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PTEN is known to be frequently mutated in uterine cancer and also dephosphorylates FAK. Here, we examined the impact of PTEN alterations on the response to treatment with a FAK inhibitor (GSK2256098). In vitro and in vivo therapeutic experiments were carried out using PTEN-mutated and PTEN-wild-type models of uterine cancer alone and in combination with chemotherapy. Treatment with GSK2256098 resulted in greater inhibition of pFAKY397 in PTEN-mutated (Ishikawa) than in PTEN-wild-type (Hec1A) cells. Ishikawa cells were more sensitive to GSK2256098 than the treated Hec1A cells. Ishikawa cells were transfected with a wild-type PTEN construct and pFAKY397 expression was unchanged after treatment with GSK2256098. Decreased cell viability and enhanced sensitivity to chemotherapy (paclitaxel and topotecan) in combination with GSK2256098 was observed in Ishikawa cells as compared with Hec1a cells. In the Ishikawa orthoptopic murine model, treatment with GSK2256098 resulted in lower tumor weights and fewer metastases than mice inoculated with Hec1A cells. Tumors treated with GSK2256098 had lower microvessel density (CD31), less cellular proliferation (Ki67), and higher apoptosis (TUNEL) rates in the Ishikawa model when compared with the Hec1a model. From a large cohort of evaluable patients, increased FAK and pFAKY397 expression levels were significantly related to poor overall survival. Moreover, PTEN levels were inversely related to pFAKY397 expression. These preclinical data demonstrate that PTEN-mutated uterine cancer responds better to FAK inhibition than does PTEN wild-type cancer. Therefore, PTEN could be a biomarker for predicting response to FAK-targeted therapy during clinical development. Mol Cancer Ther; 14(6); 1466–75. ©2015 AACR.

Mean mouse weights in orthotopic mouse models of uterine cancer.

Background: In contrast with the decreasing incidence seen for most cancers, endometrial cancer has been increasing in the United States. We examined whether the increasing incidence and mortality from endometrial cancer are equally distributed by race/ethnicity and tumor histologic subtype.Methods: Surveillance, Epidemiology, and End Results (SEER) endometrial cancer incidence and mortality data were obtained from 2000 to 2011. Age-adjusted incidence and incidence-based mortality rates, 95% confidence intervals, and annual percent changes (APC) were calculated. Rate ratios were calculated to compare racial/ethnic groups. Five-year relative survival rates were presented to explore survival by stage at diagnosis.Results: Incidence rates for endometrial cancers are rising across all racial/ethnic groups, with the greatest APC seen among non-Hispanic black (NHB) and Asian women (APC, 2.5 for both). NHB women have significantly higher incidence rates of aggressive endometrial cancers (clear cell, serous, high-grade endometrioid, and malignant mixed Mullerian tumors) compared with non-Hispanic white (NHW) women. Hispanic and Asian women have incidence rates equal to or lower than NHW women for all tumor subtypes. For nearly every stage and subtype, the 5-year relative survival for NHB women is significantly less than NHW women, whereas Hispanic and Asian women have the same or better survival.Conclusions: Endometrial cancer incidence is increasing for all women, particularly the aggressive subtypes. The disparity associated with excess incidence for these aggressive histologic subtypes and poorer survival is limited to NHB women.Impact: Increasing rates of aggressive endometrial cancers may widen the survival disparity between NHW and NHB women. Cancer Epidemiol Biomarkers Prev; 24(9); 1407–15. ©2015 AACR.

Supplementary Table S1: Annual percent change by subtype and race and ethnicity for endometrial cancers diagnosed 2000-2007, Surveillance, Epidemiology and End Results. Supplementary Table S2: 5 year relative survival by subtype, race and ethnicity, and stage for endometrial cancers diagnosed 2000-2007, Surveillance, Epidemiology and End Results.

Human and Mouse osteoclast precursor cells express Gal-3.

Management of bone metastasis remains clinically challenging and requires the identification of new molecular target(s) that can be therapeutically exploited to improve patient outcome. Galectin-3 (Gal-3) has been implicated as a secreted factor that alters the bone microenvironment. Proteolytic cleavage of Gal-3 may also contribute to malignant cellular behaviors, but has not been addressed in cancer metastasis. Here, we report that Gal-3 modulates the osteolytic bone tumor microenvironment in the presence of RANKL. Gal-3 was localized on the osteoclast cell surface, and its suppression by RNAi or a specific antagonist markedly inhibited osteoclast differentiation markers, including tartrate-resistant acid phosphatase, and reduced the number of mature osteoclasts. Structurally, the 158–175 amino acid sequence in the carbohydrate recognition domain (CRD) of Gal-3 was responsible for augmented osteoclastogenesis. During osteoclast maturation, Gal-3 interacted and colocalized with myosin-2A along the surface of cell–cell fusion. Pathologically, bone metastatic cancers expressed and released an intact form of Gal-3, mainly detected in breast cancer bone metastases, as well as a cleaved form, more abundant in prostate cancer bone metastases. Secreted intact Gal-3 interacted with myosin-2A, leading to osteoclastogenesis, whereas a shift to cleaved Gal-3 attenuated the enhancement in osteoclast differentiation. Thus, our studies demonstrate that Gal-3 shapes the bone tumor microenvironment through distinct roles contingent on its cleavage status, and highlight Gal-3 targeting through the CRD as a potential therapeutic strategy for mitigating osteolytic bone remodeling in the metastatic niche. Cancer Res; 76(6); 1391–402. ©2016 AACR.

Mouse osteoclast precursor expresses and secretes endogenous Gal-3.

Results of immunohistochemistry in breast and prostate cancer patients with metastasis.

Anti-CRD of Gal-3 inhibits osteoclast cell fusion.

Myosin-2A is a candidate for binding partner of Gal-3.

Gal-3 is involved in osteoclastogenesis in bone tumor microenvironment.

A noninvasive screening test would significantly facilitate early detection of epithelial ovarian cancer. This study used a combination of high-throughput selection and array-based serologic detection of many antigens indicative of the presence of cancer, thereby using the immune system as a biosensor. This high-throughput selection involved biopanning of an ovarian cancer phage display library using serum immunoglobulins from an ovarian cancer patient as bait. Protein macroarrays containing 480 of these selected antigen clones revealed 65 clones that interacted with immunoglobulins in sera from 32 ovarian cancer patients but not with sera from 25 healthy women or 14 patients having other benign or malignant gynecologic diseases. Sequence analysis data of these 65 clones revealed 62 different antigens. Among the markers, we identified some known antigens, including RCAS1, signal recognition protein-19, AHNAK-related sequence, nuclear autoantogenic sperm protein, Nijmegen breakage syndrome 1 (Nibrin), ribosomal protein L4, Homo sapiens KIAA0419 gene product, eukaryotic initiation factor 5A, and casein kinase II, as well as many previously uncharacterized antigenic gene products. Using these 65 antigens on protein microarrays, we trained neural networks on two-color fluorescent detection of serum IgG binding and found an average sensitivity and specificity of 55% and 98%, respectively. In addition, the top 6 of the most specific clones resulted in an average sensitivity and specificity of 32% and 94%, respectively. This global approach to antigenic profiling, epitomics, has applications to cancer and autoimmune diseases for diagnostic and therapeutic studies. Further work with larger panels of antigens should provide a comprehensive set of markers with sufficient sensitivity and specificity suitable for clinical testing in high-risk populations. (Cancer Res 2006; 66(2): 1181-90)

Supplementary Tables 1-4 from Diagnostic Markers of Ovarian Cancer by High-Throughput Antigen Cloning and Detection on Arrays

Materials and Methods for Tissue microarray, Immunofluorescence, Quantitative Real-Time PCR, Proteomics analysis, Co-immunoprecipitation, Co-culture.

Background: Uterine serous carcinomas (USC) comprise 10-15% of all uterine cancers, but are responsible for approximately 40% of all deaths due to the disease. African American women have the highest incidence of and mortality from USC of any racial or ethnic group. Assessment of racial differences in driver mutation frequency may partially explain the survival disparity, and identification of novel alterations may provide avenues for targeted treatment. Methods: Two academic hospitals in Detroit, Michigan identified 125 women who had surgical treatment for USC and formalin fixed, paraffin-embedded tissue available for whole exome sequencing (WES). Detailed clinical and pathological data were also available, including long-term follow up. WES was performed using Illumina’s NovaSeq 6000 platform and data were processed via the Genome Analysis Toolkit (GATK), with additional filtering to account for excess artifacts resulting from formalin fixation. Functional mutations were determined by ANNOVAR and the ClinVar database, while putative driver mutations were identified via the IntOGen pipeline. Percentages were used to describe the proportion of tumors harboring a gene mutation, and the Fisher’s exact test was used to test for statistically significant differences in African American (AA) versus non-Hispanic white (NHW) mutation frequencies. Results: The majority of tumors were from AA women (n=87, 69.6%), with the remaining from NHW women (n=38, 30.4%). The overall mutational burden in tumors from AA women was similar to tumors from NHW women (median=122 and 166.5, respectively, p-value=0.12).TP53 was the most frequently mutated, with 77% of tumors from AA women and 65.8% of tumors from NHW women harboring a mutation (p-value=0.20), followed by PPP2R1A (AA=19.5%, NHW=28.9%, p-value=0.25) and PIK3CA (AA=13.8%, NHW=23.7%, p-value=0.20). Of the 66 driver genes in uterine cancer identified from IntOGen, only 3 differed significantly by race: ARID1A (AA=5.7%, NHW=28.9%; p-value=0.001), PTEN (AA=1.1%, NHW=15.8%; p-value=0.003) and FGFR2 (AA=0%, NHW=7.9%, p-value=0.02). Examination of genes with mutational frequencies ≥10% in AA or NHW tumors and with significant differences in mutation distribution by race (n=96) identified an additional 10 genes with mutations that are considered drivers in other cancer types that have not been described in uterine cancers. Conclusions: There are potential driver mutations undescribed in USC that are clinically important in other cancers. Additionally, we noted several differences in the mutation frequency by race which highlights the importance of including racially diverse samples in research, particularly AA women who have the largest burden of USC. Defining the somatic landscape of USC will lead to identification of actionable molecular targets, which will ultimately improve the prognosis of this aggressive subtype. Citation Format: Michele L. Cote, Greg Dyson, Douglas Craig, Julie J. Ruterbusch, Julie Boerner, Mohamed A. Elshaikh, Thomas P. Conrads, Nicholas W. Bateman, George L. Maxwell, Kathleen M. Darcy, Sasha Makohon-Moores, Timothy D. O'Connor, Hassan Abdallah, Logan Corey, Mira Kheil, Rouba Ali-Fehmi. Whole exome sequencing of uterine serous carcinomas reveals racial differences in known and novel driver mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 750.

Introduction: Endometrial cancer (EC) is the most common gynecologic cancer diagnosed in the United States, and high-grade cancers account for approximately 1/5 of the ECs diagnosed in non-Hispanic white (NHW) women, Hispanic women, and Asian women, but nearly 1/3 of those diagnosed in African American (AA) women. These high-grade cancers are associated with poorer outcomes, and AAs are consistently at highest risk of mortality in studies that fail to adjust adequately for potentially important treatment or comorbidity variables. Here we present survival analyses from a study of AA and NHW women with high grade EC at two academic hospitals. Methods: High-grade cancers were identified through registries at each hospital and representative slides were re-reviewed by a single gynecologic pathologist to confirm high-grade disease and subtype. The following subtypes were included: clear cell, endometrioid, mixed, and serous. We identified 258 women (n=86 NHW, n=169 AA) who were diagnosed with high-grade cancers between 1998 and 2010. Utilizing medical records and the Surveillance, Epidemiology and End Results (SEER) registry, the following data were abstracted: height, weight, comorbid conditions, type of radiation, dose and fractions, type(s) of chemotherapy, number of cycles, recurrence, and vital status. Descriptive analyses utilized chi-square and t-tests to determine differences in clinical characteristics between AA and NHW women. Kaplan Meier survival analysis was performed to test for differences by race and subtype. To compare survival while considering competing risks of death, cause-specific hazard and cumulative incidence functions were compared using Gray's test. Results: The majority of the women had ECs classified as serous carcinomas (46.1%), followed by endometrioid (39.5%), clear cell carcinomas (9.7%) and mixed cell types (4.7%). AA women with endometrial cancer had slightly higher mean body mass index (BMI) compared to NHW women (34.6 and 32.2, respectively, p-value=0.06). NHW survived significantly longer after diagnosis compared to AA women (173 months versus 87 months, respectively, log-rank p-value=0.006). This difference remained after stratification by subtype, with similar findings for endometrioid cancers (log-rank p-value=0.06) and serous cancers (log-rank p-value=0.03). When examining survival considering competing risks (death due to EC versus other causes), AA women had a greater risk of death (HR: 1.84, 95% CI: 1.10-3.03) compared to their NHW counterparts; however, no difference was seen by race for other causes of death (HR: 1.29, 95% CI: 0.71-2.32). Further analyses, showing survival differences persist despite adjustments for BMI, comorbidities, and detailed treatment, will be presented. Conclusions: AA women continue to experience greater mortality from high-grade EC despite adjustments for demographic, clinical and treatment data, warranting continued efforts to identify molecular and social factors associated with poorer survival. Citation Format: Michele L. Cote, Julie J. Ruterbusch, Tara Rangarajan, Remonda Khalil, Mohamed Elshaikh, Rouba Ali-Fehmi. High-grade endometrial cancers: Persistent racial differences in survival [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C120.

PTEN is known to be frequently mutated in uterine cancer and also dephosphorylates FAK. Here, we examined the impact of PTEN alterations on the response to treatment with a FAK inhibitor (GSK2256098). In vitro and in vivo therapeutic experiments were carried out using PTEN-mutated and PTEN-wild-type models of uterine cancer alone and in combination with chemotherapy. Treatment with GSK2256098 resulted in greater inhibition of pFAKY397 in PTEN-mutated (Ishikawa) than in PTEN-wild-type (Hec1A) cells. Ishikawa cells were more sensitive to GSK2256098 than the treated Hec1A cells. Ishikawa cells were transfected with a wild-type PTEN construct and pFAKY397 expression was unchanged after treatment with GSK2256098. Decreased cell viability and enhanced sensitivity to chemotherapy (paclitaxel and topotecan) in combination with GSK2256098 was observed in Ishikawa cells as compared with Hec1a cells. In the Ishikawa orthoptopic murine model, treatment with GSK2256098 resulted in lower tumor weights and fewer metastases than mice inoculated with Hec1A cells. Tumors treated with GSK2256098 had lower microvessel density (CD31), less cellular proliferation (Ki67), and higher apoptosis (TUNEL) rates in the Ishikawa model when compared with the Hec1a model. From a large cohort of evaluable patients, increased FAK and pFAKY397 expression levels were significantly related to poor overall survival. Moreover, PTEN levels were inversely related to pFAKY397 expression. These preclinical data demonstrate that PTEN-mutated uterine cancer responds better to FAK inhibition than does PTEN wild-type cancer. Therefore, PTEN could be a biomarker for predicting response to FAK-targeted therapy during clinical development. Mol Cancer Ther; 14(6); 1466–75. ©2015 AACR.

Introduction: A history of benign breast disease (BBD) is common and certain established pathologic features are associated with increased breast cancer risk. These associations have been reported primarily from studies of white women, where incidence of BBD peaks in the 4th or 5th decade of life. Previous work in an African American (AA) cohort of women with BBD showed AA women were younger at their first BBD diagnosis. Thus investigating whether different features of benign lesions may be associated with age and/or subsequent breast cancer risk in this population is warranted. Methods: Benign breast biopsies from 1,867 AA women with BBD diagnosed from 1997-2003 were microscopically reviewed for 15 benign features (apocrine metaplasia (AM), ductal hyperplasia (DH), atypical ductal hyperplasia (ADH), lobular hyperplasia (LH), calcifications (Calc), cysts, duct ectasisa (DE), fibroadenoma (FA), fibrosis, intraductal papilloma (IDP), radial scar (RS), sclerosing adenosis (SA), columnar cell alterations (CC), mucocele-like tumors (MLT), and atropy), and followed for subsequent breast cancer in metropolitan Detroit, Michigan. Data from 439 women under 40 and 1,428 women 40 and older at BBD diagnosis were available for analysis, with a mean follow-up time of 14 years. Differences between age categories for BBD features were compared using chi-square tests, and risk of breast cancer was estimated with odds ratios (OR) and 95% confidence intervals (95% CI) calculated from logistic regression analysis. Results: Women 40 and over were more likely to be diagnosed with nearly all of the benign characteristics compared to younger women, including: AM, DH, Calc, cysts, CC, and ADH (all p-values Conclusions: Characteristics of BBD differ by age, with more women over the age of 40 being diagnosed with various conditions. Risk of subsequent cancer also varies, although RS, CC and ADH appear to increase risk in both age groups. Citation Format: Michele L Cote, Julie J Ruterbusch, Sudeshna Bandyopadhyay, Quratulain Ahmed, Barra Alosh, Eman Abdulfatah, Haitham Arabi, Rouba Lynn Ali-Fehmi. Characteristics of benign breast disease and subsequent risk of breast cancer differ by age among African Americans [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-14-06.

Rationale: MicroRNAs (miRNAs) are recently described novel small non-coding endogenous RNAs which critically regulate cancer progression, invasion and metastasis. Altered expression of miRNAs has been proposed to control the invasive capability of cancer cells. Modulating altered miRNAs is a novel approach for targeted therapy for cancer. Breast cancer is the most common cancer among women in the US. Breast cancer-related mortality and morbidity are primarily due to metastatic disease especially brain metastasis which also impacts patients’ quality of life. Molecular mechanisms of brain metastasis of breast cancer are largely unknown. Study Objectives: Identifying molecular miRNA signatures in breast cancers which metastasize to the brain can assist in designing novel targeted therapies to prevent and eliminate brain metastasis. Design: RNA was extracted from formalin fixed paraffin embedded tumor tissues from a cohort of breast cancer patients with brain metastasis, and age, stage and follow-up matched breast cancer cases without brain metastasis. miRNA expression profiling was done using EQIXON microarray. Quantitative real-time PCR (qRT-PCR) was used to validate abnormal expression of miRNAs. Data was statistically analyzed using Kruskal-Wallis test to determine the clinical significance of the findings. Results: Over 2000 unique miRNA sequences were profiled in each case. The upregulated miRNAs included miR-3927-5p, miR-216b and miR-10b and the down regulated miRNAs were miR-4280, miR-3174 and miR-1244 and miR20b. Validation of the deregulated miRNAs by q RT-PCR showed statistically significant difference in the expression levels in the breast cancers with brain metastasis compared to breast cancers without brain metastasis (Kruskal-Wallis test; p < 0.001). Conclusions: A unique set of miRNAs were deregulated in breast cancers with brain metastasis. This panel of altered miRNAs have clinical relevance since they can be silenced by antagomirs (chemically modified anti-miRNA oligonucleotides) to treat and prevent brain metastasis. These molecular microRNA signature-based novel targeted prophylactic and therapeutic strategies could improve patients’ quality of life and overall survival in the era of personalized and precision medicine. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-15-07.

Introduction: Obesity is a risk factor for breast cancer, including the more aggressive triple-negative (TN) subtype, but the relevance of obesity to prognosis remains unclear. Unlike other subtypes, triple-negative breast cancer (TNBC) is not hormonally responsive and is characterized by a lack of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 expression. Thus, obesity-related development of TN tumors is unlikely to rely on the peripheral aromatization of androgens to estrogens in fat. Chronic, low-grade inflammation elicited by obesity could increase risk of TNBC. Here we sought to assess which mechanisms mediate obesity’s effect on normal tissue and TN tumors using a gene expression approach. Because African American women are more likely to be obese and twice as likely to develop TNBC compared to white women, understanding the mechanisms of obesity-related risk of TNBC is critical for this high-risk group. Methods: We performed whole-genome expression profiling on formalin-fixed, paraffin-embedded samples from 104 African American women with TNBC (59 tumor, 45 adjacent normal). Body mass index was obtained by medical record abstraction, and women with BMI at least 30 kg/m2 were classified as obese. Gene Ontology (GO) was used to identify biologic processes enriched in differentially expressed genes by obesity status in tumors and adjacent normal tissue (p-value Results: 28 (47%) TNBC tumor and 29 (64%) adjacent normal samples were from obese women. Among genes more highly expressed in tumors from obese compared to nonobese women, GO analysis revealed enrichment for proinflammatory processes involving regulation of immune system, activation of immune responses, leukocyte activation, and neutrophil activation (FDR-corrected p-value Conclusions: Obesity modifies the immune cell environment present not only in TN tumors but also in the surrounding normal tissue. Obesity promotes a more proinflammatory setting within TN tumors, and in contrast, an anti-inflammatory setting in normal tissue adjacent. These findings may have important implications for understanding how obesity influences TNBC risk and prognosis, particularly among African American women who are at high risk for both. Citation Format: Asra N. Shaik, Julie L. Boerner, Michele L. Cote, Gregory Dyson, Rouba Ali-Fehmi, Sudeshna Bandyopadhyay, Kristen S. Purrington. Immune cell infiltrates differ by obesity in tumor and adjacent normal breast tissue in African American women with triple-negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B01.

Introduction: Obesity is associated with an increased breast cancer (BrCa) incidence. Adipose inflammation, marked by crown-like lesions in the breast (CLS-B) or dying adipocytes surrounded by macrophages, has been previously associated with BMI, aromatase expression, and systemic inflammation - all BrCa risk correlates. However, CLS-B has not been well described in normal or pre-malignant tissue, nor ever described in African American women (AAW). Here we examined whether CLS-B is associated with risk of benign breast disease (BBD) and BrCa in AAW, who suffer a higher incidence of breast cancer, poorer breast cancer outcomes, and a higher prevalence of obesity than women of other ethnicities. Methods: We assessed breast biopsies from three age-matched groups including 50 AAW with no history of BBD or BrCa from the Komen Normal Tissue Bank (KTB) and AAW with BBD from our Detroit cohort who developed cancer (55 BBD cases) or did not develop breast cancer (47 BBD controls). Slides were assessed by pathologists (KK, RAF) for CLS-B presence. Associations between tissue type and CLS-B presence among KTB and BBD samples were assessed using chi-square tests. Association between tissue types and CLS-B adjusting for BMI was assessed using the Mantel-Haenszel test. Results: The KTB, BBD controls and BBD cases groups were matched for age, consisted of approximately 15% CLS-B presence by study group and BMIKTBBBD controlsBBD casesN (%) with CLS-B presenceN=44N=44N=42BMI Conclusions: These findings suggest that CLS-B may serve as an important histological marker of BrCa risk in benign breast biopsies. Our study population exhibited higher rates of obesity than other BBD and CLS-B studies of European American women highlighting the need to include diverse populations in future studies examining BrCa risk. These findings have potential implications for modeling BrCa risk, particularly among AAW, for whom obesity is prevalent. Citation Format: Asra N. Shaik, Katrin Kiavash, Karri Stark, Julie L. Boerner, Julie J. Ruterbusch, Rouba Ali-Fehmi, Michele L. Cote. Adipose inflammation and the risk of benign and malignant breast disease in African American women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-337.

Benign breast disease, a known risk factor for subsequent breast cancer, includes a histological spectrum of lesions that can be subdivided based on the overall impression into non-proliferative lesions, proliferative lesions without atypia, and atypical hyperplasia. Yet little is known about the molecular characteristics of benign breast tissue from African American women, who suffer from disproportionately high breast cancer mortality rates. 72 breast samples from African American women were obtained. RNA was extracted from archival formalin-fixed, paraffin-embedded (FFPE) blocks. Gene expression profiling was performed on these samples using the Affymetrix HTA2.0 exon array chip. A fit linear model using generalized least squares identified probe sets with differential expression in benign-in situ and benign-invasive breast cancer paired lesions. 36 benign and 36 breast cancer paired lesions were included in the study. In the benign-in situ set (n=20), 978 probe sets were differentially expressed (threshold: fold-change, 1.50; p < 0.05). Probe sets mapped to 125 annotated genes, of which 69 (55.2%) were involved in cancer. The benign-invasive set (n=52) identified 351 differentially expressed probe sets that mapped to 84 annotated genes, of which 61 (72.6%) had known cancer significance. Genes involved in cellular growth and proliferation were significantly over-expressed in both benign-in situ and benign-invasive lesions (p-values < 0.0104). In the population of 36 paired samples, differentially expressed genes were found to regulate the estrogen receptor (ESR1) through distinct network associations. Many genes are differentially expressed by benign and breast cancer lesions, and in situ/invasive histology contribute to the distinct molecular characteristics and pathways of breast malignancy. Our findings highlight the first study to assess expression profiling of paired benign and breast cancer lesions among African American women. Citation Format: Andreana Natalie Holowatyj, Julie J. Ruterbusch, Rouba Ali-Fehmi, Sudeshna Bandyopadhyay, Christine Mehner, Melody Stallings Mann, Gregory Dyson, Derek Radisky, Michele L. Cote. Expression profiling of paired benign and breast cancer lesions in African American women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4253. doi:10.1158/1538-7445.AM2017-4253

Introduction: Atypical hyperplasia (also known as proliferative disease with atypia), while categorized as a benign finding, has been consistently associated with an increased risk of subsequent breast cancer that persists for decades after initial diagnosis. There are various other lesions that are classified as benign breast disease (BBD) that are routinely identified by pathologists that may also increase risk and be of use to inform breast cancer risk models. We sought to identify which BBD lesions were associated with increased risk of breast cancer in an African American (AA) cohort. Methods: Benign breast biopsies from 3,895 AA women diagnosed with BBD between 1997 and 2010 in metropolitan Detroit were reviewed for 12 benign features including columnar alterations, ductal ectasia, ductal hyperplasia, fibrosis, apocrine metaplasia, lobular hyperplasia, calcifications, cysts, intraductal papilloma, radial scar, sclerosing adenosis, and fibroadenomas. Women were followed for subsequent breast cancer using the Metropolitan Detroit Cancer Surveillance System, part of the Surveillance, Epidemiology, and End Results (SEER) cancer registry. Associations between BBD features and subsequent breast cancer were examined using chi-square tests. Features that had a significant chi-square test result were also combined into scores describing the overall number of BBD features identified, termed busy breast score. Multivariable log-binomial regression with backward selection based on BIC criteria was performed to assess risk ratio and 95% confidence intervals of breast cancer on 12 candidate features. Multivariable log-binomial regression was performed for busy breast score as well. All regression models were adjusted for age at biopsy and overall impression for presence of proliferative disease with or without atypia using non-proliferative disease as the reference. Models were checked for multicollinearity using a variable inflation factor (VIF). Results: Of the 3,895 AA women in the BBD cohort, 210 developed a subsequent breast cancer. The median age at biopsy among those without a subsequent cancer (controls) was 47 years of age, while cases were 53 years of age (p-value Conclusions: Columnar alterations confer increased risk of breast cancer beyond the risks associated with atypical hyperplasia, as does the presence of multiple types of BBD lesions in a single biopsy. These estimates may help improve the current risk assessment models for African American women and highlight the need for additional research regarding the utility of closer surveillance and potentially chemoprevention for reduction of breast cancer in these women. Citation Format: Michele L. Cote, Wei Chen, Julie J. Ruterbusch, Eman Abdulfatah, Visakha Pardeshi, Asra N. Shaik, Marcel T. Ghanim, MHD Fayez Daaboul, Daniel W. Visscher, Sudeshna Bandyopadhyay, Rouba Ali-Fehmi. Benign breast disease and subsequent breast cancer risk: The Detroit cohort. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr A25.

Introduction: The majority of the 1.6 million breast biopsies performed annually in the United States are benign; however, several breast cancer risk models consider a benign biopsy a factor that increases risk of subsequent breast cancer. Fibroadenomas (FA), benign tumors of epithelial and stromal tissue, occur frequently in premenopausal women and more frequently in African American (AA) women than European American (EA) women. A small increased risk of subsequent breast cancer due to FA has been reported in some studies of EA women. We sought to investigate whether the risk of this lesion differs for AA women. Methods: Benign breast biopsies from 3895 AA women diagnosed between 1997 and 2010 in metropolitan Detroit were reviewed for 12 benign features including FA, ductal ectasia, fibrosis, apocrine metaplasia, ductal hyperplasia, lobular hyperplasia, calcifications, cysts, intraductal papilloma, radial scar, sclerosing adenosis, and columnar alterations. These features were also used to categorize FA into simple and complex FA, where complex FA occurs when FA is accompanied by at least one of the following features: cysts, calcifications, apocrine metaplasia or intraductal papilloma. Women were followed for subsequent breast cancer using the Detroit Surveillance, Epidemiology, and End Results (SEER) cancer registry. Associations between FA and other benign lesions were examined using chi-square tests. Risk of breast cancer was estimated by relative risk ratios and 95% confidence intervals calculated using logistic regression. All models were adjusted for age at biopsy and additionally adjusted for presence of proliferative disease with or without atypia. Results: Of the 3895 AA women, 46.5% presented with FA on biopsy. FA occurred more frequently in biopsies of younger women (p-value < 0.001) and were less likely to include the other benign lesions assessed (all p-value < 0.001). Of the 210 identified breast cancers that developed in this cohort, 72 cancers developed in women with FA on biopsy. FA were associated with a reduction in risk of breast cancer after adjusting for age at biopsy (RR=0.64, 95% CI: 0.48, 0.86) compared to women without FA on biopsy. Reduction in risk was somewhat attenuated when analysis was adjusted for proliferative disease with or without atypia (RR = 0.67, 95%CI: 0.48, 0.936). Similar associations were seen with simple FA (RR =0.61, 95% CI: 0.35, 1.01) and complex FA (RR =0.70, 95% 0.35, 1.01) after adjustment for age at biopsy and proliferative disease with or without atypia. Conclusions: FA are negatively associated with other benign breast disease features. Risk of breast cancer may be reduced in women with FA compared to women with other types of benign lesions. These findings have important implications for modeling breast cancer risk particularly among AA women for whom FAs are common. Citation Format: Asra N. Shaik, Julie J. Ruterbusch, Eman Abdulfatah, Marcel T. Ghanim, MHD Fayez Daaboul, Visakha Pardeshi, Rouba Ali-Fehmi, Daniel W. Visscher, Sudeshna Bandyopadhyay, Michele L. Cote. Fibroadenomas on benign breast biopsy and subsequent breast cancer risk in an African American cohort. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr A16.

Introduction: Most clinical models to estimate risk of invasive breast cancer include history of benign breast disease (BBD) as a covariate, as these women represent a higher risk group compared to the general population. A better understanding of the association between BBD and breast cancer is necessary to improve the utility of these risk models, particularly with respect to tumor subtype. This may be especially important for African American women who are more likely to present with aggressive cancers compared to white women. Here we present tumor subtypes from a higher risk cohort of African American women with a history of BBD. Methods: Benign breast biopsies from 3,865 African American women with BBD diagnosed from 1997-2010 were examined for 14 benign features, and followed for subsequent breast cancers in metropolitan Detroit, Michigan using medical records and data from the Detroit Surveillance, Epidemiology and End Results (SEER) program. Immunohistochemistry analysis was performed for the following 6 markers: estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), Ki-67, epidermal growth factor receptor (EGFR) and cytokeratin 5/6 (CK 5/6) in order to categorize the subsequent breast cancers by subtype. Briefly, ER and PR were utilized to classify tumors as luminal or non-luminal, and then further classification was made based HER2. Luminal tumors were also classified by Ki-67 expression, and triple negative tumors (ER/PR/HER2 negative) were further classified based on expression of either CK5/6 or EGFR, resulting in 6 categories. Results: 210 women (5.4% of the total cohort) with a subsequent breast cancer were identified over a median follow-up time of 12.3 years (range: 0.6 - 18.0). Analysis of all 6 markers is complete for half of the tumors (104). The majority of the subsequent cancers were invasive (n=72, 69.2%). Most of the invasive tumors were luminal B, HER2- (37.5%), followed by luminal A (31.9%), triple negative (19.4%), non-luminal, HER2+ (6.9%) and luminal B, HER2+ (4.2%). Of the 14 triple negative cancers (19.4%), 8 were negative for CK5/6 and EGFR (5 negative phenotype, 57.1%) and 6 were core basal (42.9%). Among the 32 in situ tumors, the majority were luminal A (n=26, 81.3%), followed by luminal B, HER2- (n=5, 15.6%) and there was a single tumor classified as 5 negative. Compared to population-based SEER data from 5,268 African American women with invasive breast cancer and available data on 3 markers (ER, PR, and HER2) diagnosed in 2010, our cohort is similar with respect to tumor subtype. Conclusions: The women with a previous benign breast biopsy in our cohort who develop a subsequent breast cancer have subtypes that are similar to the general African American population in the United States. Thus, our BBD cohort represents the full spectrum of invasive breast cancers with respect to subtype, including triple negative tumors. Citation Format: Julie J. Ruterbusch, Michele L. Cote, Julie Boerner, Eman Abdulfatah, Baraa Alosh, Vishakha Pardeshi, MHD Fayez Daaboul, Woodlyne Roquiz, Rouba Ali-Fehmi, Sudeshna Bandyopadhyay. Breast cancer subtype subsequent to a benign breast biopsy among African American women. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr A15.

Introduction: Benign breast disease (BBD) is an established risk factor for developing breast cancer, and certain pathologic features in benign breast tissue are more strongly associated with breast cancer risk. Most of the studies evaluating BBD and breast cancer risk have been done in primarily white populations. Our previous work among African American (AA) women with BBD suggested the presence of cysts was associated with increased breast cancer risk. This finding may be unique to AA women as other studies among white populations have not replicated these findings. We sought to further explore the association between breast cysts and breast cancer risk in our expanded AA BBD cohort. Methods: Biopsies from AA women initially diagnosed with BBD from 1997 to 2009 were examined for 14 pathologic features, including the microscopic presence of cysts, and followed for subsequent breast cancer. The association between cysts and the other pathologic features were compared using chi-square tests, and the risk of developing breast cancer was estimated using logistic regression and summarized with odds ratios (OR) and 95% confidence intervals (95% CI). Results: A total of 3,360 AA women with BBD have been identified and their benign biopsies reviewed. 190 women have developed a subsequent breast cancer with a mean follow-up time of 11.5 years. Cysts were present on 1,366 (38%) of the biopsies, and were significantly associated with nearly all of the other benign features evaluated: apocrine metaplasia, ductal hyperplasia, calcifications, duct ectasia, fibrodenomas, fibrosis, intra-ductal papillomas, sclerosing adenosis, columnar alterations, mucocelle-like lesions, radial scars, and proliferation with and without atypia (all p Conclusion: Among AA women, cysts are highly correlated with other BBD features that increase subsequent breast cancer risk, but the risk associated with cysts does not appear to be independent of hyperplasia with atypia. Understanding the etiology of BBD and cyst development may provide insight into breast tumorigenesis, and the interplay between cysts and other BBD features warrant further investigation. Citation Format: Julie J. Ruterbusch, Michele L. Cote, Sudeshna Bandyopadhyay, Baraa Alosh, Eman Abdulfatah, Vishakha Pardeshi, Woodlyne Roquiz, Daniel Visscher, Rouba Ali-Fehmi. Presence of cysts in benign breast tissue and the risk of subsequent breast cancer in African American 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 1769.

Background: Unlike the decreasing incidence seen for most cancers, incidence rates of endometrial cancer have been increasing in the United States over the last decade. Earlier studies have shown that mortality rates from endometrial cancer are significantly higher for non-Hispanic black women compared to non-Hispanic white women, but this has not been established for other racial/ethnic groups. Our objective was to determine whether the increasing incidence and mortality from endometrial cancer are equally distributed by race/ethnicity and tumor histologic subtype. Methods: Data from the Surveillance, Epidemiology and End Results (SEER) registry were used to identify women diagnosed with endometrial cancer from 2000-2011. A total of 120,513 women, including 90,621 non-Hispanic white (NHW) women (75.2%), 11,386 Hispanic women (9.4%), 10,365 non-Hispanic black women (NHB) (8.6%) and 8,141 Asian women (6.8%) comprised the study population. Age-adjusted incidence and incidence-based mortality rates, with 95% confidence intervals and annual percent changes (APC), were calculated by race/ethnicity (4 groups) overall and for 7 histologic subtypes (low grade endometrioid, high grade endometrioid, clear cell, mixed, MMMT, serous, and other), along with rate ratios to compare racial/ethnic groups, using NHW as the referent group. In addition, 5-year survival rates were calculated by race/ethnic group, histologic subtype, and stage at diagnosis (localized, regional, distant). Differences between NHW and NHB women in the percentage surviving 5 years were described by calculating (%NHW-%NHB)/%NHW) overall and for each histologic subtype and each stage at diagnosis (21 comparisons). Results: Incidence rates for endometrial cancers are rising across all racial/ethnic groups, with the greatest annual percent change (APC) seen among NHB and Asian women (APC=2.5 for both). Low-grade endometrioid endometrial cancers are the most commonly diagnosed subtype among all women, with highest rates in NHW women, but these rates have stabilized or decreased over the last decade for all women with the exception of NHB women (APC=1.0). High grade endometrioid endometrial cancers have significantly decreased incidence rates over the last decade, particularly among NHW women (APC=-2.5). NHB women have the highest incidence rates of this and other aggressive subtypes of endometrial cancers (clear cell, serous, and malignant mixed Mullerian tumors) compared to NHW women. Hispanic and Asian women had incidence rate ratios equal to or lower than NHW women for all tumor subtypes. For every subtype and stage of disease, the 5-year survival for NHB women is lower than for NHW women, and significantly lower for nearly each comparison. The smallest percent difference seen is for women with localized endometrioid cancers, where NHB women have 6% lower survival, and the largest is 59% lower survival for distant stage clear cell cancers. Hispanic and Asian women have the same or slightly better survival rates compared to NHW women across all stages and subtypes. Conclusions: The lower survival rates among NHB women with endometrial cancer persist at nearly every stage and histologic subtype examined. Various factors, including socioeconomic status (SES), comorbid conditions, access to care, and treatment decisions may all impact this disparity to some extent, yet Hispanic women who have many of the same challenges are at lower risk of occurrence and have outcomes similar to NHW women after diagnosis. Additionally, the most aggressive types of endometrial cancer are also more common among NHB women, and are among the endometrial cancer subtypes with largest increasing incidence rates. We have yet to fully account for these disparities seen primarily in NHB women and, without intervention, they are likely to persist and potentially widen as endometrial cancer emerges as a significant cause of morbidity and mortality in the decades to come. Citation Format: Michele L. Cote, Julie J. Ruterbusch, Sara H. Olson, Karen H. Lu, Rouba Ali-Fehmi. Racial disparities in endometrial cancer incidence and mortality are limited to non-Hispanic black women. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr B62.

Although the association between benign breast disease (BBD) and risk of subsequent breast cancer is well-established, no previous studies have compared characteristics of breast cancers in women with a history of BBD to characteristics of cancers in the general population. In this study, we compared the characteristics of 109 breast cancers that developed in a population of African-American women with a history of benign breast disease (BBD population) to 10,601 breast cancers that developed in a general population of African-American women whose cancers were recorded by the Metropolitan Detroit Cancer Surveillance System (MDCSS population). The populations were compared on demographic characteristics such as age, marital status, and previous cancers, as well as clinical characteristics such as tumor hormone receptor status, grade, stage, behavior, size, and treatment. Overall and breast cancer-specific survival were also compared between populations. Women in the BBD population developed lower grade, earlier stage cancers that were more likely to be hormone receptor-positive and less likely to exhibit invasive behavior. Women in the BBD population were also significantly less likely to die from breast cancer after ten years of follow-up. These results suggest that although women with a history of BBD are at greater breast cancer risk, their breast cancers may be more likely to be detected early, leading to better breast cancer-specific survival. Citation Format: Susanna D. Mitro, Rouba Ali-Fehmi, Sudeshna Bandyopadhyay, Baraa Alosh, Bassam Albashiti, Quratulain Ahmed, Derek C. Radisky, Marlene H. Frost, Amy C. Degnim, Julie J. Ruterbusch, Michele L. Cote. Clinical characteristics of breast cancers in African American women with benign breast disease: A comparison to the Surveillance, Epidemiology and End Results Program. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr B39. doi:10.1158/1538-7755.DISP13-B39

Objective: Historically, cervical adenocarcinomas have been viewed as more aggressive than squamous cell carcinoma (SCC) in multiple small cohorts. We analyzed the largest Latino cohort of early stage cancer to determine the impact of histologic type. Methods: Retrospective analysis of patients with SCC and adenocarcinoma stages IA1-IB2 at the Mexican Oncology Hospital from 2000-2010 was performed for: age, stage, tumor size, lymphovascular invasion (LVI), invasion depth, lymph node status, recurrence and survival. Pathologic review proceeded inclusion. 64 patients with SCC were recruited between 2000-2003. 101 patients with adenocarcinoma were recruited between 2000-2010. Categorical variables were analyzed by chi square and continuous variables using one-way ANOVA analysis. Results: Results are summarized in Table 1. Adenocarcinomas tended to be higher grade (p= 0.01), while SCC's were larger with deeper invasion (p Conclusion: Patients with early stage adenocarcinomas have smaller, higher grade tumors than patients with SCC with no difference in LVI, lymph node involvement, recurrence rate or survival. . A potential confounding factor was higher rate of adjuvant RT in adenocarcinoma vs. SCC patients. Overall, these findings suggest the need for more aggressive therapy in the treatment of early stage cervical adenocarcinoma should be investigated further, potentially reducing morbidity in this cohort of patients. Adenocarcinoma (n = 101) Squamous (n = 64) p-value Age (Median) 51 (35–80) 51 (22–86) NS Stage NS IA1 3 (3%) 1 (1.6%) IA2 1 (1%) 0 (0%) IB1 96 (95%) 54 (84.4%) IB2 1 (1%) 9 (14%) Lymph Node NS Positive 16 (15.8%) 13 (20.3%) Negative 85 (84.2%) 51 (79.7%) Grade p = 0.01 1 19 (18.8%) 14 (21.9%) 2 50 (49.5%) 45 (70.3%) 3 32 (31.7%) 5 (7.8%) LVI NS Positive 26 (25.7%) 21 (32.8%) Negative 75 (74.3%) 43 (67.2%) Missing 0 (0%) 0 (0%) Tumor Diameter(Mean cm) 1.99 (1.8–2.4) 2.77 (2.5–3.03) p < 0.0001 Invasion Depth (Mean cm) 0.78 (0.7–0.86) 1.6 (1.3–1.6) p < 0.0001 Treatment p = 0.001 Surgery 29 (28.7%) 34 (53%) Surgery+RT 72 (71.3%) 30 (47%) Recurrence NS Yes 5 (5.0%) 5 (7.9%) No 76 (75.2%) 56 (87.5%) Missing 20 (19.8%) 3 (4.6%) Survival NS Alive 78 (77.3%) 56 (88.9%) Alive with Disease 3 (3.0%) 4 (6.3%) Dead 1 (0.9%) 3 (4.8%) Missing 19 (18.8%) 0 (%) Follow-up (Median yrs) 4 (1–8) 4 (1–8) NS Citation Format: Ira Winer, Isabel Alvarado-Cabrero, Shelly Seward, Raquel Valencia-Cedillo, Adnan Munkarah, Rouba Ali-Fehmi. The significance of squamous vs. adenocarcinoma subtypes in early-stage cervical carcinoma. [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 168. doi:10.1158/1538-7445.AM2013-168

Background: Ninety percent of ovarian cancers are epithelial in nature (EOC); the standard approach for treatment is surgery followed by platinum and taxane based chemotherapy. Gemcitabine has been evaluated recently in combination with platinum and taxane for platinum sensitive recurrence and as a single agent for platinum refractory or resistant recurrent EOC. ERCC1 and RRM1 are involved in DNA synthesis and repair derived from genotoxic stress, and they have also been reported as predictive markers for therapeutic efficacy in patients with lung and pancreatic cancers. Their expression, association and clinical significance in ovarian carcinoma remain uncertain. Design: 198 archived cases of epithelial cell ovarian cancer were reviewed and divided into three subtypes: borderline tumor (BLT), Type I and Type II. 2mm TMAs were developed with duplicate cores per case. Immunofluorescence combined with Automated Quantitative Analysis (AQUA) was used to assess the expression of ERCC1 and RRM1. The average of duplicate cores was used for analysis and Greedy search was used for establishing the high and low score cutoff points. Results: 44 cases (22%) were BLT, 29 (15%) were Type I tumors, 121 (61%) were Type II tumors, and 4 cases (4%) were unclassified. Type II tumors were significantly higher among elderly Caucasian women (p Conclusion: Our study suggests that low expression of ERCC1 and high expression of RRM1 are associated with poor survival in ovarian cancer patients. Large studies are warranted to elucidate whether or not the expression of ERCC1 and RRM1 can be used as prognostic or predictive markers. Citation Format: Jun Zhou, Quratulain Ahmed, Wei Chen, Xin Li, Robert Morris, Rouba Ali-Fehmi, Gerold Bepler. Excision repair cross complementing group 1 (ERCC1) and regulatory subunit of Ribonucleotide Reductase (RRM1) as prognostic and predictive markers for ovarian cancer. [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 3472. doi:10.1158/1538-7445.AM2013-3472

Endometrial cancer is the most common gynecologic cancer, with an estimated 42,000 new cases in 2010. Histologic types of endometrial cancer and stage at diagnosis differ substantially between African Americans (AA) and whites, but AA women experience poorer survival even after accounting for these factors. Additionally, other research suggests this disparity persists after controlling for co-morbid conditions, access to care, and treatment decisions. We hypothesize that there are differences in the molecular biology of tumors from white and AA women, beyond histologic type and grade, which may lead to the increased risk of death seen in AA women after an endometrial cancer diagnosis. After IRB approval, we performed a case-only retrospective analysis of patients with endometrial cancer, for whom we had tumor blocks, diagnosed from 1990-2005 at a single institution. Demographic and clinical variables were obtained from medical record review. Tumor histologic type, stage, and grade were obtained from the Metropolitan Detroit Cancer Surveillance System, part of the SEER program. Tumor histologic type and grade were confirmed by a gynecologic pathologist by slide review. We selected 150 archived tumors, including all high grade cases of any race (35 white, 40 AA), all low grade, endometroid tumors from AA women (n=44), and 31 low grade tumors from white women. Tumor DNA was extracted from formalin fixed paraffin embedded tissue using standard methods. We examined 238 mutations in 19 common oncogenes using the OncoCarta Assay v1.0 (Sequenom). Chi-square tests and Fisher's exact tests were used to assess differences in distribution of clinical and demographic variables by race or oncogene mutation status. We identified 20 mutations in 2 oncogenes in tumors from 19 women (12.7%). The most common mutation was in PIK3CA, the gene coding for the catalytic subunit p110α of PI3K, representing 15/20 (75%) of detected mutations. In PIK3CA, the following mutations were identified: R88Q in the p85-binding domain, E542K, M1043I and P539R in the helical domain, and H1047R in the kinase domain. Previous data suggest these mutations induce a gain of PI3K function and prognosis may vary by location. An additional 4 samples had activating mutations in KRAS (1 G12D, 1 G12V and 2 Q61H). No other mutations were identified. 13% of endometroid tumors harbored mutations, (11 PIK3CA and 2 KRAS). Among tumors from women with low grade endometroid cancers, race was significantly associated with harboring a mutation (p=0.04), with all 7 PIK3CA mutations were identified in AA women. All 4 KRAS mutations were found in AA women (p=0.13). This study provides preliminary evidence that the underlying molecular biology of some subtypes of histologically similar endometrial cancers differ by race. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1137. doi:10.1158/1538-7445.AM2011-1137

Background: Human papillomaviruses (HPVs) have been causally associated with several types of human cancers. With the path breaking discovery of the effective prophylactic HPV vaccine against cervical cancer, it is in public health interest to interrogate the possibility of expanding this vaccine to other HPV-associated cancers including head and neck squamous cell carcinoma (HNSCC). A major limitation is the limited number of studies in this field and a wide range of HPV detection rates, measured by various methodologies. Objectives: (1) To determine the status of HPV and its genotypes in HNSCC using highly sensitive assays; (2) To correlate these with clinical and pathologic variables to develop a clinical algorithm for risk stratification of HNSCC patients. Experimental procedures: DNA from 385 HNSCC formalin-fixed, paraffin embedded (FFPE) tissue blocks which were identified through a population-based cancer registry in Metropolitan Detroit were interrogated for HPV status using a sensitive broad-spectrum PCR technique specifically suitable for FFPE samples (DNA Enzyme Immuno Assay, followed by Line Probe Assay broad-spectrum assay). Clinical and pathologic variables obtained from the registry database were correlated with the HPV status. Results: HPV positivity was detected in 113 (29.35%) HNSCC cases, high risk genotype HPV 16 in 90 (79.65%) cases; HPV 18 in 2(1.77%) cases, dual HPV 16 & 18 in 3 (2.65%) cases and low risk HPV 6 in 2(1.77%) cases. Of the 81 oropharyngeal cases, 50.6% were HPV positive and 45.7 % were HPV 16 positive (p= Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3201. doi:10.1158/1538-7445.AM2011-3201

Endometrial cancer is the most common gynecologic cancer, with an estimated 42,000 new cases in 2010. The reported difference in overall five year survival between white women and African American (AA) women represents significant survival disparity in cancer. Histologic types of endometrial cancer and stage at diagnosis differ substantially between AAs and whites, but AA women experience poorer survival even after adjusting for these factors. After IRB approval, we performed a case-only retrospective analysis of 362 patients with surgically treated endometrioid endometrial cancer. Data from 120 AA and 242 white women, diagnosed from 1990-2005 at a single institution were analyzed to examine risk factors associated with survival. Age at diagnosis, co-morbid conditions in the 5 years prior to diagnosis, BMI, and smoking history were obtained from medical record review. Tumor histologic type, 1988 FIGO stage, grade, vital status and number of months surviving were obtained from the Metropolitan Detroit Cancer Surveillance System, part of the SEER program. Differences in stage, co-morbid conditions (using a modified Charlson Comorbidity Index, CCI), and BMI were examined by race. Chisquare tests were used to assess differences in distribution of clinical and demographic variables. Log-rank tests and Cox proportional hazards models were used to assess the risk of all-cause and endometrial cancer-related deaths. AA women were more likely than white women to have high grade tumors (p=0.009), hypertension (p=0.0005) and higher mean BMI (p=0.009). No differences by race were identified among the total group for age (p=0.98), stage at diagnosis (p=0.78), categorical modified CCI (p=0.51) or smoking history (p=0.96). When data were stratified by grade, hypertension (p=0.0009) and high BMI (p=0.002) were more frequent among AAs compared to whites with low grade tumors, but not high grade tumors. Among women with high grade tumors, AAs had a greater number of co-morbid conditions (p=0.005) and were more likely to be current or former smokers compared to whites (p=0.003). In univariate survival analysis, age at diagnosis, CCI, stage, and grade were all significantly associated with any cause survival, whereas race was not. When examining deaths due to endometrial cancer, only stage (HR=3.37,95% CI: 2.52-4.51), grade (HR=4.32,95% CI: 2.89-6.47) and race (HR=2.12,95% CI: 1.13-3.97) were predictors of survival. Analysis of endometrial cancer-related deaths by grade suggest this difference in survival by race is seen for high grade (p=0.03) but not low grade (p=0.87) tumors. In this single institution study, race was not a predictor of overall survival, but was associated with endometrial cancer-related survival. Excess of co-morbid conditions was associated with AA race, and overall survival, but not endometrial cancer-related survival in this population. A larger, more comprehensive study, including information regarding socio-economic factors, molecular tumor markers, and treatment modality is necessary to elucidate the causes underlying the large disparity in endometrial cancer survival between AA and white women. Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):A111.