarian cancer and breast cancer are well-established risk factors for ovarian cancer, but few studies have examined this association in African American (AA) and white women by histotype. We assessed first- and second-degree FH of ovarian and breast cancer and risk of epithelial ovarian cancer in the Ovarian Cancer in Women of African Ancestry Consortium. Analyses included 1052 AA cases, 2328 AA controls, 2380 white cases and 3982 white controls. Race-specific odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multilevel logistic regression with adjustment for covariates. Analyses were stratified by histotype (high-grade serous vs others). First-degree FH of ovarian cancer was associated with high-grade serous carcinoma in AA (OR = 2.32, 95% CI: 1.50, 3.59) and white women (OR = 2.48, 95% CI: 1.82, 3.38). First-degree FH of breast cancer increased risk irrespective of histotype in AAs, but with high-grade serous carcinoma only in white women. Associations with second-degree FH of ovarian cancer were observed for overall ovarian cancer in white women and with high-grade serous carcinoma in both groups. First-degree FH of ovarian cancer and of breast cancer, and second-degree FH of ovarian cancer is strongly associated with high-grade serous ovarian carcinoma in AA and white women. The association of FH of breast cancer with high-grade serous ovarian carcinoma is similar in white women and AA women, but may differ for other histotypes.

Age at initiation of screening mammography by family history of breast cancer in the breast cancer surveillance consortium.

Women with a first-degree family history of breast cancer (FHBC) are sometimes advised to initiate screening mammography when they are 10 years younger than the age at which their youngest relative was diagnosed, despite a lack of unambiguous evidence that this is an effective strategy. It is unknown how often this results in women initiating screening earlier (< 40 years) than screening guidelines recommend for average-risk women. We examined screening initiation age by FHBC and age at diagnosis of the youngest relative using data collected by the Breast Cancer Surveillance Consortium on 74,838 first screening mammograms performed between 1996 and 2016. Of the 74,838 women included in the study, nearly 9% reported a FHBC. Approximately 16.8% of women who initiated mammography before 40 years reported a FHBC. More women with a FHBC than without initiated screening < 40 years (48% vs. 23%, respectively). Among women with a FHBC who initiated screening < 40 years, 65% were 10 years younger than the age at which their relative was diagnosed. Women with a first-degree relative diagnosed with breast cancer were more likely to start screening before 40 years than women reporting no FHBC, especially if their relative was diagnosed before 50 years.

Personalizing Breast Cancer Screening Based on Polygenic Risk and Family History.

BackgroundWe assessed the clinical utility of a first-degree breast cancer family history and polygenic risk score (PRS) to inform screening decisions among women aged 30-50 years.MethodsTwo established breast cancer models evaluated digital mammography screening strategies in the 1985 US birth cohort by risk groups defined by family history and PRS based on 313 single nucleotide polymorphisms. Strategies varied in initiation age (30, 35, 40, 45, and 50 years) and interval (annual, hybrid, biennial, triennial). The benefits (breast cancer deaths averted, life-years gained) and harms (false-positive mammograms, overdiagnoses) were compared with those seen with 3 established screening guidelines.ResultsWomen with a breast cancer family history who initiated biennial screening at age 40 years (vs 50 years) had a 36% (model range = 29%-40%) increase in life-years gained and 20% (model range = 16%-24%) more breast cancer deaths averted, but 21% (model range = 17%-23%) more overdiagnoses and 63% (model range = 62%-64%) more false positives. Screening tailored to PRS vs biennial screening from 50 to 74 years had smaller positive effects on life-years gained (20%) and breast cancer deaths averted (11%) but also smaller increases in overdiagnoses (10%) and false positives (26%). Combined use of family history and PRS vs biennial screening from 50 to 74 years had the greatest increase in life-years gained (29%) and breast cancer deaths averted (18%).ConclusionsOur results suggest that breast cancer family history and PRS could guide screening decisions before age 50 years among women at increased risk for breast cancer but expected increases in overdiagnoses and false positives should be expected.

Use of detailed family history data to improve risk prediction,with application to breast cancer screening.

BackgroundAs breast cancer represents a major morbidity and mortality burden in the U.S., with about one in eight women developing invasive breast cancer over her lifetime, accurate low-cost screening is an important public health issue. First-degree family history, often simplified as a dichotomous or three-level categorical variable (0/1/>1) based on number of affected relatives, is an important risk factor for many conditions. However, detailed family structure information such as the total number of first-degree relatives, and for each, their current or death age, and age at diagnosis are also important for risk prediction.MethodsWe develop a family history score under a Bayesian framework, based on first-degree family structure. We tested performance of the proposed score using data from a large prospective cohort study of women with a first-degree breast cancer family history. We used likelihood ratio tests to evaluate whether the proposed score added additional information to a Cox model with known breast cancer risk factors and the three-level family history variable. We also compared prediction performance through Receiver Operating Characteristic (ROC) curves and goodness-of-fit testing.ResultsOur proposed Bayesian family history score improved fit compared to the commonly used three-level family history score, both without and with adjustment for other risk factors (likelihood ratio tests p = 0.003 without adjustment for other risk factors, and p = 0.007 and 0.009 under adjustment with two candidate sets of risk factors). AUCs of ROC curves for the two models were similar, though in all cases were higher after addition of the BFHS.ConclusionsCapturing detailed family history data through the proposed family history score can improve risk assessment and prediction. Such approaches could enable better-targeted personalized screening schedules and prevention strategies.

Race/Ethnicity and Accuracy of Self-Reported Female First-Degree Family History of Breast and Other Cancers in the Northern California Breast Cancer Family Registry.

Few studies have evaluated accuracy of self-reported family history of breast and other cancers in racial/ethnic minorities. We assessed the accuracy of cancer family history reports by women with breast cancer (probands) from the Northern California Breast Cancer Family Registry compared with 2 reference standards: personal cancer history reports by female first-degree relatives and California Cancer Registry records. Probands reported breast cancer in first-degree relatives with high accuracy, but accuracy was lower for other cancers. Sensitivity (percentage correctly identifying relatives with cancer) was 93% [95% confidence interval (CI), 89.5-95.4] when compared with the relatives' self-report of breast cancer as the reference standard and varied little by proband race/ethnicity and other demographic factors, except for marginally lower sensitivity for Hispanic white probands (87.3%; 95% CI, 78.0-93.1; P = 0.07) than non-Hispanic white probands (95.1%; 95% CI, 88.9-98.0). Accuracy was also high when compared with cancer registry records as the reference standard, with a sensitivity of 95.5% (95% CI, 93.4-96.9) for breast cancer, but lower sensitivity for Hispanic white probands (91.2%; 95% CI, 84.4-95.2; P = 0.05) and probands with low English language proficiency (80%; 95% CI, 52.8-93.5; P < 0.01). Non-Hispanic white, African American, and Asian American probands reported first-degree breast cancer family history with high accuracy, although sensitivity was lower for Hispanic white probands and those with low English language proficiency. Self-reported family history of breast cancer in first-degree relatives is highly accurate and can be used as a reliable standard when other validation methods are not available.

Association of Prepubertal and Adolescent Androgen Concentrations With Timing of Breast Development and Family History of Breast Cancer

Early breast development is a risk factor for breast cancer, and girls with a breast cancer family history (BCFH) experience breast development earlier than girls without a BCFH. To assess whether prepubertal androgen concentrations are associated with timing of breast development (analysis 1) and to compare serum androgen concentrations in girls with and without a BCFH (analysis 2). Prospective cohort study of 104 girls aged 6 to 13 years at baseline using data collected between August 16, 2011, and March 24, 2016, from the Lessons in Epidemiology and Genetics of Adult Cancer From Youth (LEGACY) Girls Study, New York site. Analysis 1 included serum concentrations of dehydroepiandrosterone sulfate, androstenedione, and testosterone (free and total) measured before breast development and divided at the median into high and low categories. Analysis 2 included the degree of BCFH: first-degree was defined as having a mother with breast cancer and second-degree was defined as having a grandmother or aunt with breast cancer. Analysis 1 included age at onset of breast development measured using the Pubertal Development Scale (scores range from 1-4; scores ≥2 indicate breast development), and analysis 2 included serum androgen concentrations. We also assessed breast cancer-specific distress using the 8-item Child Impact of Events Scale. Our analyses included 36 girls for the prospective model, 92 girls for the cross-sectional model, and 104 girls for the longitudinal model. Of the 104 girls, the mean (SD) age at baseline was 10.3 (2.5) years, and 41 (39.4%) were non-Hispanic white, 41 (39.4%) were Hispanic, 13 (12.5%) were non-Hispanic black, and 9 (8.7%) were other race/ethnicity. Forty-two girls (40.4%) had a positive BCFH. Girls with prepubertal androstenedione concentrations above the median began breast development 1.5 years earlier than girls with concentrations below the median (Weibull survival model-estimated median age, 9.4 [95% CI, 9.0-9.8] years vs 10.9 [95% CI, 10.4-11.5] years; P = .001). Similar patterns were observed for dehydroepiandrosterone sulfate (1.1 years earlier: age, 9.6 [95% CI, 9.1-10.1] years vs 10.7 [95% CI, 10.2-11.3] years; P = .009), total testosterone (1.4 years earlier: age, 9.5 [95% CI, 9.1-9.9] years vs 10.9 [95% CI, 10.4-11.5] years; P = .001), and free testosterone (1.1 years earlier: age, 9.7 [95% CI, 9.2-10.1] years vs 10.8 [95% CI, 10.2-11.4] years; P = .01). Compared with girls without BCFH, girls with a first-degree BCFH, but not a second-degree BCFH, had 240% higher androstenedione concentrations (geometric means: no BCFH, 0.49 ng/mL vs first-degree BCFH, 1.8 ng/mL vs second-degree, 1.6 ng/mL; P = .01), 10% higher total testosterone concentrations (12.7 ng/dL vs 14.0 ng/dL vs 13.7 ng/dL; P = .01), and 92% higher free testosterone concentrations (1.3 pg/mL vs 2.5 pg/mL vs 0.3 pg/mL; P = .14). The dehydroepiandrosterone sulfate concentration did not differ between BCFH-positive and BCFH-negative girls but was elevated in girls with breast cancer-specific distress. Our findings suggest that androgen concentrations may differ between girls with and without a BCFH and that elevated hormone concentrations during adolescence may be another factor to help explain the familial clustering of breast cancer.

Abstract P4-10-08: Family history of breast cancer and mammographic density in premenopausal women

Abstract Introduction: Mammographic density and family history of breast cancer (FHBC) are independent risk factors for breast cancer. Women with dense breasts have a 4-6-fold increased risk of breast cancer and women with FHBC have a 1.5-3-fold increased risk of breast cancer. However, there is little data on the associations of FHBC with mammographic density, especially in premenopausal women. To address this, we investigated the associations of FHBC in first-degree relatives with mammographic density in premenopausal women. Methods: We used data from 375 cancer-free premenopausal women who were during routine screening mammography at Washington University in St. Louis in 2016. We used Volpara to measure volumetric measures of density including volumetric percent density, dense volume, and non-dense volume. We collected data on first-degree relatives (mother, sister) and numbers of first degree relatives (0, 1, ≥2) with a positive FHBC. We used multivariable linear regression model, adjusted for age, BMI, parity, race, age at menarche, and alcohol consumption, to determine the associations of FHBC and log-transformed volumetric percent density, dense volume, and non-dense volume. Beta coefficients (β) were evaluated and back transformed for easier interpretation. Results: The mean age of participants was 47.5 years (range=32-58). The mean BMI was 30.8 kg/m2 (range =17.9-63.1). Volumetric percent density was 25% (p-value&amp;lt;0.001) higher in women who had a FHBC compared with women who had no FHBC. The associations appeared confined to women with a positive family history in mothers but not those with a positive family history in sisters. Volumetric percent density was 31% higher (p-value&amp;lt;0.001) among women with a positive FHBC in mothers compared to those without a positive FHBC in mothers, but 8% higher (p-value=0.45) among women with a positive FHBC in sisters compared to those without a positive FHBC in sisters. The associations of FHBC with dense volume were similar to those of volumetric percent density in all the analyses. For instance, dense volume was 16% (p-value=0.006) higher in women who had a FHBC compared with women who had no FHBC. Table 1.Associations of family history of breast cancer (FHBC) and volumetric percent density (VPD), and dense volume (DV) in 375 premenopausal women*.FHBCNVPD (%) DV (cm3 ) Beta (95% CI)P-valueBeta (95% CI)P-valueNo275Ref Ref Yes871.25 (1.12,1.41)&amp;lt;0.0011.16 (1.04,1.29)0.007Unknown131.00 (0.76,1.30)0.990.74 (0.58,0.95)0.017*Adjusted for age, BMI, parity, race, age at menarche, and alcohol consumption. Conclusions: Premenopausal women with a first-degree FHBC have higher volumetric percent density. Our findings could help identify high-risk women who may benefit from targeted screening. Citation Format: Han Y, Zong X, Colditz GA, Toriola AT. Family history of breast cancer and mammographic density in premenopausal women [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-10-08.

Evaluation of Breast Cancer Awareness Campaign, Screening Drivers

Background: King Hussein Cancer Foundation and Center (KHCF &amp; KHCC) lead Breast Cancer (BC) awareness in Jordan through the Jordan Breast Cancer Program. The program aims to reduce morbidity and mortality from BC, and shift the current state of diagnosis from late stages to earlier ones, where the disease is curable, survival rates are higher, and treatment costs are lower. In October, the international BC awareness month, many activities are organized to encourage Jordanian women to undergo screening. Aim: To find out predictors of screening visits at KHCC early detection clinic in October 2015 to evaluate echo of the campaign. In addition, we aim to find the screening rate among women at KHCC early detection clinic. Methods: This is a cross sectional study, using a self-administered questionnaire, carried out in October 2015 and follow-up was completed on August 2016. Results: 291 women responded to the questionnaire, they were categorized into two groups; screening and diagnostic. Screening rate was 57.8% (N=166). In women above 40 years old, 69.3% (N=113) were in the screening group and 30.7% (N= 50) in the diagnostic group. There was no statistically significant difference in the average ages between two groups (49.49 year, 47.82 year, P = 0.218). Positive family history of BC in a first-degree relative was found to be a strong predictor for mammogram screening in comparison with screening group (65.4% vs 16%, P = 0.05); other screening behaviors like commitment to self-breast exam, clinical breast exam and attending educational lecture about BC did not significantly affect screening rates. In addition, screened women were more likely to complete their investigations and follow-up procedures. In this sample, five women were diagnosed with BC; two in advanced stages among the diagnostic group 4%, (N=50) with mean age 54.5 year, and three in early stage among screened group 2.7%, (N=113) with a mean age of 50 year. Conclusion: First-degree family history of BC is a strong predictor of BC screening. Awareness activities might lead to higher screening rates among women in general. Further studies need to be conducted on larger scale to confirm the results of this study.

Utilization of breast cancer screening with magnetic resonance imaging in community practice.

Breast cancer screening with magnetic resonance imaging (MRI) may be a useful adjunct to screening mammography in high-risk women, but MRI uptake may be increasing rapidly among low- and average-risk women for whom benefits are unestablished. Comparatively little is known about use of screening MRI in community practice. To assess relative utilization of MRI among women who do and do not meet professional society guidelines for supplemental screening, and describe utilization according to breast cancer risk indications. Prospective cohort study conducted between 2007 and 2014. In five regional imaging registries participating in the Breast Cancer Surveillance Consortium (BCSC), 348,955 women received a screening mammogram, of whom 1499 underwent screening MRI. Lifetime breast cancer risk (< 20% or ≥ 20%) estimated by family history of two or more first-degree relatives, and Gail model risk estimates. Breast Imaging Reporting and Data System breast density and benign breast diseases also were assessed. Relative risks (RR) for undergoing screening MRI were estimated using Poisson regression. Among women with < 20% lifetime risk, which does not meet professional guidelines for supplementary MRI screening, and no first-degree breast cancer family history, screening MRI utilization was elevated among those with extremely dense breasts [RR 2.2; 95% confidence interval (CI) 1.7-2.8] relative to those with scattered fibroglandular densities and among women with atypia (RR 7.4; 95% CI 3.9-14.3.) or lobular carcinoma in situ (RR 33.1; 95% CI 18.0-60.9) relative to women with non-proliferative disease. Approximately 82.9% (95% CI 80.8%-84.7%) of screening MRIs occurred among women who did not meet professional guidelines and 35.5% (95% CI 33.1-37.9%) among women considered at low-to-average breast cancer risk. Utilization of screening MRI in community settings is not consistent with current professional guidelines and the goal of delivery of high-value care.

Accuracy of self-reported family history of cancer, mutation status and tumor characteristics in patients with early onset breast cancer

Background: The main objectives of this study were to evaluate the concordance between self-reported and registry-reported information regarding family history of breast cancer (BC), ovarian cancer (OvC) and other types of cancer in first-degree relatives of patients with early onset BC, and to determine the frequency of mutation carriers and non-mutation carriers. The secondary objective was to describe tumor characteristics for each mutation group.Material and methods: Between 1993 and 2013, 231 women who were ≤35 years old when diagnosed with BC were registered at the Oncogenetic Clinic at Skåne University Hospital in Lund, Sweden. Self-reported and registry-reported information regarding first-degree family history of cancer was collected together with information regarding tumor characteristics.Results: Almost perfect agreement was observed between self-reported and registry-reported information regarding first-degree family history of BC (κ = 0.92) and OvC (κ = 0.86). Lesser agreement was observed between reports regarding family history of other types of cancer (κ = 0.51). Mutation screening revealed pathogenic germline mutations in 30.4%; 18.8% in BRCA1, 7.1% in BRCA2 and 4.5% in other genes. Compared with other mutation groups, BRCA1 mutation carriers were more likely to be diagnosed with high-grade, ER-, PR- and triple-negative tumors.Conclusions: Our results demonstrate that physicians and genetic counselors can rely on self-reported information regarding BC and OvC in first-degree relatives. However, self-reported information regarding other types of cancer is not communicated as effectively, and there should be more focus on retrieving the correct information regarding family history of all tumor types. Furthermore, we observed that even though all BC patients fulfilled the criteria for genetic counseling and testing, a large number of patients diagnosed at ≤35 years of age did not receive genetic counseling at the Oncogenetic Clinic. This finding merits further elucidation.

Risk Factors for Breast Cancer in Gaza Strip, Palestine: a Case-Control Study.

Breast cancer (BC) is the main common cause of cancer mortality among women in the world. This study aims at investigating BC epidemiology and identifying the different risk factors associated and the most affecting ones among women in the Gaza Strip, Palestine. This study was a hospital-based case-control (1:2), as the study was carried out over the period of October 2014 to February 2015. A total of 105 BC patients, chosen from Al-Shifa Hospital in Gaza City and European hospital for the south governorate, were the case and compared to 209 women as a control group who matched the cases in age, residence, and with no history of breast problems. The age of the enrolled cases and controlled ranged between 18 to 60 years. The face-to-face interview was conducted during the patient visit to the oncology department and the control visit in their home. The result illustrated that women who had late pregnancy (> 35 years) (odds ratio [OR], 11.56; 95% confidence interval [CI], 1.64–81.35), or high body mass index (BMI; ≥ 30 kg/m2) (OR, 4.70; 95% CI, 1.62–13.69), or first-degree family history of BC (OR, 2.7; 95% CI, 1.04–7.20), or hypertensive patients (OR, 12.13; 95% CI, 1.93–76.10), or diabetic (OR, 6.84; 95% CI, 1.77–26.36) were more likely to have increased BC risk. The findings of the present study suggest that positive family history of BC, high BMI, and some common diseases (hypertension, diabetes mellitus) may be the epigenetic factors promoting the occurrence of BC.

Importance of hereditary and selected environmental risk factors in the etiology of inflammatory breast cancer: a case-comparison study.

BackgroundTo assess the importance of heredity in the etiology of inflammatory breast cancer (IBC), we compared IBC patients to several carefully chosen comparison groups with respect to the prevalence of first-degree family history of breast cancer.MethodsIBC cases (n = 141) were compared to non-inflammatory breast cancer cases (n = 178) ascertained through George Washington University (GWU) with respect to the prevalence of first-degree family history of breast cancer and selected environmental/lifestyle risk factors for breast cancer. Similar comparisons were conducted with subjects from three case–control studies: breast cancer cases (n = 1145) and unaffected controls (n = 1142) from the Cancer Genetic Markers of Susceptibility (CGEMS) study, breast cancer cases (n = 465) and controls (n = 9317) from the Women’s Health Initiative (WHI) study, and ovarian cancer cases (n = 260) and controls (n = 331) from a study by University of Toronto (UT).ResultsThe frequency of first-degree breast cancer family history among IBC cases was 17.0 % compared to 24.4 % for GWU breast cancer cases, 23.9 % and 17.9 % for CGEMS breast cancer cases and controls, respectively, 16.9 % and 12.6 % for WHI breast cancer cases and controls, respectively, and 24.2 % and 11.2 % for UT ovarian cancer cases and controls, respectively.IBC cases had a significantly lower prevalence of parous women than WHI breast cancer cases (OR = 0.46, 95 % CI:0.27–0.81) and controls (OR = 0.31, 95 % CI:0.20–0.49). Oral contraceptive use was significantly higher among IBC cases compared to WHI breast cancer cases (OR = 7.77, 95 % CI:4.82–12.59) and controls (OR = 8.14, 95 % CI:5.28–12.61). IBC cases had a significantly higher frequency of regular alcohol consumption (≥1 drink per day) compared to WHI controls (OR = 1.84, 95 % CI:1.20–2.82) and UT controls (OR = 1.86, 95 % CI:1.07–3.22) and higher (statistically non-significant) prevalence (21.3 %) compared to breast cancer cases from GWU (18.2 %) and WHI (15.2 %).ConclusionsThe prevalence of first-degree breast cancer family history among IBC cases was lower compared to breast and ovarian cancer cases but higher than unaffected individuals. Our multiple-case inflammatory and non-inflammatory breast cancer families may reflect aggregation of common genetic and/or environmental factors predisposing to both types of breast cancer. Our findings that oral contraceptive use and regular alcohol consumption may be associated with IBC warrant further investigations.

Mammographic density and breast cancer risk by family history in women of white and Asian ancestry.

Mammographic density, i.e., the radiographic appearance of the breast, is a strong predictor of breast cancer risk. To determine whether the association of breast density with breast cancer is modified by a first-degree family history of breast cancer (FHBC) in women of white and Asian ancestry, we analyzed data from four case-control studies conducted in the USA and Japan. The study population included 1,699 breast cancer cases and 2,422 controls, of whom 45% reported white (N = 1,849) and 40% Asian (N = 1,633) ancestry. To standardize mammographic density assessment, a single observer re-read all mammograms using one type of interactive thresholding software. Logistic regression was applied to estimate odds ratios (OR) while adjusting for confounders. Overall, 496 (12%) of participants reported a FHBC, which was significantly associated with breast cancer risk in the adjusted model (OR 1.51; 95% CI 1.23-1.84). There was a statistically significant interaction on a multiplicative scale between FHBC and continuous percent density (per 10 % density: p = 0.03). The OR per 10% increase in percent density was higher among women with a FHBC (OR 1.30; 95% CI 1.13-1.49) than among those without a FHBC (OR 1.14; 1.09-1.20). This pattern was apparent in whites and Asians. The respective ORs were 1.45 (95% CI 1.17-1.80) versus 1.22 (95% CI 1.14-1.32) in whites, whereas the values in Asians were only 1.24 (95% CI 0.97-1.58) versus 1.09 (95% CI 1.00-1.19). These findings support the hypothesis that women with a FHBC appear to have a higher risk of breast cancer associated with percent mammographic density than women without a FHBC.

Abstract 2597: Identification of new genes for hereditary breast cancer

Abstract Major hereditary breast cancer (BC) genes, BRCA1 and BRCA2, contribute to no more than 20-25% of familial BC clustering; therefore the majority of BC-predisposing mutations remain to be identified. We have selected for the study 95 BC cases, which showed accumulation of clinical signs of the genetic disease (e.g., occurrence of BC among multiple relatives and/or bilaterality and/or young age at onset), but could not be explained either by BRCA1/2 sequence alterations or by Russian founder mutations in CHEK2 (c.1100delC, c.444+1G&amp;gt;A, del5395) or NBN (657del5) genes. The entire coding regions of DNA repair genes were examined using high resolution melting (HRM) analysis and DNA sequencing. Three of 16 genes selected for the study (CHEK2, NBN, PALB2, BRIP1, BARD1, RAD51C, BLM, FANCG, CHEK1, PARP1, PARP2, ERCC1, XPE, BRD7, RNF8, RAD51A) contained potentially deleterious mutations. Two patients carried inactivating lesion in the PALB2 gene (p.R414X and p.Q921X); both these carriers had the bilateral form of BC disease. 1 woman harbored mutation in the FANCG gene (c.520_524delTCTAinsC), which resulted in the loss of serine at position 174 and lysine to glutamine substitution at position 175. The analysis of the BLM gene revealed two heterozygous carriers of the c.1642 C&amp;gt;T (Q548X) allele. This mutation was subjected to the extended study, which confirmed its recurrent character and strong association with BC risk: BLM c.1642 C&amp;gt;T (Q548X) heterozygotes were detected in 17/1,498 (1.1%) BC patients as compared to 2/1,093 (0.2%) healthy females (p = 0.004). As expected for BC-predisposing gene, the BLM 1670 C&amp;gt;T allele tended to be associated with first-degree family history of BC, early onset and bilateral appearance of the disease. This is the first demonstration of the role of the BLM heterozygosity in the determination of BC risk. The impact of constitutional BLM mutations in hereditary cancer predisposition deserves to be tested in other ethnic groups as well as in other tumor types. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2597. doi:1538-7445.AM2012-2597