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.

Abstract Background: Breast cancer is a heterogeneous disease with different putative therapeutic targets based upon the particular subtype. The particular subtype can have profound implications for therapy, as in the case of basal-like carcinomas which tend to be more aggressive with less therapeutic options. Although many studies have examined the transition from Ductal Carcinoma in-situ (DCIS) to Invasive Breast Cancer (IBC), the mechanisms involving the transformation are poorly understood. DCIS cases that are more likely to progress to IBC can be treated more aggressively. This study used image analysis to examine the association between predictive molecular biomarkers between pure DCIS, DCIS associated with IBC and IBC. Methods: With approval by the Institutional Review Board, we evaluated tissue microarrays comprising 453 tissue cores from 149 patients. Five immunohistochemical biomarkers were utilized: estrogen (ER), progesterone (PR), human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), and cytokeratin 5/6 (CK-5/6). We then employed the Automated Cellular Image Analysis (ACIS) to score the biomarker status. We compared regional scoring (rated 0, 1, 2, or 3) between an experienced pathologist's subjective assessment and an automated score derived from ACIS. An image library was generated and integrated to our Translational Data Mart (TraM: http://tram.uchicago. edu). Statistical analyses included a comparison of histological grade, race, age, tumor size, and lymph node status associated with the prevalence of subtypes between pure DCIS tumors and those that advanced to IBCs. Results: The concordance between ACIS-based and pathologist-based scoring was moderate (kappa = 0.38). There was more variability in the pathologist's scoring with a standard deviation of 1.14 as compared to 0.85 for ACIS. Subtypes associated with IBC were also present in DCIS. In the pure DCIS cases, there was a higher proportion of the luminal A subtype (74.1%, n = 54) as compared to DCIS adjacent to IBC (54.2%, n=24) or pure IBC cases (57.4%, n = 115) (p=0.05). In contrast, there was more basal-like subtypes in DCIS juxtaposed with IBC (20.8%) and IBC (27.8%) than in pure DCIS tumors (9.3%). Discussion: Molecular subtype analysis of DCIS could be useful in predicting DCIS with high risk of progressing to invasive cancer. The resemblance between subtypes bolsters the hypothesis that IBCs and DCIS originate from the same precursor lesion. Although the automated scoring featured by ACIS would be useful in expediting readings, it must be validated by a pathologist's assessment. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-01-06.

Abstract Abstract #904 Background: Substantial laboratory and clinical data have demonstrated the critical role of angiogenesis in breast tumor progression. A significant correlation between vascular endothelial growth factor receptor-2 (VEGFR-2) expression and cell proliferation has been described in invasive breast carcinomas, suggesting that VEGF stimulates mammary cell growth through VEGFR-2. We sought to examine whether variability in VEGFR-2 expression and activation in tumors might be due to individual genetic variations, which may also play a role in response to anti-angiogenic therapy. To our knowledge, no study has correlated genetic variation in VEGFR-2 to expression and activity in primary breast tumors. Methods: DNA from 42 primary breast tumors was extracted from fresh frozen tissue. The core promoter, 5'-untranslated region (UTR), 3'-UTR, exons and intron-exon boundary regions of VEGFR-2 were sequenced for all tumors. Tissue microarrays were constructed, and tumor and paired normal breast tissue were stained with anti-VEGFR-2 antibody (Calbiochem). Microvessel density (MVD) was determined by immunohistochemical staining using a primary antibody against platelet endothelial cell adhesion molecule (anti-CD34, Novocastra). Semiquantitative analysis was performed independently by two pathologists. VEGFR-2 expression was correlated with genotype and MVD using the Mann-Whitney test. VEGFR-2 expression in normal and tumor tissue was compared using the Wilcoxon signed-rank test. Results: Two-thirds of tumors were from self-reported African Americans (AA), and the majority were ER positive. Twenty-three different single nucleotide polymorphisms (SNPs) were identified; ten were previously reported in dbSNP. Three of these SNPs were common (minor allele frequency >10%): one was located in the core promoter region and the other two were located in exons 7 and 11 (both non-synonymous SNPs). Using PolyPhen prediction software (http://genetics.bwh.harvard.edu/pph/), the two non-synonymous SNPs were predicted to affect protein function. Of the 23 different SNPs identified, 11 were only seen in tumors from AA and 3 were only observed in tumors from Caucasians. Thirty-six of the 42 tumors (86%) had at least one SNP. VEGFR-2 expression in tumor was significantly higher than in paired normal tissue (p=0.0002). VEGFR-2 expression was significantly lower in tumors with the AA genotype of the 4032 A/G core promoter SNP as compared to those with the AG and GG genotypes combined (p=0.02). VEGFR-2 expression was significantly associated with MVD in tumor tissues (p=0.04). Discussion: Our preliminary study suggests an association between genetic variations in the VEGFR-2 gene and protein expression in tumor tissue. Future work will examine the spectrum of these genetic variations in diverse populations and their potential role in predicting response to anti-angiogenic therapy. This study was funded by the University of Chicago Breast SPORE NCI P50 CA125183. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 904.

Abstract Background: Angiogenesis is critical for breast cancer progression. Within tumors, non-neoplastic cells assist tumor growth by producing growth factors and pro-angiogenic cytokines. Studies have demonstrated that tumor-associated macrophages (TAMs) are recruited to tumors before malignant conversion and are essential for promoting angiogenesis. We sought to study the role that macrophage phenotype—classically activated (M1) and alternatively activated (M2)—plays in the subsequent activation of the angiogenic pathway, with the goal of understanding the mechanisms underlying angiogenesis in the different molecular subtypes of breast cancer.Methods: 128 matching breast tumors, DCIS and normal tissues were obtained from the University of Chicago Breast Cancer SPORE tissue bank under IRB approved protocols. Tissue microarrays were constructed and molecular subtype was assigned based on immunohistochemical (IHC) staining into the following groups: luminal A (ER+, PR+, HER2-), luminal B (ER+, HER2+ or ER+, PR-), HER2-like (ER-, HER2+) and basal-like (ER-, HER2-, EGFR+ and/or CK5/6+). Macrophage phenotype was determined using double staining with CD68/CD163 (M2) and CD68/CD80 (M1). Microvessel density (MVD) was measured by IHC staining using anti-CD34. Staining quantification was performed independently by two pathologists. To control for intra-individual correlation, linear mixed-effects models were used to compare differences in % of M1 and M2 with disease progression. To evaluate the association of MVD with % of M1 and M2, bivariate plots were generated and Pearson's correlation coefficients were calculated. Spearman's correlation coefficients were used for the correlation between macrophage phenotype and tumor stage and grade. The Kaplan-Meier method was used to calculate overall survival.Results: Of the tumors studied, 88% were stage I-II. 17% were grade 1, 39% grade 2 and 44% grade 3. 70 were luminal A, 36 basal-like, 9 HER2-like and 6 luminal B. The ratio of M2:M1 increased with disease progression from normal breast to DCIS to invasive cancer (p<0.001). Increased M2% was associated with high tumor grade, increased MVD and decreased overall survival (all p<0.001). M1% was associated with low tumor grade (<0.001), but was not significantly associated with MVD or overall survival. Both the HER2-like and basal-like subtypes have significantly higher % M2 as compared to the luminal A subtype (p<0.001).Discussion: There are several studies which suggest that activated TAMs are responsible for the secretion of pro-angiogenic cytokines which stimulate neovascularization. To our knowledge, this is the first study that has correlated macrophage phenotype to breast molecular subtype and MVD in human breast tumors. Our findings suggest that the M2 macrophage phenotype is associated with aggressive histopathologic features and poor clinical outcome. Inhibiting the M2 macrophage may prevent the release of pro-angiogenic factors, and might be an effective approach at preventing neovascularization and improving patient outcomes. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 107.

Abstract Background: Women with breast cancer are more likely to have second breast cancer. It is uncertain on the biologic relationship between the two tumor lesions. Whether the second cancer represents an independent second primary versus recurrent or metastatic disease has implications in both cancer treatment and understanding of carcinogenesis. This study was conducted to evaluate the concordance of estrogen receptor (ER) and progesterone receptor (PR) status, and examine factors that influence the concordance. This study also examined whether there is a difference in the proportion of hormone receptor positivity between two breast cancers.Methods: 37,362 patients with diagnoses of two breast cancers between 1990 and 2006 were identified through 17 cancer registries of the Surveillance, Epidemiology, and End Results program. Logistic regressions were used to assess the association in hormone receptor status between two cancers. Odds ratios (OR) and 95% confidence interval (CI) were used to indicate the strength of association. Conditional logistic regressions were used to examine the change in proportion of hormone receptor positivity.Results: The two breast cancers were contralateral in 79% of patients and ipsilateral in 21% of patients. There was a strong association in ER status between two tumors, with OR of 17.8 (CI: 14.2-22.3) for ipsilateral pairs and 8.85 (CI: 8.08-9.69) for bilateral pairs. The strength of association in ER status depended on lag interval between first and second tumor. In patients with ipsilateral cancers, the OR was 170 for synchronous tumors (<1 month) and 6.6 for metachronous cases separated by 5 years or longer. In patients with contralateral cancers, the corresponding OR was 31.5 and 4.12. The strength of association also depended on age at diagnosis. In patients with contralateral cancers, the OR was 11.7 and 7.03 for patients with first breast cancer diagnosed before and after 50 years old, respectively. There was also a strong association in PR status between two tumors, with OR of 8.39 (CI: 6.95-10.1) for ipsilateral pairs and 4.84 (CI: 4.48-5.24) for bilateral pairs. The ER positive proportion in second tumors occurred within 1 year was similar to that of first tumors. However, compared with the first tumors, the odds of ER positivity was decreased by 47% and 21%, respectively, in second ipsilateral and contralateral breast cancers occurred 1-5 years after first tumors.Conclusions: Hormone receptor status of the primary breast cancer is strongly predictive of that of the second breast cancer, occurred either in the same or in contralateral breast, and the predictive value was very good even after 5 years. These findings suggest that two breast cancers of the same patient arise in a common predisposing milieu, which is probably predetermined by genetic makeup and/or environmental exposures in early life. The second cancer occurred after 1-5 years was more likely to be hormone receptor negative compared with the first cancer, suggesting that treatment for the first cancer, possibly tamoxifen, can modify the expression of subsequent breast cancer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4144.

Abstract Abstract #4050 Triple-negative breast cancers are tumors characterized by their lack of hormone receptors (ER and PR) and HER2. They are the most aggressive form and account for 10–17% of all breast carcinomas. A subgroup of triple negative tumors with a basal-like phenotype share morphological features and similar gene expression profiles with tumors from BRCA1 mutation carriers. It has recently been shown that inactivation of BRCA1 in breast epithelial stem cells restricts subsequent progenitor cells to a basal cell phenotype and promotes expansion of ER negative cells (Liu et al 2008, PNAS). While mechanisms of BRCA1 inactivation in sporadic tumors are not completely elucidated, methylation of the BRCA1 promoter is one important mechanism that contributes to loss of BRCA1 expression in sporadic breast cancer. We hypothesize that inactivation of BRCA1 by epigenetic mechanisms such as promoter methylation contributes to the triple negative phenotype. Materials and Methods: Using a combination of methylation specific PCR and Immunohistochemistry, 120 primary breast cancers were analyzed for methylation of the BRCA1 promoter and protein expression of ER, PR and HER2. All tumors with negative staining for ER, PR and HER2 were classified as triple negative and all others were classified as non triple-negative. Results: We were able to classify 111 of the 120 (%) tumors by IHC. We found that 30 out of 111 (27%) tumors were ER, PR, and HER2 negative (triple negative). BRCA1 methylation was detected in 14 out of 30 (47%) triple negative tumors, compared with 10 out of 81 (12%) other tumor phenotypes (p<0.001). Conclusion: These data suggest that BRCA1 inactivation by mutation or methylation may in part drive breast tumor progression toward the triple negative phenotype. Ongoing work will evaluate epigenetic mechanisms regulating gene expression in triple negative breast cancers This abstract is supported by Breast Cancer Research Foundation and the Lee Jeans Entertainment Industry Fund. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4050.

Conditionally replicative adenoviruses (CRAds) represent a novel treatment strategy for malignant glioma. Recent studies suggest that the cytopathic effect elicited by these vectors is mediated through autophagy, a form of programmed cell death. Likewise, temozolomide (TMZ), a chemotherapeutic agent used for the treatment of malignant gliomas, also triggers autophagic cell death. In this study, we examined the potential to combine the two treatments in the setting of experimental glioma. In vitro, pretreatment with TMZ followed by CRAd-Surivin-pk7 enhanced cytotoxicity against a panel of glioma cell lines. Western blot analysis showed increased expression of BAX and p53, decreased expression of BCL2 and elevated level of APG5. Treatment with TMZ followed by CRAd-Survivin-pk7 (CRAd-S-pk7) led to a significant over-expression of autophagy markers, acidic vesicular organelles and light-chain 3 (LC3). These results were further evaluated in vivo, in which 90% of the mice with intracranial tumours were long-term survivors (>100 days) after treatment with TMZ and CRAd-S-pk7 (P<0.01). Analysis of tumours ex vivo showed expression of both LC3 and cleaved Caspase-3, proving that both autophagy and apoptosis are responsible for cell death in vivo. These results suggest that combination of chemovirotherapy offers a powerful tool against malignant glioma and should be further explored in the clinical setting.

Abstract #4039 Introduction: The importance of hormone receptor status in assigning treatment and the potential use of HER2 targeted therapy have made it imperative for laboratories to improve detection techniques. As inter-laboratory variability in immunohistochemical (IHC) tests may also affect epidemiologic studies of breast cancer subtypes in different countries, we conducted a validation study of breast cancer biomarkers between a well-established laboratory in the US and a field laboratory at the Institute for Medical Research and Training at the University College Hospital in Ibadan Nigeria.
 Method: 232 breast tumor blocks were evaluated for ER, PR, and HER2 at both laboratories using tissue micro arrays (TMA) technique. Web-based conferences were held periodically to discuss IHC staining protocols, standardize scoring systems and to resolve discrepant cases. Pathologists used whole slide imaging for joint review and kappa statistic (κ) was used to indicate concordance between the two laboratories. Fluorescence in situ hybridization was carried out to confirm HER2 status in all cases.
 Results: Initially, concordance analysis revealed an agreement of 91% (κ=0.52) for ER, 85% (κ=0.49) for PR, and 80% (κ=0.39) for HER2 between the two labs. Antigen retrieval techniques and scoring methods were identified as important reasons for discrepancy. After quality assurance and training, the agreement improved to 92% (κ=0.53) for ER, 88% (κ=0.64) for PR, and 94% (κ=0.75) for HER2. To date, florescence in situ hybridization (FISH) has been completed for 67 cases to confirm HER2 status, out of which 16 (24%) were shown to amplify the HER2 gene, 6 out of the 12 discordant HER2 results were resolved by FISH.
 Conclusion: We found web-based conference with TMA and digital microscopy a useful and cost-effective tool for quality assurance of IHC, consultation and collaboration between distant laboratories. Quality improvement exercises in testing of tumor biomarkers will reduce misclassification in epidemiologic study of breast cancer subtypes and provide much needed capacity building in resource poor field sites.
 Acknowledgement
 This study was carried out with the support of Breast SPORE NCI P50 CA125183, Breast Cancer Research Foundation and the Lee Jeans Entertainment Industry Fund. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4039.

9567 Background: African American (AA) women have a lower risk of breast cancer (BC) than Caucasian(C) women, but tumors in AAs are more likely to be poorly differentiated and estrogen receptor negative, leading to worse outcomes. In West Africa, the founder population of most AAs, BC is considered a rare virulent disease of young women. Thus, comparative analysis of BC in AA and Nigerian (N) populations could reveal shared genetic components of the disease. Methods: The cases were randomly selected from the tumor banks at the Universities of Chicago and Calabar (Nigeria). H&E stained slides from 148 N, 166 AA and 170 C cases were evaluated for volume corrected mitotic index (smi) expressed as mitosis/mm2, mean nuclear area (mna) aided by a digitizing interactive video overlay, and fraction of fields with tubular differentiation (ftd). Empirical distributions of and inter-relationships between the three features were examined, followed by comparisons of each feature between groups according to country of origin of the sample. Results: All morphometric features considered individually were highly associated with tumor grade and discriminant analysis indicated ftd was the most effective single variable for correctly classifying tumor grade followed by smi and mna. Mean values were significantly different among the three groups (p<.0001). The sma and mna values were largest for N, intermediate for AA, and lowest for C (smi N=26.5±14.7, AA=19.9±6.7, C=14.5±5.1; mna N=55.9±19.9, AA=47.1±12.7, C=34.3±10.3). For smi and mna, all pair wise means differed (p<0.05). The pattern was reversed for ftd, with the N cases having the smallest value (ftd N=17.8±17.0, AA=21.9±16.6, C=28.4±17.9). Conclusions: Significant differences in proliferative activity and degree of differentiation among N, AA, and C BCs exist, even after adjusting for other confounding variables like age and stage. These differences are likely genetically programmed but may be masked by genetic admixture among AA. Future work will evaluate the molecular determinants of tumor morphometry and whether these differences contribute to disparities in health outcomes. No significant financial relationships to disclose.

Purpose: Decreased expression of E-cadherin in endometrial cancer cells is associated with adverse prognostic features. This study aimed to evaluate the prognostic significance of decreased E-cadherin expression in patients with endometrial cancer. Experimental Design: Between 1992 and 1999, 102 endometrial cancer patients with stage I-III disease underwent primary surgery at the University of Chicago. Representative tissue specimens were immunostained with a monoclonal antibody to E-cadherin. A semiquantitative evaluation scale was developed based on the percentage of endometrial cancer cells with membranous E-cadherin staining. Tissue sections were scored as “3” if >75%, “2” if 25–75%, “1” if 5–25%, and “0” if <5% of cells stained. E-Cadherin staining was correlated with overall survival (OS), cause-specific survival (CSS), progression-free survival (PFS), and extrapelvic progression. Multivariate Cox proportional hazards modeling was used to estimate hazard ratios, controlling for clinicopathological characteristics and adjuvant treatment. Median follow-up for the study group was 58.5 months. Results: E-Cadherin staining was scored as 0, 1, 2, and 3 in 29.4%, 18.6%, 26.5%, 25.5% of cases, respectively. E-Cadherin expression was positively correlated with myometrial invasion (Kendall τ: 0.30, P < 0.01), and negatively correlated with grade (Kendall τ: −0.13, P = 0.15) and papillary serous or clear cell histology (Kendall τ: −0.14, P = 0.12). Five-year actuarial OS, CSS, PFS, and extrapelvic recurrence rates for negative (score = 0), heterogeneous (score = 1–2), and positive (score = 3) staining were as follows: OS, 69.2 versus 75.7 versus 81.0% (P = 0.64); CSS, 78.8 versus 91.2 versus 95.5% (P = 0.19); PFS, 69.1 versus 88.6 versus 92.2% (P = 0.079), and extrapelvic progression, 20.8 versus 7.3 versus 4.0% (P = 0.17). On multivariate Cox regression, a higher E-cadherin expression score was associated with decreased overall mortality [hazard ratio (HR), 0.59; 95% confidence interval (CI), 0.34–1.03; P = 0.066), and statistically significant decreases in endometrial cancer mortality (HR, 0.23; 95% CI, 0.055–0.94; P = 0.040), disease progression (HR, 0.28; 95% CI, 0.10–0.77; P = 0.014), and extrapelvic recurrence (HR, 0.24; 95% CI, 0.062–0.97; P = 0.045). Conclusions: Decreased E-cadherin expression is an independent prognostic factor for disease progression and mortality in pathological stage I-III endometrial cancer. Evaluation of E-cadherin expression may aid in the selection of patients for more aggressive adjuvant therapy.

9509 Background: DNA microarray studies have identified 3 distinct subtypes of breast cancers (BC) based on “Intrinsic Gene Expression” patterns: basal-like tumors (ER-, HER2-), tumors with amplification of HER2/neu (ER-/+, HER2+), and luminal tumors (ER+, HER2-) (Perou et al. Nature 2000). BRCA1-associated BCs are characterized by poor differentiation, hormone receptor negativity, and a distinct basal-like pattern of gene expression. These aggressive features also characterize BC in women of African ancestry. In this study, we examined the proportion of BC within a given “intrinsic gene expression” subtype from a random cohort of Nigerians (N). Methods: H&E stained slides from archival BC, were evaluated for volume corrected mitotic index (smi), mean nuclear area (mna), and fraction of fields with tubular differentiation (ftd). Immunohistochemical staining for ER and HER2 were performed using Anti-ER (clone 6F11; 1:40, Novocastra) and rabbit antihuman HER2 antibody (1: 200; DAKO). Results: Of the 148 cases, 66.9% were premenopausal with a mean age of 43.8±11.2 years; large tumor size (mean 4.2±1.3cm); 77.8% had histological grade 2 or 3. ER expression was present in only 22.3% and HER2 was overexpressed in 18.9%. The proportion of tumors in each subtype was: ER-HER2- 87/148 (58.8%), HER2+ 28/148 (18.9%) and ER+ 33/148 (22.3%). Subtypes showed relatively weak association with clinical stage. However, overall grade and morphomety showed significant differences that persisted after adjustment for other patient and tumor characteristics (age, tumor size, and stage).Conclusions: The majority of BCs from Nigeria are basal-like, which suggest a distinct pathogenesis probably involving genes in the BRCA1 pathway. Future work will evaluate components of this pathway to develop more effective targeted therapies. No significant financial relationships to disclose.