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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.

Excess body fatness is an established risk factor for various types of chronic disease and all-cause mortality. Most previous studies are based on body mass index (BMI) as a general measure of adiposity, but whether measures of central adiposity that better represent metabolically active visceral fat, such as waist-to-height ratio (WtHR), may be better at predicting disease and mortality risks is less known. Data from a large, prospective cohort in the U.S. including 50,618 women and 43,783 men (mean age of 67.3 years, predominantly non-Hispanic White), among whom 21,565 women and 26,758 men died during follow-up (1997-2018), were used to calculate multivariable-adjusted hazard rate ratios and 95% CIs for WtHR, BMI, and waist circumference in relation to total and cause-specific mortality. WtHR was strongly correlated with BMI (r = 0.81). After adjustment for BMI and other covariates, WtHR (≥0.55 vs. < 0.50) was positively associated with all-cause mortality risk in women (RR = 1.23, 95% CI 1.17-1.29) and men (RR = 1.11, 95% CI 1.06-1.17). BMI and WC were also independently, positively associated with subsequent mortality risk at a similar magnitude to WtHR. Associations persisted for all grouped causes of death in women and men, with the exception of cancer and Alzheimer's disease mortality in men. Mortality associations with WtHR were generally stronger among individuals younger than age 70 years compared to older individuals. WtHR was associated with all-cause, cardiovascular disease, cancer, respiratory disease, and Alzheimer's disease mortality in women and men at a magnitude similar to BMI or WC. Excess adiposity is an established major risk factor for premature death, but different measures may better predict mortality in different populations defined by age or other factors.

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. 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. 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. 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. US National Cancer Institute and National Institutes of Health.

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/µm 2 )) 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.

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.

Background Environmental and genetic factors play an important role in the etiology of breast cancer. Several small blood-based DNA methylation studies have reported risk associations with methylation at individual CpGs and average methylation levels; however, these findings require validation in larger prospective cohort studies. To investigate the role of blood DNA methylation on breast cancer risk, we conducted a meta-analysis of four prospective cohort studies, including a total of 1663 incident cases and 1885 controls, the largest study of blood DNA methylation and breast cancer risk to date. Methods We assessed associations with methylation at 365,145 CpGs present in the HumanMethylation450 (HM450K) Beadchip, after excluding CpGs that did not pass quality controls in all studies. Each of the four cohorts estimated odds ratios (ORs) and 95% confidence intervals (CI) for the association between each individual CpG and breast cancer risk. In addition, each study assessed the association between average methylation measures and breast cancer risk, adjusted and unadjusted for cell-type composition. Study-specific ORs were combined using fixed-effect meta-analysis with inverse variance weights. Stratified analyses were conducted by age at diagnosis (< 50, ≥ 50), estrogen receptor (ER) status (+/−), and time since blood collection (< 5, 5–10, > 10 years). The false discovery rate ( q value) was used to account for multiple testing. Results The average age at blood draw ranged from 52.2 to 62.2 years across the four cohorts. Median follow-up time ranged from 6.6 to 8.4 years. The methylation measured at individual CpGs was not associated with breast cancer risk ( q value > 0.59). In addition, higher average methylation level was not associated with risk of breast cancer (OR = 0.94, 95% CI = 0.85, 1.05; P  = 0.26; P for study heterogeneity = 0.86). We found no evidence of modification of this association by age at diagnosis ( P  = 0.17), ER status ( P  = 0.88), time since blood collection ( P  = 0.98), or CpG location ( P  = 0.98). Conclusions Our data indicate that DNA methylation measured in the blood prior to breast cancer diagnosis in predominantly postmenopausal women is unlikely to be associated with substantial breast cancer risk on the HM450K array. Larger studies or with greater methylation coverage are needed to determine if associations exist between blood DNA methylation and breast cancer risk.

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.

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.

Objective To document incidence rates of vulvar cancer, specifically invasive vulvar cancer, from 1973 to 2004 in the United States. Methods Nine US cancer registries from the Surveillance, Epidemiology, and End Results (SEER) databases were used to identify women aged 15-84 years, who were first diagnosed with vulvar cancer during 1973-2004. Age-adjusted incidence rates and annual percentage changes were calculated for different time periods, stage of the disease, age, race, and geographic area. Results During 1973-2004, the incidence of in situ vulvar tumors increased by an average of 3.5% per year (95% CI: 2.9%, 4.1%), while the incidence of invasive tumors increased 1.0% per year (95% CI: 0.6%, 1.4%). An increasing incidence was observed for localized and regional invasive tumors. To at least some degree, the rise of incidence rates of incidence tumors was evident in every age category, race, and geographic region. Conclusions Incidence rates of invasive vulvar cancer have increased in the United States during the last three decades. The reasons for this increase are unknown.

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.