Population-based Breast Cancer Study Research Articles

The associations of healthy lifestyle index with breast cancer incidence and mortality in a population-based study.

To investigate how a healthy lifestyle index (HLI) is associated with breast cancer risk and survival in a population-based breast cancer study. The study included 1319 breast cancer cases and 1310 controls from the population-based Long Island Breast Cancer Study Project and its follow-up study where vital status was ascertained using the National Death Index (521 deaths, 210 from breast cancer; median follow-up 214.5months). HLI scores were generated from body mass index, physical activity, intake of plant and animal foods, alcohol consumption, breastfeeding, and smoking, with higher values corresponding to healthier behaviors obtained from baseline questionnaire. Multivariable logistic and Cox regression models were used to estimate breast cancer odds ratios (ORs) and mortality hazards ratios (HRs), respectively. Compared to women in the low HLI tertile, a significant reduction in risk of breast cancer was observed for women in the intermediate (OR = 0.78, 95% CI 0.64-0.93) and high (OR = 0.73, 95% CI 0.60-0.88) tertiles; a one-point increase in HLI score was associated with a 14% reduction in breast cancer risk (OR = 0.86, 95% CI 0.80-0.93). For survival, a significant reduction in all-cause mortality was also observed in women in the intermediate (HR = 0.68, 95% CI 0.56-0.84) and high (HR = 0.72, 95% CI 0.58-0.88) HLI tertiles with a 17% reduction in all-cause mortality (HR = 0.83, 95% CI 0.76-0.91) for one-point increase in HLI score. These inverse associations were more prominent among postmenopausal women. A healthy lifestyle is beneficial not only in reducing breast cancer risk but also in improving overall survival after breast cancer diagnosis, especially among postmenopausal women.

PAM50- and immunohistochemistry-based subtypes of breast cancer and their relationship with breast cancer mortality in a population-based study.

We evaluated the prognostic ability of immunohistochemistry (IHC)-based vs. PAM50-based subtypes for breast cancer mortality in a population-based study of breast cancer. We included a total of 463 breast cancer cases from the population-based Long Island Breast Cancer Study Project (LIBCSP). IHC-based markers were abstracted from the medical records, while the PAM50-based intrinsic subtypes were assessed from tumor tissues using NanoString nCounter® Analysis System. Cox proportional hazards models were used to estimate hazards ratios (HRs) for breast cancer-specific mortality associated with subtypes. For IHC-based hormone receptor-positive (HR+) tumors (n = 361), 68.7% were classified as luminal subtypes by PAM50; for HR- tumors (n = 102), 95.1% were classified as non-luminal subtypes. Compared to HR+/HER2- subtype, HR- patients had significantly higher breast cancer mortality (HR-/HER2+: HR = 2.84, 95% CI = 1.58-5.11; triple-negative breast cancer: HR = 2.42, 95% CI = 1.44-4.06). Compared to luminal A, a higher mortality rate was observed for all other PAM50-based subtypes: luminal B (HR = 4.03, 95% CI = 1.97-8.22), HER2-enriched (HR = 6.82, 95% CI = 3.29-14.14) and basal-like (HR = 4.71, 95% CI = 2.24-9.93). Additional subtyping of HR+ patients by PAM50 provided future risk stratification where luminal B patients in this group had significant higher mortality than luminal A patients (HR = 3.93, 95% CI = 1.92-8.03). Similar results were also observed among 291 HR+/HER2- patients, but not among the HR- patients. Our study suggests that for HR+ patients, especially HR+/HER2- patients, additional PAM50-based subtyping would provide better prognostic stratification and improve disease management.

Genetic Variants in Group-Specific Component (GC) Gene Are Associated with Breast Cancer Risk among Chinese Women.

The group-specific component (GC) gene, one of the vitamin D pathway genes, seems to play an important role in cancer development. A population-based breast cancer study including 818 cases and 935 controls in a Chinese population was carried out to evaluate the potential associations of four polymorphisms (rs16847024, rs17467825, rs2298850, and rs3755967) in the GC gene with risk of breast cancer. We detected three SNPs with statistically significant effects on breast cancer development after adjusting for age, menopausal status, body mass index (BMI), family history of breast cancer, income, waist circumference, and education (rs17467825: adjusted OR = 0.80, 95% CI = 0.65–0.99; rs2298850: adjusted OR = 0.80, 95% CI = 0.65–0.98; rs3755967: adjusted OR = 0.80, 95% CI = 0.65–0.98). Stratified analysis found that when an individual had a waist circumference <80 cm, rs17467825, rs2298850, and rs3755967 could markedly reduce the risk of breast cancer. Significant interactions between polymorphisms of rs2298850 and rs3755967 and waist circumference were also observed for breast cancer risk. Combined analysis revealed a significant association among the allele numbers of protective effects with decreased breast cancer risk (Ptrend=0.043). These results indicated that, in the GC gene, genetic mutations might be related to breast cancer susceptibility in Chinese women.

Genetic variants in genes related to inflammation, apoptosis and autophagy in breast cancer risk.

BackgroundInflammation contributes to breast cancer development through its effects on cell damage. This damage is usually dealt with by key genes involved in apoptosis and autophagy pathways.MethodsWe tested 206 single nucleotide polymorphisms (SNPs) in 54 genes related to inflammation, apoptosis and autophagy in a population-based breast cancer study of women of European (658 cases and 795 controls) and East Asian (262 cases and 127 controls) descent. Logistic regression was used to estimate odds ratios for breast cancer risk, and case-only analysis to compare breast cancer subtypes (defined by ER/PR/HER2 status), with adjustment for confounders. We assessed statistical interactions between the SNPs and lifestyle factors (smoking status, physical activity and body mass index).Results and conclusionAlthough no SNP was associated with breast cancer risk among women of European descent, we found evidence for an association among East Asians for rs1800925 (IL-13) and breast cancer risk (OR = 2.08; 95% CI: 1.32–3.28; p = 0.000779), which remained statistically significant after multiple testing correction (padj = 0.0350). This association was replicated in a meta-analysis of 4305 cases and 4194 controls in the Shanghai Breast Cancer Genetics Study (OR 1.12, 95% CI: 1.03–1.21, p = 0.011). Further, we found evidence of an interaction between rs7874234 (TSC1) and physical activity among women of East Asian descent.

Abstract 3357: Heritable methylation marks associated with breast cancer risk

Abstract While most epigenetic marks are reprogrammed during early embryogenesis, some studies have reported Mendelian-like inheritance of germline DNA methylation in particular cancer susceptibility genes. We aimed to identify heritable methylation marks associated with breast cancer susceptibility by studying 25 Australian multi-generational families with multiple cases of breast cancer who were not known to carry mutations in breast cancer susceptibility genes. Peripheral blood DNA methylation was measured at approximately 480,000 genetic loci (methylation sites) for 210 members of these families using the Infinium HumanMethylation450 BeadArray. We developed and applied a new statistical method to identify heritable methylation marks based on complex segregation analysis. Carrier probabilities were estimated for the 1000 most heritable methylation marks, based on family structure but not disease status, and Cox proportional hazards survival analysis was used to test for associations between these carrier probabilities and breast cancer. After correcting for multiple testing, we identified 11 methylation marks whose corresponding carriers probabilities were significantly associated with breast cancer. Three marks clustered within 200 base pairs of the noncoding RNA miR886. We found evidence for these marks to be associated with aggressive (but not non-aggressive) prostate cancer risk in a population-based prostate cancer study. The association with breast cancer risk was replicated for three of the eleven marks in an independent population-based breast cancer study. Our work demonstrates the efficacy of our novel approach for identifying heritable methylation marks associated with breast cancer. This methodology may provide insights into other disease settings where known lifestyle exposures and genetic risk variants do not fully explain the familial relative risk. Citation Format: Melissa C. Southey, Jihoon E. Joo, James G. Dowty, Roger L. Milne, EE Ming Wong, Pierre-Antoine Dugué, Dallas English, John L. Hopper, Daivd E. Goldgar, Graham G. Giles. Heritable methylation marks associated with breast cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3357. doi:10.1158/1538-7445.AM2017-3357

Abstract LB-290: The influence of body size and weight gain on global and gene promoter methylation in a population-based breast cancer study

Abstract Purpose. Little is known about how modifiable lifestyle factors, influence the epigenome. Elevated body mass index (BMI, weight kg/height m2) and adult weight gain are associated with increased risk of postmenopausal breast cancer, but the underlying mechanisms are not well understood. We hypothesized that these anthropometric factors may modify DNA methylation status by altering sex-steroid hormones levels and inflammatory markers. Methods. Resources from a population-based study (∼650 postmenopausal cases/∼650 postmenopausal controls) were used to construct logistic regression models. We explored potential modification of the global methylation-breast cancer association by BMI and weight gain using two assays: the luminometric methylation assay (LUMA) and long interspersed elements-1 (LINE-1) in white blood cell DNA. Additionally, we estimated associations between anthropometrics and promoter methylation status in a panel of 13 breast cancer-related genes using ∼600 breast tumor tissues. Results. We observed a multiplicative interaction between LUMA and BMI (p=0.033) in relation to breast cancer. There was a greater than two-fold risk of postmenopausal breast cancer among women in the highest quartile of LUMA for each strata of BMI: age-adjusted odds ratios (95% confidence intervals) were 2.19(1.37, 3.52), 2.91(1.77, 4.80) and 2.51(1.45, 4.33) for women with BMI&amp;lt;25, BMI25-29.9 and BMI≥30, respectively. The observed estimates did not differ, statistically, across BMI categories. Additionally, we found no interactions with LINE-1 and observed no associations between anthropometrics and promoter methylation status in the genes examined. Conclusions. Our data suggest that the association between BMI, weight gain and postmenopausal breast cancer may arise from mechanisms other than DNA methylation. Citation Format: Lauren E. McCullough, Jia Chen, Alexandra J. White, Xinran Xu, Yoon Hee Cho, Patrick T. Bradshaw, Sybil M. Eng, Susan L. Teitelbaum, Mary Beth Terry, Gail Garbowski, Alfred I. Neugut, Hanina Hibshoosh, Regina M. Santella, Marilie D. Gammon. The influence of body size and weight gain on global and gene promoter methylation in a population-based breast cancer study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-290. doi:10.1158/1538-7445.AM2014-LB-290

Population-based study of breast cancer in older women: prognostic factors of relative survival and predictors of treatment

BackgroundA large proportion of women with breast cancer (BC) are elderly. However, there is a lack of information regarding BC prognostic factors and care in this population. The aims of this study were to assess the prognostic factors of relative survival (RS) among women with BC aged ≥ 75 years old and to identify the predictive factors of treatments administered to this population.MethodsA population-based study was performed using data from the Cote d’Or breast and gynaecological cancer registry. Women aged 75 years and older with primary invasive BC and resident in Cote d’Or at the time of diagnosis made between January 1998 and December 2008 were retrospectively selected. Prognostic factors of RS were estimated in a generalized linear model with a Poisson error structure. RS rate for the whole population was given at 5 years. Logistic regression models were used to identify the predictors of the treatments administered.ResultsSix hundred and eighty-one women were included. Median age at diagnosis was 80. Comorbidities (p=0.02), pT stage (p=0.04), metastases (p=<0.001), having a family doctor (p=0.03) and hormone-receptor status (p=0.006) were independent prognostic factors of RS. The RS rate at 5 years for the whole population was 78.2%, 95%CI = [72.2-83.0]. Age, pT stage, metastases, histoprognostic SBR grade, hormone receptor status and comorbidities were frequently found to be predictors of treatment with surgery alone, hormone therapy alone, breast conserving surgery plus adjuvant therapy and mastectomy plus adjuvant therapy.ConclusionsComorbid conditions adversely affect survival in older women with breast cancer. Moreover the results of this study showed that there are numerous predictors of the type of treatment administered, and that the most important were age and comorbidities.

Factors associated with concordant estrogen receptor expression at diagnosis and centralized re-assay in a Danish population-based breast cancer study

Background. Estrogen receptor (ER) expression predicts tamoxifen response, which halves the risk of breast cancer recurrence. We examined clinical factors associated with concordance between ER expression at diagnosis and centralized re-assay, and the association of concordance with breast cancer recurrence. Material and methods. We used immunohistochemistry to assess ER expression on archived fixed, paraffin-embedded breast carcinoma tissue excised from women aged 35–69 years, diagnosed 1985–2001 in Jutland, Denmark. We calculated the percentage agreement, positive predictive value (PPV) and negative predictive value (NPV) of ER status at diagnosis and re-assay. We used logistic regression to investigate factors associated with concordance, and its association with recurrence (odds ratios (OR) and associated 95% confidence intervals (95%CI)). Results. ER was re-assayed in 91% of patients (n = 1530). Concordance was better in ER + than ER– tumors (PPV = 94% vs. NPV = 75%). Factors associated with concordance included menopausal status, tumor size, surgical procedure, diagnostic period, lymph node status and time to recurrence. ER + women at diagnosis who re-assayed ER + were less likely to have recurrent disease (OR = 0.49, 95% CI = 0.28, 0.86) than those who re-assayed ER–. In originally ER– women, concordance was not associated with recurrence (OR = 0.97, 95% CI = 0.66, 1.42). Conclusions. Several clinical factors were associated with ER assay concordance. Some women were ineffectively treated with tamoxifen, or required but did not receive tamoxifen. We observed almost exactly the protective effect of endocrine therapy among tamoxifen-treated ER + women whose tumors expressed the ER on re-assay, compared with those ER– on re-assay. Diagnostic pathology results for ER + tumors appear a valid and useful resource for research studies. However, those for ER– tumors have lower validity. Study-specific considerations regarding the aims, diagnostic period, and consequences of including ER– patients with truly ER + disease ought to be examined when using diagnostic pathology results for ER– tumors in research studies.

The influence of one-carbon metabolism on gene promoter methylation in a population-based breast cancer study

Abnormal methylation in gene promoters is a hallmark of the cancer genome; however, factors that may influence promoter methylation have not been well elucidated. As the one-carbon metabolism pathway provides the universal methyl donor for methylation reactions, perturbation of this pathway might influence DNA methylation and, ultimately, affect gene functions. Utilizing approximately 800 breast cancer tumor tissues from a large population-based study, we investigated the relationships between dietary and genetic factors involved in the one-carbon metabolism pathway and promoter methylation of a panel of 13 breast cancer-related genes. We found that CCND2, HIN1 and CHD1 were the most “dietary sensitive” genes, as methylation of their promoters was associated with intakes of at least two out of the eight dietary methyl factors examined. On the other hand, some micronutrients (i.e., B2 and B6) were more “epigenetically active” as their intake levels correlated with promoter methylation status in 3 out of the 13 breast cancer genes evaluated. Both positive (hypermethylation) and inverse (hypomethylation) associations with high micronutrient intake were observed. Unlike what we saw for dietary factors, we did not observe any clear patterns between one-carbon genetic polymorphisms and the promoter methylation status of the genes examined. Our results provide preliminary evidence that one-carbon metabolism may have the capacity to influence the breast cancer epigenome. Given that epigenetic alterations are thought to occur early in cancer development and are potentially reversible, dietary modifications may offer promising venues for cancer intervention and prevention.

Breast Cancer in Hong Kong, Southern China: The First Population-Based Analysis of Epidemiological Characteristics, Stage-Specific, Cancer-Specific, and Disease-Free Survival in Breast Cancer Patients: 1997–2001

BackgroundCancer registries have been set up worldwide to provide information for cancer health planning. There are known variations in breast cancer incidence and mortality worldwide. However, breast cancer incidence, pathological characteristics, and survival data is still under-reported in Asian countries. This is the first comprehensive population-based breast cancer study performed using population database of the Hong Kong Cancer Registry.MethodsA retrospective review of medical records of 8,961 subjects who were diagnosed with breast cancer between January 1, 1997 to December 31, 2001 and followed up to December 31, 2007. Descriptive statistics were employed to analyze the epidemiological and clinical data. Estimates of overall, disease-free, and cancer-specific survival at 5 years were estimated by the Kaplan–Meier method and stage-specific relative survival rates were calculated.ResultsA total of 7,630 breast cancer patients’ medical records and dataset were available during this period, and 7,449 subjects were eligible for the final analysis. Median follow-up was 84 months. A total of 47.4% were diagnosed with breast cancer at age 49 years and younger; 22.2%, 46.9%, 10.8%, and 4.1% presented at stages I, II, III, and IV, respectively. A total of 53.5% had ER-positive cancer, and 20.3% had HER2-positive cancers; 13.4% had triple-negative cancers. The relative, cancer-specific, and disease-free survival rates at 5 years were 84%, 85.2%, and 81.2%, respectively.DiscussionWe performed the first comprehensive population-based breast cancer epidemiology study in Southern China using the Hong Kong Cancer Registry database. This provides a baseline study cohort for comparative studies with other Asian countries and Chinese who have migrated to the West.

The influence of one-carbon metabolism on gene promoter methylation in a population-based breast cancer study

The influence of one-carbon metabolism on gene promoter methylation in a population-based breast cancer study

Misconceptions about Breast Lumps and Delayed Medical Presentation in Urban Breast Cancer Patients

Despite current recommendations for women to be screened for breast cancer with mammography every 1 to 2 years, less than half of all newly diagnosed breast cancers are initially detected through screening mammography. Prompt medical attention to a new breast symptom can result in earlier stage at diagnosis, yet many patients delay seeking medical care after becoming aware of a breast symptom. In a population-based study of breast cancer, we examined factors potentially associated with patient delay in seeking health care for a breast symptom among 436 symptomatic urban breast cancer patients (146 white, 197 black, and 95 Hispanic). Race/ethnicity, socioeconomic status, health care access and utilization, and misconceptions about the meaning of breast lumps were the key independent variables. Sixteen percent of patients reported delaying more than 3 months before seeking medical advice about breast symptoms. Misconceptions about breast lumps and lacking a regular provider, health insurance, and recent preventive care were all associated with prolonged patient delay (P < 0.005 for all). Misconceptions were much more common among ethnic minorities and women of lower socioeconomic status. Reducing patient delay and disparities in delay will require educating women about the importance of getting breast lumps evaluated in a timely manner and providing greater access to regular health care.

BRCA1 Breast Cancer Risk Is Modified by CYP19 Polymorphisms in Ashkenazi Jews

Exposure to sex hormones is a major risk factor for breast cancer and current treatments include hormone modifying drugs, among them aromatase inhibitors. We studied the association of CYP19 (Val(80) and [TTTA](n)) polymorphisms, the gene translated to aromatase, and the risk of breast cancer in BRCA carriers and noncarriers. The study consisted of 958 cancer cases and 931 healthy controls, including 474 carriers and 1,415 noncarriers. Cases and controls came from a population-based study of breast cancer in Israel, enriched with BRCA carriers from a clinical familial cancer service. Val(80) G/G genotype was associated with significantly increased risk of breast cancer compared with the Val(80) A/A genotype in BRCA1 carriers ages <50 years (odds ratio, 2.81; 95% confidence interval, 1.09-7.22; P = 0.032) but not in BRCA2 carriers or noncarriers of any age. A similar magnitude suggestive association, although nonstatistically significant, was found between Val(80) polymorphism and estrogen receptor-negative status of the breast tumors. A common haplotype composed of the Val(80) G allele and three haplotype-tagging single nucleotide polymorphisms (rs727479, rs10046, and rs4646) in the CYP19 coding region showed a trend to association with breast cancer risk in BRCA1 carriers ages <50 years. Published expression data show higher estrogen levels with higher repeats in [TTTA](n) found in linkage disequilibrium with Val(80). The present study suggests that the CYP19 Val(80) polymorphism and a haplotype that includes this polymorphism are associated with increased breast cancer risk in young women with BRCA1 mutations.

Prevalence and predictors of BRCA1 and BRCA2 mutations in a population-based study of breast cancer in white and black American women ages 35 to 64 years.

Although well studied in families at high-risk, the roles of mutations in the BRCA1 and BRCA2 genes are poorly understood in breast cancers in the general population, particularly in Black women and in age groups outside of the very young. We examined the prevalence and predictors of BRCA1 and BRCA2 mutations in 1,628 women with breast cancer and 674 women without breast cancer who participated in a multicenter population-based case-control study of Black and White women, 35 to 64 years of age. Among cases, 2.4% and 2.3% carried deleterious mutations in BRCA1 and BRCA2, respectively. BRCA1 mutations were significantly more common in White (2.9%) versus Black (1.4%) cases and in Jewish (10.2%) versus non-Jewish (2.0%) cases; BRCA2 mutations were slightly more frequent in Black (2.6%) versus White (2.1%) cases. Numerous familial and demographic factors were significantly associated with BRCA1 and, to a lesser extent, BRCA2 carrier status, when examined individually. In models considering all predictors together, early onset ages in cases and in relatives, family history of ovarian cancer, and Jewish ancestry remained strongly and significantly predictive of BRCA1 carrier status, whereas BRCA2 predictors were fewer and more modest in magnitude. Both the combinations of predictors and effect sizes varied across racial/ethnic and age groups. These results provide first-time prevalence estimates for BRCA1/BRCA2 in breast cancer cases among understudied racial and age groups and show key predictors of mutation carrier status for both White and Black women and women of a wide age spectrum with breast cancer in the general population.

&lt;I&gt;BRCA1&lt;/I&gt; Mutations in a Population-based Study of Breast Cancer in Stockholm County

&lt;I&gt;BRCA1&lt;/I&gt; Mutations in a Population-based Study of Breast Cancer in Stockholm County

BRCA1 mutations in a population-based study of breast cancer in Stockholm County.

The mutation frequency of BRCA1 and BRCA2 in women with breast cancer varies according to family history, age at diagnosis and ethnicity. The contribution of BRCA1 and BRCA2 mutations in breast cancer populations, unselected for age and family history, has been examined in several studies reporting mutation frequencies between 1% and 12% by screening methods, population sizes, and to what extent the gene/s were screened differed in the studies. We wanted to clarify the proportion of breast cancer attributable to mutations in BRCA1 in an unselected breast cancer population from the Stockholm region. All incident breast cancer patients treated surgically in a 19-month period were eligible for the study and 70% (489/696) participated. Exon 11 of BRCA1 was screened for mutations using the protein truncation test, and the mutation frequency was estimated from that. In previous studies on high-risk families from Stockholm, more than 70% of the mutations were detected in exon 11. Two mutations were found, both in patients with a family history or their own medical history of ovarian cancer, giving a mutation frequency in exon 11 of 0.4% and an estimated BRCA1 mutation frequency of <1%. Mutations in BRCA1 in unselected breast cancer cases in our region are rare and likely to be found only in high-risk families. Our BRCA1 prevalence is the lowest of all studies on unselected breast cancer patients, probably reflecting the comparatively low rates detected also in high-risk breast cancer families from the region.

Rapid reporting of cancer incidence in a population-based study of breast cancer: one constructive use of a central cancer registry.

To support a study of genetic risk factors for breast cancer, the North Carolina Central Cancer Registry has implemented a rapid reporting procedure for hospitals in the study area. This system permits the identification of newly diagnosed breast cancer cases within a very short time period (less than one month). The procedures are straightforward, cost-effective, and greatly benefit the objectives of tissue collection and interviews with the cases. This article describes the rapid reporting procedures and their potential impact for population-based research. For the objective of making generalizable risk statements, the necessity of population-based research is stressed; participation with central cancer registries is endorsed for this and other molecular epidemiologic applications.