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Background Inflammatory Breast Cancer (IBC) is a rare and aggressive type of breast cancer treated by multimodality therapy. Due to the presence of dermal lymphatic involvement by disease it is unknown whether a skin sparing mastectomy (SSM) would be safe, even after completion of preoperative chemotherapy, therefore immediate breast reconstruction (BR) following modified radical (MRM) is discouraged. We sought to explore the patterns of BR outcomes in IBC patients (pts) and to evaluate their surgical outcomes. Methods A retrospective analysis was performed using an IRB-approved database of IBC pts evaluated at Dana Farber Cancer Institute (DFCI) from 1997 until 2014. Pts with stage III IBC who received preoperative systemic therapy followed by MRM and post-mastectomy radiation (PMRT) were analyzed. Receipt and timing of BR, post-operative morbidity and subsequent esthetic issues were collected. We also analyzed oncologic events which may have hindered receipt of BR. Results 318 pts were enrolled in the IBC registry at DFCI between 1997 and 2014. 181 pts with stage III IBC were identified, with a median follow-up of 57 months (mo) from MRM. 33/181 pts (18%) underwent BR; 2 pts were not evaluable due to lack of details concerning BR. 12 pts had immediate BR, 10 of which were performed elsewhere, prior to initial evaluation at DFCI. These included 3 tissue expander (TE) reconstructions, 3 single stage implants, 1 deep inferior epigastric perforator (DIEP) flap, 4 transverse rectus abdominis myocutaneous (TRAM) flaps, 1 latissimus dorsi (LD) flap. 19 had delayed BR. These included 1 TE, 5 DIEP flaps, 2 LD flap, 1 TE+LD flap, 10 TRAM flaps. Delayed BR occurred at a median of 13 mo (range 3-64 mo) following completion of PMRT. Complications post-BR were rare. Among the immediate BR pts, 1 pt with a TRAM flap BR required a reoperation 15 days (d) following BR for a partial TRAM flap necrosis. Among the delayed BR pts, one had a reoperation for abdominal TRAM flap donor site wound dehiscence 29 d after BR. Another delayed BR pt, who had a TE+LD flap BR, had her reconstruction implant removed due to chronic hematoma 79 mo after her initial BR; this occurred following 3 operative attempts to salvage her reconstruction by evacuating the hematoma. Overall, 12 reoperations were performed including 6 immediate BR (6/19 (31.6%) and 6 delayed BR pts (6/12 (50.0%); 6 of these reoperations (50%) were done for minor esthetic issues, such as reconstruction revisions for fat necrosis and capsular contracture, in addition to the more significant surgeries described above. Among 148 pts who did not undergo BR, 69 (47%) had disease recurrence following MRM (66 distant +/- local-regional recurrence (LRR); 3 LRR only); within 12 mo of MRM disease recurrence developed in 22% of pts (33/148). Conclusion Only 11% of pts presenting with stage III IBC recieved delayed BR in this retrospective analysis of 181 pts. The majority of these pts achieved successful BR, except for 1 pt. It is possible that BR was not sought more frequently due to a fairly high rate of distant disease relapse (47% in this cohort). Further studies addressing the outcomes of BR in IBC pts are needed in order to assist in counseling pts regarding their reconstructive expectations. Citation Format: Nakhlis F, Regan M, Chun YS, Dominici LS, Jacene HA, Yeh ED, Bellon JR, Warren LE, Hirko K, Hirshfield-Bartek J, Hazra A, Overmoyer BA. Patterns of breast reconstruction in patients diagnosed with inflammatory breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-18-02.

Introduction: Inflammatory breast cancer (IBC) is a rare and highly lethal form of breast cancer, accounting for approximately 10% of breast cancer mortality in the US. The clinical presentation of IBC includes rapid onset of symptoms, erythema > 1/3 of the breast, and edema. The genomic changes underlying the clincopathologic manifestations of IBC are yet unknown. Identification of a unique molecular signature in de novo IBC may provide insight into the biology of this disease, allowing further investigation into the etiology and treatment of this aggressive disease. In previous studies, supervised analysis of gene expression data from surgical tissue specimens identified a molecular-subtype independent 79-gene signature associated with IBC compared to locally-advanced non-IBC. In this study, we propose to identify a gene expression signature associated with IBC using breast specimens collected from patients with non-metastatic IBC prior to initiating preoperative systemic treatment. Methods: Formalin fixed paraffin embedded (FFPE) core biopsy specimens were collected from patients with inflammatory breast cancer prior to initiating systemic therapy. All specimens underwent centralized pathology review at Brigham and Women's Hospital, and the clinical diagnosis was confirmed through evaluation by the Dana Farber Cancer Institute Inflammatory Breast Cancer Program. Sufficient RNA and DNA were simultaneously extracted from 14 biopsy specimens using the Qiagen AllPrep Kit. The RNA was amplified using the Sensation kit and profiled using the Affymetrix Human Transcriptome Array (HTA) 2.0. DNA was profiled for druggable somatic mutations and genome-wide copy number variations using the Affymetrix OncoScan Array. Results: Pearson correlation coefficients for overall gene expression for 4 technical replicates included in the HTA ranged from r=0.993 - 0.994 and suggest excellent reproducibility in archival biopsy tissue. In preliminary analyses, 765 mRNA transcripts and 335 non-coding transcripts were differentially expressed based on clinical presentation features. The strongest differential association for rapid onset of disease was observed for alternately spliced variants in the TSPAN1 gene. Somatic mutations in PIK3CA were detected in 3 of the IBC patients. Additional paired assays as well as single-gene and pathway analyses, and integrated analyses of the genome and transcriptome using the R/Bioconductor packages are ongoing. Conclusion: An understanding of the genomic changes that contribute to the unique presentation and biologic features associated with IBC should lead to a significant impact on identifying etiologic risk factors and in optimizing treatment strategies. Our findings to date suggest a robust and reproducible method for genomic investigation using standard diagnostic breast core biopsies among IBC patients, and may inform profiling of biopsy specimens for other cancer types. The completion of this study will provide biological insights into the molecular mechanisms driving IBC and may identify clinically actionable targets for novel IBC therapies that warrant further exploration. Citation Format: Hazra A, Warren L, Nakhlis F, Bellon JR, Hirshfield-Bartek J, Jacene H, Yeh ED, Dominici L, Schlosnagle E, Hirko K, Overmoyer B. Tumor profiling of inflammatory breast cancer: Advancing the tools needed for precision medicine. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-18-03.

Cancer is the end result of a network of interacting factors, genetic and environmental. Unraveling this complexity could provide a foundation for more focused and effective prevention and detection strategies. The nascent fields of molecular and genetic epidemiology—constrained by technology and

This study aims to gain insights into the molecular mechanisms of obesity driving breast cancer etiology and prognosis as post-menopausal women with high body mass index (BMI) have increased breast cancer risk and poorer prognosis. We examined the differential gene expression of breast tumors from 441 post-menopausal women part of the Nurses’ Health Studies. Primary analysis was performed between women with BMI of In the primary analysis, differentially expressed genes associated with BMI were identified in pairwise analyses comparing women with BMI ≥35 with women in lower BMI categories ( These molecular insights have further elucidated breast cancer etiology in post-menopausal women with high BMI. Citation Format: Yu Jing Jan Heng, Jun Wang, Aditi Hazra, David J. Hunter, A. Heather Eliassen, Rulla M. Tamimi, Susan E. Hankinson, Andrew H. Beck. The molecular mechanisms of obesity driving breast cancer etiology and prognosis in post-menopausal women. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 805.

Background Sex steroid hormone signaling is critical in the development and progression of breast cancers, though the role of androgens remains unspecified. Large epidemiologic studies have found a consistent association between circulating androgens and increased breast cancer risk, though it is unknown whether circulating androgens reflect the androgenic milieu in the breast. An interaction between androgen receptor (AR) and estrogen receptor (ER) signaling in the breast has been postulated, wherein AR signaling antagonizes ER signaling in estrogen-rich environments, and AR signaling induces proliferative effects in estrogen-deplete environments. Methods We evaluated the association between AR expression and subsequent breast cancer risk in a nested case-control study of women with benign breast disease (BBD) within the Nurses’ Health Studies. Cases were women with BBD that subsequently developed breast cancer (median 9 years later) while controls had BBD but did not develop breast cancer. Tissue microarrays were constructed containing normal terminal ductal lobular unit (TDLU) tissue from the BBD biopsy. AR expression was assessed by immunohistochemistry and the percent of positive-staining nuclei was digitally quantified for 61 breast cancer cases and 184 controls. Logistic regression models adjusting for the year of BBD biopsy, age at cancer diagnosis, years since BBD biopsy, and BBD lesion type were used to calculate odds ratios and 95% confidence intervals for the association between the tertile of AR expression and breast cancer risk. We further evaluated the impact of AR and ER co-expression, each dichotomized at the median, in a sub-analysis of 31 cases and 82 controls. Finally, we assessed AR expression as a predictor of subsequent ER tumor status using polytomous logistic regression. Results Overall, women in the highest tertile of AR expression experienced non-significant 1.32-fold increased odds of breast cancer (95% CI: 0.64-1.73, p-trend = 0.559) compared to the lowest tertile. A significant interaction was detected between AR and ER co-expression in normal breast TDLUs and subsequent breast cancer risk (p-interaction = 0.003). Among women with low ER expression, increased AR expression was associated with 2.52-fold increased odds (95% CI: 0.68-9.34) of developing breast cancer. In contrast, among women with high ER expression, high AR expression was associated with a 91% decrease in the odds (OR = 0.09, 95% CI: 0.01-0.62) of breast cancer. AR expression was not predictive of subsequent ER tumor status. Conclusions There was little evidence for an overall association between AR expression in normal breast tissue and breast cancer risk, though we observed a significant interaction between AR and ER expression. Our findings support the hypothesis that AR interacts with ER to promote cell proliferation in estrogen-deprived environments and inhibit growth in estrogen-rich environments. Citation Format: Kevin Kensler, Andrew Beck, Francisco Beca, Laura Collins, Stuart Schnitt, Aditi Hazra, Susan Hankinson, Myles Brown, Rulla Tamimi. Androgen receptor expression in normal breast TDLUs and subsequent breast cancer risk. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4295.

Introduction Epigenetic changes are reversible features of the genome that regulate gene transcription and protein expression on several levels including DNA methylation, histone modification or miRNA expression. We investigated the association between inherited variation in genes of key epigenetic processes and risk of multiple cancers within the GAME-ON consortium. Methods We performed a pathway based meta-analysis using genotypes from more than 50,000 cases of breast, lung, prostate, ovarian and colorectal cancer cases and more than 60,000 controls from various genome wide association studies participating in the GAME-ON consortium to estimate associations with cancer risk. Using the 1000GenomeProject database, we selected 505,702 genotyped and imputed single nucleotide polymorphisms in 551 genes (flanking region +/- 250kb) related to DNA methylation, histone modification or chromatin remodeling based on GO and GeneCard databases. In order to allow variants to be associated with only a subset of traits we used subset based meta-analysis. False-discovery rate (FDR) corrected p-values (q-values) lower than 0.05 were considered significant. Results and Discussion 582 SNPs were significantly associated with risk of at least one cancer. We identified nine major regions that showed significant associations with more than one cancer type. Among the most interesting regions was the region around PHC3 (3q36), which showed associations with prostate and colorectal cancer and clear cell ovarian carcinomas. PHC3 is involved in chromatin remodeling and plays a role in epithelial neoplasms. Significant Odds ratios (ORs) ranged from 0.80 to 1.31. The number of risk and protective alleles in this region was similarly distributed (19 and 18, respectively). One of the strongest associations was observed for rs76925190 (intronic in PRKC1), which increased the risk of colorectal and prostate cancer (q-value 4.28*10-10). Variants in this region were previously associated with prostate cancer. Polymorphisms in the region (19q13) around BABAM1 (RISC and BRCA1 A complex member 1), were associated with lung, breast, ovarian and prostate cancer. BABAM1 is associated with the BRCA1-complex. Its function in histone modification and DNA repair emphasizes its importance in carcinogenesis. Significant ORs ranged from 0.88 to 1.14 with similar distribution of risk and protective alleles in this region (19 and 17, respectively). The strongest association was observed for rs4808076 (intronic in ANKLE1), which increased the risk of squamous lung, serous ovarian and ER- -breast cancer (q-value 2.40*10-6). Variants in this region were previously associated with risk of breast and ovarian cancer. Conclusions This study emphasizes the importance of variants in genes of epigenetic processes on cancer risk and further provides insights into novel, pleiotropic epigenetic mechanisms of cancer development. Citation Format: Dominique Scherer, Reka Toth, Linda Kelemen, Angela Risch, Aditi Hazra, Jean Pierre Issa, Victor Moreno, Rosalind A. Eeles, John Quackenbush, Ellen L. Goode, Shuji Ogino, Rayjean Hung, Cornelia M. Ulrich. Genetic variants in epigenetic pathways and risk of multiple cancer types in the GAME-ON consortium. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4612. doi:10.1158/1538-7445.AM2015-4612

Tumor necrosis factor-related apoptosis-inducing ligand stimulates the extrinsic apoptoticpathway by binding to death receptors 4 (DR4) and 5 (DR5). In DR4 exon 4, a C--G polymorphism at amino acid 626 located immediately 3' to one of the main receptor ligand interface regions, results in a threonine--arginine change. We found that the DR4 exon 4 G/G genotype was associated with an overall decreased risk of bladder cancer in Caucasians [odds ratio (OR) = 0.58; 95% confidence interval (CI), 0.38-0.88]. This protective effect was more apparent in younger individuals (OR = 0.42; 95% CI, 0.20-0.87) than in older individuals (OR = 0.60; 95% CI, 0.35-1.02) and in women (OR = 0.45; 95% CI, 0.20-0.99) than in men (OR = 0.60; 95% CI, 0.36-0.99). Moreover, the protective effect was greater for light smokers (OR = 0.19; 95% CI, 0.06-0.59) compared with heavy smokers (OR = 0.83; 95% CI, 0.41-1.69). These data provide the first large-scale molecular epidemiological evidence that the DR4 polymorphism is associated with environmental exposure and bladder cancer risk, possibly through modulating the capacity of the receptor ligand complex to engage the apoptotic pathway.

Background: In contrast to the well-established role of estrogens in breast cancer risk and survival, the role of androgens in breast carcinogenesis is unclear. Previous studies have shown that, in postmenopausal women, higher body mass index (BMI) and being less physically active are associated with an increased risk of invasive breast cancer, and the associations generally are stronger for estrogen receptor (ER) and/or progesterone receptor (PR) positive tumors. Although the androgen pathway also may play a mechanistic role with these breast cancer risk factors, no prior studies have specifically evaluated these associations by tumor androgen receptor (AR) status. Observing differential associations by AR status would provide etiologic insights into the contribution of the androgen pathway in breast carcinogenesis. Methods: We evaluated the associations of adult body size and physical activity with risk of incident invasive breast cancer by AR status in the Nurses’ Health Study. We used validated questionnaires to assess height, weight, and physical activity. AR status was determined using immunohistochemistry on sections from tumor tissue microarrays (TMAs); ER and PR status were determined using TMAs or medical record pathology reports. We applied a constrained competing risk survival model to evaluate these associations by AR status while controlling for ER/PR status and established breast cancer risk factors. Results: A total of 2,198 cases (1,701 AR+; 497 AR- tumors) were documented during 26 years of follow-up of 96,966 eligible women. After adjusting for ER/PR status and other breast cancer risk factors, higher BMI was associated with an increased risk of both AR+ and AR- tumors. The multivariable hazard ratios (MV HRs) and 95% confidence intervals (95%CIs) for every 5 kg/m2 increase in BMI were 1.05 (0.99, 1.10) for AR+ and 1.10 (1.00, 1.22) for AR- tumors (p-value for heterogeneity=0.46). Further, women engaged in higher amounts of total physical activity including brisk walking were at a lower risk of developing breast cancer. The MV HRs (95%CIs) per approximately 5 hours of brisk walking per week were 0.87 (0.72, 1.05) for AR+ and 0.69 (0.46, 1.04) for AR- tumors (p-value for heterogeneity=0.32). We further examined these associations by the combinations of ER/PR/AR status and observed that only BMI associations differed significantly across these subtypes (p-value for heterogeneity=0.03). The MV HRs (95%CIs) for 5 kg/m2 increase in BMI were 1.15 (1.08, 1.23) for ER+PR+AR+, 1.23 (1.04, 1.45) for ER+PR+AR-, 0.88 (0.75, 1.03) for ER+PR-AR+, 1.08 (0.92, 1.28) for ER-PR-AR+, 1.19 (1.01, 1.39) for ER-PR-AR-, 0.92 (0.70,1.22) for ER+PR-AR-. Conclusion: In postmenopausal women, higher adult body size was associated with an increased risk of both AR+ and AR- tumors while physical activity, including brisk walking, was associated with a reduced risk of both subtypes. The strongest associations observed with the ER+PR+AR- and ER+PR+AR+ tumors (i.e., subtypes with the most active estrogen signaling) supports the important role of estrogen signaling in the postmenopausal BMI/breast cancer relationship. Further, the positive association observed between BMI and ER-PR-AR- tumors suggests pathways other than sex steroids (e.g., the insulin pathway) also might play an etiologic role and more studies are warranted to confirm and extend these findings. Citation Format: Xuehong Zhang, A. Heather Eliassen, Rulla Tamimi, Aditi Hazra, Andrew H. Beck, Myles Brown, Laura C. Collins, Bernard Rosner, Susan E. Hankinson. Adult body size and physical activity in relation to risk of breast cancer defined by tumor androgen receptor status. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-275. doi:10.1158/1538-7445.AM2014-LB-275

Rationale: Genome-wide association studies (GWAS) of breast cancer have identified 71 risk alleles, majority of which are located in intergenic or intronic regions. We used a network medicine approach to associate breast cancer risk single nucleotide polymorphisms (SNPs) with transcript abundance in formalin fixed paraffin embedded (FFPE) breast tissue. Identification of expression quantitative loci (eQTLs) may help to better understand the regulatory mechanisms by which these risk variants influence breast cancer susceptibility. Method: We identified invasive postmenopausal breast cancer cases in the Nurses’ Health Study (NHS) diagnosed from 1990-2004 with GWAS data and sufficient RNA for expression profiling in breast tumor and normal adjacent breast tissue. RNA was extracted using the Qiagen AllPrep RNA isolation kit, amplified using the NuGen Ovation FFPE WTA kit, and profiled using the Affymetrix Human Transcriptome Array (HTA 3.0v1). The HTA includes 6,892,960 features for measuring gene expression, alternative splicing, coding SNPs, and noncoding transcripts. After filtering and removing probes with a low dynamic range in our samples, we included 25,000 gene expression probes in our QTL analyses. We mapped these probes to genes using hg19. Results: Analyses were conducted separately for 376 breast tumor and 274 normal adjacent samples. We conducted quality control analyses, corrected for assay plate-to-plate variation and included patient's age at diagnosis and year of diagnosis as covariates in the multivariate linear regression model. We identified 11 trans eQTLs in normal adjacent breast tissue, 11 trans eQTLs in estrogen receptor (ER)+ breast tumor samples, and 12 trans eQTLs in ER- breast tumor samples (permutation adjusted p-value Conclusion: In summary, our results provide functional insights on the underlying biology of loci identified in breast cancer GWAS in the specimen type that is most impactful in translation to clinical practice. Identification of gene transcripts that can be measured in FFPE tissue and are associated with breast cancer risk loci is critical in understanding the mechanism by which these variants affect risk and mediate disease processes. Citation Format: Alejandro Quiroz-Zarate, Benjamin J. Harshfield, Rong Hu, Nick Knoblauch, Andrew H. Beck, Vincent Carey, Susan E. Hankinson, Rulla M. Tamimi, David J. Hunter, John Quackenbush, Aditi Hazra. QTLs in breast tumor and breast normal adjacent FFPE specimens from the Nurses’ Health Study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3269. doi:10.1158/1538-7445.AM2014-3269

Background: The role of androgens in breast cancer etiology has been hypothesized but not confirmed. Androgen receptors (AR) have important physiological effects in normal breast development and are expressed in malignant breast tissue. Clinical studies indicate that AR may be a prognostic factor for breast cancer survival; however, studies addressing its role in breast cancer development are limited. Alcohol consumption, a confirmed breast cancer risk factor, has been hypothesized to exert its effect, at least partially, through the AR signaling pathway. We previously reported that alcohol consumption during adult life was positively associated with breast cancer risk (per 10 grams/day: hazard ratio [HR] = 1.10, 95% confidence interval [CI] = 1.07-1.12), and the association appeared stronger for estrogen receptor (ER) positive tumors. However, no epidemiologic studies have so far investigated alcohol and breast cancer risk according to AR status. Methods: We assessed this association in a prospective study of 105,858 women enrolled in the Nurses' Health Study. Alcohol consumption was first assessed through food frequency questionnaire at baseline (1980) and updated six times during follow-up; cumulative average alcohol use was calculated by averaging alcohol intake over time starting at baseline. Tumor AR status was determined through immunohistochemical staining using sections from a tumor tissue microarray (TMA); ER and progesterone receptor (PR) status was obtained from the TMA, or secondarily from the medical record pathology report. We applied a constrained competing risk survival model that allows for assessment of the alcohol and breast cancer association by AR status while controlling for ER and PR status, as well as other breast cancer risk factors. Results: During over 2.2 million person-years of follow-up from 1980 to 2006, 2706 invasive breast cancer cases with complete tumor marker data (i.e. AR, ER and PR) contributed to the analysis. When considering AR separately without adjustment of ER and PR status, alcohol consumption was positively associated with risk of invasive breast cancer among tumors expressing AR but not among AR-negative tumors (per 11 grams/day [equivalent to 1 drink/day] HR [95%CI]: 1.10 [1.05 - 1.16] and 1.02 [0.93 - 1.12], respectively; P-value for heterogeneity test = 0.14). After taking into account both ER and PR status, alcohol intake remained positively associated with risk of invasive breast cancer among AR-positive tumors but not among AR-negative tumors (per 11 grams/day HR [95%CI]: 1.10 [1.05 - 1.15] and 1.04 [0.96 - 1.12], respectively). However, the difference in relative risks between AR-positive and AR-negative tumors was not statistically significant (P-value for heterogeneity = 0.24). Conclusion: Our data suggest a positive association between alcohol intake and breast cancer risk for AR-positive tumors, but larger studies will be needed to confirm this. Citation Format: Jun Wang, Xuehong Zhang, Andrew H. Beck, Laura C. Collins, Wendy Chen, Rulla M. Tamimi, Aditi Hazra, Bernard Rosner, Susan E. Hankinson. Lifetime alcohol consumption and risk of breast cancer, by tumor androgen receptor expression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1270. doi:10.1158/1538-7445.AM2014-1270

Repressive histone tail modifications have been previously characterized in breast cancer, but the relationship between these marks, tumor features and breast cancer molecular subtypes has not been studied in depth. We have tissue microarray data with marker information on 971 incident breast cancers that developed from 1976-2000 in women enrolled in the Nurses’ Health Study. Tissue microarray sections were stained for repressive H3K9 trimethylation (H3K9me3) and H3K27 trimethylation (H3K27me3) marks, and tumors with 50% or more positively stained cells were scored as histone mark positive. We found that 73.3% of tumors were H3K9me3 positive, and 84.9% of tumors were H3K27me3 positive. The relationships between histone marks and tumor features (tumor size, grade, stage, nodal involvement and hormone receptor status) were analyzed. While we found no association between H3K9me3 and tumor features, age-adjusted analyses suggested that H3K27me3 was associated with lower grade tumors (OR=5.51, 95% CI 2.64-11.50), p Citation Format: Megan A. Healey, Andrew H. Beck, Stuart J. Schnitt, Rulla M. Tamimi, Aditi Hazra. Repressive histone marks in breast cancer in relation to molecular phenotype: results from the Nurses’ Health Study. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3637. doi:10.1158/1538-7445.AM2013-3637