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Background: Primary (PAS) and secondary angiosarcoma (SAS) of breast account for < 1% of all breast neoplasms. SAS develops following radiation therapy (RT) to the breast or chest wall for treatment of breast cancer. The rarity of this tumor type makes it challenging to determine prognostic factors and develop optimal treatment strategies. Historically, large NCI cancer centers have reported a median overall survival ranging from 28 – 100 months with recurrence rate of 55%. Methods: We reviewed demographic, tumor, and treatment characteristics of breast AS patients diagnosed and treated at our institution between 1990 and 2015. Overall (OS) and recurrence free (RFS) survival were compared using standard statistical methods at a significance level of 0.05. Results: Of 12155 breast cancers, 22 patients (0.008%) with AS (PAS in 34%, SAS in 66%) were identified. Median age of PAS patients was significantly lower than SAS – 45 vs 71 years (p < 0.001). Median tumor size was 6.9 cm (7.3 cm vs 6.9 cm, p = 0.93) with multifocal disease seen in 22.7%. Tumor was high grade in 14 (50% vs 83.3%, p = 0.34). Median time from RT to SAS diagnosis was 7.8 years. Treatment included: mastectomy in 17 (77.3%), wide excision in 4 (18.2%), adjuvant RT in 4 (18.2%), taxane based chemotherapy in 11 (50%) and chemo-RT in 1 (4.5%). No significant differences were noted in tumor (p = 0.9) or treatment characteristics (p = 0.4) between PAS and SAS. Recurrence rate (mainly distant) was 36% (8 pts). The 5-year OS and RFS rates were 51% (95% CI 27–72%) and 36% (95% CI 14–58%) with estimated medians of 64.2 and 55.5 months, respectively with no significant difference between the two groups. Black ethnicity (11.6 vs 64.2 months, p = 0.015), multifocal disease (15.5 vs 64.2 months, p = 0.004) and tumor size of > 6.9 cm (8.3 vs 64.2 months, p = 0.03) were associated with poorer outcomes. Tumor grade was not related to OS. Adjuvant treatment (RT p = 0.49, chemotherapy p = 0.36) conferred no RFS or OS benefit. Conclusions: Patients with PAS were younger than SAS. Black race, multifocal presentation and larger tumor size predict worse clinical outcomes. Our institutional experience confirms the poor prognosis of angiosarcoma, and highlights the need for further research. Citation Format: Ammannagari N, Attwood K, Cheney R, Young JS, Kane JM, Salerno KE, Opyrchal M. Factors predicting treatment outcomes of angiosarcoma of breast: A 25 year single institution experience [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-41.

Backgrounds: Evading the immune system is one of the Hallmarks of Cancer. Indeed, tumor infiltrating immune cells has been shown to play critical roles in suppression of cancer progression. Genetic aberration of DNA repair genes is known to increase immunogenicity in breast cancer. However, the patient survival relevance of tumor infiltrating immune cells in regard to DNA repair genes has not yet elucidated in large cohort of breast cancer patients. We hypothesized that DNA repair gene deficiency is related to increased global genomic instability that leads to increased mutation burden, which recruits infiltrating immune cells to tumor microenvironment that result in better prognosis of breast cancer. Patients and Methods: Integrated and unbiased transcriptomics approach was conducted on genomic and clinicopathological information of 3614 breast cancer patients. We utilized The cancer Genome Atlas (TCGA) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) to evaluate the association between the aberration of DNA repair genes and tumor infiltrating immune cell composition in breast cancer tumors, as well as its significant clinical relevance, utilizing bioinformatics and biostatistics pipelines. Results:Low expression level of double-strand break repair genes; BRCA1, PRKDC, and RECQL4,demonstrated significantlybetter prognosis in TCGA cohort (p=0.018, p=0.036, and p=0.0002, respectively). This result was consistent in METABRIC cohort (p=0.021, p=0.00021, and p<0.000001, respectively). Utilizing CIBERSORT system that estimate the fraction of 22 immune cell types, we found that low expression of BRCA1 significantly associated with high levels of CD8 positive cell composition in both cohorts (TCGA, p=4.67E-08; METABRIC, p=0.0038), which implicate that tumor infiltrating lymphocytes are attracted to BRCA1 low expressing tumors. Further, low expression of BRCA1 showed significantly better survival in HER2 positive subtype population, but not in the other populations (TCGA, p=0.027; METABRIC, p=0.13). Finally, significantly poor prognosis was observed in breast cancers low in immune-response markers; PD-1, PD-L1, TIM3, LAG3, and CTLA4, in combination with high expression of BRCA1 (p=0.0016, p=0.0041, p=0.015, p=0.0041, and p=0.0043, respectively), which is in agreement with the dogma that intact DNA repair induce less immune-response that result is worse survival. Conclusions: We conclude that our immunogenomics approach identify the interplay between DNA repair genes, especially gene expression of BRCA1, and tumor infiltrating immune cells, and it could have significant prognostic relevance in breast cancer. Citation Format: Takabe K, Kawaguchi T, Yan L, Peng X, Qi Q, Okano M, Young J, Liu S. Immunogenomics approach elucidating clinical significance of DNA repair genes and tumor infiltrating immune cells in breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-06-06.

BACKGROUND: MicroRNAs (miRNAs) are small noncoding RNAs, which regulate the expression of target genes post-transcriptionally by RNA interference. They have emerged as one of the crucial regulators of cancer progression. Some miRNAs are reported to be related to the response of breast cancer to tamoxifen (TAM). In this study, we investigated whether the levels of TAM-resistant miRNA (miR-221/222) and TAM-sensitive miRNA (miR-342) translate to breast cancer patient survival, using multiple large databases. MATERIALS AND METHODS: The Cancer Genome Atlas (TCGA; n=1049), Gene Expression Omnibus (GEO; GSE19536 n=96, GSE22220 n=210), and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC; n=2509) datasets were used and Gene Set Enrichment Analysis (GSEA) was performed. RESULTS: MiR-342 was identified as a TAM-sensitive miRNA, and miR-221/222 were identified as TAM-resistant miRNAs by literature search. Patients with high expression of miR-342 were shown to have better survival in TCGA (OS, p=0.02; DFS, p=0.03, respectively) and in two other independent GEO cohorts (OS, p=0.02 and p=0.0007, respectively) as well as in the METABRIC cohort (OS, miR-342-3p, p=0.006; miR-342-5p, p=0.00009). By subtype analyses, high expression of miR-342 was significantly associated with better survival in ER-positive patients (p=0.04), but not in ER-negative or triple negative patients in the TCGA cohort. This association was not observed in the METABRIC cohort. Within TCGA cohort, expression of TAM-resistant miR-221/222 did not significantly impact survival. Unexpectedly, increased expression of miR-221 was shown to have increased overall survival in all patients (p=0.00904) as well as in ER-negative patients (p=0.0479) and non-triple negative patients (p=0.0106) within the METABRIC cohort. On the other hand, low expression of miR-222 was associated with increased survival of all patients (p=0.00802) as well as in non-triple negative patients (p=0.041). Lastly, GSEA demonstrated that lower miR-342 expression was significantly seen in TAM-resistant gene sets, and higher miR-342 expression was seen TAM-sensitive gene sets, but miR-221/222 did not show any significant enrichment with TAM-resistant or TAM-sensitive gene sets. Taken together with survival data, expression levels of miR-342 reflect its TAM-sensitivity related function, however, that of miR-221/222 reflect other functions in breast cancer patients. CONCLUSION: For the first time, we used “big data” from the TCGA, GEO and METABRIC cohorts to analyze multiple miRNAs with respect to TAM sensitivities and its survival impact. We demonstrated that expression of miR-342 reflected the sensitivity of the cancer cells to TAM sensitivity, however, that of miR-221/222 reflected other functions in breast cancer patients. Citation Format: Young JS, Kawaguchi T, Yan L, Qi Q, Liu S, Takabe K. Survival relevance of tamoxifen sensitivity-related microRNAs, miR-342 and miR-221/222, in breast cancer patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-07-08.