Long-term cardiovascular disease risk after anthracycline and trastuzumab treatments in U.S. breast cancer survivors.

BACKGROUND: Although breast cancer survivors are at risk for cardiovascular disease (CVD) from treatment late effects, evidence to inform long-term and age-specific cardiovascular surveillance recommendations is lacking. METHODS: We conducted a retrospective cohort study of 10,211 women diagnosed with first primary unilateral breast cancer in Kaiser Permanente Washington or Colorado (aged 20+, survived ≥1 year). We estimated multivariable adjusted hazard ratios (aHR) for associations between initial chemotherapy regimen type (anthracycline and/or trastuzumab, other chemotherapies, no chemotherapy [reference]) and CVD risk, adjusted for patient characteristics, other treatments, and CVD risk factors. Cumulative incidence was calculated considering competing events. RESULTS: After 5.79 median years, 14.67% of women developed CVD (cardiomyopathy/heart failure (CM/HF), ischemic heart disease (IHD), stroke). Women treated with anthracyclines and/or trastuzumab had a higher risk of CVD compared with no chemotherapy (aHR=1.53,95%CI=1.31-1.79), persisting 5+years post-diagnosis (aHR5-<10 years=1.85,95%CI=1.44-2.39;aHR10+ years=1.83,95%CI=1.34-2.49). CM/HF risks were elevated among women treated with anthracyclines and/or trastuzumab compared with no chemotherapy, especially for ages<65 (aHR20-54years=2.97,95%CI=1.72-5.12;aHR55-64years=2.21,95%CI=1.52-3.21), differing for older women (aHR65+years=1.32,95%CI=0.97-1.78), and 5+years post-diagnosis (aHR5-<10years=1.89,95%CI=1.35-2.64;aHR10+years=2.21,95%CI=1.52-3.20). Anthracyclines and/or trastuzumab receipt was associated with increased IHD risks after 5+years (aHR5-<10years=1.51,95%CI=1.06-2.14;aHR10+years=1.86,95%CI=1.18-2.93) with no clear age effects, and stroke risk (aHR=1.33,95%CI=1.05-1.69) which did not vary by time or age. There was some evidence of long-term CM/HF and IHD risks with other chemotherapies. Among women aged<65 treated with anthracyclines and/or trastuzumab, up to 16% developed CVD by 10-years (20-54=6.91%;55-64=16.00%), driven by CM/HF (20-54=3.90%;55-64=9.78%). CONCLUSIONS: We found increased long-term risks of CM/HF and IHD among breast cancer survivors treated with anthracyclines and/or trastuzumab, and increased CM/HF risk among women aged<65.

Proteogenomic analysis of enriched HGSOC tumor epithelium identifies prognostic signatures and therapeutic vulnerabilities.

We performed a deep proteogenomic analysis of bulk tumor and laser microdissection enriched tumor cell populations from high-grade serous ovarian cancer (HGSOC) tissue specimens spanning a broad spectrum of purity. We identified patients with longer progression-free survival had increased immune-related signatures and validated proteins correlating with tumor-infiltrating lymphocytes in 65 tumors from an independent cohort of HGSOC patients, as well as with overall survival in an additional 126 HGSOC patient cohort. We identified that homologous recombination deficient (HRD) tumors are enriched in pathways associated with metabolism and oxidative phosphorylation that we validated in independent patient cohorts. We further identified that polycomb complex protein BMI-1 is elevated in HR proficient (HRP) tumors, that elevated BMI-1 correlates with poor overall survival in HRP but not HRD HGSOC patients, and that HRP HGSOC cells are uniquely sensitive to BMI-1 inhibition.

Differences in polygenic score distributions in European ancestry populations: implications for breast cancer risk prediction.

The 313-variant polygenic risk score (PRS313) provides a promising tool for breast cancer risk prediction. However, evaluation of the PRS313 across different European populations which could influence risk estimation has not been performed. Here, we explored the distribution of PRS313 across European populations using genotype data from 94,072 females without breast cancer, of European-ancestry from 21 countries participating in the Breast Cancer Association Consortium (BCAC) and 225,105 female participants from the UK Biobank. The mean PRS313 differed markedly across European countries, being highest in south-eastern Europe and lowest in north-western Europe. Using the overall European PRS313 distribution to categorise individuals leads to overestimation and underestimation of risk in some individuals from south-eastern and north-western countries, respectively. Adjustment for principal components explained most of the observed heterogeneity in mean PRS. Country-specific PRS distributions may be used to calibrate risk categories in individuals from different countries.

A population-level digital histologic biomarker for enhanced prognosis of invasive breast cancer.

Breast cancer is a heterogeneous disease with variable survival outcomes. Pathologists grade the microscopic appearance of breast tissue using the Nottingham criteria, which are qualitative and do not account for noncancerous elements within the tumor microenvironment. Here we present the Histomic Prognostic Signature (HiPS), a comprehensive, interpretable scoring of the survival risk incurred by breast tumor microenvironment morphology. HiPS uses deep learning to accurately map cellular and tissue structures to measure epithelial, stromal, immune, and spatial interaction features. It was developed using a population-level cohort from the Cancer Prevention Study-II and validated using data from three independent cohorts, including the Prostate, Lung, Colorectal, and Ovarian Cancer trial, Cancer Prevention Study-3, and The Cancer Genome Atlas. HiPS consistently outperformed pathologists in predicting survival outcomes, independent of tumor-node-metastasis stage and pertinent variables. This was largely driven by stromal and immune features. In conclusion, HiPS is a robustly validated biomarker to support pathologists and improve patient prognosis.

Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel.

BACKGROUND: Polygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women. METHODS: We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel. RESULTS: In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28). CONCLUSIONS: Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women.

A population-level computational histologic signature for invasive breast cancer prognosis.

Breast cancer is a heterogeneous disease with variable survival outcomes. Pathologists grade the microscopic appearance of breast tissue using the Nottingham criteria, which is qualitative and does not account for non-cancerous elements within the tumor microenvironment (TME). We present the Histomic Prognostic Signature (HiPS), a comprehensive, interpretable scoring of the survival risk incurred by breast TME morphology. HiPS uses deep learning to accurately map cellular and tissue structures in order to measure epithelial, stromal, immune, and spatial interaction features. It was developed using a population-level cohort from the Cancer Prevention Study (CPS)-II and validated using data from three independent cohorts, including the PLCO trial, CPS-3, and The Cancer Genome Atlas. HiPS consistently outperformed pathologists' performance in predicting survival outcomes, independent of TNM stage and pertinent variables. This was largely driven by stromal and immune features. In conclusion, HiPS is a robustly validated biomarker to support pathologists and improve prognosis.

Risk of second primary cancer among women in the Kaiser Permanente Breast Cancer Survivors Cohort.

BACKGROUND: Breast cancer survivors are living longer due to early detection and advances in treatment and are at increased risk for second primary cancers. Comprehensive evaluation of second cancer risk among patients treated in recent decades is lacking. METHODS: We identified 16,004 females diagnosed with a first primary stage I-III breast cancer between 1990 and 2016 (followed through 2017) and survived ≥ 1 year at Kaiser Permanente (KP) Colorado, Northwest, and Washington. Second cancer was defined as an invasive primary cancer diagnosed ≥ 12 months after the first primary breast cancer. Second cancer risk was evaluated for all cancers (excluding ipsilateral breast cancer) using standardized incidence ratios (SIRs), and a competing risk approach for cumulative incidence and hazard ratios (HRs) adjusted for KP center, treatment, age, and year of first cancer diagnosis. RESULTS: Over a median follow-up of 6.2 years, 1,562 women developed second cancer. Breast cancer survivors had a 70% higher risk of any cancer (95%CI = 1.62-1.79) and 45% higher risk of non-breast cancer (95%CI = 1.37-1.54) compared with the general population. SIRs were highest for malignancies of the peritoneum (SIR = 3.44, 95%CI = 1.65-6.33), soft tissue (SIR = 3.32, 95%CI = 2.51-4.30), contralateral breast (SIR = 3.10, 95%CI = 2.82-3.40), and acute myeloid leukemia (SIR = 2.11, 95%CI = 1.18-3.48)/myelodysplastic syndrome (SIR = 3.25, 95%CI = 1.89-5.20). Women also had elevated risks for oral, colon, pancreas, lung, and uterine corpus cancer, melanoma, and non-Hodgkin lymphoma (SIR range = 1.31-1.97). Radiotherapy was associated with increased risk for all second cancers (HR = 1.13, 95%CI = 1.01-1.25) and soft tissue sarcoma (HR = 2.36, 95%CI = 1.17-4.78), chemotherapy with decreased risk for all second cancers (HR = 0.87, 95%CI = 0.78-0.98) and increased myelodysplastic syndrome risk (HR = 3.01, 95%CI = 1.01-8.94), and endocrine therapy with lower contralateral breast cancer risk (HR = 0.48, 95%CI = 0.38-0.60). Approximately 1 in 9 women who survived ≥ 1 year developed second cancer, 1 in 13 developed second non-breast cancer, and 1 in 30 developed contralateral breast cancer by 10 years. Trends in cumulative incidence declined for contralateral breast cancer but not for second non-breast cancers. CONCLUSIONS: Elevated risks of second cancer among breast cancer survivors treated in recent decades suggests that heightened surveillance is warranted and continued efforts to reduce second cancers are needed.

In utero exposure to diethylstilbestrol and blood DNA methylation in adult women: Results from a meta-analysis of two cohort studies.

BACKGROUND: Prenatal exposure to diethylstilbestrol (DES) is associated with several adverse health outcomes. Animal studies have shown associations between prenatal DES exposure and DNA methylation. OBJECTIVE: The aim of this study was to explore blood DNA methylation in women exposed and unexposed to DES in utero. METHODS: Sixty women (40 exposed and 20 unexposed) in the National Cancer Institute's Combined DES Cohort Study and 199 women (99 exposed and 100 unexposed women) in the Sister Study Cohort were included in this analysis. Within each study, robust linear regression models were used to assess associations between DES exposure and blood DNA methylation. Study-specific associations were combined using fixed-effect meta-analysis with inverse variance weights. Our analysis focused on CpG sites located within nine candidate genes identified in animal models. We further explored whether in utero DES exposure was associated with age acceleration. RESULTS: Blood DNA methylation levels at 10 CpG sites in six of the nine candidate genes were statistically significantly associated with prenatal DES exposure (P < 0.05) in this meta-analysis. Genes included EGF, EMB, EGFR, WNT11, FOS, and TGFB1, which are related to cell proliferation and differentiation. The most statistically significant CpG site was cg19830739 in gene EGF, and it was associated with lower methylation levels in women prenatally exposed to DES compared with those not exposed (P < 0.0001; false discovery rate<0.05). The association between prenatal DES exposure in utero and age acceleration was not statistically significant (P = 0.07 for meta-analyzed results). CONCLUSIONS: There are few opportunities to investigate the effects of prenatal DES exposure. These findings suggest that in utero DES exposure may be associated with differential blood DNA methylation levels, which could mediate the increased risk of several adverse health outcomes observed in exposed women. Our findings need further evaluation using larger data sets.

DNA methylation age in paired tumor and adjacent normal breast tissue in Chinese women with breast cancer.

BACKGROUND: Few studies have examined epigenetic age acceleration (AA), the difference between DNA methylation (DNAm) predicted age and chronological age, in relation to somatic genomic features in paired cancer and normal tissue, with less work done in non-European populations. In this study, we aimed to examine DNAm age and its associations with breast cancer risk factors, subtypes, somatic genomic profiles including mutation and copy number alterations and other aging markers in breast tissue of Chinese breast cancer (BC) patients from Hong Kong. METHODS: We performed genome-wide DNA methylation profiling of 196 tumor and 188 paired adjacent normal tissue collected from Chinese BC patients in Hong Kong (HKBC) using Illumina MethylationEPIC array. The DNAm age was calculated using Horvath's pan-tissue clock model. Somatic genomic features were based on data from RNA sequencing (RNASeq), whole-exome sequencing (WES), and whole-genome sequencing (WGS). Pearson's correlation (r), Kruskal-Wallis test, and regression models were used to estimate associations of DNAm AA with somatic features and breast cancer risk factors. RESULTS: DNAm age showed a stronger correlation with chronological age in normal (Pearson r = 0.78, P < 2.2e-16) than in tumor tissue (Pearson r = 0.31, P = 7.8e-06). Although overall DNAm age or AA did not vary significantly by tissue within the same individual, luminal A tumors exhibited increased DNAm AA (P = 0.004) while HER2-enriched/basal-like tumors exhibited markedly lower DNAm AA (P = < .0001) compared with paired normal tissue. Consistent with the subtype association, tumor DNAm AA was positively correlated with ESR1 (Pearson r = 0.39, P = 6.3e-06) and PGR (Pearson r = 0.36, P = 2.4e-05) gene expression. In line with this, we found that increasing DNAm AA was associated with higher body mass index (P = 0.039) and earlier age at menarche (P = 0.035), factors that are related to cumulative exposure to estrogen. In contrast, variables indicating extensive genomic instability, such as TP53 somatic mutations, high tumor mutation/copy number alteration burden, and homologous repair deficiency were associated with lower DNAm AA. CONCLUSIONS: Our findings provide additional insights into the complexity of breast tissue aging that is associated with the interaction of hormonal, genomic, and epigenetic mechanisms in an East Asian population.

Treatment-related thoracic soft tissue sarcomas in US breast cancer survivors: a retrospective cohort study.

BACKGROUND: Soft tissue sarcoma is a rare but serious side-effect of radiotherapy to treat breast cancer, and rates are increasing in the USA. We evaluated potential co-factors in two complimentary cohorts of US breast cancer survivors. METHODS: In this retrospective cohort study, we sourced data from the Kaiser Permanente (KP) cohort and the Surveillance, Epidemiology, and End Results (SEER) 13 registries cohort, both in the USA. The KP cohort included 15 940 women diagnosed with breast cancer from Jan 1, 1990, to Dec 31, 2016, in KP Colorado, KP Northwest (which serves Oregon and Southwest Washington state), or KP Washington, with detailed treatment data and comorbidities (including hypertension and diabetes at or before breast cancer diagnosis) from electronic medical records. The SEER cohort included 457 300 women diagnosed with breast cancer from Jan 1, 1992, to Dec 31, 2016, within the 13 SEER registries across the USA, with initial treatment data (yes vs no or unknown). Eligibility criteria in both cohorts were female breast cancer survivors (stage I-III) aged 20-84 years at diagnosis who had breast cancer surgery, and had survived at least 1 year after breast cancer diagnosis. The outcome of interest was any second thoracic soft tissue sarcoma (angiosarcomas and other subtypes) that developed at least 1 year after breast cancer diagnosis. Risk factors for thoracic soft tissue sarcoma were assessed using multivariable Poisson regression models. FINDINGS: In the KP cohort, median follow-up was 9·3 years (IQR 5·7-13·9) and 19 (0·1%) of 15 940 eligible, evaluable women developed a thoracic soft tissue sarcoma (11 angiosarcomas, eight other subtypes). Most (94·7%; 18 of 19) thoracic soft tissue sarcomas occurred in women treated with radiotherapy; thus, radiotherapy was associated with a significantly increased risk of developing a thoracic soft tissue sarcoma (relative risk [RR] 8·1 [95% CI 1·1-60·4]; p=0·0052), but there was no association with prescribed dose, fractionation, or boost. The RR of angiosarcoma after anthracyclines was 3·6 (95% CI 1·0-13·3; p=0·058). Alkylating agents were associated with an increased risk of developing other sarcomas (RR 7·7 [95% CI 1·2-150·8]; p=0·026). History of hypertension (RR 4·8 [95% CI 1·3-17·6]; p=0·017) and diabetes (5·3 [1·4-20·8]; p=0·036) were each associated with around a five-times increased risk of angiosarcoma. In the SEER cohort, 430 (0·1%) of 457 300 patients had subsequent thoracic soft tissue sarcomas (268 angiosarcomas and 162 other subtypes) after a median follow-up of 8·3 years (IQR 4·3-13·9). Most (77·9%; 335 of 430) cases occurred after radiotherapy; thus, radiotherapy was associated with a significantly increased risk of developing a thoracic soft tissue sarcoma (RR 3·0 [95% CI 2·4-3·8]; p<0·0001) and, for angiosarcomas, the RR for breast-conserving surgery plus radiotherapy versus mastectomy plus radiotherapy was 1·9 (1·1-3·3; p=0·012). By 10 years after radiotherapy, the cumulative incidence of thoracic soft tissue sarcoma was 0·21% (95% CI 0·12-0·34) in the KP cohort and 0·15% (95% CI 0·13-0·17) in SEER. INTERPRETATION: Radiotherapy was the strongest risk factor for thoracic soft tissue sarcoma in both cohorts. This finding, along with the novel findings for diabetes and hypertension as potential risk factors for angiosarcomas, warrant further investigation as potential targets for prevention strategies and increased surveillance. FUNDING: US National Cancer Institute and National Institutes of Health.

Methylation-based markers of aging and lifestyle-related factors and risk of breast cancer: a pooled analysis of four prospective studies.

BACKGROUND: DNA methylation in blood may reflect adverse exposures accumulated over the lifetime and could therefore provide potential improvements in the prediction of cancer risk. A substantial body of research has shown associations between epigenetic aging and risk of disease, including cancer. Here we aimed to study epigenetic measures of aging and lifestyle-related factors in association with risk of breast cancer. METHODS: Using data from four prospective case-control studies nested in three cohorts of European ancestry participants, including a total of 1,655 breast cancer cases, we calculated three methylation-based measures of lifestyle factors (body mass index [BMI], tobacco smoking and alcohol consumption) and seven measures of epigenetic aging (Horvath-based, Hannum-based, PhenoAge and GrimAge). All measures were regression-adjusted for their respective risk factors and expressed per standard deviation (SD). Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional or unconditional logistic regression and pooled using fixed-effects meta-analysis. Subgroup analyses were conducted by age at blood draw, time from blood sample to diagnosis, oestrogen receptor-positivity status and tumour stage. RESULTS: None of the measures of epigenetic aging were associated with risk of breast cancer in the pooled analysis: Horvath 'age acceleration' (AA): OR per SD = 1.02, 95%CI: 0.95-1.10; AA-Hannum: OR = 1.03, 95%CI:0.95-1.12; PhenoAge: OR = 1.01, 95%CI: 0.94-1.09 and GrimAge: OR = 1.03, 95%CI: 0.94-1.12, in models adjusting for white blood cell proportions, body mass index, smoking and alcohol consumption. The BMI-adjusted predictor of BMI was associated with breast cancer risk, OR per SD = 1.09, 95%CI: 1.01-1.17. The results for the alcohol and smoking methylation-based predictors were consistent with a null association. Risk did not appear to substantially vary by age at blood draw, time to diagnosis or tumour characteristics. CONCLUSION: We found no evidence that methylation-based measures of aging, smoking or alcohol consumption were associated with risk of breast cancer. A methylation-based marker of BMI was associated with risk and may provide insights into the underlying associations between BMI and breast cancer.

Mammographic Density Decline, Tamoxifen Response, and Prognosis by Molecular Characteristics of Estrogen Receptor-Positive Breast Cancer.

BACKGROUND: Mammographic breast density (MBD) decline post-tamoxifen initiation is a favorable prognostic factor in estrogen receptor (ER)-positive breast cancer (BC) and has potential utility as a biomarker of tamoxifen response. However, the prognostic value of MBD decline may vary by molecular characteristics among ER-positive patients. METHODS: We investigated associations between MBD decline (≥10% vs <10%) and breast cancer-specific mortality (BCSM) among ER-positive breast cancer patients aged 36-87 years at diagnosis treated with tamoxifen at Kaiser Permanente Northwest (1990-2008). Patients who died of BC (case patients; n = 62) were compared with those who did not (control patients; n = 215) overall and by tumor molecular characteristics (immunohistochemistry [IHC]-based subtype [luminal A-like: ER-positive/progesterone receptor [PR]-positive/HER2-negative/low Ki67; luminal B-like: ER-positive and 1 or more of PR-negative, HER2-positive, high Ki67] and modified IHC [mIHC]-based recurrence score of ER/PR/Ki67). Percent MBD was measured in the unaffected breast at baseline mammogram (mean = 6 months before tamoxifen initiation) and follow-up (mean = 12 months post-tamoxifen initiation). Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed from logistic regression models. All statistical tests were 2-sided. RESULTS: MBD decline was statistically significantly associated with reduced risk of BCSM overall (OR = 0.38, 95% CI = 0.15 to 0.92). This association was, however, stronger among women with aggressive tumor characteristics including luminal B-like (OR = 0.17, 95% CI = 0.04 to 0.73) vs A-like (OR = 0.74, 95% CI = 0.19 to 2.92); large (OR = 0.26, 95% CI = 0.08 to 0.78) vs small (OR = 0.41, 95% CI = 0.04 to 3.79) tumors; PR-negative (OR = 0.02, 95% CI = 0.001 to 0.37) vs PR-positive (OR = 0.50, 95% CI = 0.18 to 1.40) disease; and high (OR = 0.25, 95% CI = 0.07 to 0.93) vs low (OR = 0.44, 95% CI = 0.10 to 2.09) mIHC3 score. CONCLUSION: The findings support MBD decline as a prognostic marker of tamoxifen response among patients with aggressive ER-positive BC phenotypes, for whom understanding treatment effectiveness is critical.

The influence of treatment on hormone receptor subgroups and breast cancer-specific mortality within US integrated healthcare systems.

PURPOSE: Estrogen receptor (ER) + /progesterone receptor (PR) - or ER-/PR + breast cancer prognosis has not been well-described outside of clinical trials. We evaluated the relationship between ER/PR (ER + /PR-, ER-/PR + , ER + /PR + , ER-/PR-) subgroups and breast cancer-specific mortality within a general community setting in the US. METHODS: A Retrospective cohort of 11,737 women diagnosed with breast cancer between 1990 and 2016 within US integrated healthcare systems (median follow-up = 7 years; 1,104 breast cancer-specific deaths) were included in this analysis. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) adjusting for site, demographic and clinicopathological characteristics, and treatment (surgery/radiotherapy, chemotherapy, endocrine therapy). RESULTS: Breast cancer-specific mortality was higher for those with ER + /PR- (n = 1,233) compared with ER + /PR + tumors (n = 8,439) before (HR = 1.43; 95% CI = 1.17-1.75) and after treatment adjustment (HR = 1.58; 95% CI = 1.27-1.97). ER + /PR- breast cancer-specific mortality remained higher than ER + /PR + tumors when stratified by treatment received. Breast cancer-specific mortality was similar in ER-/PR + (n = 161) compared with ER + /PR + tumors. CONCLUSION: Our findings suggest that ER + /PR- tumors may have worse breast cancer-specific mortality than ER + /PR + tumors in a community setting.

Endocrine therapy initiation among women with stage I-III invasive, hormone receptor-positive breast cancer from 2001-2016.

PURPOSE: This retrospective cohort study examined patterns of endocrine therapy initiation over time and by demographic, tumor, and treatment characteristics. METHODS: We included 7777 women from three U.S. integrated healthcare systems diagnosed with incident stage I-III hormone receptor-positive breast cancer between 2001 and 2016. We extracted endocrine therapy from pharmacy dispensings, defining initiation as dispensings within 12 months of diagnosis. Demographic, tumor, and treatment characteristics were collected from electronic health records. Using generalized linear models with a log link and Poisson distribution, we estimated initiation of any endocrine therapy, tamoxifen, and aromatase inhibitors (AI) over time with relative risks (RR) and 95% confidence intervals (CI) adjusted for age, tumor characteristics, diagnosis year, other treatment, and study site. RESULTS: Among women aged 20+ (mean 62 years), 6329 (81.4%) initiated any endocrine therapy, and 1448 (18.6%) did not initiate endocrine therapy. Tamoxifen initiation declined from 67 to 15% between 2001 and 2016. AI initiation increased from 6 to 69% between 2001 and 2016 in women aged ≥ 55 years. The proportion of women who did not initiate endocrine therapy decreased from 19 to 12% between 2002 and 2014 then increased to 17% by 2016. After adjustment, women least likely to initiate endocrine therapy were older (RR = 0.81, 95% CI 0.77-0.85 for age 75+ vs. 55-64), Black (RR = 0.93, 95% CI 0.87-1.00 vs. white), and had stage I disease (RR = 0.88, 95% CI 0.85-0.91 vs. stage III). CONCLUSIONS: Despite an increase in AI use over time, at least one in six eligible women did not initiate endocrine therapy, highlighting opportunities for improving endocrine therapy uptake in breast cancer survivors.

Mammary collagen architecture and its association with mammographic density and lesion severity among women undergoing image-guided breast biopsy.

BACKGROUND: Elevated mammographic breast density is a strong breast cancer risk factor with poorly understood etiology. Increased deposition of collagen, one of the main fibrous proteins present in breast stroma, has been associated with increased mammographic density. Collagen fiber architecture has been linked to poor outcomes in breast cancer. However, relationships of quantitative collagen fiber features assessed in diagnostic biopsies with mammographic density and lesion severity are not well-established. METHODS: Clinically indicated breast biopsies from 65 in situ or invasive breast cancer cases and 73 frequency matched-controls with a benign biopsy result were used to measure collagen fiber features (length, straightness, width, alignment, orientation and density (fibers/µm2)) using second harmonic generation microscopy in up to three regions of interest (ROIs) per biopsy: normal, benign breast disease, and cancer. Local and global mammographic density volumes were quantified in the ipsilateral breast in pre-biopsy full-field digital mammograms. Associations of fibrillar collagen features with mammographic density and severity of biopsy diagnosis were evaluated using generalized estimating equation models with an independent correlation structure to account for multiple ROIs within each biopsy section. RESULTS: Collagen fiber density was positively associated with the proportion of stroma on the biopsy slide (p < 0.001) and with local percent mammographic density volume at both the biopsy target (p = 0.035) and within a 2 mm perilesional ring (p = 0.02), but not with global mammographic density measures. As severity of the breast biopsy diagnosis increased at the ROI level, collagen fibers tended to be less dense, shorter, straighter, thinner, and more aligned with one another (p < 0.05). CONCLUSIONS: Collagen fiber density was positively associated with local, but not global, mammographic density, suggesting that collagen microarchitecture may not translate into macroscopic mammographic features. However, collagen fiber features may be markers of cancer risk and/or progression among women referred for biopsy based on abnormal breast imaging.

Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies candidate susceptibility genes for breast and ovarian cancer.

Familial, sequencing, and genome-wide association studies (GWASs) and genetic correlation analyses have progressively unraveled the shared or pleiotropic germline genetics of breast and ovarian cancer. In this study, we aimed to leverage this shared germline genetics to improve the power of transcriptome-wide association studies (TWASs) to identify candidate breast cancer and ovarian cancer susceptibility genes. We built gene expression prediction models using the PrediXcan method in 681 breast and 295 ovarian tumors from The Cancer Genome Atlas and 211 breast and 99 ovarian normal tissue samples from the Genotype-Tissue Expression project and integrated these with GWAS meta-analysis data from the Breast Cancer Association Consortium (122,977 cases/105,974 controls) and the Ovarian Cancer Association Consortium (22,406 cases/40,941 controls). The integration was achieved through application of a pleiotropy-guided conditional/conjunction false discovery rate (FDR) approach in the setting of a TWASs. This identified 14 candidate breast cancer susceptibility genes spanning 11 genomic regions and 8 candidate ovarian cancer susceptibility genes spanning 5 genomic regions at conjunction FDR < 0.05 that were >1 Mb away from known breast and/or ovarian cancer susceptibility loci. We also identified 38 candidate breast cancer susceptibility genes and 17 candidate ovarian cancer susceptibility genes at conjunction FDR < 0.05 at known breast and/or ovarian susceptibility loci. The 22 genes identified by our cross-cancer analysis represent promising candidates that further elucidate the role of the transcriptome in mediating germline breast and ovarian cancer risk.

Lack of transgenerational effects of ionizing radiation exposure from the Chernobyl accident.

Effects of radiation exposure from the Chernobyl nuclear accident remain a topic of interest. We investigated germline de novo mutations (DNMs) in children born to parents employed as cleanup workers or exposed to occupational and environmental ionizing radiation after the accident. Whole-genome sequencing of 130 children (born 1987-2002) and their parents did not reveal an increase in the rates, distributions, or types of DNMs relative to the results of previous studies. We find no elevation in total DNMs, regardless of cumulative preconception gonadal paternal [mean = 365 milligrays (mGy), range = 0 to 4080 mGy] or maternal (mean = 19 mGy, range = 0 to 550 mGy) exposure to ionizing radiation. Thus, we conclude that, over this exposure range, evidence is lacking for a substantial effect on germline DNMs in humans, suggesting minimal impact from transgenerational genetic effects.

Risk factors for contralateral breast cancer in postmenopausal breast cancer survivors in the NIH-AARP Diet and Health Study.

PURPOSE: The role of established breast cancer risk factors and clinical characteristics of the first breast cancer in the development of contralateral breast cancer (CBC) among postmenopausal women is unclear. METHODS: We identified 10,934 postmenopausal women diagnosed with a first primary breast cancer between 1995 and 2011 in the NIH-AARP Diet and Health Study. CBC was defined as a second primary breast cancer diagnosed in the contralateral breast ≥ 3 months after the first breast cancer. Exposures included pre-diagnosis risk factors (lifestyle, reproductive, family history) and clinical characteristics of the first breast cancer. We used multivariable Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Over a median follow-up of 6.8 years, 436 women developed CBC. We observed an increasing trend in CBC risk by age (p-trend = 0.002) and decreasing trend by year of diagnosis (p-trend = 0.001) of the first breast cancer. Additional risk factor associations were most pronounced for endocrine therapy (HR 0.68, 95% CI 0.53-0.87) and family history of breast cancer (HR 1.38, 95% CI 1.06-1.80, restricted to invasive first breast cancer). No associations were found for lifestyle (body mass index, physical activity, smoking, alcohol) or reproductive factors (age at menarche, parity, age at first birth, age at menopause). CONCLUSIONS: This study suggests that clinical characteristics of the first breast cancer and family history of breast cancer, but not pre-diagnosis lifestyle and reproductive factors, are strongly associated with CBC risk among postmenopausal women. Future studies are needed to understand how these factors contribute to CBC etiology and to identify further opportunities for prevention.