Subsequent Breast Cancer Risk Research Articles

Subsequent Breast Cancer in Female Childhood Cancer Survivors in the St Jude Lifetime Cohort Study (SJLIFE).

Anthracycline-associated risk for subsequent breast cancer in childhood cancer survivors is hypothesized to be mediated by TP53 mutation-related gene-environment interactions. We characterized treatment/genetic risks and the impact of screening for breast cancer in the St Jude Lifetime Cohort. Female participants underwent risk-based assessments, prior health event validation, chest radiation dosimetry, and whole genome sequencing. Breast biopsy reports were reviewed. A subgroup (n = 139) underwent both breast magnetic resonance imaging and mammography. Multivariable regression was used to calculate hazard ratios (HRs) and 95% CIs. Among 1,467 women, 56 developed 68 breast cancers at a median age 38.6 (range, 24.5 to 53.0) years. Cumulative incidences at age 35 years were 1% (no chest radiation) and 8% (≥ 10 Gy of chest radiation). In adjusted models, breast cancer was associated with 20 Gy or more of chest radiation versus none (HR, 7.6; 95% CI, 2.9 to 20.4), anthracycline exposure versus none (1 to 249 mg/m2: HR, 2.6; 95% CI, 1.1 to 6.2; ≥ 250 mg/m2: HR, 13.4, 95% CI, 5.5 to 32.5), and having a breast cancer predisposition gene mutation (HR, 23.0; 95% CI, 7.3 to 72.2). Anthracyclines 250 mg/m2 or greater remained significantly associated with increased risk of breast cancer in models excluding survivors with cancer predisposition gene mutations, chest radiation 10 Gy or greater, or both. Sensitivity/specificity were 53.8%/96.3% for mammography, 69.2%/91.4% for magnetic resonance imaging, and 85.8%/99.7% for dual imaging. Breast cancers detected by imaging and/or prophylactic mastectomy compared with physical findings were more likely to be in situ carcinomas, smaller, without lymph node involvement, and treated without chemotherapy. Higher doses of anthracyclines are associated with increased risk of breast cancer independent of mutations in known cancer predisposition genes. Surveillance imaging identifies breast cancers less likely to require chemotherapy than those detected by physical findings.

Diabetes, obesity, and subsequent risk of postmenopausal breast cancer among white and black women in the Southern Community Cohort Study.

Meta-analyses have reported a small but positive association between diabetes and postmenopausal breast cancer risk, with summary relative risks of approximately 1.15. We analyzed data from the Southern Community Cohort Study (SCCS) following an underserved population with high diabetes prevalence to prospectively examine whether diabetes was associated with subsequent postmenopausal breast cancer risk and whether obesity modified this effect. Women with incident breast cancer were identified through linkage with state cancer registries and the National Death Index (213 white, 418 black cases). Person-years were calculated from date of entry into the SCCS until the earliest of date of breast cancer diagnosis, date of death, or date of last follow-up (8,277 white, 16,458 black noncases). Data on diabetes diagnosis were obtained through baseline and follow-up surveys. Cox regression was applied to examine the association between diabetes and postmenopausal breast cancer risk. After adjustment for confounding, there was no association between self-reported diabetes and postmenopausal breast cancer risk among white (hazard ratio [HR] 1.02, 95% confidence interval [CI] 0.75-1.40) or black (HR 1.00, 95% CI 0.81-1.22) women. Nor was there evidence that obesity modified the effect of diabetes on postmenopausal breast cancer in women of either race. We found no evidence of the hypothesized increased risk of breast cancer among women with diabetes. The breast cancer risks among those with diabetes in this population suggest that the association between these two illnesses is complex.

A Linkage Between Thyroid and Breast Cancer: A Common Etiology?

Breast and thyroid cancers are two malignancies with highest incidence in women. These cancers often occur metachronously. Women with thyroid cancer are at increased risk for subsequent breast cancer; women with breast cancer have an increased incidence of later development of thyroid cancer, suggesting a common etiology. This bidirectional relationship is reported worldwide; however, the underlying reasons for this co-occurrence are unknown. In this review, we summarize the current epidemiologic evidence and putative mechanisms of these metachronous or synchronous cancers. Key potential causative factors are chemotherapy and radiotherapy of the primary tumor, genetic variants linking the two diseases, hormonal signaling both from the thyroid gland and from estrogens, and lifestyle and environmental factors. There is a critical need for additional epidemiologic studies focused on gender and regional incidence together with molecular investigations on common tumorigenic pathways in these endocrine cancers. Understanding the putative mechanisms will aid in the diagnosis and clinical management of both diseases.

Plasma RANKL levels are not associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers.

BackgroundAberrant progesterone/receptor activator of nuclear factor κβ (RANK) signaling has been implicated in BRCA1 breast cancer development. Furthermore, lower circulating RANKL has been reported among women with a BRCA mutation compared to non-carriers; however, there have been no reports of plasma RANKL levels and subsequent breast cancer risk. We prospectively evaluated the relationship between plasma RANKL and breast cancer risk among women with a BRCA1 or BRCA2 mutation.MethodsAn enzyme-linked immunosorbent assay was used to quantify plasma RANKL levels in 184 BRCA mutation carriers. Women were stratified into high vs. low RANKL based on the median levels of the cohort (5.24 pg/ml). Kaplan-Meier survival analysis was used to estimate the cumulative incidence of breast cancer by baseline plasma RANKL and cox proportional hazards models were used to estimate the adjusted hazard ratios (HRs) and 95% confidence intervals (CI) for the association between plasma RANKL and risk.ResultsOver a mean follow-up of 6.3 years (0.02-19.24), 15 incident breast cancers were identified. The eight-year cumulative incidence was 10% in the low RANKL group and 12% in the high RANKL group (P-log-rank = 0.85). There was no significant association between plasma RANKL levels and breast cancer risk (multivariate HR high vs. low = 1.06; 95%CI 0.34-3.28; P-trend = 0.86).ConclusionsThese findings suggest that circulating RANKL levels are not associated with breast cancer among BRCA mutation carriers. Pending validation in a larger sample, these findings suggest that RANKL is likely not a biomarker of breast cancer risk among BRCA mutation carriers.

Prophylactic irradiation to the contralateral breast for BRCA mutation carriers with early-stage breast cancer

Women who carry germ-line mutations in BRCA1/2 are at very high risk of developing breast and ovarian cancer. Breast conserving therapy is associated with a similar risk of ipsilateral cancer recurrence in BRCA carriers compared with non-carriers. However, the risk of subsequent contralateral breast cancer in carriers is markedly increased. Therefore, mastectomy of the diseased breast along with risk reducing mastectomy of the contralateral breast is often advocated for BRCA carriers who are treated for early breast cancer. Yet, many BRCA carriers forgo this option for fear of harmful effects and choose breast conserving treatment and observation instead. In Israel, BRCA-associated breast cancer is relatively common. Accordingly, a national protocol was devised for this enriched population. In this Institutional Review Board-approved phase II trial, the option of prophylactic irradiation to the contralateral breast, in addition to standard loco-regional treatment, was offered to BRCA carrier patients treated for early breast cancer who declined contralateral mastectomy. The primary end point was contralateral breast cancer. Between May 2007 and October 2017, 162 patients were enrolled. Eighty-one patients opted for standard loco-regional treatment including surgery and radiation to the involved side (control arm) and 81 patients chose additional contralateral breast irradiation (intervention arm). At a median follow-up of 58 months, 10 patients developed contralateral breast cancer in the control arm at a median of 32 months, as compared with 2 patients in the intervention arm who developed contralateral breast cancer 80 and 105 months after bilateral breast irradiation (log-rank P = 0.011). Among BRCA carrier patients treated for early breast cancer, the addition of contralateral breast irradiation was associated with a significant reduction of subsequent contralateral breast cancers and a delay in their onset. Phase II, comparative two-arm trial (NCT00496288).

Abstract P3-05-01: Age-related methylation signals of breast cancer risk in blood

Abstract BACKGROUND: Age is the biggest risk factor for developing breast cancer, which suggests that the biological aging process is a direct driver of cancer etiology. In all normal tissues, DNA methylation status changes systematically with age and is believed to mediate the biological consequences of aging. DNA methylation patterns, commonly referred to as 'Epigenetic Clocks', can be used as measures of aging. However, the chronologic and epigenetic ages can have subtle differences in different individuals. We hypothesize that accelerated epigenetic aging (i.e. DNA methylation indicating an older age than the chronologic age of the individual) is a risk factor for breast cancer development. METHODS: We used DNA methylation data from blood samples and clinical data from n=2,107 participants in the Women's Health Initiative (WHI) and tested the association between breast cancer risk and two of the most commonly used epigenetic clocks by Horvath (based on 353 CpGs) and Hannum et al. (based on 71 CpGs). DNA methylation in whole blood was measured using the Illumina HumanMethylation450 BeadChip. We used Cox proportional hazard models to assess the association between two epigenetic age predictors (calculated using the algorithms by Horvath and Hannum et al.) and subsequent risk of breast cancer. The model was adjusted for several breast cancer risk factors including: chronologic age at the time of blood sampling, observational vs. clinical trial, clinical trial arm, race/ethnicity, education, BMI, waist-hip ratio, smoking, alcohol, age at menopause, age at menarche, number of pregnancies, age at first birth, previous mastectomy, months breastfed, and cell count estimates. Family history data and BRCA mutation status was incomplete in the WHI and therefore could not be included in our analysis. RESULTS: Increased epigenetic age determined by the Horvath clock relative to chronological age was associated with increased future incidence of invasive breast cancer, even after adjusting for known risk factors (HR=1.04, P=0.03). Utilizing the Hannum clock, we found no significant association between epigenetic age and breast cancer risk (HR=1.01, P=0.568). When we included both age predictors as independent variables in a single model, the strength of the association between the Horvath epigenetic age and breast cancer risk increased (Horvath HR=1.09, P=6.3e-5; Hannum HR=0.95, p=0.077), such that every one year increase in epigenetic age relative to chronological age was associated with a 9% increased risk of future breast cancer. These results suggest that the aging signal in the Horvath clock that is unique from that captured by Hannum is what drives the specific association with breast cancer. CONCLUSIONS: Our results support the hypothesis that “accelerated” epigenetic aging measured in the blood increases breast cancer risk. We also demonstrate that the two epigenetic clocks capture different aspects of aging, only some of which have implications for breast cancer risk. Epigenetic clocks may assist in targeting breast cancer screening to higher risk populations in the future, and understanding the biological mechanisms that are altered by the epigenetic changes may lead to new risk reduction strategies. Citation Format: Hofstatter EW, Levine M, Hatzis C, Pusztai L. Age-related methylation signals of breast cancer risk in blood [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-05-01.

Abstract ES8-1: Windows of susceptibility across the lifecourse and breast cancer

Abstract With increasing knowledge regarding the role of various factors in the development of breast cancer, a concept that has attracted substantial attention is that of windows of susceptibility. This concept suggests that there are periods over the lifecourse during which a woman may be particularly vulnerable to the influence of modifiable factors in determining long-term risk of breast cancer. This concept is not new; for example, among atomic bomb survivors in Japan, it has been observed that the effect of radiation exposure on subsequent breast cancer risk is substantially higher if women were exposed earlier in life than in their later years. However, the impact of hormonally-active agents that are ubiquitous in environment has raised concern that the risk of breast cancer may be altered during windows of susceptibility, such as during the in utero period, the pubertal transition, or between puberty and first full-term pregnancy. In order to better understand the interplay of environmental and lifestyle factors with timing of exposures during the lifecourse, the National Cancer Institute and the National Institute for Environmental Health Sciences established the Breast Cancer and the Environment Research Program, including both laboratory and epidemiologic studies to investigate the potential role of hormonally-active agents in altering early life factors that may influence breast cancer risk. These include, for example, epidemiologic studies that have focused on impacts on age-at-onset of puberty, and others that focus on impacts on breast density. In conjunction with other studies that have examined body size or other metabolic parameters measured at different periods over the lifecourse, a growing body of literature indicates that breast cancer risk factors may operate differently depending on when exposures to these risk factors occur. These observations indicate that establishment of breast cancer risk is complex, and that approaches to prevention likely need to recognize the importance of windows of susceptibility in influencing long-term likelihood of developing breast cancer. This presentation will review some of the key concepts and findings underlying this growing area of interest in the epidemiology of breast cancer. Citation Format: Kushi L. Windows of susceptibility across the lifecourse and breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr ES8-1.

Population-Based Assessment of the Association Between Magnetic Resonance Imaging Background Parenchymal Enhancement and Future Primary Breast Cancer Risk.

To evaluate comparative associations of breast magnetic resonance imaging (MRI) background parenchymal enhancement (BPE) and mammographic breast density with subsequent breast cancer risk. We examined women undergoing breast MRI in the Breast Cancer Surveillance Consortium from 2005 to 2015 (with one exam in 2000) using qualitative BPE assessments of minimal, mild, moderate, or marked. Breast density was assessed on mammography performed within 5 years of MRI. Among women diagnosed with breast cancer, the first BPE assessment was included if it was more than 3 months before their first diagnosis. Breast cancer risk associated with BPE was estimated using Cox proportional hazards regression. Among 4,247 women, 176 developed breast cancer (invasive, n = 129; ductal carcinoma in situ,n = 47) over a median follow-up time of 2.8 years. More women with cancer had mild, moderate, or marked BPE than women without cancer (80% v 66%, respectively). Compared with minimal BPE, increasing BPE levels were associated with significantly increased cancer risk (mild: hazard ratio [HR], 1.80; 95% CI, 1.12 to 2.87; moderate: HR, 2.42; 95% CI, 1.51 to 3.86; and marked: HR, 3.41; 95% CI, 2.05 to 5.66). Compared with women with minimal BPE and almost entirely fatty or scattered fibroglandular breast density, women with mild, moderate, or marked BPE demonstrated elevated cancer risk if they had almost entirely fatty or scattered fibroglandular breast density (HR, 2.30; 95% CI, 1.19 to 4.46) or heterogeneous or extremely dense breasts (HR, 2.61; 95% CI, 1.44 to 4.72), with no significant interaction (P = .82). Combined mild, moderate, and marked BPE demonstrated significantly increased risk of invasive cancer (HR, 2.73; 95% CI, 1.66 to 4.49) but not ductal carcinoma in situ (HR, 1.48; 95% CI, 0.72 to 3.05). BPE is associated with future invasive breast cancer risk independent of breast density. BPE should be considered for risk prediction models for women undergoing breast MRI.

Assessment of Levels of Knowledge towards Hormonal Related Breast Cancer Risk Factors in Qurayyat, Northern Saudi Arabia

Background: Continued exposure to sex hormones such as estrogen is a critical risk for subsequent breast cancer. Thus the present study aimed to assess the levels of knowledge towards hormonal related breast cancer risk factors in Qurayyat, Northern Saudi Arabia. Methodology: This descriptive study included 737 Saudi volunteers living in the city of Qurayyat, Northern Saudi Arabia. For females, only those agreeing to participate in the breast self-examination workshop were included, and non-respondents were included in the questionnaire. Results: For the question apropos “Inheritance as a risk factor for BC,” 405/607 (66.7%) females signposted certainly “Yes,” as well as, 70/130 (54%) males signposted certainly “Yes.” The odds ratio (OR) and 95% confidence interval (95% CI) were not statistically significant, but the level of knowledge was relatively higher among females OR (95% CI) = 1.4321 (0.9597 to 2.1370), P = 0.0786. “Are early puberty and late menopause risk factors for breast cancer?” No statistical significant differences were eminent between males and females, OR (95% CI) = 0.8878 (0.5932 to 1.3287), P = 0.5629. Conclusion: Saudi women are enthusiastically willing to raise their knowledge and awareness of breast cancer prevention and control. Although women have greater knowledge about breast cancer risk factors compared to men, still some gaps need to be filled.

Polygenic Determinants for Subsequent Breast Cancer Risk in Survivors of Childhood Cancer: The St Jude Lifetime Cohort Study (SJLIFE).

The risk of subsequent breast cancer among female childhood cancer survivors is markedly elevated. We aimed to determine genetic contributions to this risk, focusing on polygenic determinants implicated in breast cancer susceptibility in the general population. Whole-genome sequencing (30×) was performed on survivors in the St Jude Lifetime Cohort, and germline mutations in breast cancer predisposition genes were classified for pathogenicity. A polygenic risk score (PRS) was constructed for each survivor using 170 established common risk variants. Relative rate (RR) and 95% confidence interval (95% CI) of subsequent breast cancer incidence were estimated using multivariable piecewise exponential regression. The analysis included 1,133 female survivors of European ancestry (median age at last follow-up = 35.4 years; range, 8.4-67.4), of whom 47 were diagnosed with one or more subsequent breast cancers (median age at subsequent breast cancer = 40.3 years; range, 24.5-53.0). Adjusting for attained age, age at primary diagnosis, chest irradiation, doses of alkylating agents and anthracyclines, and genotype eigenvectors, RRs for survivors with PRS in the highest versus lowest quintiles were 2.7 (95% CI, 1.0-7.3), 3.0 (95% CI, 1.1-8.1), and 2.4 (95% CI, 0.1-81.1) for all survivors and survivors with and without chest irradiation, respectively. Similar associations were observed after excluding carriers of pathogenic/likely pathogenic mutations in breast cancer predisposition genes. Notably, the PRS was associated with the subsequent breast cancer rate under the age of 45 years (RR = 3.2; 95% CI, 1.2-8.3). Genetic profiles comprised of small-effect common variants and large-effect predisposing mutations can inform personalized breast cancer risk and surveillance/intervention in female childhood cancer survivors.

Maternal reproductive hormones and angiogenic factors in pregnancy and subsequent breast cancer risk.

Breast cancer risk associated with pregnancy characteristics may be mediated by maternal hormones or angiogenic factors. We conducted a prospective breast cancer case-control study among women in the Avon Longitudinal Study of Parents and Children (ALSPAC) and Norwegian Mother and Child Cohort Study (MoBa) related to maternal pregnancy prolactin (n = 254 cases and 374 controls), placental growth factor (PlGF, n = 252 and 371), soluble fms-like tyrosine kinase-1 (sFlt-1, n = 118 and 240) and steroid hormone concentrations (ALSPAC only, n = 173 and 171). Odds ratios (OR) and 95% confidence intervals (CI) for a 1 SD change in analytes were estimated using unconditional logistic regression with matching factors (cohort, mother's birth year, serum/plasma, blood collection timing) and gestational age. Breast cancer ORs (95% CI) were 0.85 (0.51-1.43) for estradiol, 0.86 (0.67-1.09) for testosterone, 0.89 (0.71-1.13) for androstenedione, 0.97 (0.71-1.34) for hCG, 0.93 (0.75, 1.15) for prolactin, 1.00 (0.78-1.27) for PlGF and 1.91 (1.00-3.65 ALSPAC) and 0.94 (0.73-1.21 MoBa) for sFlt-1, and were similar adjusting for potential confounders. Results were similar by blood collection timing, parity, age at first birth or diagnosis, and time between pregnancy and diagnosis. These data do not provide strong evidence of associations between maternal hormones or angiogenic factors with subsequent maternal breast cancer risk.

A Biological Signature for Breast Ductal Carcinoma In Situ to Predict Radiotherapy Benefit and Assess Recurrence Risk.

Ductal carcinoma in situ (DCIS) patients and their physicians currently face challenging treatment decisions with limited information about the individual's subsequent breast cancer risk or treatment benefit. The DCISionRT biological signature developed in this study provides recurrence risk and predicts radiotherapy (RT) benefit for DCIS patients following breast-conserving surgery (BCS). A biological signature that calculates an individualized Decision Score (DS) was developed and cross-validated in 526 DCIS patients treated with BCS ± RT. The relationship was assessed between DS and 10-year risk of invasive breast cancer (IBC) or any ipsilateral breast event (IBE), including IBC or DCIS. RT benefit was evaluated by risk group and as a function of DS. The DS was significantly associated with IBC and IBE risk, HR (per 5 units) of 4.2 and 3.1, respectively. For patients treated without RT, DS identified a Low Group with 10-year IBC risk of 4% (7% IBE) and an Elevated Risk Group with IBC risk of 15% (23% IBE). In analysis of DS and RT by group, the Elevated Risk Group received significant RT benefit, HR of 0.3 for IBC and IBE. In a clinicopathologically low-risk subset, DS reclassified 42% of patients into the Elevated Risk Group. In an interaction analysis of DS and RT, patients with elevated DS had significant RT benefit over baseline. The DS was prognostic for risk and predicted RT benefit for DCIS patients. DS identified a clinically meaningful low-risk group and a group with elevated 10-year risks that received substantial RT benefit over baseline.

Background parenchymal enhancement and fibroglandular tissue on breast MRI in women with high genetic risk: Are changes before and after risk-reducing salpingo-oophorectomy associated with breast cancer risk?

BackgroundParenchymal enhancement and fibroglandular tissue on breast MRI in women with high genetic risk: are changes before and after risk-reducing salpingo-oophorectomy associated with breast cancer risk? ObjectiveTo evaluate changes in the level of background parenchymal enhancement (BPE) and amount of fibroglandular tissue (FGT) on breast MRI before and after risk-reducing oophorectomy (RRSO), and to determine whether these changes correlate with ultimate breast cancer risk. Materials and methodsThe cohort included 146 women with high genetic risk who had undergone pre- and post-RRSO breast MRI. BPE level and FGT amount were retrospectively graded according to BI-RADS classification. Initial values and changes were compared in women with or without later breast cancer after RRSO. Hazard ratios (HR) were estimated using Cox univariate models. ResultsPatients with initial moderate (BI-RADS C category) BPE had a higher risk of subsequent breast cancer of HR = 3.9 (95% CI [1.1–14.3]; p = 0.04) compared to patients with initial minimal (BI-RADS A) BPE. A categorical BPE decrease after RRSO, versus no change, was associated with a higher cancer risk (HR 2.2, 95% CI [1.04–4.8]; p = 0.04). Initially dense (BI-RADS 3 category) FGT correlated with an increased cancer risk compared to fatty (BI-RADS 1 category) parenchyma (HR 8.3, 95% CI [1.1–64]; p = 0.04). After RRSO, there was a trend for higher cancer risk related to a categorical FGT decrease (HR 2.3, 95% CI [0.9–35.4]; p = 0.06). ConclusionPatients in whom BPE decreases after RRSO might be at higher risk of subsequent breast cancer compared to patients with stable BPE. This finding is consistent with the concept of increased risk associated with high initial BPE, which could be of higher clinical relevance than post-RRSO BPE reduction. A similar trend was observed with high initial FGT.

Hormone Levels in Pregnancy and Subsequent Risk of Maternal Breast and Ovarian Cancer: A Systematic Review.

Some maternal hormone levels in pregnancy are associated with a higher risk of breast and ovarian cancer. This study systematically assessed the association between blood hormone levels measured in pregnancy and future risk of these cancers. Two reviewers independently conducted a literature search of MEDLINE and EMBASE databases from January 1970 to August 2017. Studies were included that measured one or more serum hormone levels in pregnancy and later assessed for cancer. Cancer outcomes were considered by cancer type, each in relation to a specific maternal hormone. Eleven studies were included, comprising a total of 57 967 women. The interval between pregnancy and cancer onset varied from 4.1 to 20.5 years. Elevated serum chorionic gonadotropin (two of four studies) and alpha fetoprotein (two of three studies) were each associated with a lower risk of maternal breast cancer, whereas elevated estrone levels suggested a higher risk (one of three studies). Elevated testosterone (one of one study) and androstenedione (one of one study) were each associated with a significantly greater risk of sex-cord stromal ovarian tumours. Higher serum 17-hydroxyprogesterone was associated with an increased risk of sex-cord stromal (one of one study) and epithelial (one of one study) ovarian cancer. Observational studies suggest some degree of association between serum hormones measured in pregnancy and a woman's future risk of breast and ovarian cancer. More data are needed to determine sufficiently whether certain blood hormone levels measured in pregnancy are predictive of future cancer risk.

Long-term Subsequent Breast Cancer Risk and Overall Survival in Older Women with Estrogen Receptor Positive Early Stage Breast Cancer Treated in a Community Health Plan

Long-term Subsequent Breast Cancer Risk and Overall Survival in Older Women with Estrogen Receptor Positive Early Stage Breast Cancer Treated in a Community Health Plan

Breast Cancer Outcomes in a Racially and Ethnically Diverse Cohort of Insured Women.

It is unknown how subsequent breast cancer outcomes vary by biologic subtype and race/ethnicity in a diverse cohort of breast cancer survivors. We conducted a prospective cohort study of 6,154 insured breast cancer survivors (AJCC TNM stages 0-IV) diagnosed between 1996-2007 and followed them through 1/1/2010 for subsequent breast cancer events (recurrence, contralateral breast cancer, metastasis, mortality). We compared subsequent breast cancer rates by race/ethnicity groups and biologic subtype (luminal A, luminal B, HER2-enriched, and triple negative). We calculated hazard ratios (HRs) with 95% CIs using multivariable Cox proportional hazards models, adjusted for sociodemographics, cancer treatments, and tumor characteristics. The cohort was diverse: 62.4% non-Hispanic White, 13.2% Hispanic, 14.9% African American, and 9.5% Asian. We identified 1,456 subsequent breast cancer events over 22,830 person-years. Although certain Asian women had higher crude subsequent breast cancer rates compared with Whites, within each biologic subtype category, these disparities disappeared in the multivariable analyses. After accounting for race/ethnicity, compared with women with luminal A tumors (reference), women with luminal B (adjusted HR=3.65, 95% CI: 3.08-4.32), HER2-enriched (adjusted HR=2.81, 95% CI: 2.25-3.51) and triple negative (adjusted HR=1.25, 95% CI: 1.01-1.54) tumors had statistically increased risks of subsequent breast cancer. Factors that were statistically significantly associated with increased risk included higher stage, larger tumor size, positive lymph nodes, and no adjuvant endocrine or chemotherapy (all P<.025). Our data suggest that disparities in subsequent breast cancer outcomes were more strongly associated with tumor characteristics and non-use of adjuvant treatments than race/ethnicity.

1590P - Body shape trajectories and risk of breast cancer: Results from the SUN study project

Background: Obesity is a well-known risk factor for some types of cancer including post-menopausal breast cancer. Nevertheless, the influence of adiposity over life course on cancer risk remains poorly understood. The objective of this study was to assess body shape trajectories in early and middle life in relation to subsequent risk of breast cancer in a Mediterranean cohort. Methods: We used a group-based modelling approach to assess body shape trajectories from age 5 to 40 years, among 10679 women from the SUN cohort study from 1999 to 2014. Four distinct body shape trajectories were identified (lean-heavy increase, medium-stable, medium-heavy increase and heavy-stable). Cox regression models were used to estimate the hazard ratio (HR) for breast cancer according to the assigned body shape trajectory. Results: Among 106,537 women-years of follow-up a total of 133 probable incident cases of breast cancer were identified (70 of these cases were confirmed). When compared to those in the medium-stable category, women who were lean and had a marked increase (lean-heavy increase category) showed a subsequent higher risk of probable breast cancer (HR = 1.55, 95%CI 1.05-2.29). When stratifying according to menopausal status, there was a higher risk of probable postmenopausal breast cancer for women in the lean-heavy increase category (HR = 2.0, 95%CI 1.06- 3.80) compared to the medium-stable group. The statistical power was reduced and significance was lost when we considered only confirmed cases.Table: 1590POverall breast cancerPremenopausal breast cancerPostmenopausal breast cancerProbable casesCases / woman-yearsHR (95% CI)Cases / woman-yearsHR (95% CI)Cases / woman-yearsHR (95% CI)Lean-heavy increase43 / 183601.55 (1.05-2.29)13/124561.34 (0.69-2.61)21/54742.0 (1.06-3.80)Medium-stable65 / 570611 (ref.)28/466021 (ref.)19/93431 (ref.)Medium-heavy increase22 / 237380.81 (0.50-1.32)12/200480.93 (0.46-1.87)7/32811.03 (0.43-2.47)Heavy -stable3 / 73780.55 (0.17-1.76)Confirmed casesLean-heavy increase20/ 184531.22 (0.70-2.13)8/124561.14 (0.49-2.67)9/54741.32 (0.54-3.26)Medium-stable37/ 572101 (ref.)18/466021 (ref.)11/93431 (ref.)Medium-heavy increase13/ 238110.86 (0.45-1.62)8/200480.88 (0.37- 2.10)4/32810.24 (0.39-4.0) Open table in a new tab Hazard ratio (HR) and 95% confidence interval (95% CI) of breast cancer according to body shape trajectory in the SUN Project, 1999-2016. Adjusted for potential confounders and age as underlying time variable. Conclusions: This is the first Mediterranean cohort to suggest that a marked increase in body shape from age 5 to 40 years is associated with a higher risk of breast cancer, especially for postmenopausal women, indicating a role for lifetime adiposity in breast carcinogenesis. Legal entity responsible for the study: The Seguimiento Universidad de Navarra (SUN) Project. Funding: Spanish Government-Instituto de Salud Carlos III, the European Regional Development Fund, the Navarra Regional Government and the University of Navarra. Disclosure: All authors have declared no conflicts of interest.

Androgen receptor expression in normal breast tissue and subsequent breast cancer risk

Sex steroid hormone signaling is critical in the development of breast cancers, although the role of the androgen receptor remains unclear. This study evaluated androgen receptor (AR) expression in normal breast tissue as a potential marker of breast cancer risk. We conducted a nested case–control study of women with benign breast disease (BBD) within the Nurses’ Health Studies. Epithelial AR expression was assessed by immunohistochemistry in normal tissue from the BBD biopsy and the percent of positive nuclei was estimated in ordinal categories of 10% for 78 breast cancer cases and 276 controls. Logistic regression models adjusting for the matching factors and BBD lesion type were used to calculate odds ratios (ORs) for the association between AR expression (tertiles: ≤10%, 11–30%, and >30%) and breast cancer risk. AR expression in normal breast tissue was not associated with subsequent breast cancer risk (ORT3vsT1 = 0.9, 95% CI = 0.4–1.8, p trend = 0.68). In comparison with low AR/low ER women, ORs of 0.4 (95% CI = 0.1–1.2) for high AR/high ER women, 1.8 (95% CI = 0.4–7.8) for low AR/high ER women, and 0.7 (95% CI = 0.3–1.6) for high AR/low ER women were observed (p interaction = 0.21). Ki67 did not modify the association between AR expression and breast cancer risk (p interaction = 0.75). There was little evidence for an overall association between AR expression in normal breast tissue and breast cancer risk. These findings did not show that the AR association varied by Ki67 expression in normal breast tissue, though there was suggestive heterogeneity by ER expression.

Pregnancy complications and subsequent breast cancer risk in the mother: a Nordic population-based case-control study.

Certain features of pregnancy are important risk factors for breast cancer, such as protection afforded by young age at first birth. Preeclampsia, a pregnancy complication, is associated with reduced maternal breast cancer risk. However, questions remain regarding causality, biological mechanisms and the relation of other hypertensive conditions to risk. We conducted a population-based case-control study of breast cancer cases (n = 116,196) in parous women identified through linkage of birth and cancer registries in Denmark, Finland, Norway and Sweden (1967-2013), including up to 10 matched controls per case (n = 1,147,192) sampled from the birth registries (complete data were not available on all variables). Odds ratios (ORs) with 95% confidence intervals (CIs) were derived from unconditional logistic regression models including matching factors (country, maternal birth year) and parity. Hypertension diagnosed before pregnancy (OR 0.87; 95% CI 0.78-0.97), gestational hypertension (OR 0.90; 95% CI 0.86-0.93) and preeclampsia (OR 0.91; 95% CI 0.88-0.95) were associated with reduced breast cancer risk. Results remained similar after adjustment for smoking and maternal body mass index before first pregnancy, and were generally similar stratified by parity, age at breast cancer diagnosis, time since first and last birth, sex of the offspring and calendar time. Except for retained placenta (OR 1.14; 95% CI 0.98-1.32), no other pregnancy complication appeared associated with breast cancer risk. The mechanisms mediating the modest risk reductions for history of preeclampsia or hypertension preceding or arising during pregnancy, and possible increased risk with history of retained placenta are unknown and warrant further laboratory, clinical and epidemiological investigation.

Abstract 3007: Monogenic and polygenic associations with subsequent breast cancer risk in survivors of childhood cancer: The St. Jude Lifetime Cohort Study (SJLIFE)

Abstract The allelic spectrum of the genetic architecture of breast cancer (BC) susceptibility includes at least 172 common variants with small effect sizes (per-allele odds ratio range: 1.03-1.31), plus rare variants with high (BRCA1, BRCA2, CHD1, PTEN, STK11, TP53) or moderate penetrance (ATM, CHEK2, NBN, NF1, PALB2). While these common variants confer modest risk individually, their combined effect in the form of a polygenic risk score (PRS) may be substantial. The SJLIFE whole-genome sequencing (WGS) data provide a unique opportunity to evaluate common and rare sets of genetic variants jointly, along with treatment exposures, for their contributions to subsequent BC risk in adult survivors of childhood cancer. This analysis utilized WGS data from 1131 females of European ancestry [median age at last follow-up: 34.9 years (range: 6.2-68.6)] of whom 47 were diagnosed with a subsequent BC (median age at BC 40.3 years, range: 25.5-53.0). The PRS (mean, 10.1; range, 8.3-12.2) was calculated using a weighted sum of the number of risk alleles and their log per-allele odds ratio from Michailidou et al. (Nature, Nov. 2017). A total of 34 (3.0%) survivors were carriers of pathogenic or likely pathogenic (P/LP) variants in the 11 BC predisposition genes (listed above). The standardized incidence ratio (SIR) for BC was 6.7 (95% CI, 5.0-8.9) for survivors relative to the SEER population. The SIR varied from 3.7 (95% CI, 1.4-8.1) for survivors with PRS in the 1st quintile to 3.6 (95% CI, 1.2-8.3), 7.3 (95% CI, 3.8-12.7), 7.6 (95% CI, 3.6-14.0), and 11.4 (95% CI, 6.8-18.1) in the 2nd, 3rd, 4th, and 5th quintiles, respectively. In the multivariable model adjusting for age at diagnosis, chest irradiation, alkylating agents, anthracyclines, attained age, and significant genotype eigenvectors, the relative rates (RR) of BC were 16.5 (95% CI, 6.4 - 42.6), 11.5 (95% CI, 4.4-29.9), and 47.8 (95% CI, 8.2-278.3) for carriers vs. non-carriers of the P/LP variants among all survivors, and survivors with and without chest irradiation, respectively. The RR per one standard deviation of PRS were 1.5 (95% CI, 1.1-1.9), 1.6 (95% CI, 1.2-2.0) and 1.3 (95% CI, 0.7-2.2), respectively, for the same three groups. Importantly, PRS was significantly associated with the rate of subsequent BC under the age of 45 (RR, 1.7; 95% CI, 1.3-2.2) but not over 45 (RR, 0.9; 95% CI, 0.6-1.5). To our knowledge, this is the first assessment of the joint effects of rare and common genetic variations implicated in the etiology of BC in the general population, among long-term survivors of childhood cancer. Clinically, we anticipate that an individual genetic profile utilizing common susceptibility loci in combination with rare P/LP variants will inform an improved strategy for personalized BC risk stratification and management for childhood cancer survivors. Further replication studies are warranted to confirm and refine our findings. Citation Format: Zhaoming Wang, Carmen L. Wilson, Qi Liu, John Easton, Heather L. Mulder, Michael Rusch, Michael Edmonson, Shawn Levy, Aman Patel, Ying Shao, Ti-Cheng Chang, Stephen V. Rice, Yadav Sapkota, Russell J. Brooke, Wonjong Moon, Evadnie Rampersaud, Xiaotu Ma, Cynthia Pepper, Xin Zhou, Xiang Chen, Wenan Chen, Angela Jones, Braden Boone, Matthew J. Ehrhardt, Rebecca M. Howell, Nicholas Phillips, Courtney Lewis, Chimene A. Kesserwan, Gang Wu, Kim E. Nichols, James R. Downing, Melissa M. Hudson, Jinghui Zhang, Yutaka Yasui, Leslie L. Robison. Monogenic and polygenic associations with subsequent breast cancer risk in survivors of childhood cancer: The St. Jude Lifetime Cohort Study (SJLIFE) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3007.