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Supplemental Table 1 shows univariate odds ratios, Supplemental Table 2 shows adjusted odds ratios stratified by race, and SupplementalTable 3 compares associations using mode of detection derived using a 1 year vs. 2 year interval.

Flowchart of eligibility criteria.

Supplemental Figure 2. The association between smoking and ESR1-defined breast cancer subtypes.

Supplementary Table 5 - PDF file 46K, Clinicopathologic characteristics by the Active/Inactive extratumoral microenvironment subtype

Supplementary Table 3 - PDF file 23K, Overlaps in genes among biologically relevant signatures

HRs of all-cause mortality associated with parity and birth recency, in the CBCS Phases I and II

Supplemental Figure 3. The association between smoking and LS-defined breast cancer subtypes.

Agreement between manual and automated methods for quantification of biomarker expression data in tissue microarrays.

Agreement between IHC-based and RNA-based intrinsic subtyping

Supplementary Figure 1 - Principle component analysis showed considerable homogeneity of global gene expression in the test and training data sets.

Background: Parity and time since last birth influence breast cancer risk and vary by intrinsic tumor subtype, but the independent effects of these factors on prognosis have received limited attention.Methods: Study participants were 1,140 invasive breast cancer patients from phases I and II of the population-based Carolina Breast Cancer Study, with tissue blocks available for subtyping using immunohistochemical markers. Breast cancer risk factors, including pregnancy history, were collected via in-person interviews administered shortly after diagnosis. Vital status was determined using the National Death Index. The association of parity and birth recency with breast cancer–specific and overall survival was assessed using Cox proportional hazards models.Results: During follow-up (median = 13.5 years), 450 patients died, 61% due to breast cancer (n = 276). High parity (3+ births) and recent birth (Conclusions: Parity and recent birth are associated with worse survival among breast cancer patients, particularly among luminal breast cancers and long-term survivors.Impact: The biologic effects of parity and birth recency may extend from etiology to tumor promotion and progression. Cancer Epidemiol Biomarkers Prev; 25(1); 60–67. ©2015 AACR.

Introduction: Overall survival of early-stage breast cancer patients is similar for those who undergo breast-conserving therapy (BCT) and mastectomy; however, 10% to 15% of women undergoing BCT suffer ipsilateral breast tumor recurrence. The risk of recurrence may vary with breast cancer subtype. Understanding the gene expression of the cancer-adjacent tissue and the stromal response to specific tumor subtypes is important for developing clinical strategies to reduce recurrence risk.Methods: We utilized two independent datasets to study gene expression data in cancer-adjacent tissue from invasive breast cancer patients. Complementary in vitro cocultures were used to study cell–cell communication between fibroblasts and specific breast cancer subtypes.Results: Our results suggest that intrinsic tumor subtypes are reflected in histologically normal cancer-adjacent tissue. Gene expression of cancer-adjacent tissues shows that triple-negative (Claudin-low or basal-like) tumors exhibit increased expression of genes involved in inflammation and immune response. Although such changes could reflect distinct immune populations present in the microenvironment, altered immune response gene expression was also observed in cocultures in the absence of immune cell infiltrates, emphasizing that these inflammatory mediators are secreted by breast-specific cells. In addition, although triple-negative breast cancers are associated with upregulated immune response genes, luminal breast cancers are more commonly associated with estrogen-response pathways in adjacent tissues.Conclusions: Specific characteristics of breast cancers are reflected in the surrounding histologically normal tissue. This commonality between tumor and cancer-adjacent tissue may underlie second primaries and local recurrences.Impact: Biomarkers derived from cancer-adjacent tissue may be helpful in defining personalized surgical strategies or in predicting recurrence risk. Cancer Epidemiol Biomarkers Prev; 24(2); 406–14. ©2014 AACR.

Supplementary Figure 1 - PDF file 385K, Representative pictures of breast composition by digital pathological image analysis

Supplemental Table 2. In vivo and In vitro triple negative genomic signatures

Supplementary Table 8 - PDF file 43K, The association of breast composition percentage with Active/Inactive subtype and mammographic density

Supplementary Table 3 - Significant biological pathways of breast tissue composition signatures

Supplemental Figure 1. The association between smoking and ER-defined breast cancer subtypes.

Characteristics of study population by parity, in the CBCS Phases I and II.

Supplementary Table 7 - PDF file 49K, Adjusted relationship of biologically relevant signatures with the Active/Inactive extratumoral microenvironment subtype, mammographic density, and breast composition

Supplementary Table 2 - XLSX file 159KB, Gene list of the Active signature

Background: Classification of breast cancer into intrinsic subtypes has clinical and epidemiologic importance. To examine accuracy of IHC-based methods for identifying intrinsic subtypes, a three-biomarker IHC panel was compared with the clinical record and RNA-based intrinsic (PAM50) subtypes.Methods: Automated scoring of estrogen receptor (ER), progesterone receptor (PR), and HER2 was performed on IHC-stained tissue microarrays comprising 1,920 cases from the African American Breast Cancer Epidemiology and Risk (AMBER) consortium. Multiple cores (1–6/case) were collapsed to classify cases, and automated scoring was compared with the clinical record and to RNA-based subtyping.Results: Automated analysis of the three-biomarker IHC panel produced high agreement with the clinical record (93% for ER and HER2, and 88% for PR). Cases with low tumor cellularity and smaller core size had reduced agreement with the clinical record. IHC-based definitions had high agreement with the clinical record regardless of hormone receptor positivity threshold (1% vs. 10%), but a 10% threshold produced highest agreement with RNA-based intrinsic subtypes. Using a 10% threshold, IHC-based definitions identified the basal-like intrinsic subtype with high sensitivity (86%), although sensitivity was lower for luminal A, luminal B, and HER2-enriched subtypes (76%, 40%, and 37%, respectively).Conclusion: Three-biomarker IHC-based subtyping has reasonable accuracy for distinguishing basal-like from nonbasal-like, although additional biomarkers are required for accurate classification of luminal A, luminal B, and HER2-enriched cancers.Impact: Epidemiologic studies relying on three-biomarker IHC status for subtype classification should use caution when distinguishing luminal A from luminal B and when interpreting findings for HER2-enriched cancers. Cancer Epidemiol Biomarkers Prev; 25(3); 470–8. ©2015 AACR.

Supplementary Table 4 - XLSX file 52K, Gene ID and corresponding standard vector of the biologically relevant signatures

This file describes immunohistochemistry staining for ER, PR and HERs in tissue microarrays, in addition to automated quantification of staining.

Supplementary Figure 2 - Boxplots of the ratios of epithelium to non-fatty stroma and non-fatty stroma to adipose by age groups

Supplementary Table 1 - PDF file 23K, Pearson correlation coefficient between evaluation approaches by breast composition

Background: Breast tissue composition (epithelium, non-fatty stroma, and adipose) changes qualitatively and quantitatively throughout the lifespan, and may mediate relationships between risk factors and breast cancer initiation. We sought to identify relationships between tissue composition, risk factors, tumor characteristics, and gene expression.Methods: Participants were 146 patients from the Polish Breast Cancer Study, with data on risk factor and clinicopathological characteristics. Benign breast tissue composition was evaluated using digital image analysis of histologic sections. Whole-genome microarrays were performed on the same tissue blocks.Results: Mean epithelial, non-fatty stromal, and adipose proportions were 8.4% (SD = 4.9%), 27.7% (SD = 24.0%), and 64.0% (SD = 24.0%), respectively. Among women P < 0.01). The variation in epithelial proportion with age was modest (0.1% per year). Higher epithelial proportion was associated with obesity (7.6% in nonobese vs. 10.1% in obese; P = 0.02) and with poorly differentiated tumors (7.8% in well/moderate vs. 9.9% in poor; P = 0.05). Gene expression signatures associated with epithelial and stromal proportion were identified and validated. Stroma-associated genes were in metabolism and stem cell maintenance pathways, whereas epithelial genes were enriched for cytokine and immune response pathways.Conclusions: Breast tissue composition was associated with age, body mass index, and tumor grade, with consequences for breast gene expression.Impact: Breast tissue morphologic factors may influence breast cancer etiology. Composition and gene expression may act as biomarkers of breast cancer risk and progression. Cancer Epidemiol Biomarkers Prev; 23(12); 2810–8. ©2014 AACR.

Background: Smoking is a possible risk factor for breast cancer and has been linked to increased risk of estrogen receptor–positive (ER+) disease in some epidemiologic studies. It is unknown whether smoking has quantitative effects on ER expression.Methods: We examined relationships between smoking and ER expression from tumors of 1,888 women diagnosed with invasive breast cancer from a population-based study in North Carolina. ER expression was characterized using binary (±) and continuous measures for ER protein, ESR1 mRNA, and a multigene luminal score (LS) that serves as a measure of estrogen signaling in breast tumors. We used logistic and linear regression models to estimate temporal and dose-dependent associations between smoking and ER measures.Results: The odds of ER+, ESR1+, and LS+ tumors among current smokers (at the time of diagnosis), those who smoked 20 or more years, and those who smoked within 5 years of diagnosis were nearly double those of nonsmokers. Quantitative levels of ESR1 were highest among current smokers compared with never smokers overall [mean (log2) = 9.2 vs. 8.7, P < 0.05] and among ER+ cases; however, we did not observe associations between smoking measures and continuous ER protein expression.Conclusions: In relationship to breast cancer diagnosis, recent smoking was associated with higher odds of the ER+, ESR1+, and LS+ subtype. Current smoking was associated with elevated ESR1 mRNA levels and an elevated LS, but not with altered ER protein.Impact: A multigene LS and single-gene ESR1 mRNA may capture tumor changes associated with smoking. Cancer Epidemiol Biomarkers Prev; 27(1); 67–74. ©2017 AACR.

Supplemental Figure Legends

Supplementary Figure 2 - PDF file 138KB, The Creighton method to evaluate the association of gene expression profile of each patient with pre-defined biological signatures

Supplemental Tables 1, 3-6. Supplemental Table 1. Characteristics of Polish Women's Breast Cancer Study Patients (test set) and the TCGA dataset (validation dataset) with gene expression profiles. Supplemental Table 3. Biological functions associated with genes differentially expressed in cancer adjacent tissue of Claudin-low, Basal-like, Luminal B and Luminal A tumors. Supplemental Table 4. Pathways associated with genes differentially expressed in cancer adjacent tissue of Claudin-low, Basal-like, Luminal B and Luminal A tumors. Supplemental Table 5. Biological functions associated with genes differentially expressed in Basal-like and Claudin-low cocultures. Supplemental Table 6. Pathways associated with genes differentially expressed in in Basal-like and Claudin-low cocultures.

Supplementary Table 2 - Gene list of breast tissue composition signatures

Characteristics of study population by last birth recency group, in the CBCS Phases I and II

Agreement between IHC-based and RNA-based intrinsic subtyping using tumor grade in addition to ER, PR and HER2 expression

Supplemental Table 1. Estimated biomarker expression values for the effect of categorical smoking measures among all cases; Supplemental Table 2. Estimated biomarker expression values for the effect of categorical smoking measures among ER+ cases.

Supplementary Figure 3 - PDF file 55K, Cluster discovery consensus matrix and dendrogram of gene expression level of the 3194 genes of the published Active/Inactive signature

Overall survival by parity and last birth recency, overall, among luminal tumors, and basal- tumors

Supplementary Table 6 - PDF file 52K, Participant and clinicopathologic characteristics by mammographic density measures

Background: Circulating tumor DNA (ctDNA) has been increasingly used in the clinical care of patients with cancer. This systematic review summarizes current data on the utility of ctDNA in breast cancer clinical research and practice and provides insights for integrating ctDNA into drug development and patient treatment. Methods: The Embase database was used to identify original clinical research articles of ctDNA in breast cancer published from 2015 to 2020. ctDNA clinical utilities were reviewed and summarized, focusing on 3 areas: early diagnosis, prognostication, and monitoring disease progression/treatment response. Associations of ctDNA with disease-free survival (DFS) and overall survival (OS) were estimated in the embedded meta-analysis. Pooled estimates were calculated using fixed-effect or random-effect models depending on study heterogeneity. Results: After screening and review, 72 articles were included. ctDNA studies have increased in recent years, with 59.7% of included articles published in 2019 or 2020. Overall, 61.1% of the studies were in patients with advanced stage/metastatic cancer; 45.8% were restricted to patients with specific cancer subtypes. ctDNA was minimally used in diagnosis; it was predominantly used in clinical outcome prediction with differences by stage. In patients with early-stage disease, the meta-analyses found that overall ctDNA detection/positivity was associated with shorter DFS (n=697; HR, 5.37; 95% CI, 2.94-9.80) and OS (n=238; HR, 4.60; 95% CI, 2.56-8.26). Specific gene mutations in ctDNA were mainly assessed in patients with advanced/metastatic disease, with mutations of ERBB, ESR1, and TP53 linked to shorter DFS in the meta-analyses (P Conclusions: Recent studies demonstrate ctDNA application in breast cancer prognostication/monitoring, suggesting an important role in patient stratification, molecular relapse identification, and personalized treatment. Large, multicenter clinical trials and real-world longitudinal data sets are needed to validate findings and to address challenges related to ctDNA to improve clinical utility and to integrate ctDNA testing into clinical practice and drug development. Citation Format: Xuezheng Sun, Nicholas Ballew, Linda Kalilani, Kelesitse Phiri, Kelly Bell, Alexander Slowly, Magdalena Zajac, Erin Hofstatter, Angela Silvestro, Zebin Wang, Jeanne Schilder. Utility of circulating tumor DNA in breast cancer clinical research and practice: systematic review and meta-analysis. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6695.

Purpose: Improved risk stratification and predictive biomarkers of treatment response are needed for non–muscle-invasive bladder cancer (NMIBC). Here we assessed the clinical utility of targeted RNA and DNA molecular profiling in NMIBC. Experimental Design: Gene expression in NMIBC samples was profiled by NanoString nCounter, an RNA quantification platform, from two independent cohorts (n = 28, n = 50); targeted panel sequencing was performed in a subgroup (n = 50). Gene signatures were externally validated using two RNA sequencing datasets of NMIBC tumors (n = 438, n = 73). Established molecular subtype classifiers and novel gene expression signatures were assessed for associations with clinicopathologic characteristics, somatic tumor mutations, and treatment outcomes. Results: Molecular subtypes distinguished between low-grade Ta tumors with FGFR3 mutations and overexpression (UROMOL-class 1) and tumors with more aggressive clinicopathologic characteristics (UROMOL-classes 2 and 3), which were significantly enriched with TERT promoter mutations. However, UROMOL subclasses were not associated with recurrence after bacillus Calmette-Guérin (BCG) immunotherapy in two independent cohorts. In contrast, a novel expression signature of an inflamed tumor microenvironment (TME) was associated with improved recurrence-free survival after BCG. Expression of immune checkpoint genes (PD-L1/PD-1/CTLA-4) was associated with an inflamed TME, but not with higher recurrence rates after BCG. FGFR3 mutations and overexpression were both associated with low immune signatures. Conclusions: Assessment of the immune TME, rather than molecular subtypes, is a promising predictive biomarker of BCG response. Modulating the TME in an immunologically “cold” tumor warrants further investigation. Integrated transcriptomic and exome sequencing should improve treatment selection in NMIBC.

BACKGROUND Polychlorinated biphenyls (PCBs), a diverse class of chemicals, are hypothesized mammary carcinogens. We examined plasma levels of 17 PCBs as individual congeners and as a mixture in association with breast cancer using a novel approach based on quantile g-computation. METHODS This study included 845 White and 562 Black women who participated in the population-based, case-control Carolina Breast Cancer Study Phase I. Cases (n = 748) were women with a first diagnosis of histologically confirmed, invasive breast cancer residing in 24 counties in central and eastern North Carolina; controls (n = 659) were women without breast cancer from the same counties. PCBs were measured in plasma samples obtained during the study interview. We estimated associations [covariate-adjusted odds ratios (ORs) and 95% confidence intervals (CIs)] between individual PCB congeners and breast cancer using multivariable logistic regression. We assessed PCB mixtures using quantile g-computation and examined effect measure modification by race. RESULTS Comparing highest and lowest tertiles of PCBs resulted in ORs of 1.3 (95% CI = 0.95, 1.8) for congener 74, 1.4 (95% CI = 1.0, 1.9) for 99, 1.3 (95% CI = 0.91, 1.8) for 194, and 1.2 (95% CI = 0.90, 1.7) for 201. Among all women, we estimated a joint effect of the PCB mixture with an OR of 1.3 (95% CI = 0.98, 1.6) per tertile change. In race-stratified analyses, associations for tertiles of PCB mixtures were stronger among Black women (OR = 1.5; 95% CI = 1.0, 2.3) than among White women (OR = 1.1; 95% CI = 0.81, 1.6). CONCLUSION Our results are consistent with the hypothesis that exposure to PCB mixtures increase the risk of breast cancer, but studies of populations with different exposure profiles are needed.

Evidence suggests that fruit and vegetable consumptions may improve mental health among general population. However, their associations among breast cancer survivors are unclear. We planned to investigate this association via a nationwide survey in the USA. We identified 7988 breast cancer survivors from 2009 Behavioral Risk Factor Surveillance System (BRFSS). Fruit juice, fruit, and vegetable consumptions were categorized as ordinal variables to approximate tertiles. Survivors who were mentally unhealthy for at least 14 days in the past 30 days were defined as having frequent mental distress (FMD). Multivariable logistic regression treating FMD as the outcome was used to calculate adjusted odd ratios (aORs) and 95% confidence intervals (CIs) for exposures. Quadratic model was used to depict the dose-response pattern in primary analysis. Subgroup analyses by adverse lifestyle behaviors were conducted; Wald tests were used to examine if there were interactions between these factors and exposures in relation to FMD. Overall, 825 (10.3%) survivors had FMD. Mean age was 67.2 years, and 89.7% of survivors were white. Juice showed non-significant associations with FMD. Moderate (aOR = 0.81, 95% CI = 0.68–0.98) and high (aOR = 0.79, 95% CI = 0.63–0.98) fruit consumptions, as well as moderate vegetable consumption (aOR = 0.78, 95% CI = 0.64–0.94), were significantly and inversely associated with FMD. The dose-response curves were consistent with results in primary analysis. No interaction was identified for adverse lifestyle behaviors. Fruit and vegetable, but not fruit juice, show potential preventive effects against FMD among breast cancer survivors. The conclusion should be verified by studies with clear temporality in future.

undifferentiated pancreatic carcinoma with osteoclastic giant cells (UOC) is a rare pancreatic malignancy composed of three unique cell types. Currently, the histopathologic origin of UOCs remains unclear. Some studies considered that it was differentiated from epithelial tissues, while others favored a mesenchymal derivation.we present the case of a 59-year-old UOC patient with a tumor (3.0 cm × 3.0 cm × 2.5 cm) in the pancreatic neck. He underwent an en bloc resection of the distal pancreas associated with the spleen.light microscopic examination revealed two typical types of UOC cells, with one type absent. The immunohistochemical staining was positive for pancytokeratin, epithelial membrane antigen, vimentin and cluster of differentiation 68, which indicated different derivations for these two kinds of cells.UOC is a rare condition with unique imaging and pathological features. Endoscopic ultrasonography and fine needle aspiration are dispensable preoperatively. Radical resection should be tried for UOC treatments. In our opinion, osteoclastic giant cells are reactive cells derived from histocytes. The case presented here will be of interest to the whole UOC cohort.