Predictor Of Breast Cancer Incidence Research Articles

Abstract PO-178: Metabolic syndrome and risk of breast cancer by molecular subtype: Analysis of the Mechanisms for Novel and Established Risk Factors for Breast Cancer in Women of Nigerian Descent (MEND) study

Abstract Background: The African continent experiences the highest age-standardized breast cancer mortality globally, with Nigeria reporting the highest rate within the continent. Breast cancer in Nigeria is characterized by several striking epidemiological features. These cancers are disproportionately pre-menopausal, diagnosed at late-stages with high-grade disease, and characterized by the highly-aggressive triple-negative subtype. However, few studies have focused on understanding the differentially patterned risk factors associated with high breast cancer burden among Nigerian women. Metabolic syndrome is characterized by a cluster of biological irregularities and is known to be a significant predictor of breast cancer incidence. The purpose of this analysis was to examine the association of metabolic syndrome with breast cancer and molecular subtypes among Nigerian women for first time. Methods: Metabolic syndrome was defined as having at least 3 out of 5 of: high blood pressure (≥130/85 mm Hg), reduced HDL (<50 mg/dL), elevated triglyceride (>150 mg/dL), high waist circumference (≥80 cm), and prior diagnosis of diabetes or elevated fasting glucose level (≥100 mg/dL). Among 296 newly diagnosed breast cancer cases and 259 healthy controls, multivariable logistic regression models were utilized to estimate adjusted odds ratios (aOR) and 95% confidence intervals (95% CI) for the association between metabolic syndrome and breast cancer overall. Multinomial logistic regression models were used to evaluate each molecular subtype (Luminal A, Luminal B, HER2-enriched and triple-negative). Results: Cases compared to controls were significantly more likely to have metabolic syndrome (30% vs. 17%; p<0.001). After adjusting for age, socio-demographic and reproductive risk factors, there was a positive association between metabolic syndrome and breast cancer (aOR: 1.84, 95% CI: 1.07, 3.16). In stratified analyses, metabolic syndrome was associated with breast cancer regardless of BMI status; however, the estimate was significant only among normal weight women (aOR: 3.85; 95% CI: 1.25, 11.90). Metabolic syndrome was significantly associated with the triple-negative breast cancer subtype (aOR: 4.37, 95% CI: 1.67, 11.44); associations for other molecular subtypes were not statistically significant. Conclusions: Metabolic syndrome appears to be a robust risk factor for breast cancer, particularly for triple-negative breast cancer. Public health and clinical interventions can provide substantial benefits in reducing the burden of metabolic syndrome and preventing breast cancer among Nigerian women. Citation Format: Tomi Akinyemiju. Metabolic syndrome and risk of breast cancer by molecular subtype: Analysis of the Mechanisms for Novel and Established Risk Factors for Breast Cancer in Women of Nigerian Descent (MEND) study [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-178.

Association of Imaging-Based Body Fat Distribution and Mammographic Density in the Multiethnic Cohort Adiposity Phenotype Study.

As the stronger association of obesity with postmenopausal breast cancer in Asian than white women may be due to body fat distribution, we examined the relation of adiposity measures with percent mammographic density (PMD), a strong predictor of breast cancer incidence. A total of 938 women from five ethnic groups (69.1 ± 2.7 years) in the Adiposity Phenotype Study (APS) underwent DXA and MRI imaging. PMD was assessed in routine mammograms using a computer-assisted method. Spearman correlation coefficients were computed and general linear models were applied to estimate regression coefficients (β) for PMD per 0.5 SD units of adiposity measures while adjusting for known confounders, including DXA total body fat. For 701 (75%) of the participants (69.1 ± 2.7 years), valid mammograms were obtained. Whereas total body fat, the trunk-to-periphery fat ratio (TPFR), visceral fat (VAT), and subcutaneous fat (SAT) were inversely correlated with PMD (P < 0.0001), the VAT/SAT ratio correlated positively (r spearman = 0.10; P = 0.01). In fully adjusted models, PMD remained inversely related to TPFR and SAT and disappeared for VAT, while it was strengthened for VAT/SAT (β = 0.51; P = 0.009). This relation was stronger in Japanese Americans than other ethnic groups. This is the first study to show an association of a high VAT/SAT ratio with greater PMD, a marker of breast cancer risk after taking into account total body fat. The results indicate a link between the propensity to accumulate VAT and the amount of fat in the breast (1-PMD), which may influence the relation of obesity with breast cancer incidence.

Selected Articles from This Issue

With rising costs of cancer care, concerns about financial hardship are increasingly reported in the United States by providers and patients. Using recent data from a nationally representative survey, Han and colleagues found that medical financial hardship and nonmedical financial sacrifices due to cancer were common, with greater intensity for those ages 18 to 64 years than 65+ years. Moreover, lower socioeconomic status, comorbidity, lack of private insurance coverage, extended employment change, and recent cancer treatment were also associated with higher hardship intensity and/or sacrifices. The findings highlight the need to mitigate financial hardship for cancer survivors, especially for those at high risk.Personalized colorectal cancer (CRC) screening could optimize screening effectiveness and resource allocation. There are multiple CRC risk prediction tools with modest discriminatory ability. Ladabaum and colleagues explored the potential clinical and economic impact of CRC screening tailored to predicted CRC risk. This decision analysis suggests that tailored screening is preferable over a uniform approach if it is guided by a highly accurate and affordable risk prediction tool. However, a uniform approach may be preferred if risk stratification involves even modest levels of risk misclassification or modest incremental costs. Higher intensity screening in those with predicted higher risk could improve outcomes despite misclassification, but lower intensity screening in those with predicted lower risk may worsen outcomes due to misclassification.The reported stronger association of obesity with postmenopausal breast cancer in Asian compared to white women may be due to differences in the relative distribution of visceral and subcutaneous fat. Maskarinec and colleagues examined the relation of adiposity measures with percent mammographic density (PMD), a strong predictor of breast cancer incidence, among participants of the Multiethnic Cohort. The analysis of abdominal MRI images and PMD showed that a higher ratio of visceral to subcutaneous adipose tissue was positively associated with PMD and indicates a link between the propensity to accumulate fat as visceral fat and the amount of fat in the breast.High incidence and mortality rate suggest the desirability to identify high-risk Asian never-smoking females (NSF) who may benefit from low-dose CT (LDCT) screening. On the basis of an age-matched case–control study and an estimated age-specific 6-year lung cancer incidence rate among Taiwanese NSFs, Chien and colleagues developed the Taiwanese NSF Lung Cancer Risk Models (TNSF-SQ) using standard epidemiologic and genetic information. Validation studies suggest that TNSF-SQ seems potentially useful in selecting Taiwanese NSFs for LDCT screening and hence helps inform clinical practice and screening program design. Similar models could be developed for never-smoking females in other parts of Asia.

Type 2 diabetes, obesity, and breast cancer risk among Japanese women of the atomic bomb survivor cohort

BackgroundMuch less is known about diabetes than obesity as a predictor of breast cancer incidence and most previous studies have been conducted in white populations. Therefore, this project within the Radiation Effects Research Foundation’s cohort of Japanese atomic bomb survivors aimed to determine the independent contributions of obesity and diabetes to develop breast cancer. MethodsAfter excluding women with unknown A-bomb radiation dose, a radiation dose of ≥100 mGy, a pre-existing history of breast cancer, and missing body mass index (BMI), the analysis included 29,818 women. Breast cancer status and deaths until 2009 were identified from cancer registries and vital records. Cox regression with age as the time metric was applied to estimate hazard ratios (HR) and 95% confidence intervals (CI) for BMI and diabetes status as time-varying exposures alone and in combination while adjusting for known confounders. ResultsDiabetes prevalence increased from 2.6% to 5.3% and 7.5% from the first to the second and third data collection. During 27.6 ± 12.2 years of follow-up, 703 women had developed breast cancer (mean age of 66.0 ± 12.9 years) and 31 (4.4%) had been diagnosed with diabetes. A diagnosis of diabetes was not significantly associated with breast cancer incidence without (HR 1.12, 95% CI 0.77–1.64) and with BMI (HR 1.01, 95% CI 0.69–1.49) as a covariate. The respective HRs for overweight and obesity were 1.61 (95% CI 1.34–1.93) and 2.04 (95% CI 1.40–2.97). ConclusionsAmong a long-time Japanese cohort, excess body weight but not a diabetes diagnosis was significantly associated with breast cancer risk.

Dairy Consumption in Adolescence and Early Adulthood and Risk of Breast Cancer

Background: Carcinogenic exposure in early life may be critical for subsequent breast cancer risk. Dairy consumption was examined during adolescence and early adulthood in relation to incident breast cancer in the Nurses' Health Study II cohort.Methods: For the analyses of early adulthood dairy consumption, we included 90,503 premenopausal women ages 27 to 44 years in 1991 who reported dairy consumption using a validated food-frequency questionnaire. From 1991 to 2013, 3,191 invasive breast cancer cases were identified. In 1998, 44,264 women recalled adolescent dairy consumption. This subgroup of women was followed up from 1998 to 2013; 1,318 invasive breast cancer cases were identified. Multivariate hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using the Cox proportional hazard regression.Results: Adolescent and early adulthood total dairy consumption was not associated with overall breast cancer risk (each serving/day during adolescence, total dairy HR = 1.02, 95% CI, 0.97-1.07; for early adulthood total dairy HR = 1.01, 95% CI, 0.97-1.04), as were intakes of calcium, vitamin D, and lactose. Adolescent consumption of total and high-fat dairy was associated with higher risk of estrogen and progesterone receptor negative (each serving/day: total dairy HR = 1.11, 95% CI, 1.00-1.24; high-fat dairy HR = 1.17, 95% CI, 1.04-1.31). However, higher adolescent high-fat dairy consumption was associated with lower risk of estrogen and progesterone receptor positive tumors (each serving/day HR = 0.91, 95% CI, 0.86-0.97).Conclusions: Our results suggest no overall association between dairy consumption during adolescence or early adulthood and breast cancer risk, but the findings may differ by hormone receptor status of tumors.Impact: Dairy consumption in adolescence or early adulthood may not be a significant predictor of breast cancer incidence. Cancer Epidemiol Biomarkers Prev; 27(5); 575-84. ©2018 AACR.

A comprehensive tool for measuring mammographic density changes over time

BackgroundMammographic density is a marker of breast cancer risk and diagnostics accuracy. Density change over time is a strong proxy for response to endocrine treatment and potentially a stronger predictor of breast cancer incidence. We developed STRATUS to analyse digital and analogue images and enable automated measurements of density changes over time.MethodRaw and processed images from the same mammogram were randomly sampled from 41,353 healthy women. Measurements from raw images (using FDA approved software iCAD) were used as templates for STRATUS to measure density on processed images through machine learning. A similar two-step design was used to train density measures in analogue images. Relative risks of breast cancer were estimated in three unique datasets. An alignment protocol was developed using images from 11,409 women to reduce non-biological variability in density change. The protocol was evaluated in 55,073 women having two regular mammography screens. Differences and variances in densities were compared before and after image alignment.ResultsThe average relative risk of breast cancer in the three datasets was 1.6 [95% confidence interval (CI) 1.3–1.8] per standard deviation of percent mammographic density. The discrimination was AUC 0.62 (CI 0.60–0.64). The type of image did not significantly influence the risk associations. Alignment decreased the non-biological variability in density change and re-estimated the yearly overall percent density decrease from 1.5 to 0.9%, p < 0.001.ConclusionsThe quality of STRATUS density measures was not influenced by mammogram type. The alignment protocol reduced the non-biological variability between images over time. STRATUS has the potential to become a useful tool for epidemiological studies and clinical follow-up.

Light at night and breast cancer incidence in Connecticut: An ecological study of age group effects

The aim of this study was to test the prediction that within the state of Connecticut, USA, communities with high nighttime outdoor light level would have higher breast cancer incidence rates. Breast cancer cases were identified from the Connecticut Tumor Registry, the oldest within the United States, for years 2005 and 2009 and geocoded to the 829 census tracts in the state. Nighttime light level (LAN) was obtained from the Defense Meteorological Satellite Program (DMSP), 1996/97 satellite image, providing a 10-year lag. Regression models were used incorporating the LAN levels and census level data on potential confounders for the whole female population of the state, and for separate age groups. Light level emerged as a significant predictor of breast cancer incidence. After taking account of several potential confounders, the excess risk in the highest LAN level census tracts compared to the lowest was about 63% (RR=1.63; 95% CI=1.41, 1.89). The association of LAN with breast cancer incidence weakened with age; the association was strongest among premenopausal women.

Adolescent and Early Adulthood Dietary Carbohydrate Quantity and Quality in Relation to Breast Cancer Risk.

We investigated quantity and quality of dietary carbohydrate as well as insulin load and insulin index during adolescence and also early adulthood in relation to risk of breast cancer in the Nurses' Health Study II. During 20 years of follow-up of 90,534 premenopausal women who completed a diet questionnaire in 1991, 2,833 invasive breast cancer cases were documented. In 1998, 44,263 of these women also completed a questionnaire about their diet during high school; among these women, we documented 1,118 cases of breast cancer. Multivariable-adjusted Cox proportional hazards regression was used to model relative risks (RR) and 95% confidence intervals (95% CI) for breast cancer across categories of dietary carbohydrate, glycemic index (GI), glycemic load (GL), as well as insulin load and insulin index scores. Adolescent or early adult intakes of GI or GL were not associated with risk of breast cancer. Comparing women in the highest versus lowest quintile, the multivariable-adjusted RRs were 1.14 (0.95-1.38) for adolescent GI scores and 1.03 (0.91-1.16) for early adulthood GI scores. We also did not observe associations with insulin index and insulin load scores in adolescence or early adulthood and breast cancer risk. We found that diets high in GI, GL, insulin index, and insulin load during adolescence or early adulthood were not associated with an increased risk of breast cancer in this cohort study. Diets with a high glucose or insulin response in adolescence or early adulthood were not significant predictors of breast cancer incidence.

Downregulation of microRNAs 145-3p and 145-5p is a long-term predictor of postmenopausal breast cancer risk: The ORDET prospective study.

miRNAs have been implicated in the regulation of key metabolic, inflammatory, and malignant pathways; hence, they might be considered both predictors and players of cancer development. Using a case-control study design nested in the ORDET prospective cohort study, we addressed the possibility that specific mRNAs can serve as early predictors of breast cancer incidence in postmenopausal women. We compared leukocyte miRNA profiles of 133 incident postmenopausal breast cancer cases and profiles of 133 women who remained healthy over a follow-up period of 20 years. The analysis identified 20 differentially expressed miRNAs, 15 of which were downregulated. Of the 20 miRNAs, miR145-5p and miR145-3p, each derived from another arm of the respective pre-miRNA, were consistently and significantly downregulated in all the databases that we surveyed. For example, analysis of more than 1,500 patients (the UK Metabric cohort) indicated that high abundance of miR145-3p and miR145-5p was associated with longer, and for miR145-3p also statistically significant, survival. The experimental data attributed different roles to the identified miRNAs: Although the 5p isoform was associated with invasion and metastasis, the other isoform seems related to cell proliferation. These observations and the prospective design of our study lend support to the hypothesis that downregulation of specific miRNAs constitutes an early event in cancer development. This finding might be used for breast cancer prevention. The identification of the miRNAs as long-term biomarkers of breast cancer may have an impact on breast cancer prevention and early detection.

Prospective study of breast MRI in BRCA1 and BRCA2 mutation carriers: effect of mutation status on cancer incidence

Annual MRI screening is recommended as an adjunct to mammography for BRCA1 and BRCA2 mutation carriers. Prophylactic oophorectomy has been shown to decrease breast cancer risk in BRCA1/2 mutation carriers. Here, we aimed to examine the combined effects of MRI and oophorectomy. For this purpose, 93 BRCA1/2 mutation carriers were screened with yearly mammograms and yearly MRI scans. Study endpoints were defined as date of breast cancer diagnosis, date of prophylactic mastectomy, or date of most recent contact. Of 93 women, with a median age of 47, 80 (86%) had prophylactic oophorectomy. Fifty-one women (55%) had BRCA1 mutations. A total of 283 MRI scans were performed. Eleven breast cancers (9 invasive, 2 ductal carcinoma in situ) were detected in 93 women (12%) with a median follow-up of 3.2 years (incidence 40 per 1,000 person-years). Six cancers were first detected on MRI, three were first detected by mammogram, and two were "interval cancers." All breast cancers occurred in BRCA1 mutation carriers (incidence 67 per 1,000 person-years). Apart from BRCA1 vs. BRCA2 mutation status, there were no other significant predictors of breast cancer incidence. Most invasive breast cancers were estrogen receptor negative (7 of 9) and lymph node negative (7 of 9). There have been no systemic recurrences with a median follow-up of 19 months after cancer diagnosis. Finally, it was concluded that all breast cancers occurred in BRCA1 mutation carriers, in most cases despite oophorectomy. These data suggest that surveillance and prevention strategies may have different outcomes in BRCA1 and BRCA2 mutation carriers.

Longitudinal Study on the Role of Body Size in Premenopausal Breast Cancer

A high body mass index (BMI) has been related to a reduced risk of breast cancer in premenopausal women. The mechanisms underlying this association have not been elucidated. We explored whether factors affecting ovulation may explain the inverse association between BMI (calculated as weight in kilograms divided by the square of height in meters) and breast cancer in 113,130 premenopausal participants in the Nurses' Health Study II. During 1,225,520 person-years of prospective follow-up between 1989 and 2003, 1398 incident cases of invasive breast cancer were diagnosed. Weight, height, ovulatory infertility, menstrual cycle patterns, and a multitude of covariates were assessed throughout follow-up. Cox proportional hazards regression was used to compute hazard ratios and 95% confidence intervals (CIs). We observed a significant linear inverse trend between current BMI and breast cancer incidence (P<.001) that was not explained by menstrual cycle characteristics or infertility due to an ovulatory disorder (covariate-adjusted hazard ratio for breast cancer in women with a BMI > or =30 vs 20.0-22.4, 0.81; 95% CI, 0.68-0.96). We found BMI at age 18 years to be the strongest predictor of breast cancer incidence (covariate-adjusted hazard ratio for breast cancer in women with a BMI at age 18 years > or =27.5 vs 20.0-22.4, 0.57; 95% CI, 0.41-0.81). Body size during the early phases of adult life seems to be particularly important in the development of premenopausal breast cancer. Factors other than anovulation are likely to mediate the protection conferred by a high BMI.

Anthropometric predictors of breast cancer incidence and survival in a multi-ethnic cohort of female residents of Hawaii, United States.

The purpose of the study was to describe the associations between height and body mass index (BMI) (wt/ht2) and breast cancer incidence and survival among female residents of Hawaii. The study sample is a randomly-selected, multi-ethnic cohort of 17,628 women. A total of 378 incident breast cancer cases were identified via linkage to the Hawaii Tumor Registry over an average follow-up period of 14.9 years. Using age 50 as a cut-point, 86 were considered premenopausal cases, and 292 were postmenopausal. Proportional hazards analysis was used to describe the risks associated with height and BMI, after adjustment for age, education, race/ethnicity, and drinking status. For mortality analyses, there were 34 breast cancer deaths among the 365 breast cancer cases for which staging information was available. The risk of postmenopausal breast cancer was found to increase progressively across approximate tertiles of the distribution of height (P = 0.02 for trend test), with a significantly excess risk among women in the tallest tertile (risk ratio [RR] = 1.5, 95 percent confidence interval [CI] = 1.1-2.1). Baseline levels of BMI were related positively to breast cancer incidence among postmenopausal women, after control for the above covariates (P = 0.01 for trend test). Among postmenopausal women in the highest quintile of the BMI distribution, the RR was 1.5 (CI = 1.0-2.3, P = 0.04). Further analyses indicated the association between BMI and postmenopausal breast cancer incidence was strongest among women aged 65 years and older. After statistical control for the above covariates and stage of disease, pre-morbid levels of BMI were significantly predictive of death from breast cancer, with an approximate nine percent increase in risk per unit increase in BMI (P = 0.01). Compared with women in the lowest two quartiles, the RR among the heaviest women was 2.2 (CI = 0.9-5.4,P = 0.08). Height was not associated with risk of breast cancer mortality. Relative weight may be an important modifiable risk factor for both breast cancer incidence and prognosis. The association between height and breast cancer incidence is more difficult to interpret, but may underscore the importance of early life exposures in the development of breast cancer.

Early body size and subsequent weight gain as predictors of breast cancer incidence (Iowa, United States).

We examined whether associations of adult weight gain with the risk of postmenopausal breast cancer vary by stature, waist-hip ratio (WHR), and early adult size in a cohort of 37,105 Iowa (United States) women. Both low body mass index (kg/m2) (BMI) at age 18 and high subsequent weight-gain were associated independently with increased risk of incident postmenopausal breast cancer. After stratifying on BMI at age 18, high weight gain was associated with increased risk irrespective of whether early BMI was low (relative risk [RR] = 1.92, 95 percent confidence interval [CI] = 1.45-2.53) or high (RR = 1.59, Ci = 1.19-2.12). Women with lower BMI at 18 were at a higher risk at all levels of weight change, but having low BMI at age 18 and low subsequent weight gain conferred no significantly excess risk over those with high BMI at 18 and low gain. An inconsistent increase in risk was associated with taller stature; there was no additional risk associated with high WHR. Part of the observed risk from lower early size may reflect greater weight gain by lighter women. Limiting adult weight gain thus may be a feasible method to avoid increasing an individual's risk of breast cancer. Reasons for different effects of early cf late weight gain are not established, but benefits of a greater size at age 18 are likely to be offset by increased risks of other weight-related diseases at older ages.