10510 Background: Triple-negative (ER-, PR-, and HER2-) breast cancer (TNBC) is the most aggressive form of breast disease and is overrepresented in young women and women of African ancestry. Molecular mechanisms specific for TNBC are largely unknown; there is no targeted therapy available. A subgroup of sporadic TNBCs with a basal-like phenotype (BLBC) has morphological features and gene expression profiles similar to tumors from BRCA1 mutation carriers. Promoter methylation inhibit BRCA1 expression resulting in tumor phenotypes similar to those of hereditary BRCA1-mutated tumors. We hypothesize that in sporadic tumors BRCA1inactivation by promoter methylation contributes to the development of TN and BL phenotypes. Methods: Using a combination of methylation-specific PCR, IHC and cDNA microarrays, 198 primary breast cancers were analyzed for methylation of the BRCA1 promoter and expression of ER, PR, HER2, EGFR and ck5/6. Tumor subtypes were determined in191 tumors and correlation with BRCA1 methylation and clinicopathologic features was performed using Stata 9.2 (StataCorp, College Station, TX). Results: Of the 191 tumors, 28% were TNBCs vs 72% Non-TNBCs. Of 174 tumors classified by IHC, 19% were BLBCs, 12% were HER2+/ER-, 52% were Luminal A, 12% were Luminal B and 5% were unclassified cases. BRCA1 methylation was detected in 43% (23/53) TNBCs, compared with 17% (24/138) non-TNBCs (p < 0.0001). The proportion of BRCA1 methylation differed by subtype and was predominant in BLBC (48%, p = 0.002). Luminal A and B tumors were BRCA1 methylated in 18% and 30% of the cases, respectively. In contrast, BRCA1 methylation was less likely to occur in HER2+/ER- tumors (4%). When gene expression signatures were analyzed, BLBC showed the highest proportion of BRCA1-methylated tumors (33%, 5/15) versus other tumor subtypes (5%, 2/39; p = 0.014). Conclusions: BRCA1 inactivation via promoter methylation occurs in almost half of both TNBC and BLBC, suggesting that this epigenetic event drives breast tumor progression toward the TN and BL phenotypes. Our findings justify a common targeted therapy such as PARP inhibitors for both hereditary BRCA1-mutated and sporadic BRCA1-methylated TNBCs. No significant financial relationships to disclose.

1602 Background: Breast cancer is a complex disease with diversity between tumors and within tumor. Major differences exist in incidence and mortality rates across populations, making it imperative to investigate molecular pathogenesis in various populations. Methods: To identify molecular subtypes of breast cancer we collected Formalin-fixed and Paraffin-Embedded (FFPE) tissue blocks from Ilorin. Pathologic features and patients' data were extracted from histology reports. Tissue microarrays were constructed from FFPE tumor samples and adjacent normal breast tissue at the University of Chicago. Immunohistochemical assays were performed using a DAKO immunostainer (DAKO, Carpinteria, CA) with antibodies and antigen unmasking. Breast cancer subtypes were defined as luminal A (ER+ and/or PR+, HER2-), luminal B (ER+ and/or PR+, HER2+), basal-like (ER-, PR-, HER2-, CK5/6+, and/or EGFR+), HER2+/ER- (HER2+, ER-, PR-), and unclassified (negative for all five markers). Results: From 2003 to 2007, 203 histologicaly confirmed breast cancer patients were enrolled, including 5 males and 5 bilateral breast cancers. Median age at diagnosis was 46 yrs. Majority of patients (59%) presented with large tumors (≥ 5 cm) as median time from symptoms onset to cancer diagnosis was 6 months (interquartile range 3-12 months). Proportion of ER+, PR+ and HER2+ tumors were 27%, 16%, and 30%, respectively. Commonest breast cancer subtype was basal-like (25%), followed by unclassified (24%), luminal A (20%), HER2+/ER- (19%), and luminal B (11%). Patients with ER+ tumors had longer duration of symptoms (median 8 months) than patients with ER- tumors (5 months) but ER+ patients had smaller tumors (median 5 cm) than ER- patients (6 cm, p = 0.02). Conclusions: This study replicates previous findings that triple negative breast cancer was over-represented in African population in a different geographic region of North Central Nigeria as found in the Southwest earlier on. Patients seek medical help after many months of cancer symptoms, suggesting lack of awareness of breast cancer in the population. Study also showed that ER- breast cancer grows faster than ER+ breast cancer, underscoring urgent need to develop effective breast cancer awareness and early detection programs in Africa. No significant financial relationships to disclose.