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BackgroundMedian overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC.Patients and methodsExpression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies.ResultsExpression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02-2.71; P < 0.001]. Median survival [HR (95% CI)] by gene expression score quintile was 9.5 (8.3 to -), 5.4 (4.6-7.0), 3.8 (3.3-4.6), 3.2 (2.9-3.7) and 2.3 (2.1-2.6) years.ConclusionThe OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.

Purpose: Associations between sun exposure (a primary source of vitamin D) and risk of ovarian cancer have been inconsistent. Furthermore, studies have not investigated whether sun exposure at different periods in the lifetime of a person results in differences in risk associations, and little is known about differences according to histological subtype.Methods: Using a population-based case-control study of 1,334 non-Hispanic white women diagnosed with epithelial ovarian cancer in western Washington State between 2002 and 2009 and 1,679 non-Hispanic white controls, we assessed the relation of epithelial ovarian cancer with constitutional pigmentation characteristics, sun exposure behaviors, and an index of ultraviolet (UV) exposure based on residential history. Information was collected through in-person interviews. Logistic regression was used to compute odds ratios, 95 % confidence intervals, and trend p values (P(trend)).Results: We noted no association with residence-based measures of UV exposure or self-reported sun exposure, either over the lifetime or within specific age intervals. Also, we observed little evidence of association between constitutional pigmentation characteristics and risk, save for a suggestion of increased risk among women who reported increased ability to suntan upon prolonged sun exposure (P(trend) = 0.03).Conclusions: Results from this study suggest that sun exposure has little influence on the risk of epithelial ovarian cancer. Additional studies in populations with a wider gradient of sun exposure may yet be warranted. [ABSTRACT FROM AUTHOR]

Purpose: To determine the relationship between germline pathogenic variants (PVs) in cancer predisposition genes and the risk of ductal carcinoma in situ (DCIS)., Methods: Germline PV frequencies in breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, PALB2, RAD51C, and RAD51D) were compared between DCIS cases and unaffected controls, and between DCIS and infiltrating ductal carcinoma (IDC) cases from a clinical-testing cohort (n=9,887), a population-based cohort (n=3,876) and the UK Biobank (n=2421). The risk of contralateral breast cancer for DCIS cases with PVs was estimated in the population-based cohort., Results: Germline PVs were observed in 6.5% and 4.6% of women with DCIS in the clinical-testing and population-based cohorts, respectively. BRCA1, BRCA2, and PALB2 PVs frequencies were significantly lower among women with DCIS than IDC (clinical cohort: 2.8% vs. 5.7%; population-based cohort: 1.7% vs. 3.7%), whereas the PV frequencies for ATM and CHEK2 were similar. ATM, BRCA1, BRCA2, CHEK2, and PALB2 PVs were significantly associated with an increased risk of DCIS (OR>2.0), but only BRCA2 PVs were associated with high-risk (OR>4) in both cohorts. The cumulative incidence of contralateral breast cancer among carriers of PVs in high penetrance genes with DCIS was 23% over 15 years., Conclusions: The enrichment of PVs in ATM, BRCA1, BRCA2, CHEK2 and PALB2 among women with DCIS suggests that multigene panel testing may be appropriate for women with DCIS. Elevated risks of contralateral breast cancer in carriers of PVs in high penetrance genes with DCIS confirmed the utility of testing for surgical decision-making.

Background: Breast cancer has been associated with monogenic, polygenic, and epidemiologic (clinical, reproductive, and lifestyle) risk factors, but studies evaluating the combined effects of these factors have been limited., Methods: We extended previous work in breast cancer risk modeling, incorporating pathogenic variants (PV) in six breast cancer predisposition genes and a 105-SNP polygenic risk score (PRS), to include an epidemiologic risk score (ERS) in a sample of non-Hispanic White women drawn from prospective cohorts and population-based case-control studies, with 23,518 cases and 22,832 controls, from the Cancer Risk Estimates Related to Susceptibility (CARRIERS) Consortium., Results: The model predicts 4.4-fold higher risk of breast cancer for postmenopausal women with no predisposition PV and median PRS, but with the highest versus lowest ERS. Overall, women with CHEK2 PVs had >20% lifetime risk of breast cancer. However, 15.6% of women with CHEK2 PVs and a family history of breast cancer, and 45.1% of women with CHEK2 PVs but without a family history of breast cancer, had low (<20%) predicted lifetime risk and thus were below the threshold for MRI screening. CHEK2 PV carriers at the 10th percentile of the joint distribution of ERS and PRS, without a family history of breast cancer, had a predicted lifetime risk similar to the general population., Conclusions: These results illustrate that an ERS, alone and combined with the PRS, can contribute to clinically relevant risk stratification., Impact: Integrating monogenic, polygenic, and epidemiologic risk factors in breast cancer risk prediction models may inform personalized screening and prevention efforts., (©2024 American Association for Cancer Research.)

Importance: Pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2 , and PALB2 are associated with increased breast cancer risk. However, it is unknown whether breast cancer risk differs by PV type or location in carriers ascertained from the general population., Objective: To evaluate breast cancer risks associated with PV type and location in ATM, BRCA1, BRCA2, CHEK2 , and PALB2 ., Design: Age adjusted case-control association analysis for all participants, subsets of PV carriers, and women with no breast cancer family history in population-based and clinical testing cohorts., Setting: Twelve US population-based studies within the Cancer Risk Estimates Related to Susceptibility (CARRIERS) Consortium, and breast cancer cases from the UK-Biobank and an Ambry Genetics clinical testing cohort., Participants: 32,247 women with and 32,544 age-matched women without a breast cancer diagnosis from CARRIERS; 237 and 1351 women with BRCA2 PVs and breast cancer from the UKBB and Ambry Genetics, respectively., Exposures: PVs in ATM, BRCA1, BRCA2, CHEK2, and PALB2., Main Outcomes and Measures: PVs were grouped by type and location within genes and assessed for risks of breast cancer (odds ratios (OR), 95% confidence intervals (CI), and p-values) using logistic regression. Mean ages at diagnosis were compared using linear regression., Results: Compared to women carrying BRCA2 exon 11 protein truncating variants (PTVs) in the CARRIERS population-based study, women with BRCA2 ex13-27 PTVs (OR=2.7, 95%CI 1.1-7.9) and ex1-10 PTVs (OR=1.6, 95%CI 0.8-3.5) had higher breast cancer risks, lower rates of ER-negative breast cancer (ex13-27 OR=0.5, 95%CI 0.2-0.9; ex1-10 OR=0.5, 95%CI 0.1-1.0), and earlier age of breast cancer diagnosis (ex13-27 5.5 years, p<0.001; ex1-10 2.4 years, p=0.17). These associations with ER-negative breast cancer and age replicated in a high-risk clinical cohort and the population-based UK Biobank cohort. No differences in risk or age at diagnosis by gene region were observed for PTVs in other predisposition genes., Conclusions and Relevance: Population-based and clinical high-risk cohorts establish that PTVs in exon 11 of BRCA2 are associated with reduced risk of breast cancer, later age at diagnosis, and greater risk of ER-negative disease. These differential risks may improve individualized risk prediction and clinical management for women carrying BRCA2 PTVs., Key Points: Question: Does ATM , BRCA1 , BRCA2 , CHEK2 and PALB2 pathogenic variant type and location influence breast cancer risk in population-based studies? Findings: Breast cancer risk and estrogen receptor status differ based on the type and location of pathogenic variants in BRCA2 . Women carrying protein truncating variants in exon 11 have a lower breast cancer risk in the population-based cohorts, older age at diagnosis and higher rates of estrogen receptor negative breast cancer than women with exon 1-10 or exon 13-27 truncation variants in population-based and clinical testing cohorts. Meaning: Incorporating pathogenic variant type and location in cancer risk models may improve individualized risk prediction.

The tumor immune microenvironment (TIME) plays key roles in tumor progression and response to immunotherapy. Previous studies have identified individual germline variants associated with differences in TIME. Here, we hypothesize that common variants associated with breast cancer risk or cancer-related traits, represented by polygenic risk scores (PRSs), may jointly influence immune features in TIME. We derived 154 immune traits from bulk gene expression profiles of 764 breast tumors and 598 adjacent normal tissue samples from 825 individuals with breast cancer in the Nurses' Health Study (NHS) and NHSII. Immunohistochemical staining of four immune cell markers were available for a subset of 205 individuals. Germline PRSs were calculated for 16 different traits including breast cancer, autoimmune diseases, type 2 diabetes, ages at menarche and menopause, body mass index (BMI), BMI-adjusted waist-to-hip ratio, alcohol intake, and tobacco smoking. Overall, we identified 44 associations between germline PRSs and immune traits at false discovery rate q < 0.25, including 3 associations with q < 0.05. We observed consistent inverse associations of inflammatory bowel disease (IBD) and Crohn disease (CD) PRSs with interferon signaling and STAT1 scores in breast tumor and adjacent normal tissue; these associations were replicated in a Norwegian cohort. Inverse associations were also consistently observed for IBD PRS and B cell abundance in normal tissue. We also observed positive associations between CD PRS and endothelial cell abundance in tumor. Our findings suggest that the genetic mechanisms that influence immune-related diseases are also associated with TIME in breast cancer., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Clinical genetic testing identifies variants causal for hereditary cancer, information that is used for risk assessment and clinical management. Unfortunately, some variants identified are of uncertain clinical significance (VUS), complicating patient management. Case-control data is one evidence type used to classify VUS, and previous findings indicate that case-control likelihood ratios (LRs) outperform odds ratios for variant classification. As an initiative of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Analytical Working Group we analyzed germline sequencing data of BRCA1 and BRCA2 from 96,691 female breast cancer cases and 303,925 unaffected controls from three studies: the BRIDGES study of the Breast Cancer Association Consortium, the Cancer Risk Estimates Related to Susceptibility consortium, and the UK Biobank. We observed 11,227 BRCA1 and BRCA2 variants, with 6,921 being coding, covering 23.4% of BRCA1 and BRCA2 VUS in ClinVar and 19.2% of ClinVar curated (likely) benign or pathogenic variants. Case-control LR evidence was highly consistent with ClinVar assertions for (likely) benign or pathogenic variants; exhibiting 99.1% sensitivity and 95.4% specificity for BRCA1 and 92.2% sensitivity and 86.6% specificity for BRCA2 . This approach provides case-control evidence for 785 unclassified variants, that can serve as a valuable element for clinical classification.

Importance: Little is known about the causes of second primary cancers among individuals with a history of cancer. Descriptive studies have suggested that lifestyle factors, including excess body weight, may be important., Objective: To investigate whether excess body weight is associated with the risk of a second primary malignant neoplasm among cancer survivors., Design, Setting, and Participants: This cohort study of adults in 21 states in the US used data from the Cancer Prevention Study II Nutrition cohort, a large prospective study that invited participants to respond to a survey in 1992 and biennial surveys starting in 1997, and who were followed-up through 2017. Eligible participants included those who received a diagnosis of a first primary nonmetastatic invasive cancer between 1992 and 2015. Data analysis occurred from September 2023 to March 2024., Exposure: Body mass index (BMI), computed from self-reported height and weight at the time of the first primary cancer diagnosis (mean [SD] years to diagnosis, 1.7 [1.5] years)., Main Outcome and Measures: Main outcomes included a second primary cancer or an obesity-related second cancer. Cancer diagnoses were reported on biennial surveys and verified through medical record abstraction or linkage with state cancer registries., Results: This cohort included 26 894 participants who received a diagnosis of a first nonmetastatic primary cancer (mean [SD] age at first cancer diagnosis, 72.2 [6.5] years; 15 920 male [59.2%]). At the time of first diagnosis, 11 497 participants (42.8%) had overweight and 4684 (17.2%) had obesity. During a median (IQR) follow-up time of 7.9 (3.4-13.6) years, 3749 (13.9%) participants received a diagnosis of a second primary cancer, of which 1243 (33.2%) were obesity-related second primary cancers. Compared with cancer survivors whose BMI was in the normal range (18.5 to <25), there was 15% increased risk of any second primary cancer for those who had overweight (25 to <30; adjusted hazard ratio [aHR], 1.15; 95% CI, 1.07-1.25) and a 34% increased risk for those who had obesity (BMI ≥30; aHR, 1.34; 95% CI, 1.21-1.48), with greater risk for obesity-related second primary cancers, including a 40% increased risk for those with overweight (aHR, 1.40; 95% CI, 1.22,-1.61) and a 78% increased risk for those with obesity (aHR, 1.78; 95% CI, 1.51-2.11)., Conclusions and Relevance: In this cohort study of older survivors of nonmetastatic cancer, those who had overweight or obesity at the time of their first cancer diagnosis were at higher risk of developing a second cancer, especially an obesity-related second cancer. Given the high prevalence of overweight and obesity among cancer survivors, it is important to promote survivorship care guidelines recommending weight management and increase awareness of second cancers among physicians and cancer survivors.

Purpose: Trials demonstrating benefits of tamoxifen for women with ductal carcinoma in situ (DCIS) were published > 20 years ago; yet subsequent uptake of endocrine therapy was low. We estimated endocrine therapy initiation in women with DCIS between 2001 and 2018 in a community setting, reflecting more recent years of diagnosis than previous studies., Methods: This retrospective cohort included adult females ≥ 20 years diagnosed with first primary DCIS between 2001 and 2018, followed through 2019, and enrolled in one of three U.S. integrated healthcare systems. We collected data on endocrine therapy dispensings (tamoxifen, aromatase inhibitors [AIs]) from electronic pharmacy records within 12 months after DCIS diagnosis. Using generalized linear models with a log link and Poisson distribution, we estimated endocrine therapy initiation rates over time and by patient, tumor (including estrogen receptor [ER] status), and treatment characteristics., Results: Among 2020 women with DCIS, 587 (29%) initiated endocrine therapy within 12 months after diagnosis (36% among 1208 women with ER-positive DCIS). Among women who used endocrine therapy, 506 (86%) initiated tamoxifen and 81 (14%) initiated AIs. Age-adjusted endocrine therapy initiation declined from 34 to 21% between 2001 and 2017; between 2015 and 2018, AI use increased from 8 to 35%. Women less likely to initiate endocrine therapy were ER-negative or had borderline/unknown or no ER test results, ≥ 65 years at diagnosis, Black, and received no radiotherapy., Conclusion: One-third of women diagnosed with DCIS initiated endocrine therapy, and use decreased over time. Understanding why women eligible for endocrine therapy do not initiate is important to maximizing disease-free survival following DCIS diagnosis., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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 years and older, survived ≥1 year). We estimated multivariable adjusted hazard ratios (HRs) for associations between initial chemotherapy regimen type (anthracycline and/or trastuzumab, other chemotherapies, no chemotherapy [referent]) 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 and/or heart failure [HF], ischemic heart disease, stroke). Women treated with anthracyclines and/or trastuzumab had a higher risk of CVD compared with no chemotherapy (adjusted HR = 1.53, 95% confidence interval [CI] = 1.31 to 1.79), persisting at least 5 years postdiagnosis (adjusted HR5-<10 years = 1.85, 95% CI = 1.44 to 2.39; adjusted HR≥10 years = 1.83, 95% CI = 1.34 to 2.49). Cardiomyopathy and/or HF risks were elevated among women treated with anthracyclines and/or trastuzumab compared with no chemotherapy, especially for those aged younger than 65 years (adjusted HR20-54years = 2.97, 95% CI = 1.72 to 5.12; adjusted HR55-64years = 2.21, 95% CI = 1.52 to 3.21), differing for older women (adjusted HR≥65 years = 1.32, 95% CI = 0.97 to 1.78), and at least 5 years postdiagnosis (adjusted HR5-<10years = 1.89, 95% CI = 1.35 to 2.64; adjusted HR≥10 years = 2.21, 95% CI = 1.52 to 3.20). Anthracyclines and/or trastuzumab receipt was associated with increased ischemic heart disease risks after 5 or more years (adjusted HR5-<10years = 1.51, 95% CI = 1.06 to 2.14; adjusted HR≥10 years = 1.86, 95% CI = 1.18 to 2.93) with no clear age effects, and stroke risk (adjusted HR = 1.33, 95% CI = 1.05 to 1.69), which did not vary by time or age. There was some evidence of long-term cardiomyopathy and/or HF and ischemic heart disease risks with other chemotherapies. Among women aged younger than 65 treated with anthracyclines and/or trastuzumab, up to 16% developed CVD by 10 years (20-54 years = 6.91%; 55-64 years = 16.00%), driven by cardiomyopathy and/or HF (20-54 years = 3.90%; 55-64 years = 9.78%)., Conclusions: We found increased long-term risks of cardiomyopathy and/or HF and ischemic heart disease among breast cancer survivors treated with anthracyclines and/or trastuzumab and increased cardiomyopathy and/or HF risk among women aged younger than 65 years., (Published by Oxford University Press 2024.)

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., (© 2024. The Author(s).)

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., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

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., Competing Interests: Competing interests: BCAC conflict of interest: MWB conducts research funded by Amgen, Novartis and Pfizer. PAF conducts research funded by Amgen, Novartis and Pfizer. He received Honoraria from Roche, Novartis and Pfizer. JV is one ofthe inventors of diagnosis and treatment of ERCC3-mutant cancer. AWK has a research funding for his institution from Myriad Genetics for an unrelated project (funding dates 2017–2019). UM has research collaborations with Mercy BioAnalytics, RNA Guardian, Dana Farber and iLOF (Intelligent Lab on Fiber). RAM is a consultant for Pharmavite., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2023. Published by Elsevier Inc.)

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., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

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., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

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&lt;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., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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., (© 2022. The Author(s).)

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., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

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., (Published by Oxford University Press 2022.)

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., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., (© 2021. The Author(s).)

Background: Breast cancer survivors are at increased risk for developing second primary cancers compared with the general population. Little is known about whether body mass index (BMI) increases this risk. We examined the association between BMI and second cancers among women with incident invasive breast cancer., Methods: This retrospective cohort included 6481 patients from Kaiser Permanente Colorado and Washington of whom 822 (12.7%) developed a second cancer (mean follow-up was 88.0 months). BMI at the first cancer was extracted from the medical record. Outcomes included: 1) all second cancers, 2) obesity-related second cancers, 3) any second breast cancer, and 4) estrogen receptor-positive second breast cancers. Multivariable Poisson regression models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for second cancers associated with BMI adjusted for site, diagnosis year, treatment, demographic, and tumor characteristics., Results: The mean age at initial breast cancer diagnosis was 61.2 (SD = 11.8) years. Most cases were overweight (33.4%) or obese (33.8%) and diagnosed at stage I (62.0%). In multivariable models, for every 5 kg/m2 increase in BMI, the risk of any second cancer diagnosis increased by 7% (RR = 1.07, 95% CI = 1.01 to 1.14); 13% (RR = 1.13, 95% CI = 1.05 to 1.21) for obesity-related cancers, 11% (RR = 1.11, 95% CI = 1.02 to 1.21) for a second breast cancer, and 15% (RR = 1.15, 95% CI = 1.04 to 1.27) for a second estrogen receptor-positive breast cancer., Conclusions: We observed a statistically significant increased risk of second cancers associated with increasing BMI. These findings have important public health implications given the prevalence of overweight and obesity in breast cancer survivors and underscore the need for effective prevention strategies., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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.