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e17559 Background: High grade serous ovarian cancer (HGSC) is the most common and fatal epithelial ovarian cancer and is often diagnosed in late stages. DNA methylation has emerged as a potential biomarker for the early detection of cancer, including ovarian cancer. Studies examining DNA methylation in ovarian tumor tissue have used adjacent non-tumor tissues or tissues from unaffected women as the control; however, few have used paired tissue and research is sparse on how results may vary by the control non-tumor tissue type. Therefore, we examined DNA methylation signatures in HGSC tumor tissue using different control non-tumor tissue types. Methods: We examined DNA methylation signatures using the Illumina Infinium MethylationEPIC BeadChip (850k) in formalin-fixed paraffin-embedded tissue. In women with HGSC, we compared DNA methylation patterns between paired adjacent non-tumor ovary (n = 74) and fallopian tube (n = 80) tissues. We compared DNA methylation patterns in these adjacent non-tumor tissues with non-tumor ovary (n = 8) and fallopian tube (n = 8) tissues from unaffected women without ovarian cancer carrying a pathogenic variant in BRCA1/2 ( BRCA1/2+). Lastly, we compared the overlap in differentially methylated CpGs identified in HGSC tumor tissue compared to paired adjacent non-tumor ovary (n = 50) and fallopian tube (n = 52) tissues. We processed the methylation data and used principal components analysis (PCA) and the adjusted Rand Index to compare the non-tumor tissue type methylation patterns. We used a paired t-test between individual-matched tumor and adjacent non-tumor tissue for each CpG site and then applied Bonferroni’s method to adjust the obtained p-values. Results: PCA comparing methylation patterns between paired adjacent non-tumor ovary and fallopian tube tissues from women with HGSC showed an adjusted Rand Index of 0.78, revealing separate clusters that cannot be combined. PCA comparing methylation patterns from the adjacent non-tumor tissues from women with HGSC and the non-tumor tissues from unaffected BRCA1/2+ women showed an adjusted Rand Index of -0.10 and 0.07 for the ovary and fallopian tube tissues, respectively, revealing overlapping clusters that can be combined. Lastly, comparison of the top differentially methylated CpGs identified in HGSC tumor tissue when using paired adjacent non-tumor ovary versus fallopian tube tissues as the control showed minimal overlap (6.8% and 4.0% for hypermethylated and hypomethylated CpGs, respectively). Conclusions: These results suggest that paired adjacent non-tumor ovary and fallopian tube tissues from women with HGSC have different DNA methylation patterns and result in different methylation signatures identified in HGSC tumor tissue. When comparing results across studies, including for validation, the type of non-tumor tissue control must be considered.

12057Background: The PI3K/Akt/mTOR pathway is a known regulator of oncogenic growth in BC. In addition, this pathway also modulates host immune function and may indirectly affect tumorigenesis. Cli...

e12109 Background: The PAM (PI3K/Akt/mTOR) signaling pathway has been implicated in the oncogenesis of multiple solid malignancies, including breast cancer (BC). Our aim is to characterize the TIM in a series of patients with operable stage I-III BC treated with MK-2206, an allosteric Akt inhibitor within a presurgical trial. In NCT01319539 , patients received 2 doses of MK-2206 with first dose at day -9 and second at day -2 from surgery. Methods: mIHC was performed using immune biomarkers (DAPI, CD3, CD8, CD4, FOXP3, CD68, Pancytokeratin) on full section (4uM) tissue slides from core biopsy specimens and postsurgical specimens of 10 patients - 5 treated with MK-2206, 5 paired controls. Images were taken using Vectra, a novel pathology workstation and analyzed using inForm software to perform cell classification and phenotyping. T- tests were used to compare biomarker changes before and after MK-2206. Results: Our preliminary analysis demonstrates that patients treated with MK-2206 exhibited an increase in median cytotoxic T-cells (CD3CD8+) density, as compared to the control population , which was statistically significant (87% vs.0.2%, p < 0.05). We did not identify a change in macrophage (CD68) or T helper/T reg (CD4/CD4FOXP3+) density following MK-2206 treatment in this small cohort. We are currently expanding our myeloid panel as well as performing additional tissue analysis to validate our findings. As data is exploratory no correction was made for multiple comparisons. Conclusions: Tumor infiltrating lymphocytes (TILs) are both prognostic of overall survival as well as predictive of response to neoadjuvant chemotherapy in BC. At present, there are currently both FDA approved therapies, as well as agents in clinical development that exert antineoplastic activity through the PAM pathway. Investigations that endeavour to understand the impact of these therapies on the tumor immune microenvironment may lead to both an increased understanding of the bioactivity of these agents and potentially identify aspects of the immune response which can be exploited in future therapeutics.

2613 Background: The PI3K/Akt signaling pathway is an important signaling pathway in breast cancer (BC). MK-2206 is the first allosteric Akt inhibitor in clinical development. The purpose of this p...

560 Background: Hispanic women have a higher mortality rate and lower incidence of breast cancer (BC) compared to Caucasian women. Studies report higher tumor proliferation in African American (AA) women compared to Caucasian women. The 21-gene assay (OncotypeDX) Recurrence Score (Score) is based on the expression of 16 cancer related genes, including 5 proliferation genes that are grouped to provide the proliferation axis score (PAS). We evaluated the differences in the Score and PAS between Hispanic and Caucasian women with early-stage BC in a matched cohort analysis. Methods: Women with early-stage BC who had a Score obtained from 2005- 2011 were identified. Hispanic women were matched to Caucasians in a 1:2 ratio, based on age (+/- 10 years), stage, and nodal status. Lymphovascular invasion (LVI) and grade were collected. The Score result, 10-year distant recurrence, ER/PR/HER2 expression, and PAS were obtained from the OncotypeDX assay. Assuming equal variances, we expected > 90% power to detect a difference in the mean PAS between Hispanic and Caucasian women Results: We identified 219 women who had OncotypeDX testing (74 Hispanic: 145 Caucasian). Of the 74 Hispanic women, 84% were from the Dominican Republic or Puerto Rico. Mean age was similar between groups (56.3 and 56.8). All but 8 patients were node(-). Mean PAS was higher in Hispanic (5.53, range: 3.9-7.8) vs Caucasian women (5.26, 3.7-7.3) (p=0.03, 95% CI: 0.03-0.51). The mean Score was 18.3 (0-54) and 16.3 (1-50) for Hispanic vs Caucasian women. There was no statistical difference in Score (p= 0.17) or 10-year distant recurrence (p=0.13) between groups. No differences were observed in median ER (9.8% vs 9.9%: Hispanic vs Caucasian), PR (7.3% vs 7.6%), or HER2 (9.1% vs 9.0%) by RT-PCR. Rates of LVI and grade 3 tumors were also not statistically different. Conclusions: Similar to higher PAS in AA women, Hispanic women with ER/PR(+), HER2(-) early-stage BC have higher tumor proliferation markers, measured by RT-PCR in the Oncotype DX assay, than Caucasian women. This may contribute to ethnic differences in BC mortality. We plan to evaluate ethnic differences in the 5 single PAS genes (CCNB1, MKI17, MYBL2, BIRC5, AURKA) to determine which are driving proliferation differences.

879 Background: For patients with locally advanced breast cancer neoadjuvant chemotherapy is considered the standard of care, but the optimal regimen has yet to be defined. Methods: This phase II study evaluates the efficacy of neoadjuvant Docetaxel 50mg/m2 and Doxorubicin 35mg/m2 q2 weeks for 6 cycles in locally advanced breast cancer patients (pts). Eligible subjects were stage IIB-IIIB, had measurable disease, ECOG PS≤2. Results: Between Dec 01-Dec 03, 12 pts were evaluable; median age: 59 (32–72), stage IIB/IIIA/IIIB: 1/4/7, median tumor size: 4.5cm (2.3–7.8), ER+/PR+: 7/7, Her-2/neu+: 8, ECOG PS 0/1/2: 9/2/1. All 12 pts completed 6 cycles. Out of 72 total cycles, 3 treatment delays occurred due to low WBC, mucositis and a line infection, respectively. The main toxicity was neutropenia, grade 4 (3 pts) and 3 (2), but no episodes of neutropenic fever. 8 pts received prophylactic Ciprofloxicin, 5 G-CSF. Treatment of 12 pts resulted in 5 PR, 6 SD and 1 PD. There were no complete pathologic responses; med...