Breast Cancer Risk Estimation Research Articles

Abstract 1189: Association between female breast cancer period prevalence and residential exposure to environmental hazards at Hermosillo municipality, Sonora, Mexico: A retrospective observational study based on clinical databases from years 2013 to 2019 and INEGI census 2010

Abstract Background: Breast cancer is the leading cause of female cancer-related deaths in Mexico. Breast cancer risk may increase given residential exposure to environmental hazards, such as industrial-produced air pollutants (HAPs), and residual water sites (RWS). Hermosillo is one municipality with high breast cancer prevalence in Sonora, Mexico. However, the association of environmental hazards with breast cancer remains a matter of debate for this community. Objectives: This retrospective observational study aims to evaluate associations between breast cancer period prevalence (years 2013 - 2019) and residential exposure to potentially hazardous sites (PHS) in Hermosillo. Methods: The study collected the data from 912 female breast cancer cases from 6-year old hospital files (2013 to 2019) in Hermosillo. INEGI Census 2010 provided the PHS coordinates, and ArcGIS software (version 10.7.1) projected the data onto a map by conversion to UTM 12 N. Cluster analysis identified regions of high breast cancer period prevalence. Additionally, PHS-proximity is used as a criterion to define subpopulations of interest. The odds ratio (OR) estimated breast cancer risk among the Hermosillo subpopulations to find a difference between them. Age distribution analysis assessed putative residential exposure between PHS-exposed and non-PHS-exposed breast cancer cases. Results: Findings indicate high-high clusters in six neighborhoods across Hermosillo, and from those, three are contiguous. Significant associations with breast cancer risk were the following: residence in highly-industrialized (≥ 7 industries) vs low-industrialized neighborhoods (≤ 6 industries) with an OR = 1.69 (1.41, 2.02) (p-value < 0.0001); residence within ≤ 4 km to gas power plants (GPP) vs those ≥ 4 km (OR = 1.55, (1.36, 1.77)) (p -value < 0.0001); residence within ≤ 3 km to RWS vs residences ≥ 3 km (OR = 1.45, (1.26, 1.66)) (p-value < 0.0001). In comparison to non-PHS-exposed locations, cumulative residential exposure to highly-industrialized neighborhoods within ≤ 4 km to GPP and RWS (PHS-exposed) had an OR = 2.29 (1.80, 2.91) (p-value < 0.0001). Moreover, older breast cancer patients (≥ 58 years old) are in PHS-exposed subpopulation. Conclusions: This study shows a difference in breast cancer prevalence for highly industrialized neighborhoods closer to HAPs' sources (GPP) and RWS. Age distribution showed an older population in the PHS-exposed group. Further studies with larger cohorts are needed to confirm or reject these findings. Citation Format: Diana E. Villa-Guillen, Enrique Avila-Monteverde, Jose H. Gonzalez-Zepeda, Luis F. Munguia-Ibarra, Baldemar Corral-Villegas, Karla Aguilar-Gutierrez, Cynthia Rojas-Camarena, Luis C. Durazo-Cons, Carlos D. Luque-Morales, Wendy B. Aguilar-Peraza, Jorge A. Cordon-Guillen, Leticia Garcia-Rico, Martin Jara-Marini, Ana I. Valenzuela-Quintanar, Graciela Caire-Juvera, Ivan Anduro-Corona, Eduardo Ruiz-Bustos, Jorge A. Villa-Carrillo. Association between female breast cancer period prevalence and residential exposure to environmental hazards at Hermosillo municipality, Sonora, Mexico: A retrospective observational study based on clinical databases from years 2013 to 2019 and INEGI census 2010 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1189.

Abstract 4613: Cross-ancestry genome-wide association study identifies six new loci for breast cancer in women of African and european ancestry

Abstract Background: Over 180 genetic variants have been identified as risk loci for breast cancer. However, most loci were discovered using European ancestry populations. As some common susceptibility loci are shared across populations, we aim to discover new risk loci for breast cancer using a cross-ancestry genome-wide association study (GWAS) approach. Methods: Data from five GWAS studies in women of African ancestry with a combined sample size of 9241 cases and 10192 controls were used to generate pooled breast cancer risk estimates in a fixed effect meta-analysis, and this served as the discovery dataset. Summary statistics from the GWAS conducted in European ancestry populations (Breast Cancer Association Consortium, 122977 cases and 105974 controls) served as the validation dataset. The variants that were associated with breast cancer risk at P < 0.01 in the GWAS of African ancestry were meta-analyzed with the GWAS in European ancestry. A locus was considered novel if the lead index variant was genome-wide significant (5 × 10−8) in the cross-ancestry meta-analysis and >500kb away from known breast cancer risk loci. Conditional on the lead index variants, we searched for additional signals in each locus using multivariable logistic regression. Analyses were done separately for ER-positive, ER-negative and overall breast cancer risk. Results: We discovered four novel loci for overall breast cancer risk (1p13.3, 5q31.1, 15q24, and 15q26.3) and two novel loci for ER-negative breast cancer (1q41 and 7q11.23) at the genome-wide significance level of P < 5 × 10−8. Three index single nucleotide polymorphism (SNPs) lie within introns of genes (KCNK2, C5orf56, and SIN3A) and the other index SNPs are located in intergenic regions (close to GSTM4 and AMPD2, CASTOR2, and the antisense DNA RP11-168G16.2). The direction of the associations was consistent between the GWASs of African and European descendants. At the 15q24 locus, we found an additional SNP (in the intron of the SCAMP2 gene) to be independently associated with overall breast cancer risk. Conclusions: We have identified six new risk loci that may contribute to better prediction of breast cancer risk in African ancestry populations and provide new insights into mechanisms of breast cancer carcinogenesis. Replication of these loci in multiple populations and functional studies can help to identify causal variants. Citation Format: Babatunde Adedokun, Zhaohui Du, Guimin Gao, Thomas Ahearn, Kathryn L. Lunetta, Gary Zirpoli, Jonine Figueroa, Esther M. John, Leslie Bernstein, Wei Zheng, Jennifer J. Hu, Regina G. Ziegler, Sarah Nyante, Elisa V. Bandera, Sue A. Ingles, Michael F. Press, Sandra L. Deming, Jorge L. Rodriguez-Gil, Song Yao, Temidayo O. Ogundiran, Oladosu Ojengbede, William Blot, Melissa Troester, Katherine L. Nathanson, Anselm Hennis, Barbara Nemesure, Stefan Ambs, Lara E. Sucheston-Campbell, Jeannette T. Bensen, Stephen J. Chanock, Andrew F. Olshan, Christine B. Ambrosone, David V. Conti, Olufunmilayo I. Olopade, Montserrat Garcia-Closas, Julie R. Palmer, Christopher A. Haiman, Dezheng Huo. Cross-ancestry genome-wide association study identifies six new loci for breast cancer in women of African and european ancestry [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4613.

Robust Estimation of Breast Cancer Incidence Risk in Presence of Incomplete or Inaccurate Information.

Purpose:To evaluate the robustness of multiple machine learning classifiers for breast cancer risk estimation in the presence of incomplete or inaccurate information. Data and methods:Open data for this study was obtained from the BCSC Data Resource (http://breastscreening.cancer.gov/). We conducted two ablation-type experiments to compare the robustness of different classifiers where we randomly switched known information to missing with a missing probability of pm in one experiment, and randomly corrupted the existing information with a probability of pc in another experiment. We considered three prominent machine-learning classifiers such as Logistic regression (LR), Random Forests (RF) and a custom Neural Network (NN) architecture and compared their degradation of discrimination performance as a function of increasing probability of missing or inaccurate data. Results:LR, RF and custom NN resulted in an Area Under Curve (AUC) of 0.645, 0.643 and 0.649, respectively, on a test set with 500,000 total observations. When we manipulated the data by varying probabilities pm and pc from 0 to 1, NN resulted in better performance in terms of AUC compared to RF and LR as long as less than half the data was missing/inaccurate (that is, for values of pm < 0.5 and pc < 0.5). However, for missing (pm) or corruption (pc) probabilities above 0.5, LR gave similar performance as the custom NN. RF resulted in overall poorer performance when the data had additional missing or incorrect entries. Conclusion:In cases where the input information is missing or inaccurate, our experiments show that the proposed custom NN provides reliable risk estimates in medical datasets like BCSC. These results are particularly important in health care applications where not every attribute of the individual participant might be available.

Breast cancer risk after hysterectomy with and without salpingo-oophorectomy for benign indications

Breast cancer risk has been extensively studied in women with genetic predisposition, that is, mutations in breast cancer genes 1 and 2. Although there are guidelines for performing bilateral salpingo-oophorectomies in individuals with specific genetic risks, oophorectomies are also performed in many women considered to be at average risk of developing breast cancer. The risk of breast cancer in women with average risk who undergo hysterectomy with bilateral salpingo-oophorectomy for benign indications is less clear. This study aimed to estimate breast cancer risk after hysterectomy with and without concomitant bilateral salpingo-oophorectomy for benign indications. From 2001 to 2015, women aged 18 years and older from Kaiser Permanente Northern California who underwent hysterectomy alone and hysterectomy with bilateral salpingo-oophorectomy were identified using the International Classification of Diseases, Ninth Revision, procedure and Current Procedural Terminology codes. Women with a breast cancer gene mutation and previous history of breast cancer or gynecologic cancer were excluded. Descriptive and bivariate analyses were used to describe and compare demographic and clinical characteristics. Breast cancer incidence rates were calculated per 100,000 person-years. Survival analysis and Cox proportional hazard models were conducted to compare the risk of developing breast cancer. Of 49,215 women who underwent hysterectomy, 19,826 had hysterectomy with bilateral salpingo-oophorectomy. Whites, Hispanics, blacks, Asians, and other or unknown comprised 51.2%, 20.3%, 12.7%, 10.4%, and 5.3% of the study population, respectively. The average age of women with hysterectomy alone was 45.5 years compared with 50.8 years for those who had hysterectomy with bilateral salpingo-oophorectomy. During the study period, 915 women received a diagnosis of breast cancer. Age-specific breast cancer incidence rates were higher in women older than 60 years with oophorectomy than hysterectomy alone (471.2 [95% confidence interval, 386.2-556.2] vs 463.0 [95% confidence interval, 349.6-576.5], respectively). After controlling for age, race, income, and Charlson Comorbidity Index, women with bilateral salpingo-oophorectomy had a 14% lower risk of breast cancer than women with hysterectomy alone (hazard ratio, 0.86; 95% confidence interval, 0.75-0.98). All-cause mortality was higher with oophorectomy than hysterectomy alone (64.4% vs 35.6%, P<.0001, respectively). Women with concurrent bilateral salpingo-oophorectomy for benign indications had a lower risk of breast cancer than those who had hysterectomy alone. However, all-cause mortality was higher in women with oophorectomy. Perimenopausal patients undergoing hysterectomy for benign indications should be counseled on the risks and benefits of oophorectomy at the time of surgery.

Primary Care Providers Underutilize Breast Screening MRI for High-Risk Women

ObjectiveSupplemental MRI screening for women at high risk for breast cancer is underutilized. Our study assessed how primary care providers in our healthcare network identify high-risk women and recommend high-risk screening breast MRI. MethodsAn electronic survey was distributed to providers in OB/GYN, family, and internal medicine departments between 1/14/19 and 3/22/19. The survey inquired about methods used to assess breast cancer risk, familiarity with the American Cancer Society's definition of high-risk, and whether screening breast MRI is recommended for high-risk women. ResultsResponse rate was 17% (89/524). After excluding providers who ordered ≤10 mammograms per year, the study included 75 respondents, who mostly ordered 10-1000 mammograms per year and supported annual/biennial screening mammogram starting at age 40-50 years. More providers reported estimating breast cancer risk qualitatively (with family, clinical history, and/or breast density) than quantitatively with risk calculators (73/75, 97% vs 22/75, 29%). A minority of providers (23/75, 31%) correctly defined high lifetime risk. Only 9/75 (12%) providers recommended screening MRI for high-risk women. Use of quantitative risk calculators or ability to correctly define high-risk were not associated with likelihood of recommending MRI screening. More providers had recommended MRI for screening in the setting of dense breasts than for high-risk screening (23/75, 31% vs 9/75, 12%). ConclusionPrimary care providers at our institution did not routinely recommend screening MRI for high-risk women. Risk assessment and reporting at the time of mammography may improve MRI utilization and is an opportunity for radiologists to add value and directly participate in patient-centered care.

Impact of Age, Race, and Socioeconomic Status on Women's Perceptions and Preferences Regarding Communication of Estimated Breast Cancer Risk

Performing breast cancer risk assessment at the time of screening mammography has potential to increase high-risk identification, appropriate supplemental screening, and risk management. The study's goal is to investigate women's interest in risk assessment and preferred method of risk communication in a diverse patient population. Surveys in English and five non-English languages were distributed to women presenting for screening mammography at eight screening mammography facilities between February and May 2019 to assess their interest in risk assessment, preferred method, and level of detail of estimated risk communication in hypothetical scenarios where estimated risks are average and elevated. Among 683 survey respondents, 592 (87%) expressed interest in learning about their estimated lifetime risk of breast cancer. Controlling for age, race/ethnicity, and education, women with higher income were more interested in risk assessment than comparison group (p<0.05). The most preferred method of average risk communication was by a mailed letter accompanying mammographic results (57%), but more women exclusively preferred face-to-face communications of elevated risk than of average risk estimate (191, 28% vs. 128, 19%, p<0.0001). Phone communication was more preferred by younger women, electronic communication was less preferred by older women and those with lower income, and non-Hispanic blacks and older women preferred less detailed communication (p<0.05). Sociodemographic factors influence women's interest in risk assessment and preference in risk communication about breast cancer. Screening Mammogram facilities implementing risk assessment should consider risk communication strategies that are most effective for their patient population.

Investigating the Link between Lynch Syndrome and Breast Cancer.

Lynch syndrome is an inherited genetic disorder associated with a predisposition to early-onset colorectal and endometrial cancers, but breast cancer risk in these patients is debated. The aim of this study is to evaluate breast cancer rates in a cohort of Lynch syndrome patients, as well as to identify women who may be eligible for additional breast cancer specific genetic testing or enhanced breast surveillance (contrast-enhanced magnetic resonance imaging (MRI) screening). Using a hereditary colorectal cancer registry at a single academic institution for identification of patients with Lynch syndrome, a retrospective chart review was performed of 188 women with DNA mismatch repair (MMR) mutations. The Tyrer-Cuzick model was used to estimate breast cancer risk in patients without breast cancer. The prevalence of breast cancer differed based on mutation type (p=0.0043), as 27% of women with a PMS2 mutation were diagnosed with breast cancer, compared to 3%, 4%, and 9% in MLH1, MSH2, and MSH6 patients. The average age at diagnosis for women with a PMS2 mutation was 46.7 years. Additionally, 7.5% of unaffected women had an estimated lifetime risk of breast cancer greater than 20%. 46/188 (24.4%) of patients were eligible for breast specific genetic testing. Our analysis suggests that Lynch syndrome patients with PMS2 mutations may be at higher risk of developing breast cancer. Additionally, the personal and family history of cancer suggests crossover in eligibility for breast specific genetic testing in a significant number of patients (16.5-24.4%). Also, many women are eligible for enhanced breast surveillance (7.5%) which would otherwise not be offered.

Inorganic arsenic methylation capacity and breast cancer by immunohistochemical subtypes in northern Mexican women

BackgroundPreviously we reported that inorganic arsenic (iAs) methylation capacity was associated with breast cancer (BC). BC risk factors may vary according to immunohistochemical subtype. Here we explored the relationships between the capacity to methylate iAs and the risk of BC by subtype. MethodsA population-based case-control study was performed in northern Mexico. Patients with available information about BC subtypes (n = 499) were age-matched with healthy controls. Sociodemographic, reproductive, and lifestyle characteristics were obtained. Tumor marker information was obtained from medical records. Cases were classified as HR+ [estrogen receptor (ER+) and/or progesterone (PR+), and human epidermal growth factor receptor 2 (HER2-)], HER2+, or triple negative (TN). Urinary arsenic species were determined by high performance liquid chromatography inductively coupled plasma mass spectrometry (HPLC-ICP-MS), and methylation capacity parameters calculated. Conditional logistic regression models were used to estimate BC risk by subtypes. ResultsUrinary total arsenic varied from 0.60 to 303.29 μg/L. A significant positive association was found between % monomethylarsonic acid (%MMA) and HR + BC: one percent increase resulted in OR%MMA continuous = 2.73, 95% CI: 1.48, 5.05), and this association remained even when %iAs or % dimethylarsinic acid (%DMA) were added to the models with %MMA. MMA/iAs was positively associated with HR + BC (ORMMA/iAs continuous = 2.03, 95% CI: 1.33–3.10). A significant negative association was observed between DMA/MMA and HR + BC (ORDMA/MMA continuous = 0.43, 95% CI: 0.26, 0.71). MMA/iAs was positively associated with TN BC (OR MMA/iAs continuous = 4.05; 95% CI: 1.63, 10.04). ConclusionAltered iAs methylation capacity resulting in higher %MMA was associated with HR+ and TN BC but not with HER2+. MMA is the iAs metabolite more likely to be related to BC. Further research is needed to confirm these results and elucidate the underlying biological mechanisms.

Abstract P5-07-06: Performance of a polygenic risk score combined with clinical assessment for breast cancer risk

Abstract Background: Polygenic risk scores (PRS) based on a large number of SNPs associated with breast cancer have recently been made available in combination with multigene panel testing for clinical management of breast cancer risk. Breast cancer risk assessment has historically been performed using various non-genetic risk models, which predict lifetime risk of breast cancer in unaffected women based on personal and family history information. While clinical use of PRS in combination with these models continues to increase, the predictive performance of a PRS combined with clinical information in real-world patient populations has not been thoroughly investigated. Methods: We assessed a 100-SNP breast cancer PRS in combination with the Tyrer-Cuzick model-estimated lifetime breast cancer risk in 5,374 Caucasian women from the case-control Mayo Clinic Breast Cancer Study (MCBCS), comprised of 3,373 breast cancer cases and 2,001 unaffected controls seen at Mayo Clinic from 2004 to 2016. Clinical, family history, and demographic information was collected on all MCBCS participants via questionnaires and medical record review. SNPs were selected for the PRS if they exceeded genome-wide significance in ≥2 large-scale breast cancer genome wide association studies (GWAS) in women of European descent. Selected SNPs were then used to construct a population standardized PRS, accounting for per-allele odds ratios reported in the largest GWAS to date and population-specific allele frequencies. PRS and Tyrer-Cuzick model associations with breast cancer and related clinical features were tested using multivariate logistic regression. Results: Among cases and controls, mean±SD age at diagnosis and study enrollment was 56.4±12.4 and 56.2±14.1, respectively. Approximately 36.9% of cases and 16.9% of controls had ≥1 first- or second-degree relative with breast or ovarian cancer, respectively. Among unaffected women, the median (IQR) estimated lifetime risk of breast cancer to age 85 based on Tyrer-Cuzick alone was 8.3% (6.9%), and 2.6% had a clinically actionable lifetime risk of ≥20%. The mean±SD sum of the risk alleles across 100 SNPs was significantly higher for cases vs. controls (94.8±6.3 vs. 92.7±6.2, p&amp;lt;0.001). Compared to women in the lowest quartile of PRS, those in the 2nd, 3rd and 4th quartiles were 1.47 (95% CI: 1.26-1.72), 1.87 (95% CI: 1.60-2.19), and 2.22 (95% CI: 1.89-2.61) times more likely to have breast cancer after adjustment for age and family history. The AUC was 0.59 (95% CI: 0.58-0.61) for PRS and 0.60 (95% CI: 0.58-0.61) for Tyrer-Cuzick model estimated risk alone; but when combined, the model achieved an AUC of 0.63 (95% CI: 0.62-0.65). Among unaffected women, 6.7% had ≥20% lifetime risk of breast cancer based on the combined PRS-clinical model. Conclusions: These findings suggest that the 100-SNP PRS significantly improves estimation of breast cancer risk based on non-genetic models, and can be used to further identify women at increased lifetime risk who would otherwise not be identified by clinical assessment alone. Citation Format: Mary Helen Black, Shuwei Li, Holly LaDuca, Sebastian Armasu, Eric C. Polley, Patrick Fitz-Gibbon, Chris G. Scott, Stacey J. Winham, Janet E. Olson, Kathryn J. Ruddy, Celine M. Vachon, Fergus J. Couch. Performance of a polygenic risk score combined with clinical assessment for breast cancer risk [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-07-06.

Abstract OT3-15-01: Pilot of lifestyle InterventiON to reducE brEast cancer Risk (PIONEER): A randomised study

Abstract Background: Breast cancer causes more deaths than any other medical condition in women aged 30-50 years in the UK. Around 23% of breast cancers are preventable, yet many women are unaware of the modifiable risk factors. Risk factors for breast cancer can be broadly divided into fixed: family history of breast cancer and genetic factors, mammographic breast density, benign proliferative breast disease, hormonal and reproductive risk factors, and modifiable lifestyle factors such as increased weight, decreased physical activity and alcohol consumption. The latter are the focus of this study. Trial Design In this feasibility study women who have attended a symptomatic clinic and do not have cancer will be randomised into three intervention arms (see below) with a further 2-way randomisation to single-nucleotide polymorphism (SNP) testing (or not). All women will be told their estimated breast cancer risk as calculated by the Tyrer-Cuzick model. Women will be asked to set goals related to behaviour change. The primary end point is whether these goals have been met. Goal setting, information and changes are mapped to the Behaviour Change Wheel model. Eligibility criteria FemaleAge 30 - 60 yearsAttending the symptomatic breast clinic at our facilityBenign or normal diagnosisAgree to receive their personalised breast cancer riskAvailable to participate in a 1 year risk reduction programme NOTE: after risk assessment, women with a less than population risk of breast cancer will be excluded from participating in the behavioural change elements. Specific aims To assess which of the interventions is most suitable to take forward into a large-scale study based on acceptability, impact on behaviour and scalability. This will give useful guidance to the future development of a national study with the aim of a meaningful reduction in breast cancer risk. Trial arms Standard breast cancer risk information book (control)Website with information and bespoke goal-setting exerciseWebsite as above + group coaching Standard breast cancer risk information book (control) Website with information and bespoke goal-setting exercise Website as above + group coaching 2-way randomisation to SNP testing or not for each arm, hence 6 possibilities Statistical methods Population: 240 participants who were randomised and did not withdraw following their randomisation allocation (per-protocol analysis). The reason is in this feasibility study we are most interested in the effect of different interventions on those who actually participate in the study. Secondary analyses will include an intention-to-treat basis using everyone randomised. Exploratory analyses to adjust for non-compliance will also be undertaken. Comparisons The main comparisons of interest are between the control and intervention arms, in particular the proportion achieving their goal. Mean change in weight, alcohol intake and physical activity will also be assessed. Further comparisons will be by SNP testing group. Secondary comparisons are as follows: Acceptability of study - proportion of women approached who consentAcceptability of randomisation - proportion of women who withdraw after randomisationImpact of SNP testing - mean change and proportion of women who achieve goal in the SNP testing and no SNP testing groupsEfficacy - mean change in each modifiable risk factor in each of the intervention groupsCancer-related anxiety - mean change in score for cancer anxiety at 12 months by SNP testing and intervention group and correlation between initial score and change in risk-factorsRetention - proportion of women who complete their end of study questionnaire, according to study groupChemoprevention - proportion of women in the high and moderate risk groups taking endocrine therapy at one year according to study groupScalability - estimate of cost per participant Accrual None to date. Recruitment of 240 women will start in September 2019. Contact Pioneer.study@nhs.net Citation Format: Rebekah SL Law, Carol Pitches, Katherine Krupa, Adam Brentnall, Jennifer Rusby. Pilot of lifestyle InterventiON to reducE brEast cancer Risk (PIONEER): A randomised study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT3-15-01.

Abstract PD3-01: Population-based breast cancer risk estimates for predisposition gene mutations: Results from the CARRIERS study

Abstract Germline mutations in several cancer predisposition genes included in hereditary multigene testing panels have been associated with increased breast cancer risk. However, estimates of breast cancer risks for each gene have in large part been derived from studies of high-risk populations enriched for family history of breast and ovarian cancer, young age of breast cancer diagnosis, or founder mutations. The breast cancer risks associated with mutations in many of these genes in the general population remain to be clearly defined. As clinical hereditary cancer genetic testing is already provided to many women at increased risk and may soon be offered to all breast cancer patients, population-based risk estimates associated with predisposition gene mutations will be needed for appropriate clinical management of mutation carriers. The “CAnceR RIsk Estimates Related to Susceptibility” (CARRIERS) consortium of 17 cohort-based case-control, population-based case-control, and family studies focused on estimation of population-based breast cancer risks and penetrance analysis for mutations in known and candidate breast cancer predisposition genes. Germline DNA from 39486 breast cancer cases and 35868 matched controls was subjected to dual bar-coded QIAseq multiplex amplification of 1733 target regions in 37 predisposition genes. Products from sets of 768 samples were pooled and sequenced in each lane of a HiSeq 4000 system. Mutations were called by GATK Haplotype Caller and Verdict. High quality sequence data was obtained for 99.3% of target regions. Here we report on results from 34741 population-based breast cancer cases and 32728 matched unaffected controls. The mean age of breast cancer diagnosis for cases was 61.2 years and mean age for controls was 61.1 years. Overall, 20.9% of cases and 14.3% of controls had a family history of breast cancer. Furthermore, 74.3% of cases and 75.8% of controls were non-Hispanic white, whereas 13.3% of cases and 15.3% of controls were African American. Among cases with tumor information available, 81.7% were ER-positive and 7.7% were triple negative breast cancers (TNBC). We assessed mutation frequencies in 24 genes including 12 established breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, RAD51C, RAD51D, andTP53). The overall mutation frequency was 6.2% in cases and 2.7% in controls. Case-control association analysis after adjusting for study, age, family history of breast cancer, and race/ethnicity showed that BRCA1(OR=7.45; 95%CI:5.24-10.95) and BRCA2(OR=5.31; 95%CI:4.15-6.88) were associated with high risks of breast cancer in the general population. However, PALB2mutations were only associated with moderate risks (OR=3.63; 95%CI:2.57-5.26). ATMmutations conferred attenuated risks (OR=1.83; 95%CI:1.47-2.28) relative to studies of high-risk families or young onset breast cancers. NBNmutations were not associated with increased breast cancer risk. Mutations in BARD1, RAD51C, RAD51Dand XRCC2were specifically significantly associated with moderate risks of ER-negative breast cancer and TNBC, whereas mutations in ATM, CDH1and CHEK2were specifically significantly associated with ER-positive disease. On the basis of these findings age-related absolute breast cancer risks for commonly mutated genes were estimated. Overall, results from the CARRIERS study establish that mutations in predisposition genes are associated with lower risks of breast cancer in the general population than in enriched populations including high-risk families and young onset, bilateral, or multiple primary cases. We anticipate that the results from this study will inform cancer screening and other risk management strategies for women in the general population with mutations in predisposition genes. Citation Format: Fergus J Couch, Chunling Hu, Steven N Hart, Rohan Gnanaolivu, Kun Y Lee, Jie Na, Chi Gao, Nicholas J Boddicker, Bruce Eckloff, Raed Samara, Josh Klebba, Christine B Ambrosone, Hoda Anton-Culver, Paul Auer, Leslie Bernstein, Mia M Gaudet, Christopher Haiman, Esther M John, Susan Neuhausen, Janet E Olson, Tuya Pal, Julie R Palmer, Dale P Sandler, Jack A Taylor, Amy Trentham-Dietz, Celine M Vachon, Clarice Weinberg, Song Yao, Jeffrey N Weitzel, David E Goldgar, Susan M Domchek, Katherine L Nathanson, Peter Kraft, Eric C Polley. Population-based breast cancer risk estimates for predisposition gene mutations: Results from the CARRIERS study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD3-01.

Abstract PD3-02: Polygenic risk scores provide clinically meaningful risk stratification among women carrying moderate penetrance pathogenic variants in breast cancer predisposition genes: Results from the CARRIERS study

Abstract Background: Pathogenic variants detected in multi-gene cancer predisposition panels are increasingly used to counsel women regarding their risk for breast cancer. However, the clinical implications of moderate penetrance genes (e.g. CHEK2, ATM) remain unclear. Breast MRI is indicated for women with a lifetime risk of breast cancer of &amp;gt;20%, and polygenic risk scores (PRS) based on common variants discovered in recent genome-wide association studies (GWAS) may identify women with pathogenic variants in CHEK2 and ATM who are above or below this level of risk. PRS may also stratify carriers with substantially elevated lifetime risks of breast cancer. Previous work found that PRS modified breast cancer risk in carriers of pathogenic variant in BRCA1 or BRCA2, but the joint effects of pathogenic variants and PRS have not been studied in samples drawn from the general population. There is also no published study evaluating the effect of PRS among women with pathogenic variants in genes other than BRCA1/2 and CHEK2. Here, we evaluated the joint effects of PRS and pathogenic variants in ten established breast cancer predisposition genes in a population-based case-control sample. Method: We analyzed 43,144 non-Hispanic European-ancestry individuals (20,988 controls and 22,120 cases) drawn from 7 cohorts and 2 population-based case-control studies in the CAnceR RIsk Estimates Related to Susceptibility” (CARRIERS) consortium. Targeted sequencing was performed using a dual bar-coded QIAseq panel of breast cancer predisposition genes. Variant calling was conducted with Haplotype Caller and Vardict. The PRS was calculated based on 106 common variants using effect estimates from the largest published breast cancer GWAS. Genetic status was evaluated for 10 breast cancer predisposition genes: ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, NF1, PALB2 and TP53. Lasso Penalized regression was performed to assess the combined effect on overall breast cancer of pathogenic variants and common variants (including main and interaction effects between age, family history, carrier status and PRS). The fraction of women at &amp;gt;2-fold increased risk (which is associated with approximately 20% lifetime risk of breast cancer) was calculated for pathogenic variant carriers and non-carriers of different family history and age groups (&amp;lt;40, 40-50, 50-60, 60-70, &amp;gt;70yrs old). Results: Among non-carriers, one standard deviation change in the PRS was associated with a 1.63x change in odds of breast cancer. The best-fitting risk model did not include any PRS-by-carrier interaction terms, implying the relative risk gradient associated with PRS among women with pathogenic variants is similar to that among non-carriers. For carriers of pathogenic variants in moderate penetrance genes with no family history of breast cancer, the PRS can identify 60.6% of ATM pathogenic variant carriers and 30% of CHEK2 pathogenic variant carriers that have less than 2-fold risk of breast cancer; when carriers have a family history of breast cancer, the PRS can identify 30% of ATM pathogenic variant carriers and 11.8% of CHEK2 pathogenic variant carriers with less than 2-fold risk of breast cancer. Conclusion: In our large, population-based case-control study, the effect of the PRS among pathogenic variant carriers was not significantly different than among non-carriers. However, the PRS may be particularly important for estimating breast cancer risk among carriers of pathogenic variants in moderate penetrance genes such as CHEK2 and ATM, enabling a more precise approach for MRI screening strategy and breast cancer risk management. Citation Format: Chi Gao, Eric C. Polley, Chunling Hu, Steven N. Hart, Rohan Gnanaolivu, Kun Y. Lee, Jie Na, Nicholas J. Boddicker, Raed Samara, Paul Auer, Leslie Bernstein, Mia Gaudet, Amy Trentham-Dietz, Song Yao, Christopher Haiman, Janet E. Olson, Susan Neuhausen, Jeffrey N. Weitzel, David E. Goldgar, Susan Domchek, Katherine L. Nathanson, Fergus J. Couch, Peter Kraft, on behalf of the CARRIERS consortium. Polygenic risk scores provide clinically meaningful risk stratification among women carrying moderate penetrance pathogenic variants in breast cancer predisposition genes: Results from the CARRIERS study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD3-02.

Levonorgestrel-releasing intrauterine system and breast cancer risk: A systematic review and meta-analysis.

Epidemiological studies have shown that some hormonal contraceptive methods are associated with increased breast cancer risk, especially if used over long periods. Our objective was to conduct a systematic review and meta-analysis of the literature on the risk of breast cancer development in women using the 52-mg levonorgestrel-releasing intrauterine system (LNG-IUS). We performed a thorough review of peer-reviewed publications from 10 January 1999, through 31 July 2019, using combinations of search terms for breast cancer risk and LNG-IUS in the Medline, EMBASE, LILACS (Latin American and Caribbean Health Sciences Literature), and Scielo databases. This review was registered in PROSPERO (CRD42017059076). Studies reporting breast cancer risk estimates among healthy users of LNG-IUS were included according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analysis) criteria. Two authors performed data extraction, and a third author resolved disagreements. The quality of evidence was evaluated using the Downs and Black instrument. A funnel plot was generated, and a linear regression test of funnel plot asymmetry was used to assess publication bias. Finally, we performed a random-effects model (owing to high study heterogeneity) meta-analysis of seven suitable studies, stratified by the age distribution of patients (<50years, ≥50years, and mixed). We identified 96 studies and manually cross-referenced and excluded duplicate articles. Seventy articles were excluded on the basis of the inclusion and exclusion criteria, resulting in the assessment of 26 full-text articles. Eight articles were considered adequate for inclusion in this systematic review, and seven studies were included in the meta-analysis. Three publications were case-control studies and five were cohort studies. According to the Downs and Black instrument, 5 studies were rated as "good" and 3 studies were deemed "fair". Our meta-analysis results indicated increased breast cancer risk in LNG-IUS users: for all women, odds ratio (OR)=1.16 (95% CI 1.06-1.28, I2 =78%, P<.01); for women aged <50years, OR=1.12 (95% CI 1.02-1.22, I2 =66%, P=.02); and for women aged ≥50years, OR=1.52 (95% CI 1.34-1.72, I2 =0%, P=.84). Current evidence suggests that LNG-IUS users have an increased breast cancer risk regardless of age and indication. The effect of LNG-IUS on breast cancer risk seems to be larger in older users. However, our systematic review detected methodological issues across the available studies, and confounding factors may be responsible for at least a fraction of the risk effects associated with LNG-IUS use. Nevertheless, users of LNG-IUS should be aware of these trends. We believe that caution is needed, and risks should be balanced against proven health benefits (eg effective treatment of heavy menstrual bleeding and avoidance of surgical interventions), when prescribing LNG-IUS for long periods of use, especially in women with other known breast cancer risk factors such as old age, obesity, and familial predisposition.

Protons Show Greater Relative Biological Effectiveness for Mammary Tumorigenesis with Higher ERα- and HER2-Positive Tumors Relative to γ-rays in APCMin/+ Mice

Exposure to ionizing radiation increases risk of breast cancer. Although proton radiation is encountered in outer space and in medicine, we do not fully understand breast cancer risks from protons owing to limited invivo data. The purpose of this study was to comparatively assess the effects of γ-rays and protons on mammary tumorigenesis in APCMin/+ mice. Female APCMin/+ mice were exposed to 1 GeV protons (1.88 or 4.71 Gy) and 137Cs γ-rays (2 or 5 Gy). Mice were euthanized 100 to 110 days after irradiation, at which point mammary tumors were scored, tumor grades were assessed, and relative biological effectiveness was calculated. Molecular phenotypes were determined by assessing estrogen receptor α (ERα) and human epidermal growth factor receptor 2 (HER2) status. ERα downstream signaling was assessed by immunohistochemistry. Exposure to proton radiation led to increased mammary tumor frequency at both proton radiation doses compared with γ-rays. The calculated relative biological effectiveness for proton radiation-induced mammary tumorigenesis was 3.11 for all tumors and >5 for malignant tumors relative to γ-rays. Tumor frequency per unit of radiation was higher at the lower dose, suggesting a saturation effect at the higher dose. Protons induced more adenocarcinomas relative to γ-rays, and proton-induced tumors show greater ERα and HER2 positivity and higher activation of the ERα downstream PI3K/Akt and cyclin D1 pathways relative to γ-rays. Our data demonstrate that protons pose a higher risk of mammary tumorigenesis relative to γ-rays. We also show that proton radiation-induced tumors in APCMin/+ mice are ERα- and HER2-positive, which is consistent with our previous data on radiation-induced estrogenic response in wild-type mice. Although this study establishes APCMin/+ as a model with adequate signal-to-noise ratio for space radiation-induced mammary tumorigenesis, further studies will be required to address the uncertainties in space radiation-induced breast cancer risk estimation.

&lt;p&gt;Do Preferred Risk Formats Lead to Better Understanding? A Multicenter Controlled Trial on Communicating Familial Breast Cancer Risks Using Different Risk Formats&lt;/p&gt;

PurposeCounselees’ preferences are considered important for the choice of risk communication format and for improving patient-centered care. We here report on counselees’ preferences for how risks are presented in familial breast cancer counseling and the impact of this preferred format on their understanding of risk.Patients and MethodsAs part of a practice-based randomized controlled trial, 326 unaffected women with a family history of breast cancer received their lifetime risk in one of five presentation formats after standard genetic counseling in three Dutch familial cancer clinics: 1) in percentages, 2) in frequencies (“X out of 100”), 3) in frequencies plus graphical format (10×10 human icons), 4) in frequencies and 10-year age-related risk and 5) in frequencies and 10-year age-related risk plus graphical format. Format preferences and risk understanding (accuracy) were assessed at 2-week follow-up by a questionnaire, completed by 279/326 women.ResultsThe most preferred risk communication formats were numbers combined with verbal descriptions (37%) and numbers only (26%). Of the numerical formats, most (55%) women preferred percentages. The majority (73%) preferred to be informed about both lifetime and 10-year age-related risk. Women who had received a graphical display were more likely to choose a graphical display as their preferred format. There was no significant effect between the intervention groups with regard to risk accuracy. Overall, women given risk estimates in their preferred format had a slightly better understanding of risk.ConclusionThe results suggest that the accuracy of breast cancer risk estimation is slightly better for women who had received this information in their preferred format, but the risk format used had no effect on women’s risk accuracy. To meet the most frequent preference, counselors should consider providing a time frame of reference (eg, risk in the next 10 years) in a numerical format, in addition to lifetime risk.

Cancer Risks Associated With Germline PALB2 Pathogenic Variants: An International Study of 524 Families.

To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized. We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes. We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10-76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10-3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10-3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 × 10-2). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age (P for trend = 2.0 × 10-3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies (P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer. These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.

Female breast cancer risk in Bryansk Oblast, Russia, following prolonged low dose rate exposure to radiation from the Chernobyl power station accident.

Ionizing radiation is a known cause of female breast cancer, but there have been few studies of the risk after prolonged radiation exposure at low dose rates. This population-based case-control study estimated breast cancer risk after ∼25 years' exposure to radiation from the Chernobyl accident. Cases (n = 468) were women ≤55 years old when first diagnosed with invasive breast cancer during October 2008 through February 2013, who lived in Bryansk Oblast, Russia at the time of the accident and their diagnoses. Controls, individually matched to cases on birth year, administrative district of residence and urban vs non-urban settlement during the accident, were women without breast cancer who lived in Bryansk Oblast at the time of the accident and on their cases' diagnosis dates (n = 468). Subjects were interviewed regarding residence, dietary and food source histories to support individualized estimation of their radiation doses to the breast, which ranged from 0.04 - 41 centigray (cGy) (mean 1.3 cGy). In multivariable analyses, the odds ratio for breast cancer risk was 3.0 [95% confidence interval (CI): 1.3, 7.0] and 2.7 (95% CI: 1.0, 7.3) in the seventh and eighth dose octiles, respectively, relative to the lowest octile. Analyses of dose effect modification suggested that radiation-related risk may have been higher in women who were younger at the time of the accident and/or at the time of diagnosis. This study suggests that prolonged exposure to ionizing radiation at low dose rates can increase risk of breast cancer.

The impact of left truncation of exposure information in environmental case-control studies

TPS 691: Methods of measurement, design and data analysis, Exhibition Hall, Ground floor, August 28, 2019, 3:00 PM - 4:30 PM BACGROUND/AIM: Left truncation of exposure data may bias estimates of exposure effects in epidemiological studies. However its impact in environmental epidemiology settings is lacking. We analyzed the bias introduced by left truncation of exposure data on the estimation of breast cancer risk associated with environmental pollution. METHODS: A simulation study was conducted according to the characteristics of exposure data from the E3N cohort study, as well as the current evidence of pollutants effect models. Two hypotheses of historical exposure emissions, two scenarios of exposure distribution and three effect models were assumed. Each was simulated 100 times and regressed with conditional logistic regression model. The estimated odds-ratio (OR) were compared with the assumed ones in order to assess the magnitude of bias. RESULTS: In the condition of strong intra individual correlation, when considering exposure as continuous variable, left truncation resulted in overestimation of the odds-ratios (and corresponding beta) associated with cumulative dioxin exposure. The estimated beta (min-max) was 73.1 (64.5-80.8) for truncated exposure as compared to 4.35 (3.86-4.81) for total exposure. However, with no correlation no such differences were observed, the estimate was 4.33 (-15.9; 26.5) compared with 4.16 (2.18-5.91). Regarding categorical exposure variable, under strong intra-individual correlation, the truncated exposure did not seem to be associated with bias, the ORQ5 vs Q1 was 2.19 (2.00-2.40) compared to 2.16 (1.99-2.42), however the thresholds of the exposure quintiles strongly differed highlighting possible bias. With no intra-individual correlation, the truncation resulted in a slightly underestimation of the effect, ORQ5 vs Q1 was 1.02 (0.90-1.19) in the truncated data compared to 1.18 (1.07-1.27) in the complete data. CONCLUSIONS: Left truncation resulted in substantial bias of breast cancer risk associated with air pollution. Overall, studies should consider bias related to left truncation of exposure data, when interpreting the epidemiological results of air pollution.

Risk estimation, anxiety, and breast cancer worry in women at risk for breast cancer: A single-arm trial of personalized risk communication.

Elevated anxiety and breast cancer worry can impede mammographic screening and early breast cancer detection. Genetic advances and risk models make personalized breast cancer risk assessment and communication feasible, but it is unknown whether such communication of risk affects anxiety and disease-specific worry. We studied the effect of a personalized breast cancer screening intervention on risk perception, anxiety, and breast cancer worry. Women with a normal mammogram but elevated risk for breast cancer (N = 122) enrolled in the Athena Breast Health risk communication program were surveyed before and after receiving a letter conveying their breast cancer risk and a breast health genetic counselor consultation. We compared breast cancer risk estimation, anxiety, and breast cancer worry before and after risk communication and evaluated the relationship of anxiety and breast cancer worry to risk estimation accuracy. Women substantially overestimated their lifetime breast cancer risk, and risk communication somewhat mitigated this overestimation (49% pre-intervention, 42% post-intervention, 13% Gail model risk estimate, P < .001). Both general anxiety and breast cancer worry declined significantly after risk communication in women with high baseline anxiety. Baseline anxiety and breast cancer worry were essentially unrelated to risk estimation accuracy, but risk communication increased alignment of worry with accuracy of risk assessment. Personalized communication about breast cancer risk was associated with modestly improved risk estimation accuracy in women with relatively low anxiety and less anxiety and breast cancer worry in women with higher anxiety. We detected no negative consequences of informing women about elevated breast cancer risk.

Gail Model Underestimates Breast Cancer Risk in Thai Population.

Background:The Gail model is the most widely used method for breast cancer risk estimation. This model has been studied and verified for its validity in many groups but there has yet to be a study to validate the Gail model in a Thai population. This study aims to evaluate whether the Gail model can accurately calculate the risk of breast cancer among Thai women. Methods:The subjects were recruited from the Division of Head, Neck, and Breast Surgery, Department of Surgery, Siriraj Hospital. The patients attending the division were asked to enroll in the study and complete questionnaires. Gail model scores were then calculated. Relationships between parameters were examined using the Pearson’s chi-square test, Fisher’s exact test, and independent-samples t-test. Results:There were 514 women recruited. Age, parity, age at first-live birth, and history of atypical ductal hyperplasia (ADH) were significant risk factors for breast cancer. The 5-year and lifetime risk score for breast cancer calculated by the Gail model were not significantly different between the patient and the control subjects. The proportions of the subjects with lifetime risk ≥20% were significantly higher in breast cancer patients (p=0.049). Conclusion:The Gail model underestimated the risk of breast cancer in Thai women. Calibration of the model is still required before adoption in Thai population.