Decreased Risk Of Breast Cancer Research Articles

Abstract PO5-08-10: Breast cancer risk prediction performance of polygenic risk score in Taiwanese female with dense breast: A nested case-control study

Abstract Introduction: Breast cancer is the most common cancer among women in Taiwan and the incidence rate of breast cancer has been increasing steadily over the past 30 years. To address this, a nationwide screening program with biennial mammography for women aged 40-69 was implemented in 2004, which has contributed to a significant reduction in breast cancer mortality. Asian women are more likely to have dense breast tissue, and studies have shown a correlation between breast density and the risk of developing breast cancer, with higher breast density values associated with increased risk. Polygenic risk scores (PRS) are calculated based on an individual's genetic information and can estimate their risk of developing a particular disease. Although PRS can identify low-penetrance risk variants, its use in breast cancer risk estimation is typically limited to gene-only models, and integration with breast cancer screening databases is rare. Hence, the aim of this specific study was to evaluate the predictive capacity of PRS in women with dense breast tissue by exploring potential genetic markers and constructing a PRS to investigate the genetic factors associated with clinical characteristics and the risk of developing breast cancer. Methods: The PRS was developed using genetic information from the Taiwan Precision Medicine Initiative genotyping data. A total of 6335 patients were enrolled, and 101 single nucleotide polymorphisms (SNPs) were selected as candidate markers based on the PGS Catalog (PGS000001). Clinical characteristics of the study cohort were summarised using median and range, or frequency and percentage. The distribution of characteristics between breast cancer and controls was estimated using an independent two-sample t-test, chi-square, and Fisher’s exact test. The association of the PRS and related characteristics with breast cancer risk in the study cohort was estimated using univariate and multivariate binomial logistic regression. Harrel’s C-index was reported to demonstrate the predictive performance of PRS in both univariate and multivariate models. All p-values were two-sided, and a p less than .05 is considered statistically significant. All analyses were performed using R 4.1.2 (R core team, 2023) Results: The results showed that breast cancer patients constituted a higher proportion of individuals in PRS Q4 (37.8% vs 24.8% in controls). The model's predictive performance for breast cancer risk increased from 0.565 (95% CI = 0.520-0.611) to 0.699 (95% CI = 0.644-0.755) by adding related clinical characteristics compared to the PRS-only model. Patients characterized with benign breast disease (OR = 0.50, 95% CI = 0.31-0.79, P = 0.004) showed a decreased breast cancer risk, and patients with mastalgia or palpable breast lesion (OR = 6.87, 95% CI = 4.29-10.8, P < 0.001) predicted significant greater breast cancer risk. Subgroup analysis of patients without breast symptoms was conducted as they may be overlooked or underestimated for breast cancer screening. For dense breast patients without symptoms, the high PRS group (Q4) consistently showed a significantly elevated breast cancer risk compared to the low PRS group (Q1-Q3) in both univariate (OR = 2.25, 95% CI = 1.43-3.50, P < 0.001) and multivariate analyses (OR = 2.22, 95% CI = 1.41-3.46, P < 0.001). Conclusion: Breast cancer screening has undergone a shift from a general approach to a personalized, risk-based approach. Besides breast cancer screening using family history as the only risk factor, our proposed model identifies both genetic and clinical risk factors using big data analyses including the EHR, cancer screening, and registry from a single institute. The study suggests that integrating PRS into personalized screening strategies could improve risk prediction for Taiwanese females with dense breasts without prominent symptoms. Table 1. Clinical characteristics of study cohort (n=6335). Table 2. Association of the PRS quartiles in breast cancer risk. Table 3. Predictive performance of PRS for breast cancer risk. Citation Format: Chih Yean Lum, Chih Chiang Hung, Chi-Cheng Huang, Tzu-Hung Hsiao, Sin-Hua Moi. Breast cancer risk prediction performance of polygenic risk score in Taiwanese female with dense breast: A nested 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 PO5-08-10.

Association Between Polymorphisms in DNA Damage Repair Pathway Genes and Female Breast Cancer Risk.

Breast cancer risk have been discussed to be associated with polymorphisms in genes as well as abnormal DNA damage repair function. This study aims to assess the relationship between genes single nucleotide polymorphisms (SNPs) related to DNA damage repair and female breast cancer risk in Chinese population. A case-control study containing 400 patients and 400 healthy controls was conducted. Genotype was identified using the sequence MassARRAY method and expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER-2) in tumor tissues was analyzed by immunohistochemistry assay. The results revealed that ATR rs13091637 decreased breast cancer risk influenced by ER, PR (CT/TT vs. CC: adjusted odds ratio [OR] = 1.54, 95% confidence interval [CI]: 1.04-2.27, p = 0.032; CT/TT vs. CC: adjusted OR = 1.63, 95%CI: 1.14-2.35, p = 0.008) expression. Stratified analysis revealed that PALB2 rs16940342 increased breast cancer risk in response to menstrual status (AG/GG vs. AA: adjusted OR = 1.72, 95%CI: 1.13-2.62, p = 0.011) and age of menarche (AG/GG vs. AA: adjusted OR = 1.54, 95%CI: 1.03-2.31, p = 0.037), whereas ATM rs611646 and Ku70 rs132793 were associated with reduced breast cancer risk influenced by menarche (GA/AA vs. GG: adjusted OR = 0.50, 95%CI: 0.30-0.95, p = 0.033). In a summary, PALB2 rs16940342, ATR rs13091637, ATM rs611646, and Ku70 rs132793 were associated with breast cancer risk.

Development of Systemic Interventions to Decrease Breast Cancer Risk: A Group Concept Mapping Study.

As breast cancer continues to take a devasting public health toll, most primary prevention approaches are targeted at individual actions. We have proposed, instead, developing systemic, population approaches to preventing the disease. We used a combined qualitative-quantitative methodology, group concept mapping (GCM), to identify Importance and Feasibility ratings of systemic interventions across a wide spectrum of approaches and stakeholders. Participants (n = 351) from across the state of California sorted 84 potential interventions into topical piles, and then rated each intervention on perceived Importance and Feasibility. Multidimensional scaling and a cluster analysis identified eleven clusters or themes of interventions. Participants rated interventions on Importance and Feasibility differently depending on the region of the state in which they lived. The results of this study underscore the importance of sharing health information with and seeking public health solutions from community partners in general and from beyond the urban areas usually studied.

Antihypertensive drug targets and breast cancer risk: a two-sample Mendelian randomization study.

Findings on the correlation between the use of antihypertensive medication and the risk of breast cancer (BC) have been inconsistent. We performed a two-sample Mendelian randomization (MR) using instrumental variables to proxy changes in gene expressions of antihypertensive medication targets to interrogate this. Genetic instruments for expression of antihypertensive drug target genes were identified with expression quantitative trait loci in blood, which should be associated with systolic blood pressure to proxy for the effect of antihypertensive drug. The association between genetic variants and BC risk were obtained from genome-wide association study summary statistics. The summary-based MR was employed to estimate the drug effects on BC risk. We further performed sensitivity analyses to confirm the discovered MR associations such as assessment of horizontal pleiotropy, colocalization, and multiple tissue enrichment analyses. The overall BC risk was only associated with SLC12A2 gene expression at a Bonferroni-corrected threshold. One standard deviation (SD) decrease of SLC12A2 gene expression in blood was associated with a decrease of 1.12 (95%CI, 0.80-1.58) mmHg of systolic blood pressure, but a 16% increased BC risk (odds ratio, 1.16, 95% confidential interval, 1.06-1.28). This signal was further observed for estrogen receptor positive (ER +) BC (1.17, 1.06-1.28). In addition, one SD decrease in expression of PDE1B in blood was associated with 7% decreased risk of ER + BC (0.93, 0.90-0.97). We detected no evidence of horizontal pleiotropy for these associations and the probability of the causal variants being shared between the gene expression and BC risk was 81.5, 40.5 and 66.8%, respectively. No significant association was observed between other target gene expressions and BC risk. Changes in expression of SLC12A2 and PDE1B mediated possibly via antihypertensive drugs may result in increased and decreased BC risk, respectively.

Potential interplay between tumor size and vitamin D receptor (VDR) polymorphisms in breast cancer prognosis: a prospective cohort study.

Vitamin D has some anticancer properties that may decrease breast cancer risk and improve prognosis. The aim was to investigate associations between four previously studied VDR SNPs (Taq1, Tru91, Bsm1, and Fok1) and prognosis in different groups of breast cancer patients. VDR genotyping of 1,017 breast cancer patients included 2002-2012 in Lund, Sweden, was performed using Oncoarray. Follow-up was until June 30, 2019. Clinical data and patient information were collected from medical records and questionnaires. Cox regression was used for survival analyses. Genotype frequencies were as follows: Fok1 (AA 15.7%, AG 49.1%, GG 35.1%), Bsm1 (CC 37.2%, CT 46.1%, TT 16.7%), Tru91 (CC 77.8%, CT 20.7%, TT 1.5%), and Taq1 (AA 37.2%, AG 46.2%, GG 16.6%). During follow-up there were 195 breast cancer events. The homozygous variants of Taq1 and Bsm1 were associated with reduced risk of breast cancer events (adjusted HR = 0.59, 95% CI 0.38-0.92 for Taq1 and adjusted HR = 0.61, 95% CI 0.40-0.94 for Bsm1). The G allele of the Fok1 was associated with increased risk of breast cancer events in small tumors (pT1, adjusted HR = 1.83, 95% CI 1.04-3.23) but not in large tumors (pT2/3/4, adjusted HR = 0.80, 95% CI 0.41-1.59) with a borderline interaction (Pinteraction = 0.058). No interactions between VDR genotypes and adjuvant treatments regarding breast cancer prognosis were detected. VDR genotypes were associated with breast cancer prognosis and the association might be modified by tumor size. Further research is needed to confirm the findings and elucidate their potential clinical implications.

Trans-ethnic Mendelian randomization study of systemic lupus erythematosus and common female hormone-dependent malignancies.

Observational research has reported that systemic lupus erythematosus (SLE) is related to common female hormone-dependent cancers, but the underlying causal effect remains undefined. This study aimed to explore the causal association of these conditions by Mendelian randomization (MR) analysis. We selected instrumental variables for SLE from genome-wide association studies (GWASs) conducted in European and East Asian populations. The genetic variants for female malignant neoplasms were obtained from corresponding ancestry GWASs. We utilized inverse variance weighted (IVW) as the primary analysis, followed by sensitivity analysis. Furthermore, we conducted multivariable MR (MVMR) to estimate direct effects by adjusting for the body mass index and estradiol. Finally, we implemented reverse direction MR analysis and gave a negative example to test the reliability of MR results. We found SLE was significantly negatively associated with overall endometrial cancer risk (odds ratio [OR] = 0.961, 95% confidence interval [CI] = 0.935-0.987, P = 3.57E-03) and moderately inversely related to endometrioid endometrial cancer (ENEC) (OR = 0.965, 95% CI = 0.936-0.995, P = 0.024) risk in the European population by IVW. We replicated these results using other MR models and detected a direct effect by MVMR (overall endometrial cancer, OR = 0.962, 95% CI = 0.941-0.983, P = 5.11E-04; ENEC, OR = 0.964, 95% CI = 0.940-0.989, P = 0.005). Moreover, we revealed that SLE was correlated with decreased breast cancer risk (OR = 0.951, 95% CI = 0.918-0.986, P = 0.006) in the East Asian population by IVW, and the effect was still significant in MVMR (OR = 0.934, 95% CI = 0.859-0.976, P = 0.002). The statistical powers of positive MR results were all >0.9. This finding suggests a possible causal effect of SLE on the risk of overall endometrial cancer and breast cancer in European and East Asian populations, respectively, by MR analysis, which compensates for inherent limitations of observational research.

Lifestyle Quality Indices and Female Breast Cancer Risk: A Systematic Review and Meta-Analysis.

Breast cancer (BC) poses an important burden of disease, which probably could be reduced by adopting healthy lifestyles like healthy body weight, healthy diet, and physical activity, among others. Many studies have reported that adherence to healthy lifestyles may decrease BC risk. The main objective of this study was to estimate a summary association of studies evaluating a healthy lifestyle index and BC risk. A systematic review and meta-analysis following the Cochrane methodology were carried out. Observational studies, including healthy lifestyle indices and their association with BC, were searched from 4 databases. For the meta-analysis, random-effectsmodel was used to evaluate overall BC risk, BC by molecular subtype and menopausal status. Thirty-one studies were included in the systematic review, and 29 studies in the meta-analysis. When the highest vs. the lowest category to a healthy lifestyle index were compared, the study identified a 20% risk reduction for BC in prospective studies (hazard ratio [HR] 0.80 95% CI: 0.78, 0.83) and an odds ratio (OR) of 0.74 (95% CI: 0.63, 0.86) for retrospective studies. The inverse association remained statistically significant when stratified by menopausal status, except for premenopausal BC in prospective studies. Furthermore, an inverse association was found for molecular subtypes estrogen receptor (ER+)/progesterone receptor (PR+): HR = 0.68 (95%CI: 0.63, 0.73), ER+/PR-: HR = 0.78 (95% CI: 0.67, 0.90) and ER-/PR-: HR = 0.77 (95% CI: 0.64, 0.92). Most studies scored at a low risk of bias and a moderate score for the certainty of the evidence. Adherence to a healthy lifestyle reduces the risk of BC, regardless of its molecular subtypes, which should be considered a priority to generate recommendations for BC prevention at a population level. International prospective register of systematic reviews (PROSPERO) ID: CRD42021267759.

The Effect of Risk-Reducing Salpingo-Oophorectomy on Breast Cancer Incidence and Histopathological Features in Women with a BRCA1 or BRCA2 Germline Pathogenic Variant

Risk-reducing salpingo-oophorectomy (RRSO) is advised for female BRCA1/2 germline pathogenic variant (GPV) carriers to reduce tubal/ovarian cancer risk. RRSO may also affect breast cancer (BC) incidence. The aim was to investigate the effect of RRSO on BC incidence and histopathological features in female BRCA1/2 GPV carriers. Prospectively collected clinical data from BRCA1/2 GPV carriers in our hospital-based data/biobank were linked to the Dutch Nationwide Pathology Databank (PALGA) in January 2022. Multivariable Cox-proportional hazard models were used to calculate hazard ratios (HRs) with 95% confidence intervals (95% CIs), where the pre-RRSO group was considered the reference group and the primary endpoint was the first primary BC. Histopathological features of BCs pre- and post-RRSO were compared using descriptive statistics. In 1312 women, 164 incident primary BCs were observed. RRSO did not decrease BC risk for BRCA1 GPV (HR: 1.48, 95% CI: 0.91-2.39) or BRCA2 GPV (HR: 0.95, 95% CI: 0.43-2.07) carriers. BCs tended to be smaller post-RRSO (median: 12 mm) than pre-RRSO (15 mm, p: 0.08). There were no statistically significant differences in histopathological features. RRSO did not decrease BC risk or affect BC features in BRCA1/2 GPV in this study, although BCs diagnosed post-RRSO tended to be smaller.

Association between WHO First-Step Analgesic Use and Risk of Breast Cancer in Women of Working Age.

We assessed the association between breast cancer and analgesic use in women of a specific working-age group. The Korean National Health Insurance Service-National Sample Cohort database (KNHIS-NSC) data were analyzed. We calculated hazard ratios (HRs) with 95% confidence intervals (CIs) for patients' cancer risk based on whether the women participated in economic activity (PEA or not PEA (NPEA) groups) and analgesic use. Additionally, breast cancer incidence variations by age group, and PEA or NPEAs, health behavior, Charlson Comorbidity Index, and analgesic use were evaluated. The PEA group had a higher cancer risk than the NPEA group (HR = 1.542, 95% CI: 1.345-1.768, p < 0.001). Breast cancer risk was high in the PEA, high income, and no history of exercise groups, but significantly reduced in the regular-use-of-analgesics group. Notably, the working age group of 40~49 years, within the PEA group, had the highest HR of breast cancer development (HR = 1.700, 95% CI = 1.361-2.124, p < 0.001); whereas regular analgesic use in those aged 25~39 years decreased breast cancer risk (HR = 0.611, 95% CI = 0.427-0.875, p < 0.05). In conclusion, our results suggest that individuals at a high-risk of comorbidity may benefit from regular use of analgesics, which may prove to be a useful strategy for breast cancer prevention in the Young-aged group.

The Association Between the Serum Level of IGF-1 and IGFBP-3 and the Risk of Breast Cancer among Women in the Gaza Strip.

The purpose of this research was to look at the relationship between insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) levels and the risk for breast cancer (BC) among women in the Gaza Strip. This case-control study, which included 334 participants (112 women with BC as cases, and 222 women without BC as control), was conducted between January 2021 and August 2022. Research data for the cases were gathered at the Oncology Departments of the Gaza Strip's two hospitals, "Al- Shifa Hospital and Turkish Palestinian Friendship Hospital," as well as from the electronic records of the Screening Mammogram Unit at Al- Remal Clinic for controls. The information about the participants was gathered using a standardized questionnaire. The key variables related to BC were identified using multivariate logistic regression. According to multivariate logistic regression, participants' age was associated with an increase in the risk of BC (OR= 1.03; 95%CI, 1.007-1.060). There was an association between serum concentrations of fasting blood glucose (FBG) (OR= 1.027; 95% CI, 1.013-1.042), IGF-1 (OR= 1.010; 95% CI, 1.006-1.015), and the risk of BC, while there was no link between IGFBP-3 and the risk of BC. In an analysis of the risk according to menopausal status, premenopausal women were associated with an approximate 0.5 time decrease in risk of BC compared to women in post-menopause (OR= 0.428, 95% CI, 0.258, 0.710). Dairy product was also related to a decreased risk of BC. The results suggest that age, lower physical activity, increased levels of FBG, and IGF- 1 increase the BC risk among females in the Gaza Strip. Meanwhile, premenopausal women and dairy products are linked to a reduction in the risk of BC. Furthermore, no link was found between IGFBP-3 and BC risk. Improving early BC detection rates in the Gaza Strip necessitates preventative interventions and screening for BC in the public and healthcare sectors.

The relationship between Mediterranean-DASH diet intervention for the neurodegenerative delay (MIND) Diet and risk of breast Cancer: a case-control study among iranian adult women

Backgroundchoosing a healthier lifestyle and modifying dietary habits could prevent four million new people from developing cancer. Recently, a new index called the Mediterranean-dietary approach to stop hypertension (DASH) diet intervention for the neurodegenerative delay (MIND) diet has been developed. In the current study, we aimed to assess the relationship between the MIND diet and the risk of breast cancer (BC) among Tehranian adult women.MethodIn this hospital-based, case-control study, 134 Tehranian women ≥ 30 years old with recently (< 6 months) diagnosed BC, confirmed histologically and 272 women of the same age as control were included. Dietary intakes were assessed in a personal interview using a valid and reliable semi-quantitative 168-item food frequency questionnaire. The odds ratio (OR) and 95% confidence intervals (CI) of breast cancer across tertiles of the MIND diet were determined using multivariable-adjusted logistic regression analysis.ResultsIn the crude model, participants in the highest tertiles had lower odds of BC [(OR = 0.57; 95% CI,0.34–0.95), P for trend = 0.020)] than those with the lowest scores on the MIND diet. After controlling for potential confounding variables, individuals in the highest tertile of the MIND diet had a 45% lower risk of BC [(OR = 0.55; 95% CI, 0.32–0.96), P for trend = 0.021)] compared with those in the lowest tertile. Also, in women with an abortion history, higher adherence to the MIND diet was associated with a lower risk of BC [(OR = 0.15; 95% CI, 0.04–0.52, P for trend = 0.002)].ConclusionOur findings revealed that higher adherence to the MIND diet was associated with decreased BC risk, which was strongly observed among women with a history of abortion.

Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers

The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09–1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.

Physical Activity From Menarche-to-first Pregnancy And Risk Of Breast Cancer: The California Teachers Study

PURPOSE: Physical activity (PA) is associated with decreased breast cancer (BCa) risk. A longer menarche-to-first pregnancy window of susceptibility (WOS) is associated with increased BCa risk. Whether PA during the menarche-to-first pregnancy WOS offsets BCa risk is unclear. It is also unknown if differences in risk exist by BCa subtype. METHODS: We examined the prospective association between PA during the menarche-to-first pregnancy WOS and BCa risk in the California Teachers Study (N=78,940). Recreational PA levels from high school to current age, or, age 55, were recalled at cohort entry and converted to metabolic equivalent of task hours per week (MET-h/wk). We used multivariable Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of incident invasive BCa for WOS and PA. RESULTS: 5,157 invasive BCa cases developed. The median length of follow-up was 21.6 years. Longer menarche-to-first pregnancy WOS (≥20 vs. <15 years) was associated with increased BCa risk (HR=1.23, 95% CI=1.13-1.34). Women with higher PA during menarche-to-first pregnancy WOS had decreased risk of invasive BCa (≥40 vs. <9 MET-h/wk: HR=0.89, 95% CI=0.83-0.97). The inverse association between PA during the menarche-to-first pregnancy WOS and BCa risk was strongest in triple-negative BCa (TNBC: ≥40 vs. <9 MET-h/wk: HR=0.53, 95% CI=0.32-0.87; luminal A-like: ≥40 vs. <9 MET-h/wk: HR=0.92, 95% CI=0.80-1.06; luminal B-like: ≥40 vs. <9 MET-h/wk: HR=0.84, 95% CI=0.52-1.36). Higher PA level during the menarche-to-first pregnancy WOS was associated with decreased BCa risk only among women with moderate (15-19 years) menarche-to-first pregnancy intervals (≥40 vs. <9 MET-h/wk: HR=0.80, 95% CI=0.69-0.92), but not women with short (<15 years; ≥40 vs. <9 MET-h/wk: HR=0.96, 95% CI=0.86-1,06) or long (≥20 years; ≥40 vs. <9 MET-h/wk: HR=0.93, 95% CI=0.74-1.17) intervals. CONCLUSION: PA during the menarche-to-first pregnancy WOS was associated with lower BCa risk in our cohort. Understanding the timing of PA over the life course in relationship to non-modifiable reproductive risk factors such as pregnancy maybe particularly important. Supported by NIH Grant U01 CA199277; P30 CA033572; P30 CA023100; UM1 CA164917; R01-CA077398; U54 CA155850; UL1 TR002014; UL1 TR000003; and KL2 TR002015.

The 2018 World Cancer Research Fund/American Institute for Cancer Research Score and Cancer Risk: A Longitudinal Analysis in the NIH-AARP Diet and Health Study.

We examined associations between adherence to the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) Cancer Prevention Recommendations using the standardized 2018 WCRF/AICR Score and cancer risk among older U.S. adults. Participants included 215,102 adults in the NIH-AARP Diet and Health Study followed between 2004 and 2011 (mean 7.0 person-years). Scores (range: 0-7 points) were calculated from self-reported weight, physical activity, and diet and alcohol intake measures. Outcomes included 17 cancers reviewed by WCRF/AICR (cases: male n = 11,066; female n = 8,865) and top three U.S. cancers in males (total n = 4,658; lung n = 2,211; prostate n = 920; colorectal n = 1,527) and females (total n = 5,957; lung n = 1,475; post-menopausal breast n = 3,546; colorectal n = 936). Cox proportional hazard ratios (HRs) were estimated for score and cancer risk associations, stratifying by sex and smoking status. Each one-point score increase was associated with 6% to 13% reduced cancer risk across combined outcomes, except for male never smokers' risk for top three cancers and male current smokers' risk for both combined cancer outcomes. Higher scores were associated with decreased lung cancer risk only among male former smokers (HR, 0.84; 95% CI, 0.79-0.89) and female current smokers (HR, 0.89; 95% CI, 0.82-0.96). Higher scores were associated with 7% to 19% decreased breast cancer risk across smoking strata and 10% to 14% decreased colorectal cancer risk among male and female never and former smokers. Greater recommendations adherence was associated with reduced cancer risk. Findings emphasize the importance of considering combined contributions of multiple lifestyle factors for cancer prevention among older adults and the potential modifying role of smoking history.

Assessing Risk and Knowledge of Women on Breast Cancer and Providing Lifestyle Advice for the Management of Breast Cancer Risk

Breast cancer is the most common cancer and is the main cause of cancer mortality among women in the world. Overall, 1 in 28 women is likely to develop breast cancer during her lifetime. Although the mortality rate is decreasing, the incidence is persistently increasing due to urbanization and lifestyle changes. So, there is a need to assess the personal breast cancer risk and increase the knowledge of women on early detection. The present study aims to assess the risk and knowledge of women on breast cancer. The main objective of the study is to identify the women at high risk, to create awareness among women about early screening and detection and to educate lifestyle management to decrease breast cancer risk. A descriptive cross-sectional study was performed during the period of June 2019 to November 2019 in the women attended for mammographic examination. A total of 270 women responded to the study. The results showed that five-year risk is found to be high for 31.1% of women and low for 68.8% of women with a mean of 1.4 and the standard deviation is 1.24. About 14.81% of women were found to have strong lifetime risk and 30.37% of women had average lifetime risk and 54.81% women had usual lifetime risk. The mean lifetime risk of the women is 16.09 and the standard deviation is 10.2. The majority of the participants have low knowledge on breast cancer; BSE, and mammography i.e., 80% of them were lack of knowledge. The mean knowledge score is 6.34 and the standard deviation is 5.45. The women who had high five-year and strong lifetime risk are eligible for breast cancer prevention and management approaches. The women with moderate lifetime risk were advised with regular screening and Breast Self-Examination practices.

Abstract 3631: Transcriptome-wide association study identifies novel genes associated with breast cancer susceptibility in Latinas

Abstract Background: Genetic susceptibility to breast cancer has been studied extensively in European ancestry populations, but few studies have addressed genetic susceptibility in non-European women. Latinas are a genetically diverse group with contributions from European, African, and Indigenous American ancestries. Genome-wide association studies (GWAS) have identified unique variants in this population, particularly at the 6q25 locus. We conducted a transcriptome-wide association study (TWAS) to identify novel genes associated with risk of breast cancer in Latinas. Methods: We used individual level GWAS data from 2,396 Latina cases and 6,505 Latina controls from the studies in Northern California (San Francisco Bay Area Breast Cancer Study, Northern California Breast Cancer Family Registry and Kaiser Permanente Genetic Epidemiology Research on Aging Cohort), Southern California (Multi-ethnic Cohort) and Mexico (CAMA study). We analyzed the association between genetically predicted whole blood (WB) gene expression and breast cancer risk using newly developed TWAS models based on 784 Mexican American individuals. We also conducted parallel analyses using breast mammary tissue (BT) TWAS models from GTEx v8. All analyses were adjusted for age, ancestry, and study. Associations with false discovery rate (FDR) probability &amp;lt;0.05 were considered statistically significant. Results: At FDR&amp;lt;0.05, we identified 20 genes from BT and 39 genes from WB. Seven of the genes were significantly associated in both the WB models and GTEx BT models. Increased expression of MIB2 (pFDR = 4.74x10-17 (WB) and 1.22x10-4 (BT)), NBPF26 (pFDR = 1.30x10-7 (WB) and 7.43x10-8 (BT)), SLC35E2B (pFDR = 1.12x10-4 (WB) and 5.47x10-5 (BT)), and FAM30A (pFDR = 1.18x10-10 (WB) and 9.27x10-3 (BT)) was associated with increased risk of breast cancer risk, whereas increased expression of SLC35E2A (pFDR = 8.17x10-6 (WB) and 1.55x10-3 (BT)) and HCP5B (pFDR = 1.84x10-3 (WB) and 2.19x10-3 (BT)) was associated with decreased breast cancer risk. Increased expression of PDGFA was associated with increased risk (pFDR = 1.30x10-7) in GTEx BT reference models but decreased risk (pFDR = 2.34x10-10) in the ancestry-specific WB model. Conclusion: Our study is the first TWAS investigating the relationship between genetically predicted gene expression and breast cancer risk in Latinas. By leveraging gene expression prediction models that capture eQTLs that are more common in populations with Indigenous American ancestry, we have identified some novel genes associated with breast cancer risk in Latinas. Of these, MIB2 is a strong candidate for a mechanistic role in breast carcinogenesis in Latinas. MIB2 is involved in Notch signaling which plays an important role in breast carcinogenesis via its mismatched receptor-ligand interaction. Our study highlights the role of ancestry-based prediction models in TWAS analyses. Citation Format: Pooja Middha Kapoor, Angel C. Mak, Linda Kachuri, Donglei Hu, Scott Huntsman, Lawrence H. Kushi, Christopher Haiman, Esther M. John, Gabriela Torres-Mejia, Esteban G. Burchard, Susan L. Neuhausen, Laura Fejerman, Elad Ziv. Transcriptome-wide association study identifies novel genes associated with breast cancer susceptibility in Latinas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3631.

Association between circulating vitamin E and ten common cancers: evidence from large-scale Mendelian randomization analysis and a longitudinal cohort study

BackgroundThe association between vitamin E and cancer risk has been widely investigated by observational studies, but the findings remain inconclusive. Here, we aimed to evaluate the causal effect of circulating vitamin E on the risk of ten common cancers, including bladder, breast, colorectal, esophagus, lung, oral and pharynx, ovarian, pancreatic, prostate, and kidney cancer.MethodsA Mendelian randomization (MR) analytic framework was applied to data from a cancer-specific genome-wide association study (GWAS) comprising a total of 297,699 cancer cases and 304,736 controls of European ancestry. Three genetic instrumental variables associated with circulating vitamin E were selected. Summary statistic-based methods of inverse variance weighting (IVW) and likelihood-based approach, as well as the individual genotyping-based method of genetic risk score (GRS) were used. Multivariable IVW analysis was further performed to control for potential confounding effects. Furthermore, the UK Biobank cohort was used as external validation, supporting 355,543 European participants (incident cases ranged from 437 for ovarian cancer to 4882 for prostate cancer) for GRS-based estimation of circulating vitamin E, accompanied by a one-sample MR analysis of dietary vitamin E intake underlying the time-to-event analytic framework.ResultsSpecific to cancer GWAS, we found that circulating vitamin E was significantly associated with increased bladder cancer risk (odds ratios [OR]IVW = 6.23, PIVW = 3.05×10-3) but decreased breast cancer risk (ORIVW = 0.68, PIVW = 8.19×10-3); however, the significance of breast cancer was dampened (Pmultivariable IVW > 0.05) in the subsequent multivariable MR analysis. In the validation stage of the UK Biobank cohort, we did not replicate convincing causal effects of genetically predicted circulating vitamin E concentrations and dietary vitamin E intake on the risk of ten cancers.ConclusionsThis large-scale population study upon data from cancer-specific GWAS and a longitudinal biobank cohort indicates plausible non-causal associations between circulating vitamin E and ten common cancers in the European populations. Further studies regarding ancestral diversity are warranted to validate such causal associations.

Obesity and Breast Cancer Risk: The Oncogenic Implications of Metabolic Dysregulation.

Breast cancer is increasing in prevalence in parallel with rising rates of obesity worldwide. Obesity is recognized as a leading modifiable risk factor for the development of breast cancer; however, this association varies considerably by clinicopathologic features, and the underlying mechanisms are complex. Pubmed literature search using combinations of "obesity," "breast cancer risk," "diet," "exercise," "weight gain," "weight loss," "adipose tissue inflammation," "crown-like structure," "immune markers," "metformin," "gliflozins," "SGLT-2i," "GLP1-RA," and related terms. Elevated body mass index and weight gain are associated with increased risk of postmenopausal, hormone receptor-positive breast cancer. Emerging evidence suggests that adverse measures of body composition in individuals of any weight can also confer increased breast cancer risk. Mechanistically, various factors including altered adipokine balance, dysfunctional adipose tissue, dysregulated insulin signaling, and chronic inflammation contribute to tumorigenesis. Weight loss and more specifically fat mass loss through lifestyle and pharmacologic interventions improve serum metabolic and inflammatory markers, sex hormone levels, and measures of breast density, suggesting a link to decreased breast cancer risk. Incorporating markers of metabolic health and body composition measures with body mass index can capture breast cancer risk more comprehensively. Further studies of interventions targeting body fat levels are needed to curb the growing prevalence of obesity-related cancer.

Association Between Paraoxonase1 (Q192R and L55M) Gene Polymorphisms and Risk of Breast Cancer: A Meta-analysis of 12 Studies

Background: The paraoxonase1 gene (PON1) is part of the paraoxonase family of multifactorial antioxidants (EC 3.1.1.2). The functional single-nucleotide polymorphisms L55M and Q192R are located in the coding site of this gene. The association between these polymorphisms and breast cancer risk has been investigated, with contradictory results. Objectives: A meta-analysis was done to find the association between PON1 (L55M and Q192R) gene polymorphisms and breast cancer risk. Methods: We searched Embase, Pubmed, and Web of Science for related articles. Twelve eligible studies before December 2021 were selected. Statistical analysis was done by STATA 14.0. Result: We summarized 12 studies of L55M and Q192R polymorphisms and breast cancer risk, involving 5,769 subjects (2,519 controls and 3,250 patients). In all genetic models, PON1-L55M polymorphisms were significantly associated with breast cancer risk. Besides, PON1-Q192R polymorphisms decreased breast cancer risk. The PON1-Q192R allele reduced the cancer risk, particularly breast cancer (OR (R vs. Q): 0.7932). However, an association was found between the PON1-L55M allele and increased breast cancer risk (OR (M vs. L): 1.6041). Discussion: The results of 11 out of 12 studies were consistent with our results. In a non-conforming study, this was probably due to errors in conducting experiments. Nonetheless, well-designed studies with more samples are needed to confirm our findings at protein levels.

Single-Nucleotide Polymorphisms in LEP and LEPR Associated With Breast Cancer Risk: Results From a Multicenter Case-Control Study in Chinese Females.

BackgroundLeptin (LEP) plays a physiological role through its specific receptor (LEPR) and is involved in the occurrence and development of breast cancer. Our current study aimed at determining the influence of single-nucleotide polymorphisms (SNPs) in the genes coding for LEP and LEPR on breast cancer risk.MethodsIn the present study, 963 breast cancer cases and 953 controls were enrolled. Five SNPs of LEP and two of LEPR were chosen to evaluate the correlation of selected SNPs with breast cancer susceptibility among women in northern and eastern China. Analyses were further stratified by body mass index (BMI), waist–hip rate (WHR), estrogen receptor, and progesterone receptor status. The expression patterns of risk variant-associated genes were detected by expression quantitative trait locus (eQTL) analysis with eQTLGen and The Cancer Genome Atlas database.ResultsThere were significant differences between breast cancer cases and control groups in the menopausal status and family history of breast cancer. Two SNPs (rs1137101 and rs4655555) of the LEPR gene decreased overall breast cancer risk, and other five SNPs showed no significant association with breast cancer risk. rs1137101 (GA vs. GG; adjusted OR = 0.719, 95% CI = 0.578–0.894, p = 0.003) and rs4655555 (TT vs. AA; adjusted OR = 0.574, 95% CI = 0.377–0.873, p = 0.009) significantly decreased breast cancer risk after Bonferroni correction for multiple testing. In subgroup analyses, the GA and GA + AA genotypes of LEPR rs1137101 associated with decreased breast cancer risk in the subgroup of BMI ≤ 24 kg/m2 or WHR ≥ 0.85 after Bonferroni correction. Furthermore, we found that the expressions of rs4655555-associated gene LEPR and leptin receptor overlapping transcript (LEPROT) were upregulated in breast cancer tumor tissues compared with adjacent normal tissues, and a higher expression of LEPR in tumor tissues was correlated with poor prognosis of breast cancer patients using The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) data.ConclusionOur study demonstrated that the polymorphisms rs1137101 and rs4655555 located in the LEPR gene decreased breast cancer risk in Chinese females, which might be a research-worthy bio-diagnostic marker and applied for early prediction and risk assessment of breast cancer.