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Abstract Our study in the Nurses’ Health Study (NHS) and NHS2, a nested case-control study with 1260 cases and 2221 controls, investigated the association between C-peptide levels, mammographic density (MD) parameters, V (a measure of gray scale variation), and breast cancer (BC) risk. We also examined how C-peptide and BC risk vary across quartiles of mammographic features. Linear and logistic regressions were used to study the associations between C-peptide and MD parameters, and breast cancer. C-peptide was inversely associated with percent MD and positively with non-dense area, but no associations were found with dense area and V measure. C-peptide was associated with an increased risk of invasive BC risk (top vs. bottom quartile, odds ratio = 1.46, 95% CI: 1.12–1.91). No multiplicative interactions were found between C-peptide, MD parameters, and BC risk. Our results suggest a positive association between C-peptide and BC risk, and MD parameters do not seem to modify this association.

Abstract Background Elevated mammographic density (MD) for a woman’s age and body mass index (BMI) is an established breast cancer risk factor. The relationship of parity, age at first birth, and breastfeeding with MD is less clear. We examined the associations of these factors with MD within the International Consortium of Mammographic Density (ICMD). Methods ICMD is a consortium of 27 studies with pooled individual-level epidemiological and MD data from 11,755 women without breast cancer aged 35–85 years from 22 countries, capturing 40 country-& ethnicity-specific population groups. MD was measured using the area-based tool Cumulus. Meta-analyses across population groups and pooled analyses were used to examine linear regression associations of square-root (√) transformed MD measures (percent MD (PMD), dense area (DA), and non-dense area (NDA)) with parity, age at first birth, ever/never breastfed and lifetime breastfeeding duration. Models were adjusted for age at mammogram, age at menarche, BMI, menopausal status, use of hormone replacement therapy, calibration method, mammogram view and reader, and parity and age at first birth when not the association of interest. Results Among 10,988 women included in these analyses, 90.1% (n = 9,895) were parous, of whom 13% (n = 1,286) had ≥ five births. The mean age at first birth was 24.3 years (Standard deviation = 5.1). Increasing parity (per birth) was inversely associated with √PMD (β: − 0.05, 95% confidence interval (CI): − 0.07, − 0.03) and √DA (β: − 0.08, 95% CI: − 0.12, − 0.05) with this trend evident until at least nine births. Women who were older at first birth (per five-year increase) had higher √PMD (β:0.06, 95% CI:0.03, 0.10) and √DA (β:0.06, 95% CI:0.02, 0.10), and lower √NDA (β: − 0.06, 95% CI: − 0.11, − 0.01). In stratified analyses, this association was only evident in women who were post-menopausal at MD assessment. Among parous women, no associations were found between ever/never breastfed or lifetime breastfeeding duration (per six-month increase) and √MD. Conclusions Associations with higher parity and older age at first birth with √MD were consistent with the direction of their respective associations with breast cancer risk. Further research is needed to understand reproductive factor-related differences in the composition of breast tissue and their associations with breast cancer risk.

Abstract Background Early menarche is an established risk factor for breast cancer but its molecular contribution to tumor biology and prognosis remains unclear. Methods We profiled transcriptome-wide gene expression in breast tumors (N = 846) and tumor-adjacent normal tissues (N = 666) from women in the Nurses’ Health Studies (NHS) to investigate whether early menarche (age

BackgroundWe investigated the associations of reproductive factors known to influence breast cancer risk with the expression of breast stem cell markers CD44, CD24, and ALDH1A1 in benign breast biopsy samples.MethodsWe included 439 cancer-free women with biopsy-confirmed benign breast disease within the Nurses’ Health Study (NHS) and NHSII. The data on reproductive and other breast cancer risk factors were obtained from biennial questionnaires. Immunohistochemistry (IHC) was performed on tissue microarrays. For each core, the IHC expression was assessed using a semi-automated platform and expressed as % of cells that stained positive for a specific marker out of the total cell count. Generalized linear regression was used to examine the associations of reproductive factors with a log-transformed expression of each marker (in epithelium and stroma), adjusted for other breast cancer risk factors.ResultsIn multivariate analysis, the time between menarche and age at first birth was inversely associated with CD44 in epithelium (β per 5 years = −0.38, 95% CI −0.69; −0.06). Age at first birth and the time between menarche and age at first birth were inversely associated with ALDH1A1 (stroma: β per 5 years = −0.43, 95% CI −0.76; −0.10 and β = −0.47, 95% CI −0.79; −0.15, respectively; epithelium: β = −0.15, 95% CI −0.30; −0.01 and β = −0.17, 95% CI −0.30; −0.03, respectively). Time since last pregnancy was inversely associated with stromal ALDH1A1 (β per 5 years = −0.55, 95% CI −0.98; −0.11). No associations were found for CD24. The observed associations were similar in premenopausal women. In postmenopausal women, lifetime duration of breastfeeding was inversely associated with stromal ALDH1A1 expression (β for ≥24 vs. 0 to

Abstract Background Genome-wide studies of gene–environment interactions (G×E) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide G×E analysis of ~ 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer. Methods Analyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene–environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs. Results Assuming a 1 × 10–5 prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability

Abstract Extended adjuvant endocrine therapy (eET) improves outcomes in breast cancer survivors. Most studies however have been limited to postmenopausal women, and optimal eET for young survivors is uncertain. We report eET use among participants in the Young Women’s Breast Cancer Study (YWS), a multicenter prospective cohort of women age ≤40 newly diagnosed with breast cancer enrolled between 2006–2016. Women with stage I–III hormone receptor-positive breast cancer, ≥6 years from diagnosis without recurrence were considered eET candidates. Use of eET was elicited from annual surveys sent years 6–8 after diagnosis, censoring for recurrence/death. 663 women were identified as eET candidates with 73.9% (490/663) having surveys eligible for analysis. Among eligible participants, mean age was 35.5 (±3.9), 85.9% were non-Hispanic white, and 59.6% reported eET use. Tamoxifen monotherapy was the most reported eET (77.4%), followed by aromatase inhibitor (AI) monotherapy (21.9%), AI-ovarian function suppression (AI-OFS) (6.8%) and tamoxifen-OFS (3.1%). In multivariable analysis, increasing age (per year odds ratio [OR]: 1.10, 95% confidence interval [CI]: 1.04–1.16), stage (II v. I: OR: 2.86, 95% CI: 1.81–4.51; III v. I: OR: 3.73, 95%CI: 1.87–7.44) and receipt of chemotherapy (OR: 3.66, 95% CI: 2.16–6.21) were significantly associated with eET use. Many young breast cancer survivors receive eET despite limited data regarding utility in this population. While some factors associated with eET use reflect appropriate risk-based care, potential sociodemographic disparities in uptake warrants further investigation in more diverse populations.

Abstract Background We investigated the associations of alcohol with percentage of epithelium, stroma, fibroglandular tissue (epithelium + stroma), and fat in benign breast biopsy samples. Methods We included 857 cancer-free women with biopsy-confirmed benign breast disease within the Nurses’ Health Study (NHS) and NHSII cohorts. Percentage of each tissue was measured on whole slide images using a deep-learning algorithm and then log-transformed. Alcohol consumption (recent and cumulative average) was assessed with semi-quantitative food frequency questionnaires. Regression estimates were adjusted for known breast cancer risk factors. All tests were 2-sided. Results Alcohol was inversely associated with % of stroma and fibroglandular tissue (recent ≥ 22 g/day vs. none: stroma: β = − 0.08, 95% Confidence Interval [CI] − 0.13; − 0.03; fibroglandular: β = − 0.08, 95% CI − 0.13; − 0.04; cumulative ≥ 22 g/day vs. none: stroma: β = − 0.08, 95% CI − 0.13; − 0.02; fibroglandular: β = − 0.09, 95% CI − 0.14; − 0.04) and positively associated with fat % (recent ≥ 22 g/day vs. none: β = 0.30, 95% CI 0.03; 0.57; cumulative ≥ 22 g/day vs. none: β = 0.32, 95% CI 0.04; 0.61). In stratified analysis, alcohol consumption was not associated with tissue measures in premenopausal women. In postmenopausal women, cumulative alcohol use was inversely associated with % of stroma and fibroglandular tissue and positively associated with fat % (≥ 22 g/day vs. none: stroma: β = − 0.16, 95% CI − 0.28; − 0.07; fibroglandular: β = − 0.18, 95% CI − 0.28; − 0.07; fat: β = 0.61, 95% CI 0.01; 1.22), with similar results for recent alcohol use. Conclusion Our findings suggest that alcohol consumption is associated with smaller % of stroma and fibroglandular tissue and a greater % of fat in postmenopausal women. Future studies are warranted to confirm our findings and to elucidate the underlying biological mechanisms.

Abstract Background Higher circulating prolactin has been associated with increased breast cancer risk. Prolactin binding to the prolactin receptor (PRLR) can activate the transcription factor STAT5, thus, we examined the association between plasma prolactin and breast cancer risk by tumor expression of PRLR, STAT5, and the upstream kinase JAK2. Methods Using data from 745 cases and 2454 matched controls in the Nurses’ Health Study, we conducted polytomous logistic regression to examine the association between prolactin (> 11 ng/mL vs. ≤ 11 ng/mL) measured within 10 years of diagnosis and breast cancer risk by PRLR (nuclear [N], cytoplasmic [C]), phosphorylated STAT5 (pSTAT5; N, C), and phosphorylated JAK2 (pJAK2; C) tumor expression. Analyses were conducted separately in premenopausal (n = 168 cases, 765 controls) and postmenopausal women (n = 577 cases, 1689 controls). Results In premenopausal women, prolactin levels > 11 ng/mL were positively associated with risk of tumors positive for pSTAT5-N (OR 2.30, 95% CI 1.02–5.22) and pSTAT5-C (OR 1.64, 95% CI 1.01–2.65), but not tumors that were negative for these markers (OR 0.98, 95% CI 0.65–1.46 and OR 0.73, 95% CI 0.43–1.25; p-heterogeneity = 0.06 and 0.02, respectively). This was stronger when tumors were positive for both pSTAT5-N and pSTAT5-C (OR 2.88, 95% CI 1.14–7.25). No association was observed for PRLR or pJAK2 (positive or negative) and breast cancer risk among premenopausal women. Among postmenopausal women, plasma prolactin levels were positively associated with breast cancer risk irrespective of PRLR, pSTAT5, or pJAK2 expression (all p-heterogeneity ≥ 0.21). Conclusion We did not observe clear differences in the association between plasma prolactin and breast cancer risk by tumor expression of PRLR or pJAK2, although associations for premenopausal women were observed for pSTAT5 positive tumors only. While additional studies are needed, this suggests that prolactin may act on human breast tumor development through alternative pathways.

Abstract Background Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes. Methods We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes’ coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry. Results In European ancestry samples, 14 genes were significantly associated (q

TGFβ signalling is reported to regulate hormone-responsive mammary epithelial progenitors that are associated with breast cancer risk. Here, the authors find that short-term TGFBR1 inhibition prevents tumour formation in rat breast cancer models and identify a TGFBR1 inhibition-responsive sub-population of mammary epithelial cells, which is associated with human breast cancer risk.

Abstract Background We investigated the associations of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) with breast cancer risk by the status of COX-2 protein expression. Methods This study included 421 cases and 3,166 controls from a nested case–control study within the Nurses’ Health Study (NHS) and Nurses’ Health Study II (NHSII) cohorts. Information on medication use was first collected in 1980 (NHS) and 1989 (NHSII) and was updated biennially. Medication use was defined as none, past or current; average cumulative dose and frequency were calculated for all past or current users using data collected from all biannual questionnaires preceding the reference date. Immunochemistry for COX-2 expression was performed using commercial antibody (Cayman Chemical and Thermo Fisher Scientific). We used polychotomous logistic regression to quantify associations of aspirin and NSAIDs with the risk of COX2+ and COX2− breast cancer tumors, while adjusting for known breast cancer risk factors. All tests of statistical significance were two-sided. Results In multivariate analysis, we found no differences in associations of the aspirin exposures and NSAIDs with breast cancer risk by COX2 expression status. In stratified analyses by COX2 status, significant associations of these medications with breast cancer risk were observed for dosage of aspirin among current users in COX2- tumors (OR for > 5 tablets per week vs. none 1.71, 95% CI 1.01–2.88, p-trend 0.04). Regular aspirin use was marginally associated with the risk of COX2- tumors (p-trend = 0.06). Conclusions Our findings suggested no differences in associations of aspirin and other NSAIDs with COX2+ and COX2− tumors.

Abstract Background Breast tumor immune infiltration is clearly associated with improved treatment response and outcomes in breast cancer. However, modifiable patient factors associated with breast cancer immune infiltrates are poorly understood. The Nurses’ Health Study (NHS) offers a unique cohort to study immune gene expression in tumor and adjacent normal breast tissue, immune cell-specific immunohistochemistry (IHC), and patient exposures. We evaluated the association of body mass index (BMI) change since age 18, physical activity, and the empirical dietary inflammatory pattern (EDIP) score, all implicated in systemic inflammation, with immune cell-specific expression scores. Methods This population-based, prospective observational study evaluated 882 NHS and NHSII participants diagnosed with invasive breast cancer with detailed exposure and gene expression data. Of these, 262 women (training cohort) had breast tumor IHC for four classic immune cell markers (CD8, CD4, CD20, and CD163). Four immune cell-specific scores were derived via lasso regression using 105 published immune expression signatures’ association with IHC. In the remaining 620 patient evaluation cohort, we evaluated association of each immune cell-specific score as outcomes, with BMI change since age 18, physical activity, and EDIP score as predictors, using multivariable-adjusted linear regression. Results Among women with paired expression/IHC data from breast tumor tissue, we identified robust correlation between novel immune cell-specific expression scores and IHC. BMI change since age 18 was positively associated with CD4+ (β = 0.16; p = 0.009), and CD163 novel immune scores (β = 0.14; p = 0.04) in multivariable analyses. In other words, for each 10 unit (kg/m2) increase in BMI, the percentage of cells positive for CD4 and CD163 increased 1.6% and 1.4%, respectively. Neither physical activity nor EDIP was significantly associated with any immune cell-specific expression score in multivariable analyses. Conclusions BMI change since age 18 was positively associated with novel CD4+ and CD163+ cell scores in breast cancer, supporting further study of the effect of modifiable factors like weight gain on the immune microenvironment.

Abstract Background Breast parenchymal texture features, including grayscale variation (V), capture the patterns of texture variation on a mammogram and are associated with breast cancer risk, independent of mammographic density (MD). However, our knowledge on the genetic basis of these texture features is limited. Methods We conducted a genome-wide association study of V in 7040 European-ancestry women. V assessments were generated from digitized film mammograms. We used linear regression to test the single-nucleotide polymorphism (SNP)-phenotype associations adjusting for age, body mass index (BMI), MD phenotypes, and the top four genetic principal components. We further calculated genetic correlations and performed SNP-set tests of V with MD, breast cancer risk, and other breast cancer risk factors. Results We identified three genome-wide significant loci associated with V: rs138141444 (6q24.1) in ECT2L, rs79670367 (8q24.22) in LINC01591, and rs113174754 (12q22) near PGAM1P5. 6q24.1 and 8q24.22 have not previously been associated with MD phenotypes or breast cancer risk, while 12q22 is a known locus for both MD and breast cancer risk. Among known MD and breast cancer risk SNPs, we identified four variants that were associated with V at the Bonferroni-corrected thresholds accounting for the number of SNPs tested: rs335189 (5q23.2) in PRDM6, rs13256025 (8p21.2) in EBF2, rs11836164 (12p12.1) near SSPN, and rs17817449 (16q12.2) in FTO. We observed significant genetic correlations between V and mammographic dense area (r g = 0.79, P = 5.91 × 10−5), percent density (r g = 0.73, P = 1.00 × 10−4), and adult BMI (r g = − 0.36, P = 3.88 × 10−7). Additional significant relationships were observed for non-dense area (z = − 4.14, P = 3.42 × 10−5), estrogen receptor-positive breast cancer (z = 3.41, P = 6.41 × 10−4), and childhood body fatness (z = − 4.91, P = 9.05 × 10−7) from the SNP-set tests. Conclusions These findings provide new insights into the genetic basis of mammographic texture variation and their associations with MD, breast cancer risk, and other breast cancer risk factors.

Abstract Background Early age at menarche and tall stature are associated with increased breast cancer risk. We examined whether these associations were also positively associated with mammographic density, a strong marker of breast cancer risk. Methods Participants were 10,681 breast-cancer-free women from 22 countries in the International Consortium of Mammographic Density, each with centrally assessed mammographic density and a common set of epidemiologic data. Study periods for the 27 studies ranged from 1987 to 2014. Multi-level linear regression models estimated changes in square-root per cent density (√PD) and dense area (√DA) associated with age at menarche and adult height in pooled analyses and population-specific meta-analyses. Models were adjusted for age at mammogram, body mass index, menopausal status, hormone therapy use, mammography view and type, mammographic density assessor, parity and height/age at menarche. Results In pooled analyses, later age at menarche was associated with higher per cent density (β √PD = 0.023 SE = 0.008, P = 0.003) and larger dense area (β √DA = 0.032 SE = 0.010, P = 0.002). Taller women had larger dense area (β √DA = 0.069 SE = 0.028, P = 0.012) and higher per cent density (β √PD = 0.044, SE = 0.023, P = 0.054), although the observed effect on per cent density depended upon the adjustment used for body size. Similar overall effect estimates were observed in meta-analyses across population groups. Conclusions In one of the largest international studies to date, later age at menarche was positively associated with mammographic density. This is in contrast to its association with breast cancer risk, providing little evidence of mediation. Increased height was also positively associated with mammographic density, particularly dense area. These results suggest a complex relationship between growth and development, mammographic density and breast cancer risk. Future studies should evaluate the potential mediation of the breast cancer effects of taller stature through absolute breast density.

Abstract Background Mammographic density (MD) phenotypes, including percent density (PMD), area of dense tissue (DA), and area of non-dense tissue (NDA), are associated with breast cancer risk. Twin studies suggest that MD phenotypes are highly heritable. However, only a small proportion of their variance is explained by identified genetic variants. Methods We conducted a genome-wide association study, as well as a transcriptome-wide association study (TWAS), of age- and BMI-adjusted DA, NDA, and PMD in up to 27,900 European-ancestry women from the MODE/BCAC consortia. Results We identified 28 genome-wide significant loci for MD phenotypes, including nine novel signals (5q11.2, 5q14.1, 5q31.1, 5q33.3, 5q35.1, 7p11.2, 8q24.13, 12p11.2, 16q12.2). Further, 45% of all known breast cancer SNPs were associated with at least one MD phenotype at p

Abstract Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values

Abstract Background Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. Methods Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. Results Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate

Dennis et al. investigate potential breast cancer associations with rare germline copy number variants (CNVs) by conducting a genome-wide analysis in a large breast cancer case-control dataset. The authors detected associations with exonic deletions in established breast cancer susceptibility genes and suggestive associations for a number of non-coding CNVs.

BackgroundThe data on the expression of stem cell markers CD44, CD24, and ALDH1A1 in the breast tissue of cancer-free women is very limited and no previous studies have explored the agreement between pathologist and computational assessments of these markers. We compared the immunohistochemical (IHC) expression assessment for CD44, CD24, and ALDH1A1 by an expert pathologist with the automated image analysis results and assessed the homogeneity of the markers across multiple cores pertaining to each woman.MethodsWe included 81 cancer-free women (399 cores) with biopsy-confirmed benign breast disease in the Nurses’ Health Study (NHS) and NHSII cohorts. IHC was conducted with commercial antibodies [CD44 (Dako, Santa Clara, CA, USA) 1:25 dilution; CD24 (Invitrogen, Waltham, MA, USA) 1:200 dilution and ALDH1A1 (Abcam, Cambridge, United Kingdom) 1:300 dilution]. For each core, the percent positivity was quantified by the pathologist and Definiens Tissue Studio. Correlations between pathologist and computational scores were evaluated with Spearman correlation (for categorical positivity: 0, >0–10–50, and >50%) and sensitivity/specificity (for binary positivity defined with 1 and 10% cut-offs), using the pathologist scores as the gold standard. Expression homogeneity was examined with intra-class correlation (ICC). Analyses were stratified by core [normal terminal duct-lobular units (TDLUs), benign lesions] and tissue type (epithelium, stroma).ResultsSpearman correlation between pathologist and Definiens ranged between 0.40–0.64 for stroma and 0.66–0.68 for epithelium in normal TDLUs cores and between 0.24–0.60 for stroma and 0.61–0.64 for epithelium in benign lesions. For stroma, sensitivity and specificity ranged between 0.92–0.95 and 0.24–0.60, respectively, with 1% cut-off and between 0.43–0.88 and 0.73–0.85, respectively, with 10% cut-off. For epithelium, 10% cut-off resulted in better estimates for both sensitivity and specificity. ICC between the cores was strongest for CD44 for both stroma and epithelium in normal TDLUs cores and benign lesions (range 0.74–0.80). ICC for CD24 and ALDH1A ranged between 0.42–0.63 and 0.44–0.55, respectively.ConclusionOur findings show that computational assessments for CD44, CD24, and ALDH1A1 exhibit variable correlations with manual assessment. These findings support the use of computational platforms for IHC evaluation of stem cell markers in large-scale epidemiologic studies. Pilot studies maybe also needed to determine appropriate cut-offs for defining staining positivity.

Abstract Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identified two germline variants on chromosome 1, rs138569520 and rs146023652, significantly associated with breast cancer-specific survival (P = 3.19 × 10−8 and 4.42 × 10−8). In silico analysis suggested a potential regulatory effect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confirm the identified associations.

Abstract Background Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. Methods We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP

Abstract Background Adolescence and early adulthood has been identified as a critical time window for establishing breast cancer risk. Mammographic density is an independent risk factor for breast cancer that may be influenced by diet, but there has been limited research conducted on the impact of diet on mammographic density. Thus, we sought to examine the association between adolescent and early adulthood inflammatory dietary patterns, which have previously been associated with breast cancer risk, and premenopausal mammographic density among women in the Nurses’ Health Study II (NHSII). Methods This study included control participants with premenopausal mammograms from an existing breast cancer case-control study nested within the NHSII who completed a Food Frequency Questionnaire in 1998 about their diet during high school (HS-FFQ) (n = 685) and/or a Food Frequency Questionnaire in 1991 (Adult-FFQ) when they were 27–44 years old (n = 1068). Digitized analog film mammograms were used to calculate the percent density, absolute dense, and non-dense areas. Generalized linear models were fit to evaluate the associations of a pro-inflammatory dietary pattern and the Alternative Healthy Eating Index (AHEI, an anti-inflammatory dietary pattern) with each breast density measure. Results Significant associations were observed between an adolescent pro-inflammatory dietary pattern and mammographic density in some age-adjusted models; however, these associations did not remain after adjustment for BMI and other breast cancer risk factors. No associations were observed with the pro-inflammatory pattern or with the AHEI pattern in adolescence or early adulthood in fully adjusted models. Conclusions To our knowledge, this is the first study to evaluate the dietary patterns during adolescence and early adulthood in relation to mammographic density phenotypes. Our findings do not support an association between adolescent and early adulthood diet and breast density in mid-adulthood that is independent of BMI or other breast cancer risk factors.

Abstract Background We investigated the associations of reproductive factors with the percentage of epithelium, stroma, and fat tissue in benign breast biopsy samples. Methods This study included 983 cancer-free women with biopsy-confirmed benign breast disease (BBD) within the Nurses’ Health Study and Nurses’ Health Study II cohorts. The percentage of each tissue type (epithelium, stroma, and fat) was measured on whole-section images with a deep-learning technique. All tissue measures were log-transformed in all the analyses to improve normality. The data on reproductive variables and other breast cancer risk factors were obtained from biennial questionnaires. Generalized linear regression was used to examine the associations of reproductive factors with the percentage of tissue types, while adjusting for known breast cancer risk factors. Results As compared to parous women, nulliparous women had a smaller percentage of epithelium (β = − 0.26, 95% confidence interval [CI] − 0.41, − 0.11) and fat (β = − 0.34, 95% CI − 0.54, − 0.13) and a greater percentage of stroma (β = 0.04, 95% CI 0.01, 0.08). Among parous women, the number of children was inversely associated with the percentage of stroma (β per child = − 0.01, 95% CI − 0.02, − 0.00). The duration of breastfeeding of ≥ 24 months was associated with a reduced proportion of fat (β = − 0.30, 95% CI − 0.54, − 0.06; p-trend = 0.04). In a separate analysis restricted to premenopausal women, older age at first birth was associated with a greater proportion of epithelium and a smaller proportion of stroma. Conclusions Our findings suggest that being nulliparous as well as having a fewer number of children (both positively associated with breast cancer risk) is associated with a smaller proportion of epithelium and a greater proportion of stroma, potentially suggesting the importance of epithelial-stromal interactions. Future studies are warranted to confirm our findings and to elucidate the underlying biological mechanisms.

Abstract Young women with breast cancer experience unique treatment and survivorship issues centering on treatment-related amenorrhea (TRA), including fertility preservation and management of ovarian function as endocrine therapy. The Young Women’s Breast Cancer Study (YWS) is a multi-center, prospective cohort study of women diagnosed at age ≤40, enrolled from 2006 to 2016. Menstrual outcomes were self-reported on serial surveys. We evaluated factors associated with TRA using logistic regression. One year post-diagnosis, 286/789 (36.2%) experienced TRA, yet most resumed menses (2-year TRA: 120/699; 17.2%). Features associated with 1-year TRA included older age (OR ≤30vs36-40 = 0.29 (0.17–0.48), OR31-35vs36-40 = 0.67 (0.46–0.94), p = 0.02); normal body mass index (BMI) (OR ≥25vs18.5-24. =0.59 (0.41–0.83), p

Abstract Background Cancer survivors who develop breast cancer as a second malignancy (BCa-2) are common. Yet, little is known about the prognosis of BCa-2 compared to first primary breast cancer (BCa-1). Methods Using the Surveillance, Epidemiology, and End Results database, we conducted a population-based cohort study including 883,881 patients with BCa-1 and 36,313 patients with BCa-2 during 1990–2015. Compared with patients with BCa-1, we calculated hazard ratios (HRs) of breast cancer-specific mortality among patients with BCa-2, using multivariable Cox regression. Results During the follow-up (median 5.5 years), 114,964 and 3829 breast cancer-specific deaths were identified among BCa-1 and BCa-2 patients, respectively. Patients with BCa-2 had more favorable tumor characteristics and received less intensive treatment e.g., surgery and chemo−/radio-therapy, compared to patients with BCa-1. When adjusting for demographic factors, patients with BCa-2 were at similar risk of breast cancer-specific mortality (HR 1.00, 95% CI 0.97–1.03) compared to patients with BCa-1. However, when additionally controlling for tumor characteristics and treatment modes, BCa-2 patients were at an increased risk of breast cancer-specific mortality (HR 1.11, 95% CI 1.08–1.15). The risk elevation was particularly greater when the first malignancy was lung, bladder, ovarian or blood malignancy (HRs 1.16–1.85), or when the first malignancy was treated with chemotherapy and radiotherapy (HR 1.44, 95% CI 1.28–1.63). Conclusions Overall, patients with BCa-2 have worse breast cancer-specific survival, compared with their BCa-1 counterparts, although the risk elevation is mild. High-risk subgroups based on first malignancy’s characteristics may be considered for active clinical management.

Abstract Percent mammographic density (PMD) is a strong breast cancer risk factor, however, other mammographic features, such as V, the standard deviation (SD) of pixel intensity, may be associated with risk. We assessed whether PMD, automated PMD (APD), and V, yielded independent associations with breast cancer risk. We included 1900 breast cancer cases and 3921 matched controls from the Nurses’ Health Study (NHS) and the NHSII. Using digitized film mammograms, we estimated PMD using a computer-assisted thresholding technique. APD and V were determined using an automated computer algorithm. We used logistic regression to generate odds ratios (ORs) and 95% confidence intervals (CIs). Median time from mammogram to diagnosis was 4.1 years (interquartile range: 1.6–6.8 years). PMD (OR per SD:1.52, 95% CI: 1.42, 1.63), APD (OR per SD:1.32, 95% CI: 1.24, 1.41), and V (OR per SD:1.32, 95% CI: 1.24, 1.40) were positively associated with breast cancer risk. Associations for APD were attenuated but remained statistically significant after mutual adjustment for PMD or V. Women in the highest quartile of both APD and V (OR vs Q1/Q1: 2.49, 95% CI: 2.02, 3.06), or PMD and V (OR vs Q1/Q1: 3.57, 95% CI: 2.79, 4.58) had increased breast cancer risk. An automated method of PMD assessment is feasible and yields similar, but somewhat weaker, estimates to a manual measure. PMD, APD and V are each independently, positively associated with breast cancer risk. Women with dense breasts and greater texture variation are at the highest relative risk of breast cancer.

Abstract Data on the risk of breast cancer following a benign breast disease (BBD) diagnosis were derived predominantly from populations of women biopsied before the widespread use of mammographic screening and in whom these lesions were mostly incidental findings. Whether or not similar risk associations are seen when these lesions are detected in mammographically screened populations is unknown. To address this, we examined the variation in BBD and breast cancer risk associations by the calendar time of BBD diagnosis (pre- vs. post-mammography era [before vs. 1985 and after]) in a nested case–control study within the Nurses’ Health Study (NHS) and NHSII BBD subcohort (488 cases; 1908 controls). We performed logistic regression analysis, adjusting for matching factors and potential confounders, to estimate odds ratio (ORs) and 95% confidence interval (CI) for the association between BBD subtype (non-proliferative, proliferative without atypia, proliferative with atypical hyperplasia (AH)) and subsequent breast cancer risk. When compared with non-proliferative lesions, both proliferative lesions without atypia (PWA) and AHs were associated with similar levels of risk in the pre-mammographic (pre) and post-mammographic (post) time periods (PWA: OR [95% CI] = 1.73 [1.27, 2.36] pre vs. 1.12 [0.73, 1.74] post; AH: 4.41 [2.90, 6.70] pre vs. 3.69 [2.21, 6.15] post). The interaction by mammography era was not statistically significant (p-interaction = 0.47). These results suggest that the risk associations reported for BBD subtypes in the pre-mammography era remain valid for BBD detected after the widespread implementation of mammographic screening.

Breast cancer risk for BRCA1/BRCA2 mutation carriers varies depending on other genetic factors. Here, the authors perform a case-only genome-wide association study and highlight novel loci associated with breast cancer risk for BRCA1/BRCA2 mutation carriers.

Abstract Immunohistochemical (IHC) staining in breast cancer shows both gain and loss of COX2 expression with disease risk and progression. We investigated four common COX2 antibody clones and found high specificity for purified human COX2 for three clones; however, recognition of COX2 in cell lysates was clone dependent. Biochemical characterization revealed two distinct forms of COX2, with SP21 recognizing an S-nitrosylated form, and CX229 and CX294 recognizing non-nitrosylated COX2 antigen. We found S-nitrosylated and non-nitrosylated COX2 occupy different subcellular locations in normal and breast cancer tissue, implicating distinct synthetic/trafficking pathways and function. Dual stains of ~2000 breast cancer cases show early-onset breast cancer had increased expression of both forms of COX2 compared to postmenopausal cases. Our results highlight the strengths of using multiple, highly characterized antibody clones for COX2 IHC studies and raise the prospect that S-nitrosylation of COX2 may play a role in breast cancer biology.

Abstract Adolescent drinking is associated with higher risks of proliferative benign breast disease (BBD) and invasive breast cancer (BC). Furthermore, adolescent nut and fiber consumptions are associated with lower risks of benign lesions and premenopausal BC. We hypothesize that diet (nuts, fiber) may mitigate the elevated BBD risk associated with alcohol. A prospective cohort of 9031 females, 9–15 years at baseline, completed questionnaires in 1996–2001, 2003, 2005, 2007, 2010, 2013, and 2014. Participants completed food frequency questionnaires in 1996–2001. In 2005, participants (>=18 years) began reporting biopsy-confirmed BBD (N = 173 cases). Multivariable logistic regression estimated associations between BBD and cross-classified intakes (14–17 years) of alcohol and peanut butter/nuts (separately, total dietary fiber). Only 19% of participants drank in high school; drinking was associated with elevated BBD risk (OR = 1.75, 95% CI: 1.20–2.56; p = 0.004) compared to nondrinkers. Participants consuming any nuts/butter had lower BBD risk (OR = 0.64, 95% CI: 0.45–0.90; p = 0.01) compared to those consuming none. Participants in top 75% fiber intake had lower risk (OR = 0.57, 95% CI: 0.40–0.81; p = 0.002) compared to bottom quartile. Testing our hypothesis that consuming nuts/butter mitigates the elevated alcohol risk, analyzing alcohol and nuts combined found that those who consumed both had lower risk (RR = 0.47, 95% CI: 0.24–0.89; p = 0.02) compared to drinkers eating no nuts. Our analysis of alcohol and fiber together did not demonstrate risk mitigation by fiber. For high school females who drink, their BBD risk may be attenuated by consuming nuts. Due to modest numbers, future studies need to replicate our findings in adolescent/adult females. However, high school students may be encouraged to eat nuts and fiber, and to avoid alcohol, to reduce risk of BBD and for general health benefits.

Abstract Background Young women with breast cancer tend to report lower quality of life and higher levels of stress than older women with breast cancer, and this may have implications for other psychosocial factors including finances. We sought to determine if stress, anxiety, and depression at diagnosis were associated with changes in household income over 12-months in young women with breast cancer in the United States. Methods This study was a prospective, longitudinal cohort study comprised of women enrolled in the Young and Strong trial. Of the 467 women aged 18–45 newly diagnosed with early-stage breast cancer enrolled in the Young and Strong trial from 2012 to 2013, 356 (76%) answered income questions. Change in household income from baseline to 12 months was assessed and women were categorized as having lost, gained, maintained the same household income

Schizophrenia has been associated with increased risk of breast cancer, yet the risk of schizophrenia following breast cancer is unclear. Here, the authors show a bidirectional association between breast cancer and schizophrenia in Sweden and a shared genetic contribution to both diseases.

Abstract Background Previous studies of fatty acids and breast cancer risk have shown mixed results, which may be due in part to tumor heterogeneity. Prior research has also illustrated an important role of specific fatty acids in immune regulation, T cell function, and inflammation, indicating that the effects of specific fatty acids on breast cancer risk may vary by tumor expression of immuno-inflammatory markers. We therefore aimed to evaluate the relationships between prediagnostic erythrocyte membrane fatty acids and breast cancer risk by tumor tissue expression of immuno-inflammatory markers (CD4, CD8, CD20, CD163, COX-2) and fatty acid synthase (FAS). Methods We conducted a matched case-control study nested within the Nurses’ Health Study II (n = 235 cases and 235 controls). Blood samples were collected from 1996 to 1999. Tumor tissue blocks were collected for cases diagnosed after blood collection and through 2006. Unconditional nominal polytomous logistic regression adjusted for matching factors and potential confounders was used to assess whether associations between fatty acids and breast cancer risk varied by tumor expression subtype, ascertained via immunohistochemistry. Odds ratios (OR) and 95% confidence intervals (CI) were estimated separately by tumor expression subtype using unconditional logistic regression. Results Associations between fatty acids and breast cancer risk did not vary substantially by tumor CD4, CD20, CD163, or COX-2. However, n-3 polyunsaturated fatty acids (PUFAs) were inversely associated with CD8low but not CD8high cancers (CD8low ORT3 vs T1 = 0.45, 95% CI 0.23–0.87, P trend = 0.02; CD8high ORT3 vs T1 = 1.19, 95% CI 0.62–2.26, P trend = 0.62; P het = 0.04). n-6 PUFAs were suggestively inversely associated with CD8high but not CD8low cancers (CD8high ORT3 vs T1 = 0.61, 95% CI 0.32–1.14, P trend = 0.11; CD8low ORT3 vs T1 = 1.63, 95% CI 0.87–3.04, P trend = 0.12; P het = 0.02). Trans fatty acids were positively associated with FAShigh but not FASlow tumors (FAShigh ORT3 vs T1 = 2.94, 95% CI 1.46–5.91, P trend = 0.002; FASlow ORT3 vs T1 = 0.99, 95% CI 0.52–1.92, P trend = 0.97; P het = 0.01). Conclusion Results indicate that the effects of n-3 PUFAs, n-6 PUFAs, and trans fatty acids on breast cancer risk may vary by tumor tissue expression subtypes. Findings suggest potential immuno-modulatory and FAS-mediated mechanisms.

Abstract Background The International Agency for Research on Cancer classified radon and its decay-products as Group-1-human-carcinogens, and with the current knowledge they are linked specifically to lung cancer. Biokinetic models predict that radon could deliver a carcinogenic dose to breast tissue. Our previous work suggested that low-dose radon was associated with estrogen-receptor (ER)-negative breast cancer risk. However, there is limited research to examine the role of radon in breast cancer biology at the tissue level. We aim to understand molecular pathways linking radon exposure with breast cancer biology using transcriptome-wide-gene-expression from breast tumor and normal-adjacent tissues. Methods Our study included 943 women diagnosed with breast cancer from the Nurses’ Health Study (NHS) and NHSII. We estimated cumulative radon concentration for each participant up-to the year of breast cancer diagnosis by linking residential addresses with a radon exposure model. Transcriptome-wide-gene-expression was measured with the Affymetrix-Glue-Human-Transcriptome-Array-3.0 and Human-Transcriptome-Array-2.0. We performed covariate-adjusted linear-regression for individual genes and further employed pathway-analysis. All analyses were conducted separately for tumor and normal-adjacent samples and by ER-status. Results No individual gene was associated with cumulative radon exposure in ER-positive tumor, ER-negative tumor, or ER-negative normal-adjacent tissues at FDR

In breast cancer the contribution of different genetic variants to disease heritability is complex and not fully understood. Here, the authors present a network-based analysis in 84,567 patients studying ~7.3 million variants, identifying gene modules associated with breast cancer survival.

Digital pathology can efficiently assess immunohistochemistry (IHC) data on tissue microarrays (TMAs). Yet, it remains important to evaluate the comparability of the data acquired by different software applications and validate it against pathologist manual interpretation. In this study, we compared the IHC quantification of 5 clinical breast cancer biomarkers—estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), and cytokeratin 5/6 (CK5/6)—across 3 software applications (Definiens Tissue Studio, inForm, and QuPath) and benchmarked the results to pathologist manual scores.IHC expression for each marker was evaluated across 4 TMAs consisting of 935 breast tumor tissue cores from 367 women within the Nurses’ Health Studies; each women contributing three 0.6-mm cores. The correlation and agreement between manual and software-derived results were primarily assessed using Spearman’s ρ, percentage agreement, and area under the curve (AUC).At the TMA core-level, the correlations between manual and software-derived scores were the highest for HER2 (ρ ranging from 0.75 to 0.79), followed by ER (0.69–0.71), PR (0.67–0.72), CK5/6 (0.43–0.47), and EGFR (0.38–0.45). At the case-level, there were good correlations between manual and software-derived scores for all 5 markers (ρ ranging from 0.43 to 0.82), where QuPath had the highest correlations. Software-derived scores were highly comparable to each other (ρ ranging from 0.80 to 0.99). The average percentage agreements between manual and software-derived scores were excellent for ER (90.8%–94.5%) and PR (78.2%–85.2%), moderate for HER2 (65.4%–77.0%), highly variable for EGFR (48.2%–82.8%), and poor for CK5/6 (22.4%–45.0%). All AUCs across markers and software applications were ≥0.83.The 3 software applications were highly comparable to each other and to manual scores in quantifying these 5 markers. QuPath consistently produced the best performance, indicating this open-source software is an excellent alternative for future use.

Abstract Background Mammographic breast density, adjusted for age and body mass index, and a polygenic risk score (PRS), comprised of common genetic variation, are both strong risk factors for breast cancer and increase discrimination of risk models. Understanding their joint contribution will be important to more accurately predict risk. Methods Using 3628 breast cancer cases and 5126 controls of European ancestry from eight case-control studies, we evaluated joint associations of a 77-single nucleotide polymorphism (SNP) PRS and quantitative mammographic density measures with breast cancer. Mammographic percent density and absolute dense area were evaluated using thresholding software and examined as residuals after adjusting for age, 1/BMI, and study. PRS and adjusted density phenotypes were modeled both continuously (per 1 standard deviation, SD) and categorically. We fit logistic regression models and tested the null hypothesis of multiplicative joint associations for PRS and adjusted density measures using likelihood ratio and global and tail-based goodness of fit tests within the subset of six cohort or population-based studies. Results Adjusted percent density (odds ratio (OR) = 1.45 per SD, 95% CI 1.38–1.52), adjusted absolute dense area (OR = 1.34 per SD, 95% CI 1.28–1.41), and the 77-SNP PRS (OR = 1.52 per SD, 95% CI 1.45–1.59) were associated with breast cancer risk. There was no evidence of interaction of the PRS with adjusted percent density or dense area on risk of breast cancer by either the likelihood ratio (P > 0.21) or goodness of fit tests (P > 0.09), whether assessed continuously or categorically. The joint association (OR) was 2.60 in the highest categories of adjusted PD and PRS and 0.34 in the lowest categories, relative to women in the second density quartile and middle PRS quintile. Conclusions The combined associations of the 77-SNP PRS and adjusted density measures are generally well described by multiplicative models, and both risk factors provide independent information on breast cancer risk.

Abstract Background Obesity and elevated breast density are common risk factors for breast cancer, and their effects may vary by estrogen receptor (ER) subtype. However, their joint effects on ER subtype-specific risk are unknown. Understanding this relationship could enhance risk stratification for screening and prevention. Thus, we assessed the association between breast density and ER subtype according to body mass index (BMI) and menopausal status. Methods We conducted a case-control study nested within two mammography screening cohorts, the Mayo Mammography Health Study and the San Francisco Bay Area Breast Cancer SPORE/San Francisco Mammography Registry. Our pooled analysis contained 1538 ER-positive and 285 ER-negative invasive breast cancer cases and 4720 controls matched on age, menopausal status at time of mammogram, and year of mammogram. Percent density was measured on digitized film mammograms using computer-assisted techniques. We used polytomous logistic regression to evaluate the association between percent density and ER subtype by BMI subgroup (normal/underweight,

Abstract Background Epidemiologic data suggest that parity increases risk of hormone receptor-negative breast cancer and that breastfeeding attenuates this association. Prospective data, particularly on the joint effects of higher parity and breastfeeding, are limited. Methods We investigated parity, breastfeeding, and breast cancer risk by hormone-receptor (estrogen (ER) and progesterone receptor (PR)) and molecular subtypes (luminal A, luminal B, HER2-enriched, and basal-like) in the Nurses’ Health Study (NHS; 1976–2012) and NHSII (1989–2013). A total of 12,452 (ER+ n = 8235; ER− n = 1978) breast cancers were diagnosed among 199,514 women. We used Cox proportional hazards models, adjusted for breast cancer risk factors, to calculate hazard ratios (HR) and 95% confidence intervals (CI). Results Parous women had lower risk of ER+ breast cancer (vs. nulliparous, HR = 0.82 [0.77–0.88]); no association was observed for ER− disease (0.98 [0.84–1.13]; P het = 0.03). Among parous women, breastfeeding was associated with lower risk of ER− (vs. never 0.82 [0.74–0.91]), but not ER+, disease (0.99 [0.94–1.05]; P het

Abstract Background The androgen receptor (AR) is an emerging prognostic marker and therapeutic target in breast cancer. AR is expressed in 60–80% of breast cancers, with higher prevalence among estrogen receptor-positive (ER+) tumors. Androgen treatment inhibits ER signaling in ER+/AR+ breast cancer cell lines, and AR expression is associated with improved survival for this subtype in epidemiologic studies. However, whether AR expression modifies the efficacy of selective ER modulators or aromatase inhibitors for ER+ cancers remains unclear. Methods We evaluated the prognostic and predictive value of AR expression among 3021 postmenopausal ER+ breast cancer patients in the Breast International Group (BIG) trial 1–98. The BIG 1–98 study was a four-armed, double-blind, phase III randomized clinical trial that compared 5 years of tamoxifen or letrozole monotherapy, or sequences of 2 years and 3 years treatment with one drug and then the other. AR expression was measured by immunohistochemistry and the percentage of AR-positive nuclei was quantified. The association between AR expression and prognosis was evaluated using Cox proportional hazards models. Continuous AR-by-treatment interactions were assessed using Subpopulation Treatment Effect Pattern Plots (STEPP). Results Eighty-two percent of patients had AR+ (≥ 1%) tumors. Patients with AR+ cancers were more likely to have smaller, lower-grade tumors, with higher expression of ER and PR. AR expression was not associated with breast cancer-free interval (BCFI) (415 events) over a median 8.0 years of follow-up (p = 0.12, log-rank test). In multivariable-adjusted models, AR expression was not associated with BCFI (HR = 1.07, 95% CI 0.83–1.36, p = 0.60). The letrozole versus tamoxifen monotherapy treatment effect did not significantly differ for AR+ tumors (HR = 0.63, 95% CI 0.44–0.75, p = 0.003) and AR− tumors (HR = 0.39, 95% CI 0.21–0.72, p = 0.002) (p-heterogeneity = 0.16). STEPP analysis also suggested no heterogeneity of the treatment effect across the continuum of AR expression. Conclusions AR expression was not associated with prognosis, nor was there heterogeneity of the letrozole versus tamoxifen treatment effect by AR expression. These findings suggest that AR expression may not be an informative biomarker for the selection of adjuvant endocrine therapy for postmenopausal women with ER+ breast cancers. Trial registration ClinicalTrials.gov, NCT00004205, Registered 27 January 2003—Retrospectively registered, https://clinicaltrials.gov/ct2/show/study/NCT00004205.

Abstract Background Epidemiologic evidence suggests that certain dietary patterns were associated with breast cancer risk, but the results have been inconclusive. We assessed the associations between different dietary patterns and the risk of breast cancer by conducting a meta-analysis of observational studies. Methods Relevant articles were searched in PubMed, Embase, and Cochrane library databases through September 2017. Multivariable-adjusted relative risks (RRs) and 95% confidence intervals (CIs) comparing the highest and lowest categories of Western and prudent dietary patterns were combined by using the random-effects meta-analyses. Results We identified 32 eligible articles including 14 cohort and 18 case-control studies (34 Western and 35 prudent studies). The pooled analyses found that a Western dietary pattern was associated with a 14% increased risk (RR 1.14, 95% CI 1.02, 1.28), whereas a prudent dietary pattern was associated with an 18% reduced risk of breast cancer (RR 0.82, 95% CI 0.75, 0.89). In addition, sub-group analyses showed that the positive association between a Western dietary pattern and breast cancer risk was significant among postmenopausal (RR 1.20, 95% CI 1.06, 1.35), but not premenopausal women (RR 1.18, 95% CI 0.99, 1.40), and significant for hormone receptor-positive tumors (RR 1.18, 95% CI 1.04, 1.33), but not receptor-negative tumors (RR 0.97, 95% CI 0.83, 1.12). In contrast, the inverse association between a prudent dietary pattern and breast cancer was significant in premenopausal (RR 0.77, 95% CI 0.61, 0.98), but not postmenopausal women (RR 0.88, 95% CI 0.74, 1.03), and significant for both hormone receptor-positive and receptor-negative tumors. Conclusions The results of the current meta-analysis suggest a possible increased risk of breast cancer associated with a Western dietary pattern and a reduced risk with a prudent dietary pattern. Large-scale cohort studies with a high quality need to be conducted to further confirm the findings of the current meta-analysis. As dietary patterns are modifiable, these findings may provide viable strategies for breast cancer prevention through changes in dietary intake.

Abstract Background Epidemiological studies have found that high whole grain intake may be associated with a reduced risk of breast cancer. However, the evidence has not been consistent. We conducted a meta-analysis to quantitatively assess the association between whole grain intake and breast cancer risk. Methods Relevant observational studies were identified by searching PubMed, Embase, Cochrane library databases, and Google Scholar through April 2017. Summary relative risk (RR) estimates were calculated using random-effects meta-analysis. Results A total of 11 studies, including 4 cohort and 7 case-control studies and involving 131,151 participants and 11,589 breast cancer cases, were included in the current meta-analysis. The pooled RR of breast cancer for those with high versus low whole grain intake was 0.84 (95% confidence interval [CI]: 0.74 to 0.96, p = 0.009; I 2 = 63.8%, p for heterogeneity = 0.002). Subgroup analysis by study design found a significant inverse association in the case-control studies (RR: 0.69; 95% CI: 0.56 to 0.87, p = 0.001; I 2 = 58.2%, p for heterogeneity = 0.026), but not in the cohort studies (RR, 0.96; 95% CI: 0.82 to 1.14, p = 0.69; I 2 = 66.7%, p for heterogeneity = 0.029). In addition, stratified analysis suggested that sample size could be a potential source of heterogeneity. Conclusions Results of the current meta-analysis suggest that high intake of whole grains might be inversely associated with a reduced risk of breast cancer, and the inverse association was only observed in case-control but not cohort studies. More large-scale cohort studies are needed to confirm the inverse association observed.

Abstract Background Findings from a recent prospective cohort study in California suggested increased risk of breast cancer associated with higher exposure to certain carcinogenic and estrogen-disrupting hazardous air pollutants (HAPs). However, to date, no nationwide studies have evaluated these possible associations. Our objective was to examine the impacts of mammary carcinogen and estrogen disrupting HAPs on risk of invasive breast cancer in a nationwide cohort. Methods We assigned HAPs from the US Environmental Protection Agency’s 2002 National Air Toxics Assessment to 109,239 members of the nationwide, prospective Nurses’ Health Study II (NHSII). Risk of overall invasive, estrogen receptor (ER)-positive (ER+), and ER-negative (ER-) breast cancer with increasing quartiles of exposure were assessed in time-varying multivariable proportional hazards models, adjusted for traditional breast cancer risk factors. Results A total of 3321 invasive cases occurred (2160 ER+, 558 ER-) during follow-up 1989–2011. Overall, there was no consistent pattern of elevated risk of the HAPs with risk of breast cancer. Suggestive elevations were only seen with increasing 1,2-dibromo-3-chloropropane exposures (multivariable adjusted HR of overall breast cancer = 1.12, 95% CI: 0.98–1.29; ER+ breast cancer HR = 1.09; 95% CI: 0.92, 1.30; ER- breast cancer HR = 1.14; 95% CI: 0.81, 1.61; each in the top exposure quartile compared to the lowest). Conclusions Exposures to HAPs during adulthood were not consistently associated with an increased risk of overall or estrogen-receptor subtypes of invasive breast cancer in this nationwide cohort of women.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-23162-4

Abstract Background High mammographic density is a strong, well-established breast cancer risk factor. Three studies conducted in various smaller geographic settings reported inconsistent findings between air pollution and mammographic density. We assessed whether particulate matter (PM) exposures (PM2.5, PM2.5–10, and PM10) and distance to roadways were associated with mammographic density among women residing across the United States. Methods The Nurses’ Health Studies are prospective cohorts for whom a subset has screening mammograms from the 1990s (interquartile range 1990–1999). PM was estimated using spatio-temporal models linked to residential addresses. Among 3258 women (average age at mammogram 52.7 years), we performed multivariable linear regression to assess associations between square-root-transformed mammographic density and PM within 1 and 3 years before the mammogram. For linear regression estimates of PM in relation to untransformed mammographic density outcomes, bootstrapped robust standard errors are used to calculate 95% confidence intervals (CIs). Analyses were stratified by menopausal status and region of residence. Results Recent PM and distance to roadways were not associated with mammographic density in premenopausal women (PM2.5 within 3 years before mammogram β = 0.05, 95% CI –0.16, 0.27; PM2.5–10 β = 0, 95%, CI –0.15, 0.16; PM10 β = 0.02, 95% CI –0.10, 0.13) and postmenopausal women (PM2.5 within 3 years before mammogram β = –0.05, 95% CI –0.27, 0.17; PM2.5–10 β = –0.01, 95% CI –0.16, 0.14; PM10 β = –0.02, 95% CI –0.13, 0.09). Largely null associations were observed within regions. Suggestive associations were observed among postmenopausal women in the Northeast (n = 745), where a 10-μg/m3 increase in PM2.5 within 3 years before the mammogram was associated with 3.4 percentage points higher percent mammographic density (95% CI –0.5, 7.3). Conclusions These findings do not support that recent PM or roadway exposures influence mammographic density. Although PM was largely not associated with mammographic density, we cannot rule out the role of PM during earlier exposure time windows and possible associations among northeastern postmenopausal women.

Abstract Background Alcohol consumption is an established risk factor for breast cancer and the association generally appears stronger among estrogen receptor (ER)-positive tumors. However, the biological mechanisms underlying this association are not completely understood. Methods We analyzed messenger RNA (mRNA) microarray data from both invasive breast tumors (N = 602) and tumor-adjacent normal tissues (N = 508) from participants diagnosed with breast cancer in the Nurses’ Health Study (NHS) and NHSII. Multivariable linear regression, controlling for other known breast cancer risk factors, was used to identify differentially expressed genes by pre-diagnostic alcohol intake. For pathway analysis, we performed gene set enrichment analysis (GSEA). Differentially expressed genes or enriched pathway-defined gene sets with false discovery rate (FDR)

Abstract Background Radon and its decay products, a source of ionizing radiation, are primarily inhaled and can deliver a radiation dose to breast tissue, where they may continue to decay and emit DNA damage-inducing particles. Few studies have examined the relationship between radon and breast cancer. Methods The Nurses’ Health Study II (NHSII) includes U.S. female registered nurses who completed biennial questionnaires since 1989. Self-reported breast cancer was confirmed from medical records. County-level radon exposures were linked with geocoded residential addresses updated throughout follow-up. Time-varying Cox regression models adjusted for established breast cancer risk factors were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Results From 1989 to 2013, 3966 invasive breast cancer cases occurred among 112,639 participants. Increasing radon exposure was not associated with breast cancer risk overall (adjusted HR comparing highest to lowest quintile = 1.06, 95% CI: 0.94, 1.21, p for trend = 0.30). However, women in the highest quintile of exposure (≥74.9 Bq/m3) had a suggested elevated risk of ER−/PR- breast cancer compared to women in the lowest quintile (

Abstract Background Hepatocellular carcinoma (HCC), the most commonly occurring type of primary liver cancer, has been increasing in incidence worldwide. Vitamin D, acquired from sunlight exposure, diet, and dietary supplements, has been hypothesized to impact hepatocarcinogenesis. However, previous epidemiologic studies examining the associations between dietary and serum vitamin D reported mixed results. The purpose of this study was to examine the association between ambient ultraviolet (UV) radiation exposure and HCC risk in the U.S. Methods The Surveillance, Epidemiology, and End Results (SEER) database provided information on HCC cases diagnosed between 2000 and 2014 from 16 population-based cancer registries across the U.S. Ambient UV exposure was estimated by linking the SEER county with a spatiotemporal UV exposure model using a geographic information system. Poisson regression with robust variance estimation was used to calculate incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for the association between ambient UV exposure per interquartile range (IQR) increase (32.4 mW/m2) and HCC risk adjusting for age at diagnosis, sex, race, year of diagnosis, SEER registry, and county-level information on prevalence of health conditions, lifestyle, socioeconomic, and environmental factors. Results Higher levels of ambient UV exposure were associated with statistically significant lower HCC risk (n = 56,245 cases; adjusted IRR per IQR increase: 0.83, 95% CI 0.77, 0.90; p