Recommendations on statistical approaches to account for dose uncertainties in radiation epidemiologic risk models.

PURPOSE: Epidemiological studies of stochastic radiation health effects such as cancer, meant to estimate risks of the adverse effects as a function of radiation dose, depend largely on estimates of the radiation doses received by the exposed group under study. Those estimates are based on dosimetry that always has uncertainty, which often can be quite substantial. Studies that do not incorporate statistical methods to correct for dosimetric uncertainty may produce biased estimates of risk and incorrect confidence bounds on those estimates. This paper reviews commonly used statistical methods to correct radiation risk regressions for dosimetric uncertainty, with emphasis on some newer methods. We begin by describing the types of dose uncertainty that may occur, including those in which an uncertain value is shared by part or all of a cohort, and then demonstrate how these sources of uncertainty arise in radiation dosimetry. We briefly describe the effects of different types of dosimetric uncertainty on risk estimates, followed by a description of each method of adjusting for the uncertainty. CONCLUSIONS: Each of the method has strengths and weaknesses, and some methods have limited applicability. We describe the types of uncertainty to which each method can be applied and its pros and cons. Finally, we provide summary recommendations and touch briefly on suggestions for further research.

Agreement of medical record abstraction and self-report of breast cancer treatment with an extended recall window.

BACKGROUND: Medical record abstraction (MRA) and self-report questionnaires are two methods frequently used to ascertain cancer treatment information. Prior studies have shown excellent agreement between MRA and self-report, but it is unknown how a recall window longer than 3 years may affect this agreement. METHODS: The Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study is a multicenter, population-based case-control study of controls with unilateral breast cancer individually matched to cases with contralateral breast cancer. Participants who were diagnosed with a first primary breast cancer from 1985 to 2008 before the age of 55 years completed a questionnaire that included questions on treatment. First primary breast cancer treatment information was abstracted from the medical record from radiation oncology clinic notes for radiation treatment and from systemic adjuvant treatment reports for hormone therapy and chemotherapy. Agreement between MRA and self-reported treatment was assessed with the kappa statistic and corresponding 95% confidence intervals (CIs). RESULTS: A total of 2808 participants with MRA and self-reported chemotherapy treatment information, 2733 participants with MRA and self-reported hormone therapy information, and 2905 participants with MRA and self-reported radiation treatment information were identified. The median recall window was 12.5 years (range, 2.8-22.2 years). MRA and self-reported treatment agreement was excellent across treatment modalities (kappachemo, 98.5; 95% CI, 97.9-99.2; kappahorm, 87.7; 95% CI, 85.9-89.5; kapparad, 97.9; 95% CI, 97.0-98.7). There was no heterogeneity across recall windows (pchemo = .46; phorm = .40; prad = .61). CONCLUSIONS: Agreement between self-reported and MRA primary breast cancer treatment modality information was excellent for young women diagnosed with breast cancer and was maintained even among women whose recall window was more than 20 years after diagnosis.

Case-Case Genome-Wide Analyses Identify Subtype-Informative Variants That Confer Risk for Breast Cancer.

Breast cancer includes several subtypes with distinct characteristic biological, pathologic, and clinical features. Elucidating subtype-specific genetic etiology could provide insights into the heterogeneity of breast cancer to facilitate the development of improved prevention and treatment approaches. In this study, we conducted pairwise case-case comparisons among five breast cancer subtypes by applying a case-case genome-wide association study (CC-GWAS) approach to summary statistics data of the Breast Cancer Association Consortium. The approach identified 13 statistically significant loci and eight suggestive loci, the majority of which were identified from comparisons between triple-negative breast cancer (TNBC) and luminal A breast cancer. Associations of lead variants in 12 loci remained statistically significant after accounting for previously reported breast cancer susceptibility variants, among which, two were genome-wide significant. Fine mapping implicated putative functional/causal variants and risk genes at several loci, e.g., 3q26.31/TNFSF10, 8q22.3/NACAP1/GRHL2, and 8q23.3/LINC00536/TRPS1, for TNBC as compared with luminal cancer. Functional investigation further identified rs16867605 at 8q22.3 as a SNP that modulates the enhancer activity of GRHL2. Subtype-informative polygenic risk scores (PRS) were derived, and patients with a high subtype-informative PRS had an up to two-fold increased risk of being diagnosed with TNBC instead of luminal cancers. The CC-GWAS PRS remained statistically significant after adjusting for TNBC PRS derived from traditional case-control GWAS in The Cancer Genome Atlas and the African Ancestry Breast Cancer Genetic Consortium. The CC-GWAS PRS was also associated with overall survival and disease-specific survival among patients with breast cancer. Overall, these findings have advanced our understanding of the genetic etiology of breast cancer subtypes, particularly for TNBC. Significance: The discovery of subtype-informative genetic risk variants for breast cancer advances our understanding of the etiologic heterogeneity of breast cancer, which could accelerate the identification of targets and personalized strategies for prevention and treatment.

Association of breast cancer with quantitative mammographic density measures for women receiving contrast-enhanced mammography.

Women with high mammographic density have an increased risk of breast cancer. They may be offered contrast-enhanced mammography to improve breast cancer screening performance. Using a cohort of women receiving contrast-enhanced mammography, we evaluated whether conventional and modified mammographic density measures were associated with breast cancer. Sixty-six patients with newly diagnosed unilateral breast cancer were frequency matched on the basis of age to 133 cancer-free control individuals. On low-energy craniocaudal contrast-enhanced mammograms (equivalent to standard mammograms), we measured quantitative mammographic density using CUMULUS software at the conventional intensity threshold ("Cumulus") and higher-than-conventional thresholds ("Altocumulus," "Cirrocumulus"). The measures were standardized to enable estimation of odds ratio per adjusted standard deviation (OPERA). In multivariable logistic regression of case-control status, only the highest-intensity measure (Cirrocumulus) was statistically significantly associated with breast cancer (OPERA = 1.40, 95% confidence interval = 1.04 to 1.89). Conventional Cumulus did not contribute to model fit. For women receiving contrast-enhanced mammography, Cirrocumulus mammographic density may better predict breast cancer than conventional quantitative mammographic density.

A genome-wide association study of contralateral breast cancer in the Women's Environmental Cancer and Radiation Epidemiology Study.

BACKGROUND: Contralateral breast cancer (CBC) is the most common second primary cancer diagnosed in breast cancer survivors, yet the understanding of the genetic susceptibility of CBC, particularly with respect to common variants, remains incomplete. This study aimed to investigate the genetic basis of CBC to better understand this malignancy. FINDINGS: We performed a genome-wide association analysis in the Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study of women with first breast cancer diagnosed at age < 55 years including 1161 with CBC who served as cases and 1668 with unilateral breast cancer (UBC) who served as controls. We observed two loci (rs59657211, 9q32, SLC31A2/FAM225A and rs3815096, 6p22.1, TRIM31) with suggestive genome-wide significant associations (P < 1 × 10-6). We also found an increased risk of CBC associated with a breast cancer-specific polygenic risk score (PRS) comprised of 239 known breast cancer susceptibility single nucleotide polymorphisms (SNPs) (rate ratio per 1-SD change: 1.25; 95% confidence interval 1.14-1.36, P < 0.0001). The protective effect of chemotherapy on CBC risk was statistically significant only among patients with an elevated PRS (Pheterogeneity = 0.04). The AUC that included the PRS and known breast cancer risk factors was significantly elevated. CONCLUSIONS: The present GWAS identified two previously unreported loci with suggestive genome-wide significance. We also confirm that an elevated risk of CBC is associated with a comprehensive breast cancer susceptibility PRS that is independent of known breast cancer risk factors. These findings advance our understanding of genetic risk factors involved in CBC etiology.

Association of Breast Cancer Odds with Background Parenchymal Enhancement Quantified Using a Fully Automated Method at MRI: The IMAGINE Study.

Background Background parenchymal enhancement (BPE) at breast MRI has been associated with increased breast cancer risk in several independent studies. However, variability of subjective BPE assessments have precluded its use in clinical practice. Purpose To examine the association between fully objective measures of BPE at MRI and odds of breast cancer. Materials and Methods This prospective case-control study included patients who underwent a bilateral breast MRI examination and were receiving care at one of three centers in the United States from November 2010 to July 2017. Breast volume, fibroglandular tissue (FGT) volume, and BPE were quantified using fully automated software. Fat volume was defined as breast volume minus FGT volume. BPE extent was defined as the proportion of FGT voxels with enhancement of 20% or more. Spearman rank correlation between quantitative BPE extent and Breast Imaging Reporting and Data System (BI-RADS) BPE categories assigned by an experienced board-certified breast radiologist was estimated. With use of multivariable logistic regression, breast cancer case-control status was regressed on tertiles (low, moderate, and high) of BPE, FGT volume, and fat volume, with adjustment for covariates. Results In total, 536 case participants with breast cancer (median age, 48 years [IQR, 43-55 years]) and 940 cancer-free controls (median age, 46 years [IQR, 38-55 years]) were included. BPE extent was positively associated with BI-RADS BPE (rs = 0.54; P < .001). Compared with low BPE extent (range, 2.9%-34.2%), high BPE extent (range, 50.7%-97.3%) was associated with increased odds of breast cancer (odds ratio [OR], 1.74 [95% CI: 1.23, 2.46]; P for trend = .002) in a multivariable model also including FGT volume (OR, 1.39 [95% CI: 0.97, 1.98]) and fat volume (OR, 1.46 [95% CI: 1.04, 2.06]). The association of high BPE extent with increased odds of breast cancer was similar for premenopausal and postmenopausal women (ORs, 1.75 and 1.83, respectively; interaction P = .73). Conclusion Objectively measured BPE at breast MRI is associated with increased breast cancer odds for both premenopausal and postmenopausal women. Clinical trial registration no. NCT02301767 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Bokacheva in this issue.

Trends in Radiation Dose to the Contralateral Breast During Breast Cancer Radiation Therapy.

Over 4 million survivors of breast cancer live in the United States, 35% of whom were treated before 2009. Approximately half of patients with breast cancer receive radiation therapy, which exposes the untreated contralateral breast to radiation and increases the risk of a subsequent contralateral breast cancer (CBC). Radiation oncology has strived to reduce unwanted radiation dose, but it is unknown whether a corresponding decline in actual dose received to the untreated contralateral breast has occurred. The purpose of this study was to evaluate trends in unwanted contralateral breast radiation dose to inform risk assessment of second primary cancer in the contralateral breast for long-term survivors of breast cancer. Individually estimated radiation absorbed doses to the four quadrants and areola central area of the contralateral breast were estimated for 2,132 women treated with radiation therapy for local/regional breast cancers at age <55 years diagnosed between 1985 and 2008. The two inner quadrant doses and two outer quadrant doses were averaged. Trends in dose to each of the three areas of the contralateral breast were evaluated in multivariable models. The population impact of reducing contralateral breast dose on the incidence of radiation-associated CBC was assessed by estimating population attributable risk fraction (PAR) in a multivariable model. The median dose to the inner quadrants of the contralateral breast was 1.70 Gy; to the areola, 1.20 Gy; and to the outer quadrants, 0.72 Gy. Ninety-two percent of patients received ≥1 Gy to the inner quadrants. For each calendar year of diagnosis, dose declined significantly for each location, most rapidly for the inner quadrants (0.04 Gy/year). Declines in dose were similar across subgroups defined by age at diagnosis and body mass index. The PAR for CBC due to radiation exposure >1 Gy for women <40 years of age was 17%. Radiation dose-reduction measures have reduced dose to the contralateral breast during breast radiation therapy. Reducing the dose to the contralateral breast to <1 Gy could prevent an estimated 17% of subsequent radiation-associated CBCs for women treated under 40 years of age. These dose estimates inform CBC surveillance for the growing number of breast cancer survivors who received radiation therapy as young women in recent decades. Continued reductions in dose to the contralateral breast could further reduce the incidence of radiation-associated CBC.

The genomic landscape of familial glioma.

Glioma is a rare brain tumor with a poor prognosis. Familial glioma is a subset of glioma with a strong genetic predisposition that accounts for approximately 5% of glioma cases. We performed whole-genome sequencing on an exploratory cohort of 203 individuals from 189 families with a history of familial glioma and an additional validation cohort of 122 individuals from 115 families. We found significant enrichment of rare deleterious variants of seven genes in both cohorts, and the most significantly enriched gene was HERC2 (P = 0.0006). Furthermore, we identified rare noncoding variants in both cohorts that were predicted to affect transcription factor binding sites or cause cryptic splicing. Last, we selected a subset of discovered genes for validation by CRISPR knockdown screening and found that DMBT1, HP1BP3, and ZCH7B3 have profound impacts on proliferation. This study performs comprehensive surveillance of the genomic landscape of familial glioma.

The Contribution of Germline Pathogenic Variants in Breast Cancer Genes to Contralateral Breast Cancer Risk in BRCA1/BRCA2/PALB2-Negative Women.

BACKGROUND: Contralateral breast cancer (CBC) is associated with younger age at first diagnosis, family history and pathogenic germline variants (PGVs) in genes such as BRCA1, BRCA2 and PALB2. However, data regarding genetic factors predisposing to CBC among younger women who are BRCA1/2/PALB2-negative remain limited. METHODS: In this nested case-control study, participants negative for BRCA1/2/PALB2 PGVs were selected from the WECARE Study. The burden of PGVs in established breast cancer risk genes was compared in 357 cases with CBC and 366 matched controls with unilateral breast cancer (UBC). The samples were sequenced in two phases. Whole exome sequencing was used in Group 1, 162 CBC and 172 UBC (mean age at diagnosis: 42 years). A targeted panel of genes was used in Group 2, 195 CBC and 194 UBC (mean age at diagnosis: 50 years). Comparisons of PGVs burdens between CBC and UBC were made in these groups, and additional stratified sub-analysis was performed within each group according to the age at diagnosis and the time from first breast cancer (BC). RESULTS: The PGVs burden in Group 1 was significantly higher in CBC than in UBC (p = 0.002, OR = 2.5, 95CI: 1.2-5.6), driven mainly by variants in CHEK2 and ATM. The proportions of PGVs carriers in CBC and UBC in this group were 14.8% and 5.8%, respectively. There was no significant difference in PGVs burden between CBC and UBC in Group 2 (p = 0.4, OR = 1.4, 95CI: 0.7-2.8), with proportions of carriers being 8.7% and 8.2%, respectively. There was a significant association of PGVs in CBC with younger age. Metanalysis combining both groups confirmed the significant association between the burden of PGVs and the risk of CBC (p = 0.006) with the significance driven by the younger cases (Group 1). CONCLUSION: In younger BRCA1/BRCA2/PALB2-negative women, the aggregated burden of PGVs in breast cancer risk genes was associated with the increased risk of CBC and was inversely proportional to the age at onset.

MRI background parenchymal enhancement, breast density and breast cancer risk factors: A cross-sectional study in pre- and post-menopausal women.

Breast tissue enhances on contrast MRI and is called background parenchymal enhancement (BPE). Having high BPE has been associated with an increased risk of breast cancer. We examined the relationship between BPE and the amount of fibroglandular tissue on MRI (MRI-FGT) and breast cancer risk factors. This was a cross-sectional study of 415 women without breast cancer undergoing contrast-enhanced breast MRI at Memorial Sloan Kettering Cancer Center. All women completed a questionnaire assessing exposures at the time of MRI. Prevalence ratios (PR) and 95% confidence intervals (CI) describing the relationship between breast cancer risk factors and BPE and MRI-FGT were generated using modified Poisson regression. In multivariable-adjusted models a positive association between body mass index (BMI) and BPE was observed, with a 5-unit increase in BMI associated with a 14% and 44% increase in prevalence of high BPE in pre- and post-menopausal women, respectively. Conversely, a strong inverse relationship between BMI and MRI-FGT was observed in both pre- (PR = 0.66, 95% CI 0.57, 0.76) and post-menopausal (PR = 0.66, 95% CI 0.56, 0.78) women. Use of preventive medication (e.g., tamoxifen) was associated with having low BPE, while no association was observed for MRI-FGT. BPE is an imaging marker available from standard contrast-enhanced MRI, that is influenced by endogenous and exogenous hormonal exposures in both pre- and post-menopausal women.

Associations between circulating proteins and risk of breast cancer by intrinsic subtypes: a Mendelian randomisation analysis.

BACKGROUND: The aetiologic role of circulating proteins in the development of breast cancer subtypes is not clear. We aimed to examine the potential causal effects of circulating proteins on the risk of breast cancer by intrinsic-like subtypes within the Mendelian randomisation (MR) framework. METHODS: MR was performed using summary statistics from two sources: the INTERVAL protein quantitative trait loci (pQTL) Study (1890 circulating proteins and 3301 healthy individuals) and the Breast Cancer Association Consortium (BCAC; 106,278 invasive cases and 91,477 controls). The inverse-variance (IVW)-weighted method was used as the main analysis to evaluate the associations between genetically predicted proteins and the risk of five different intrinsic-like breast cancer subtypes and the weighted median MR method, the Egger regression, the MR-PRESSO, and the MRLocus method were performed as secondary analysis. RESULTS: We identified 98 unique proteins significantly associated with the risk of one or more subtypes (Benjamini-Hochberg false discovery rate < 0.05). Among them, 51 were potentially specific to luminal A-like subtype, 14 to luminal B/Her2-negative-like, 11 to triple negative, 3 to luminal B-like, and 2 to Her2-enriched-like breast cancer (ntotal = 81). Associations for three proteins (ICAM1, PLA2R1 and TXNDC12) showed evident heterogeneity across the subtypes. For example, higher levels of genetically predicted ICAM1 (per unit of increase) were associated with an increased risk of luminal B/HER2-negative-like cancer (OR = 1.06, 95% CI = 1.03-1.08, BH-FDR = 2.43 × 10-4) while inversely associated with triple-negative breast cancer with borderline significance (OR = 0.97, 95% CI = 0.95-0.99, BH-FDR = 0.065, Pheterogeneity < 0.005). CONCLUSIONS: Our study found potential causal associations with the risk of subtypes of breast cancer for 98 proteins. Associations of ICAM1, PLA2R1 and TXNDC12 varied substantially across the subtypes. The identified proteins may partly explain the heterogeneity in the aetiology of distinct subtypes of breast cancer and facilitate the personalised risk assessment of the malignancy.

Polygenic risk scores to stratify cancer screening should predict mortality not incidence.

Population-based cancer screening programs such as mammography or colonscopy generally directed at all healthy individuals in a given age stratum. It has recently been proposed that cancer screening could be restricted to a high-risk subgroup based on polygenic risk scores (PRSs) using panels of single-nucleotide polymorphisms (SNPs). These PRSs were, however, generated to predict cancer incidence rather than cancer mortality and will not necessarily address overdiagnosis, a major problem associated with cancer screening programs. We develop a simple net-benefit framework for evaluating screening approaches that incorporates overdiagnosis. We use this methodology to demonstrate that if a PRS does not differentially discriminate between incident and lethal cancer, restricting screening to a subgroup with high scores will only improve screening outcomes in a small number of scenarios. In contrast, restricting screening to a subgroup defined as high-risk based on a marker that is more strongly predictive of mortality than incidence will often afford greater net benefit than screening all eligible individuals. If PRS-based cancer screening is to be effective, research needs to focus on identifying PRSs associated with cancer mortality, an unchartered and clinically-relevant area of research, with a much higher potential to improve screening outcomes.

Association of contralateral breast cancer risk with mammographic density defined at higher-than-conventional intensity thresholds.

Mammographic dense area (MDA) is an established predictor of future breast cancer risk. Recent studies have found that risk prediction might be improved by redefining MDA in effect at higher-than-conventional intensity thresholds. We assessed whether such higher-intensity MDA measures gave stronger prediction of subsequent contralateral breast cancer (CBC) risk using the Women's Environment, Cancer, and Radiation Epidemiology (WECARE) Study, a population-based CBC case-control study of ≥1 year survivors of unilateral breast cancer diagnosed between 1990 and 2008. Three measures of MDA for the unaffected contralateral breast were made at the conventional intensity threshold ("Cumulus") and at two sequentially higher-intensity thresholds ("Altocumulus" and "Cirrocumulus") using the CUMULUS software and mammograms taken up to 3 years prior to the first breast cancer diagnosis. The measures were fitted separately and together in multivariable-adjusted logistic regression models of CBC (252 CBC cases and 271 unilateral breast cancer controls). The strongest association with CBC was MDA defined using the highest intensity threshold, Cirrocumulus (odds ratio per adjusted SD [OPERA] 1.40, 95% CI 1.13-1.73); and the weakest association was MDA defined at the conventional threshold, Cumulus (1.32, 95% CI 1.05-1.66). In a model fitting the three measures together, the association of CBC with Cirrocumulus was unchanged (1.40, 95% CI 0.97-2.05), and the lower brightness measures did not contribute to the CBC model fit. These results suggest that MDA defined at a high-intensity threshold is a better predictor of CBC risk and has the potential to improve CBC risk stratification beyond conventional MDA measures.

Cohort profile - MSK radiation workers: a feasibility study to establish a deceased worker sub-cohort as part of a multicenter medical radiation worker component in the million person study of low-dose radiation health effects.

BACKGROUND: The National Council on Radiation Protection and Measurements (NCRP) is coordinating an expansive epidemiologic effort entitled the Million Person Study of Low-Dose Radiation Health Effects (MPS). Medical workers constitute the largest occupational radiation-exposed group whose doses are typically received gradually over time. METHODS: A unique opportunity exists to establish an Institutional Review Board/Privacy Board (IRB/PB) approved, retrospective feasibility sub-cohort of diseased Memorial Sloan Kettering Cancer Center (MSK) medical radiation workers to reconstruct occupational/work history, estimate organ-specific radiation absorbed doses, and review existing publicly available records for mortality from cancer (including leukemia) and other diseases. Special emphasis will be placed on dose reconstruction approaches as a means to provide valid organ dose estimates that are as accurate and precise as possible based on the available data, and to allow proper evaluation of accompanying uncertainties. Such a study that includes validated dose measurements and information on radiation exposure conditions would significantly reduce dose uncertainties and provided greatly improved information on chronic low-dose risks. RESULTS: The feasibility sub-cohort will include deceased radiation workers from MSK who worked during the nearly seventy-year timeframe from 1946 through 2010 and were provided individual personal radiation dosimetry monitors. A feasibility assessment focused on obtaining records for about 25-30,000 workers, with over 124,000 annual doses, including personnel/work histories, specific dosimetry data, and appropriate information for epidemiologic mortality tracing will be conducted. MSK radiation dosimetry measurements have followed stringent protocols complying with strict worker protection standards in order to provide accurate dose information for radiation workers that include detailed records of work practices (including specific task exposure conditions, radiation type, energy, geometry, personal protective equipment usage, badge position, and missed doses), as well as recorded measurements. These dose measurements have been ascertained through a variety of techniques that have evolved over the years, from film badges to thermoluminescent dosimetry technology to optically stimulated luminescent methodologies. It is expected that individual total doses for the sub-cohort will have a broad range from <10 mSv to > =1000 mSv. CONCLUSIONS: MSK has pioneered the use of novel radiation diagnostic and therapeutic approaches over time (including initial work with x-rays, radium, and radon), with workplace safety in mind, resulting in a variety of radiation worker exposure scenarios. The results of this feasibility sub-cohort of deceased radiation workers, and associated lessons learned may potentially be applied to an expanded multicenter study of about 170,000 medical radiation worker component of the MPS.

First international workshop of the ATM and cancer risk group (4-5 December 2019).

The first International Workshop of the ATM and Cancer Risk group focusing on the role of Ataxia-Telangiectasia Mutated (ATM) gene in cancer was held on December 4 and 5, 2019 at Institut Curie in Paris, France. It was motivated by the fact that germline ATM pathogenic variants have been found to be associated with different cancer types. However, due to the lack of precise age-, sex-, and site-specific risk estimates, no consensus on management guidelines for variant carriers exists, and the clinical utility of ATM variant testing is uncertain. The meeting brought together epidemiologists, geneticists, biologists and clinicians to review current knowledge and on-going challenges related to ATM and cancer risk. This report summarizes the meeting sessions content that covered the latest results in family-based and population-based studies, the importance of accurate variant classification, the effect of radiation exposures for ATM variant carriers, and the characteristics of ATM-deficient tumors. The report concludes that ATM variant carriers outside of the context of Ataxia-Telangiectasia may benefit from effective cancer risk management and therapeutic strategies and that efforts to set up large-scale studies in the international framework to achieve this goal are necessary.

Smoking, Radiation Therapy, and Contralateral Breast Cancer Risk in Young Women.

Evidence is mounting that cigarette smoking contributes to second primary contralateral breast cancer (CBC) risk. Whether radiation therapy (RT) interacts with smoking to modify this risk is unknown. In this multicenter, individually matched, case-control study, we examined the association between RT, smoking, and CBC risk. The study included 1521 CBC cases and 2212 controls with unilateral breast cancer, all diagnosed with first invasive breast cancer between 1985 and 2008 aged younger than 55 years. Absorbed radiation doses to contralateral breast regions were estimated with thermoluminescent dosimeters in tissue-equivalent anthropomorphic phantoms, and smoking history was collected by interview. Rate ratios (RRs) and 95% confidence intervals (CIs) for CBC risk were estimated by multivariable conditional logistic regression. There was no interaction between any measure of smoking with RT to increase CBC risk (eg, the interaction of continuous RT dose with smoking at first breast cancer diagnosis [ever/never]: RR = 1.00, 95% CI = 0.89 to 1.14; continuous RT dose with years smoked: RR = 1.00, 95% CI = 0.99 to 1.01; and continuous RT dose with lifetime pack-years: RR = 1.00, 95% CI = 0.99 to 1.01). There was no evidence that RT further increased CBC risk in young women with first primary breast cancer who were current smokers or had smoking history.

Mammographic texture features associated with contralateral breast cancer in the WECARE Study.

To evaluate whether mammographic texture features were associated with second primary contralateral breast cancer (CBC) risk, we created a "texture risk score" using pre-treatment mammograms in a case-control study of 212 women with CBC and 223 controls with unilateral breast cancer. The texture risk score was associated with CBC (odds per adjusted standard deviation = 1.25, 95% CI 1.01-1.56) after adjustment for mammographic percent density and confounders. These results support the potential of texture features for CBC risk assessment of breast cancer survivors.

Coronary Artery Disease in Young Women After Radiation Therapy for Breast Cancer: The WECARE Study.

BACKGROUND: Radiation therapy (RT) for breast cancer increases risk of coronary artery disease (CAD). Women treated for left- vs right-sided breast cancer receive greater heart radiation exposure, which may further increase this risk. The risk of radiation-associated CAD specifically among younger breast cancer survivors is not well defined. OBJECTIVES: The purpose of this study was to report CAD risk among participants in the Women's Environmental Cancer and Radiation Epidemiology Study. METHODS: A total of 1,583 women who were <55 years of age when diagnosed with breast cancer between 1985 and 2008 completed a cardiovascular health questionnaire. Risk of radiation-associated CAD was evaluated by comparing women treated with left-sided RT with women treated with right-sided RT using multivariable Cox proportional hazards models. Effect modification by treatment and cardiovascular risk factors was examined. RESULTS: In total, 517 women who did not receive RT and 94 women who had a pre-existing cardiovascular disease diagnosis were excluded, leaving 972 women eligible for analysis. Their median follow-up time was 14 years (range 1-29 years). The 27.5-year cumulative incidences of CAD for women receiving left- vs right-sided RT were 10.5% and 5.8%, respectively (P = 0.010). The corresponding HR of CAD for left- vs right-sided RT in the multivariable Cox model was 2.5 (95% CI: 1.3-4.7). There was no statistically significant effect modification by any factor evaluated. CONCLUSIONS: Young women treated with RT for left-sided breast cancer had over twice the risk of CAD compared with women treated with RT for right-sided breast cancer. Laterality of RT is independently associated with an increased risk of CAD and should be considered in survivorship care of younger breast cancer patients.