African American Patients Research Articles

Abstract C172: Diversifying translational research models to address outcomes disparities in lung cancer

Abstract Introduction: Racial disparities in lung cancer remains a persistent and challenging problem, with African Americans experiencing the highest mortality of any race or ethnic group. Emerging evidence suggests that multiple biological factors affect the development and progression of lung cancer. Three-dimensional organoid culture models have become important instruments to use for biomarker analysis and drug sensitivity screening. Despite this strong rationale and potential, there is a lack of representative preclinical models from African American patients with lung cancer. Furthermore, there are no studies evaluating the ability to create organoids successfully using samples from different races. As such, our goal was to establish a diverse biobank of organoid models and determine the rate of successful development based on race and other factors. Methods: Patients with lung cancer from a large urban medical center were recruited to participate in the study from 2021 to 2024. Specimens were collected from surgical pulmonary resection or endobronchial biopsy. Each tissue specimen was divided into 3 pieces and allocated for genomic, transcriptomic and organoid development. Once collected, specimens allocated for organoid development were processed within 8 hours. Cells were isolated from tissues by mechanical and enzymatic dissociation and plated in Matrigel drops overlayed with optimized organoid media. Patient demographics, tumor characteristics and method of specimen collection were recorded. Results: A total of 29 patients consented to the study and had evaluable specimens collected. Mean age was 67 years. Fifty-five percent of patients (16/29) were female. White patients were 55 percent of cohort (16/29), while Black patients made up 45% (13/29). Approximately 62 (18/29) percent of patients were diagnosed with adenocarcinoma, followed by squamous cell carcinoma in 28 percent (8/29) of patients. Tumor stage was 55%, 28%, 3% and 14% for stages I, II, III and IV respectively. Overall, there was a successful organoid development rate of 69 percent (20/29). There was a strong trend toward higher success rates in Black patients compared to White patients (85% vs. 56%, p = 0.10). There were no significant differences in successful organoid development based on gender (p = 0.43), histology (p = 0.18) or tumor stage (p = 0.84). Conclusions: Establishment of a racially diverse set of organoid models will be an invaluable tool for biomarker discovery and for screening novel therapeutic agents. Black patients appear to have similar to improved propensity for successful organoid development. Future efforts should be focused on creating diverse biobanks to strengthen precision oncology efforts for Black patients, collectively helping to reduce racial outcomes disparities in patients with lung cancer. Citation Format: Amanda Pilling, Hollis Hutchings, Avi Cohen, Shirish Gadgeel, Ikenna Okereke. Diversifying translational research models to address outcomes disparities in lung cancer [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C172.

Abstract C097: PVT1 exon 9-dependent overexpression of RSAD2 is a characteristic of prostate cancer in males of African ancestry

Abstract Aggressive prostate cancer (PCa), including castrate-resistant and neuroendocrine subtypes, is projected to increase in incidence 5% each year. Aggressive PCa disproportionally impacts African American men, has limited effective treatment options and high mortality rates. Although racial disparities are established in PCa development, attributed to multiple contributory factors including systemic racism, differences in socioeconomic status and distrust in the medical system, work is still needed to understand the contribution of biological factors. We found the exon 9 region of plasmacytoma variant translocation 1 (PVT1) overexpressed in aggressive PCa cell lines derived from African American (AA) men. We found PVT1 exon 9 overexpression induced phenotypic changes to normal prostate epithelial cells in vitro and led to tumor formation in vivo. RNA-sequencing analysis revealed 156 significantly differentially expressed genes influenced by PVT1 exon 9 overexpression and radical S-adenosyl methionine domain containing 2 (RSAD2) was the top significantly overexpressed gene (log2Fold change 1.71, p-value < 0.05). We utilized the GSE223405 publicly available dataset to identify whether our identified PVT1 exon 9 downstream genes were enriched in AA prostate cancer cells. RSAD2 was significantly overexpressed in AA prostate cancer cells compared to prostate cancer cells from men of European ancestry (moEA) (log2Fold change 6.18, p-value < 0.05). Comparing normal cells to prostate cancer cells between these groups, we found that normal AA prostate cells had significantly higher expression of RSAD2 (log2fold change 4.25, p-value < 0.001) whereas moEA samples did not (log2fold change 0.837, p-value=0.150). From analysis of data obtained from cBioPortal, we found RSAD2 alteration significantly correlates (p-value < 0.001) with self-identified race and copy number overexpression of RSAD2 was found to be enriched in AA patients (18.16% moEA versus 24% AA). Finally, we found 88.6% of the significantly differentially expressed genes within our PVT1 exon 9 RNA-sequencing dataset were significantly differentially expressed in GSE223405 AA samples and of those, 51.7% of genes exhibited a similar differential expression pattern suggesting that the PVT1 exon 9/RSAD2 dependent pathway may be more prominent in AA men. Mechanistically, we found two differing pathways of RSAD2 overexpression in aggressive prostate cancer cell models, one dependent and one independent of PVT1 exon 9 overexpression, with similar but differing biological functions related to epigenetic processes and metabolism. Ongoing work is investigating the RSAD2 and PVT1 exon 9 expression axis in a diverse set of human prostate cancer tissues and investigating their utilization as a therapeutic target in prostate cancer. Citation Format: Rachel E. Sexton-Bonacci1, Murtaza Barkarar1, Chindeum Udekwu1, Olorunseun O. Ogunwobi1. PVT1 exon 9-dependent overexpression of RSAD2 is a characteristic of prostate cancer in males of African ancestry [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C097.

Abstract C147: Impact of genetic ancestry in triple-negative breast cancer subtypes

Abstract Background: Triple-negative breast cancer (TNBC) is an aggressive BC subtype characterized by significant molecular and clinical heterogeneity, influenced by genetic, phenotypic, and environmental factors, as well as interactions of the tumor with its surrounding milieu. A significant racial disparity has been observed between African American (AA) and European American (EA) women regarding the incidence and clinical progression of TNBC. TNBC frequently occurs in young parous women who self-identify as AA and in women who harbor a germline BRCA1 mutation. Notably, AA women are diagnosed with TNBC at a younger age and exhibit a higher risk of developing stage IV disease. Studies examining gene expression signatures that distinguish AA and EA TNBC have reported distinct tumor-associated immunologic profiles in AA patients. We have developed a novel cell type-driven subtyping system based on a racially diverse TNBC sample set that identified three TNBC subtypes, each with distinct biology and prognosis: CC1- immune signaling/T-cell response; CC2- pro- migratory/inflammatory; CC3- fatty acid and hormone and nuclear receptor signaling. In this study, we propose to examine ancestry-inferred differences within each TNBC subtype between patients with African and European ancestry. Methods: RNA-Sequencing data for the Louisiana Tumor Registry, a TNBC cohort of 250 diverse women [EA: 123 and AA: 127], was obtained from our collaborators at Louisiana State University Health Sciences Center. Genetic admixture was performed on 227/250 patients using the method described by Pakstis, A. J. et al. Differentially expressed genes (DEGs) were identified in pairwise comparisons at p-adj ≤ 0.05. Survival was assessed using log-rank tests. Results: We investigated DEGs within each subtype between patients with >60% African (Aa, n=102) or >60% European ancestry (Ea, n=99) (identified via admixture analysis). In all three subtypes, upregulated genes, and their associated enrichment in Aa were related to immune pathways, while DEGs in Ea patients were related to epithelial cell regulation. In CC1, Aa was associated with the upregulation of immunoglobulin genes involved in immunoglobulin production and antigen recognition, while Ea was associated with the upregulation of embryonic development genes. In CC2, Aa showed enriched complement activation and immunoglobulin genes, while Ea exhibited upregulation of basal cytokeratin and growth factor EGFR. In CC3, Aa was associated with the upregulation of inflammatory genes, whereas Ea showed upregulation of cellular senescence genes. Survival analysis demonstrated favorable outcomes for Aa in CC1 and less favorable outcomes for Aa in CC2. Conclusion: Our study highlights significant ancestry-inferred differences in gene expression within TNBC subtypes, with Aa patients showing immune pathways enrichment and Ea patients exhibiting differential epithelial cell regulation. These findings underscore the importance of considering genetic ancestry in TNBC prognosis and treatment strategies. Citation Format: Zahra Mesrizadeh, Kavitha Mukund, Fokrul Hossain, Jovanny Zabaleta, Denise Danos, Luis De Valle, Xiao-Cheng Wu, Chindo Hicks, Augusto Ochoa, Lucio Miele, Victoria L. Seewaldt, Shankar Subramaniam. Impact of genetic ancestry in triple-negative breast cancer subtypes [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C147.

Abstract C051: Impact of population pharmacogenomics on cisplatin-induced neurotoxicities

Abstract Background: Studies have shown that taxane-treated breast cancer patients with African (AFR) ancestry experience worse peripheral sensory neuropathy (PSN), while African American vincristine-treated leukemia patients have less PSN than Europeans (EUR). We hypothesized that ancestral disparities may exist for cisplatin-induced neurotoxicities and may relate to differences in allele frequency and resultant gene expression of SNPs associated with these toxicities. Methods: In our Platinum Study of 1680 genotyped testicular cancer survivors (TCS), multidimensional scaling scores were anchored by the 1000 Genomes population to classify geographic ancestry. PSN (EORTC-CIPN20) and other toxicities plus clinical and lifestyle variables were examined for associations between geographic ancestry and phenotypes using logistic regression and Wilcoxon rank sum test. Genotyped SNPs with Fst > 0.25 in 1000 Genomes were identified and evaluated with GTEx data to find expression or splicing quantitative trait loci in nerve/brain tissue or for cisplatin-associated candidate genes, across all tissues. LDmatrix was used to find linkage disequilibrium. If a block of SNPs had R2 > 0.75, one independent SNP was kept for association analysis. Logistic regression with age at questionnaire completion and 10 genetic principal components as covariates was used to calculate the association between genotype and toxicity. Results: In an analysis of patients who received 400-450 mg/m2 of cisplatin including EUR (n=681), Asian (ASN) axis (n=44) and AFR (n=13), the odds ratio (OR) for any neuropathy vs. none in the AFR vs. EUR was 7.8 (P=0.049) and in the AFR vs. ASN axis (including East Asian 1000 Genomes populations) was 10.0 (P=0.034). TCS with AFR ancestry had significantly more vertigo. There were 19,874 SNPs for analysis from the genome-wide approach and 118 SNPs from the candidate gene approach. While associations between genotype and toxicity did not reach Bonferroni threshold, some SNPs had p-values in the 10-5 range. For PSN, one SNP had increased frequency of a risk allele in the AFR population while the other had increased frequency of a protective allele, while for vertigo, four SNPs had increased frequency of risk alleles in the AFR population. Of interest was rs34904346, in which the TT vs. AA genotype had an OR of 1.9 (p=2x10-5) for any vs. no PSN, with the T allele having 90% frequency in AFR ancestry patients versus ∼60% in other populations. This SNP and three other independent SNPs associated with PSN incidence (p∼10-3) are eQTLs for RNF24 in nerve tissue, which interacts with membrane proteins that regulate intracellular calcium levels. Conclusions: We show preliminary evidence for the role of differing risk allele frequencies across populations in explaining disparities in cisplatin-induced PSN and vertigo, likely in combination with structural and environmental factors. Genotyping risk alleles could customize dosing, treatment, and post-treatment monitoring to benefit all cisplatin-treated patients. Citation Format: Swetha Nakshatri, Paul C. Dinh, Darren R. Feldman, Robert J. Hamilton, Chunkit Fung, David J. Vaughn, Christian Kollmannsberger, Robert Huddart, Lawrence H. Einhorn, Nancy J. Cox, Lois B. Travis, Eileen Dolan. Impact of population pharmacogenomics on cisplatin-induced neurotoxicities [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C051.

Abstract C037: Inflammatory breast cancer by metastatic status: Racial and ethnic and socioeconomic disparities in receipt of treatment

Abstract Background: Inflammatory breast cancer (IBC) is a relatively rare but aggressive type of breast cancer. Racial and ethnic minority patients are disproportionately affected by IBC and often face barriers to accessing cancer care and services. However, racial and ethnic disparities in receipt of treatment are not well defined among patients with IBC by metastatic status. Methods: We analyzed data from patients with IBC in the 2004-2020 U.S. National Cancer Database. Five treatment modalities were assessed: hormone therapy, chemotherapy, radiotherapy, surgery, and trimodal therapy. Metastatic status was dichotomous as “metastatic/non-metastatic.” Racial and ethnic groups included Asian or Pacific Islander, American Indian, Alaska Native, or Other, Black, Hispanic, and White. Separate logistic regression models were fit, adjusting for sociodemographic and clinicopathological characteristics, stratified by metastatic status. Adjusted odds ratios (aOR) and 95% CIs were calculated. Results: Of 33,376 patients with IBC (mean age 58 years [SD=14]), most (70.6%) identified as White, followed by 18.1% as Black, 7.0% as Hispanic, 2.5% as Asian or Pacific Islander, 1.8% as American Indian, Alaska Native, or Other; and 32.5% were metastatic. In the non-metastatic cohort, Black (72.7%; aOR 0.79, 95% CI: 0.63-0.98) or Asian or Pacific Islander (74.8%; aOR 0.59, 95% CI: 0.38-0.90) patients had lower odds of receiving hormone therapy than White patients (78.0%). Compared with White patients, Black patients had a lower likelihood of receiving chemotherapy (89.1% vs. 89.5%; aOR 0.67, 95% CI: 0.53-0.86), surgery (78.4% vs. 85.3%; aOR 0.65, 95% CI: 0.55-0.77), or trimodal therapy (81.5% vs. 87.3%; aOR 0.61, 95% CI: 0.49-0.76). American Indian, Alaska Native, or Other (65.0%; aOR 0.64, 95% CI: 0.42-0.97) and Black (63.6%; aOR 0.71, 95% CI: 0.61-0.82) patients had lower odds of receipt of radiotherapy than White patients (70.6%). In the metastatic cohort, Black patients had a lower likelihood of receiving hormone therapy (55.2% vs. 63.5%; aOR 0.61, 95% CI: 0.48-0.78), chemotherapy (78.7% vs. 78.2%; aOR 0.75, 95% CI: 0.60-0.95), surgery (28.2% vs. 35.1%; aOR 0.68, 95% CI: 0.56-0.82), or trimodal therapy (30.4% vs. 40.4%; aOR 0.63, 95% CI: 0.48-0.82) than White patients. There were no statistically significant differences in receipt of treatment between White and other racial and ethnic patients with metastatic IBC. Furthermore, we observed significantly differential rates of treatment receipts by socioeconomic factors including median household income quartile, insurance coverage, and facility type. Conclusions: In this study of a large U.S. national IBC patient cohort, racial and ethnic minority patients were less likely than White patients to have received treatment for IBC, with Black patients being the most affected. Our findings highlight racial and ethnic disparities and socioeconomic inequities in treatment receipts, suggesting the need for oncology programs to improve equitable care access and reduce these disparities in the IBC population. Citation Format: Jincong Q. Freeman, Jared H. Hara, Olasubomi J. Omoleye. Inflammatory breast cancer by metastatic status: Racial and ethnic and socioeconomic disparities in receipt of treatment [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C037.

Survival Trend in Colorectal Cancer in African American Patients Over the Last Decades

African American (AA) patients with colorectal cancer (CRC) had a lower survival rate than white Caucasians (WC) regardless of the stages of the disease. To follow the trend in survival over the years, we look at data on our CRC survival during 1963-1985 and followed the current published data on CRC survival. This is a retrospective analysis of patients with colorectal cancer seen in an inner-city teaching hospital serving mostly AA populations between 1963-1985. Data collected and analyzed were age, sex, race, insurance carriers, stage of cancer at presentation to treatment, treatment provided, and survival rate at 5 and 10 years. There were a total of 803 patients. Of those, 754 (94%) patients were African American with the mean age of the group being 68 years. Females made up 56% of the sample population and with 47% of the patients presented with rectal bleeding and bowel obstruction. Thirty-two percent of these patients were uninsured. Only 634 patients went for surgery with or without chemoradiation therapy. The TNM stages were as follows: stage 1-16%, stage 2=21%, stage 3=30%, and stage 4=32%. Of the 635 patients treated, 96 (15%) patients were lost to follow-up, and the five-year survival rate was 16%, and the 10- year survival rate was 7%. Recent published data showed the five-year survival rate from colon cancer improved slightly among AA diagnosed in early 2000 with CRC but has not reached the level of that of white patients in both male and female (AA male 22.7 and female 14.8 versus white male 15.8 and female 11.3, per 100,000 with p-value less than 0.001). These findings suggest that disparities in survival between AA patients with colorectal cancer remain high compared to WC, despite the efforts to close the differences by increased screening and improved accessibility to healthcare services. Therefore, we should develop additional strategies to close the gap

Racial Disparities in Nasopharyngeal Carcinoma Characteristics and Survival

Objective: To investigate and compare the distribution of histological subtypes, stage at presentation, and survival outcomes among Chinese American, Non-Hispanic White, and African American patients with nasopharyngeal carcinoma (NPC). Materials and methods: We identified Chinese American, Non-Hispanic White, and African American patients with NPC who were diagnosed between 2010 and 2017. Statistical analyses were conducted using the chi-square test, propensity score matching, Kaplan-Meier analysis, and multivariate Cox proportional hazards models. Results: A total of 1646 eligible patients with NPC were included. Non-Hispanic White accounted for 1049 (63.7%), African Americans for 265 (16.1%), and Chinese Americans for 332 (20.2%), and their median age at diagnosis was 59, 55, and 53 years, respectively ( P < .001). Chinese Americans most frequently harbored undifferentiated non-keratinizing squamous cell carcinoma subtype (n = 134, 40.4%) than Non-Hispanic White (n = 164, 15.6%) or African American patients (n = 44, 16.7%) ( P < .001). Histological subtype distribution was similar between Non-Hispanic White and African American patients ( P = .338). African American patients had the highest rate of stage III to IV disease (n = 206, 77.7%) compared to Non-Hispanic White (n = 704, 67.1%) and Chinese American patients (n = 210, 63.2%) ( P = .009). No significant difference in stage distribution was observed between Chinese American and Non-Hispanic White patients ( P = .494). Non-Hispanic White patients [hazard ratio (HR) 1.344, 95% confidence interval (CI) 1.007-1.479, P = .045] and African American patients (HR 2.314, 95% CI 1.405-3.813, P < .001) had significantly worse overall survival compared to Chinese American patients. However, race was not associated with NPC-specific survival in the multivariate analysis. Similar results were found after propensity score matching. Conclusions: Race influences the distribution of histological subtypes, stage at presentation, and survival outcomes in NPC.

Impact of paramagnetic rim lesions on disability and race in multiple sclerosis: mediation analysis.

Black American (BA) multiple sclerosis (MS) patients experience greater disability compared to White American (WA) patients. Here, we investigated the role of paramagnetic rim lesions (PRLs), a subset of chronic active lesions, on race-related disability in MS. We conducted a retrospective observational study comparing BA and WA MS patients. PRLs were identified through Quantitative Susceptibility Mapping (QSM) MRI. A causal mediation analysis explored the impact of PRLs on the relationship between race and disability, as measured by the Expanded Disability Status Scale (EDSS). The prevalence of PRLs in BA patients with MS was higher at 55% compared to WA patients at 39% (p = 0.022). A higher percentage of PRLs among all white matter lesions was observed with BA (8.01%) patients compared to WA (3.4%) patients (p = 0.003). In a regression analysis, controlling for significant patient-level covariates and income-level demographics, the percentage of PRLs was, on average, 4.61 points higher for BA patients than for WA patients (p = 0.003). In a separate regression analysis, accounting for covariates, BA patients exhibited significantly higher EDSS scores (p < 0.001). Further analysis demonstrated that the percentage of PRLs was a mediator in the association between BA patients and greater disability (p = 0.031). Higher proportion of PRLs in BA population accounted for 14% of the total effect of race on disability. BA patients exhibit greater disability, in part, due to their higher proportion of PRLs. This study underscores the substantial impact of chronic active lesions on disability outcomes in this specific minority MS patient population.

Abstract PR-02: Uncovering molecular differences in pancreatic ductal adenocarcinoma tissues from Black and White patients in the US

Abstract Background: Pancreatic cancer (PC) is among the leading causes of cancer-related deaths in the United States, with a 5-year survival rate of approximately 13%. Previous studies reported higher PC incidence and mortality rates among Black or African American (BAA) patients in comparison to White patients. Disadvantaged socioeconomic status (SES) and environmental exposure to chemicals are factors contributing to racial disparities in pancreatic cancer. Whether and how biological pathways play roles in disparities in pancreatic cancer is unclear. The understanding of molecular features associated racial backgrounds in pancreatic cancer will have significant impacts on both scientific inquiry on cancer biology and clinical management of pancreatic malignancy. In this study, we examined oncogene alterations and PD-L1 expression in pancreatic cancer patients of diverse racial backgrounds. Methods: We conducted our study by analyzing clinical test results of patients through a collaboration with Tempus Labs. In total, 4,249 pancreatic cancer patients’ (White: 3797 and BAA: 452) information were included in this study. DNA target panel sequencing was performed to identify genomic mutations. Genomic microsatellite instability (MSI) and tumor mutational burdens (TMB) were assessed. We also evaluated PD-L1 expression by immunohistochemistry. Results: DNA sequencing analysis revealed differential gene mutation profiles between White and BAA patients. We observed higher rates of KRAS (79.2% vs. 74.2%, q=0.14), TP53 (69.9% vs. 61.9%, q=0.014), KMT2C (6.9% vs. 2.3%, q=0.001), RNF43 (6% vs. 3.7%, q=0.14), and KMT2D (4.4% vs. 2.8%, q=0.3) mutations among BAA patients compared to White patients whereas fewer GNAS (0.2% vs 1.6%, q=0.14) mutation occur in the BAA group. Importantly, the KRAS mutant allele KRASG12R was significantly enriched in BAA compared to White patients (14.4% vs. 10.1%). Next, we compared the TMB levels and found that BAA patients showed higher average TMB levels when compared to White patients. Further, we determined the expression of PD-L1 between the two racial groups and observed BAA patients had more frequent PD-L1 overexpression than White patients (13.2% vs. 8.6%, p&amp;lt;0.05). Interestingly, the race associated difference in PD-L1 expression was even more remarkable in female groups (14.1% vs. 8%, p&amp;lt;0.05). Conclusion: We observed differences in mutation profiles of oncogenes between BAA and White patients, suggesting that such molecular-level changes may contribute to the higher incidence among BAA patients. Additionally, higher frequencies of PD-L1 upregulation in BAA patients implicate racial backgrounds influence tumor microenvironment regulation in pancreatic cancer patients. It is imperative to improve racial diversity in translational and clinical studies. Citation Format: Saurabh Mandal, Emily A Teslow, Minxuan Huang, Swathi Sridhar, Howard Crawford, Melissa C Stoppler, Albert Levin, Ling Huang. Uncovering molecular differences in pancreatic ductal adenocarcinoma tissues from Black and White patients in the US [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr PR-02.

Abstract B090: Evaluating the molecular determinants of PDAC racial health disparities

Abstract Pancreatic cancer is the 3rd leading cause of cancer-related deaths, with a 5-year survival rate of just 13%. Pancreatic ductal adenocarcinoma (PDAC), accounting for over 90% of pancreatic malignancies, has the highest incidence rate, mortality rate, and shortest survival times in non- Hispanic Black (defined here as African and/or African American ancestry) patients compared to other races. To identify molecular features that may contribute to racial health disparities in PDAC, we used quantitative mass spectrometry to determine the proteomic signatures unique to tumor racial origin in a cohort of 30 Caucasian and 12 African American patients. This analysis of the bulk tumor proteome revealed 183 proteins were differentially expressed between these groups. The protein with the highest expression in tumors from Black patients relative to Whites was Ring Finger Protein 2 (RNF2) that acts as an epigenetic transcriptional repressor in developmental processes pertaining to cellular differentiation. To determine the molecular pathways in PDAC regulated by RNF2, chromatin immunoprecipitation and sequencing (ChIP-seq) was performed on MIA-PaCa2 and a primary PDAC cell line derived from a Black patient to identify binding sites for RNF2 in PDAC cells. From the 1,142 replicated peaks identified, RNF2 peaks were localized over the transcription start site of 644 unique transcripts, including GATA6, which is an important determinant in PDAC subtype delineation with higher GATA6 expression associated with the less aggressive and more chemosensitive Classical subtype. Modulating RNF2 levels/activity by exogenous expression, short hairpin RNA (shRNA) knockdown, and small molecule inhibition confirms that GATA6 is a target of RNF2 repression in PDAC. Multi-omic (transcriptomic, proteomic, and phosphoproteomic) characterization was performed on MIA-PaCa2 cells with CRISPR-Cas9 knockout (KO) of RNF2. Differential gene expression (DE) analysis revealed changes in platinum drug resistance, EMT, and innate immune response, which are characteristic of the aggressive Inflammatory PDAC subtype we previously reported using proteomics. Total and phospho-proteomics corroborated these results identifying changes in DNA repair, inflammation response, TNFα mediated signaling, and apoptotic signaling. These results reflect the enrichment of Inflammatory subtype markers in tumors originating in Black patients. In agreement with these results, RNF2 KO shows a significant reduction in migration, as well as an increase in sensitivity to oxaliplatin. Our work identifies differences in the underlying proteome of PDAC tumors associated with tumor racial origin and describes how elevated expression of RNF2 in PDACs from Black patients contribute to inflammation and subtype delineation. This study delineates the associations between tumor racial origin, subtype specification, and response to therapy that could mitigate PDAC health disparities and be broadly applied across all PDAC patients. Citation Format: Anthony E Johansen-Sallee, Alexa M Barber, Henry C.-H. Law, Vignesh Vudatha, Jose Trevino, Nicholas T Woods. Evaluating the molecular determinants of PDAC racial health disparities [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B090.

Food Insecurity and Dietary Quality in African American Patients with Gastrointestinal Cancers: An Exploratory Study.

African American (AA) individuals experience food insecurity at twice the rate of the general population. However, few patients are screened for these measures in the oncology setting. The primary aim of this study was to evaluate associations between food insecurity and dietary quality in AA patients with gastrointestinal (GI) malignancies. The secondary aim was to evaluate differences in dietary quality and the level of food insecurity between the participants at Temple University Hospital (TUH) vs. Fox Chase Cancer Center (FCCC). A single-arm, cross-sectional study was conducted, in which 40 AA patients with GI malignancies were recruited at FCCC and TUH between February 2021 and July 2021. Participants completed the US Adult Food Security Survey Module to assess the level of food security (food secure vs. food insecure). An electronic food frequency questionnaire (VioScreenTM) was administered to obtain usual dietary intake. Diet quality was calculated using the Healthy Eating Index 2015 (HEI-2015). Dietary quality and food insecurity were summarized using standard statistical measures. Overall, 6 of the 40 participants (15%) reported food insecurity, and the mean HEI-2015 score was 64.2. No association was observed between dietary quality and food insecurity (p = 0.29). However, we noted that dietary quality was significantly lower among patients presenting at TUH (mean HEI-2015 = 57.8) compared to patients at FCCC (mean HEI-2015 = 73.5) (p < 0.01). Food insecurity scores were also significantly higher in the TUH population vs. the FCCC population (p < 0.01).

Nursing strategies to address health disparities in genomics-informed care: a scoping review.

The objective of this review was to map the available global evidence on strategies that nurses can use to facilitate genomics-informed health care to address health disparities to inform the development of a research and action agenda. The integration of genomics into health care is improving patient outcomes through better prevention, diagnostics, and treatment; however, scholars have noted concerns with widening health disparities. Nurses work across the health system and can address health disparities from a clinical, research, education, policy, and leadership perspective. To do this, a comprehensive understanding of existing genomics-informed strategies is required. Published (qualitative, quantitative, mixed methods studies, systematic and literature reviews and text and opinion papers) and unpublished (gray) literature that focuses on genomics-informed nursing strategies to address health disparities over the last 10 years were included. No limitations were placed on language. The review was conducted in accordance with the JBI methodology for scoping reviews. A search was undertaken on May 25, 2023, across 5 databases: MEDLINE (Ovid), Embase, Cochrane Library (Ovid), APA PsycINFO (EBSCOhost), and CINAHL (EBSCOhost). Gray literature was searched through websites, including the International Society of Nurses in Genetics and the Global Genomics Nursing Alliance. Abstracts, titles, and full texts were screened by 2 or more independent reviewers. Data were extracted using a data extraction tool. The coded data were analyzed by 2 or more independent reviewers using conventional content analysis and the summarized results are presented using descriptive statistics and evidence tables. In total, we screened 818 records and 31 were included in the review. The majority of papers were published in either 2019 (n=5, 16%), 2020 (n=5, 16%), or 2021 (n=5, 16%). Most papers came from the United States (n=25, 81%) followed by the Netherlands (n=3, 10%), United Kingdom (n=1, 3%), Tanzania (n=1, 3%) and written from a global perspective (n=1, 3%). Nearly half the papers discussed cancer-related conditions (n=14, 45%) and most of the others did not specify a disease or condition (n=12, 30%). In terms of population, nurse clinicians were mentioned the most frequently (n=16, 52%) followed by nurse researchers, scholars, or scientists (n=8, 26%). The patient population varied, with African American patients or communities (n=7, 23%) and racial or ethnic minorities (n=6, 19%) discussed most frequently. The majority of equity issues focused on inequitable access to genetic and genomics health services amongst ethnic and racial groups (n=14, 45%), individuals with lower educational attainment or health literacy (n=6, 19%), individuals with lower socioeconomic status (n=3, 10%), migrants (n=3, 10%), individuals with lack of insurance coverage (n=2, 6%), individuals living in rural or remote areas (n=1, 3%) individuals of older age (n=1, 3%). Root causes contributing to health disparity issues varied at the patient, provider, and system levels. Strategies were grouped into 2 categories: those to prepare the nursing workforce and those nurses can implement in practice. We further categorized the strategies by domains of practice, including clinical practice, education, research, policy advocacy, and leadership. Papers that mentioned strategies focused on preparing the nursing workforce were largely related to the education domain (n=16, 52%), while papers that mentioned strategies that nurses can implement were mostly related to clinical practice (n=19, 61%). Nurses in all domains of practice can draw on the identified strategies to address health disparities related to genomics in health care. We found a notable lack of intervention and evaluation studies exploring the impact on health and equity outcomes. Additional research informed by implementation science and that measures health outcomes is needed to identify best practices. A French-language version of the abstract of this review is available as Supplemental Digital Content [ http://links.lww.com/SRX/A65 ].

The Role of Mindfulness Meditation for the Management of Hypertension in African American Adults in the US - A Scoping Review

The prevalence of hypertension is more significant among African American adults than among individuals in other ethnic groups. Mindfulness, an ancient technique used for thousands of years, is acknowledged as a valuable tool for improving health in various ways. However, despite its traditional wisdom, there remains a gap in understanding the standalone effects of MM on hypertension control. This review aimed to discuss the role of mindfulness in managing hypertension within the African American adult population in the U. S. PubMed and Scopus were the chosen databases for this exploration. The inclusion criteria comprised papers presenting primary data studies conducted on hypertensive African American patients, specifically reporting on the independent association between mindfulness and hypertension. The exclusion criteria included nonprimary data studies and studies not primarily focused on hypertension or mindfulness. Following our search strategy, we identified a total of 32 studies. Our review incorporated five randomized controlled trials, excluding manuscripts lacking primary data, nonrandomized clinical trials, and duplicates. Within these studies, mindfulness was administered to participants through either prerecorded MP3s or guidance from trained personnel. The observed reduction in blood pressure ranged from 7.2 mmHg to 21.92 mmHg for systolic blood pressure and from null to 7.2 mmHg for diastolic blood pressure across the five studies. Notably, one study showed no change in diastolic blood pressure. The outcomes of this review can contribute to clinical practice by offering an evidence-based approach for effective hypertension control through MM. The key findings highlight the positive impact of mindfulness on blood pressure regulation and emphasize using prerecorded MP3s or trained guidance as effective mindfulness delivery methods. These insights underscore the potential significance of MM as a cost-efficient and side-effect-free approach to hypertension management.

Mitochondrial reprogramming by activating OXPHOS via glutamine metabolism in African American patients with bladder cancer.

Bladder cancer (BLCA) mortality is higher in African American (AA) patients compared with European American (EA) patients, but the molecular mechanism underlying race-specific differences are unknown. To address this gap, we conducted comprehensive RNA-Seq, proteomics, and metabolomics analysis of BLCA tumors from AA and EA. Our findings reveal a distinct metabolic phenotype in AA BLCA characterized by elevated mitochondrial oxidative phosphorylation (OXPHOS), particularly through the activation of complex I. The results provide insight into the complex I activation-driven higher OXPHOS activity resulting in glutamine-mediated metabolic rewiring and increased disease progression, which was also confirmed by [U]13C-glutamine tracing. Mechanistic studies further demonstrate that knockdown of NDUFB8, one of the components of complex I in AA BLCA cells, resulted in reduced basal respiration, ATP production, GLS1 expression, and proliferation. Moreover, preclinical studies demonstrate the therapeutic potential of targeting complex I, as evidenced by decreased tumor growth in NDUFB8-depleted AA BLCA tumors. Additionally, genetic and pharmacological inhibition of GLS1 attenuated mitochondrial respiration rates and tumor growth potential in AA BLCA. Taken together, these findings provide insight into BLCA disparity for targeting GLS1-Complex I for future therapy.

Baseline sLAG-3 levels in Caucasian and African-American breast cancer patients.

Worse survival persists for African-Americans (AA) with breast cancer compared to other race/ethnic groups despite recent improvements for all. Unstudied in outcomes disparities to date is soluble LAG-3 (sLAG-3), cleaved from the LAG-3 immune checkpoint receptor which is a proposed target for deactivation in emerging immunotherapies due to its prominent immunosuppressive function in the tumoral microenvironment. A prior study has found that lower sLAG-3 baseline level was associated with poor outcomes. In a cross-sectional study of 95 patients with primary breast cancer (n = 58 Caucasian, n = 37 AA), we measured sLAG-3 (ELISA pg/ml) in pre-treatment blood samples using the non-parametric Mann-Whitney u-Test for independent samples, and, calculated Pearson r correlation coefficients of sLAG-3 with circulating cytokines by race. Mean sLAG-3 level was lower in AA compared to Caucasian patients (1377.6 vs 3690.3, P = .002), and in patients with triple-negative breast cancer (TNBC) compared to those with non-TNBC malignancies (P = .02). When patients with TNBC tumors were excluded from analyses, the difference in sLAG-3 level between AA (n = 21) and Caucasian patients (n = 40) substantially remained (1937.4 vs 4182.4, P = .06). Among Caucasian patients, sLAG-3 was correlated with IL-6, IL-8 and IL-10 (r = .69, P < .001; r = .70, P < .001; and, r = .46, P = .01; respectively). For AA patients, sLAG-3 was correlated only with IL-6 (r = .37, P = .03). We present the first report that African-American breast cancer patients might have comparatively low pre-treatment sLAG-3 levels, independent of TNBC status, along with reduced co-expression with circulating cytokines. The mechanistic and prognostic role of cleaved LAG-3, particularly in disparate outcomes, remains to be elucidated.

Vitamin K3 derivative inhibits androgen receptor signaling in targeting aggressive prostate cancer cells.

Prostate cancer (PCa) is the second critical cause of cancer-related deaths, with African Americans dying at higher rates in the U.S. The main reasons for the higher mortality rate are ethnic differences and lack of understanding of prostate cancer biology and affordable treatments, as well as the financial burden of African American men to obtain the most effective and safe treatments. The effect of micronutrients, including Vitamin K, on various cancer cell lines has been widely studied, but the potential anticancer effect of VK3-OCH3, an analog of vitamin K3 (Menadione), on African American prostate cancer has not been evaluated. In this study, we compared the anticancer effect of VK3-OCH3 on targeting African American derived PCa cell lines namely RC77-T and MDA-PCa-2b. Our results show that VK3-OCH3 significantly inhibits the proliferation of both RC77-T and MDA-PCa-2b African American PCa cells and promotes apoptosis, and the underlying mechanism of cell death appears to be similar in both the cell lines. Notably, VK3-OCH3 inhibits colony-forming ability and induces apoptosis by blocking the cell cycle at G0 in African American PCa cells. VK3-OCH3 also acts as an anti-metastatic agent by inhibiting the migration ability of the metastatic properties of African American PCa cells. The cell death of African American PCa cells mediated by VK3-OCH3 is associated with the production of free radicals, such as intracellular and mitochondrial reactive oxygen species (ROS). Interestingly, antioxidants such as N-Acetylcysteine (NAC) and Glutathione (GSH) effectively negated the oxidative stress induced by VK3-OCH3 on PCa cell lines derived from African American patients. Of note, VK3-OCH3 reduces androgen receptor and prostate-specific antigen expression in these PCa cells. Furthermore, molecular dynamic studies reiterated that VK3-OCH3 strongly binds to the androgen receptor, suggesting that the androgen receptor is the potential molecular target of VK3-OCH3. In addition, Western blot analysis showed that VK3-OCH3 reduces the expression of androgen receptor, TRX2, and anti-apoptotic signaling molecules such as Bcl-2 and TCTP in the MDA-PCa-2b metastatic PCa cellular model. In conclusion, our results suggested that VK3-OCH3 is a promising anticancer agent that could potentially reduce the mortality rates of African American PCa patients, warranting further preclinical and translational studies.

Seeing in Color: Inclusion and Characterization of Hereditary Eye Disease in African Americans.

Hereditary eye diseases (HEDs) are individually rare but affect millions globally. The era of molecular genetics has ushered major advances in the study of these disorders; however, the inclusivity and population diversity of this research is unknown. Questions on the accuracy and applicability of these findings in diverse populations, especially African American patients, came up consistently during counselling sessions. This also raised the possibility of missed opportunities for broader understanding of these rare diseases. We conducted a literature review to measure the representation of African Americans in genomic research surrounding nine HEDs. A detailed literature search using a predetermined set of search terms for each of nine HED categories was performed across PubMed, Embase, Web of Science, and Scopus focusing on studies published between Jan 1990 and July 2021. Predetermined inclusion criteria were applied to filter the sources. We identified 46 studies clearly reporting HED characterization in African Americans. Analysis of these inclusive studies revealed unique findings demonstrating the known usefulness of including diverse cohorts in genomics research. HED characterization in diverse participants, specifically African Americans, is identified as a knowledge gap area. Genomic research is more applicable to patients when conducted in populations that share their ancestral background. Greater inclusion of African Americans in ophthalmic genetics research is a scientific imperative and a needed step in the pursuit of the best possible patient care for populations of all ancestries. This work reveals gaps in genomic research in African Americans with HEDs.

Heart Failure Mortality in Chronic Kidney Disease: The Fatal Crossover

Real-world mortality data regarding heart failure in patients with comorbid chronic kidney disease remains limited, especially following the advent of advanced heart failure therapies. Using the CDC WONDER database, we included patients ≥ 25 years old who died primarily from heart failure (2011-2020) with comorbid chronic kidney disease. We calculated age-adjusted mortality rates (AAMR) per 100,000 individuals. We determined the trends over time by estimating the annual percent change (APC) using the Joinpoint regression program. There were 82,454 heart failure deaths with comorbid chronic kidney disease. The AAMR increased from 2.34 (95% CI, 2.28- 2.41) in 2011 to 4.79 (95% CI, 4.71- 4.88) in 2020. During the study period, Heart failure deaths among patients with comorbid chronic kidney disease increased by 149.0% compared to 59.9% in those without. Men had higher AAMR than women (3.92 [95% CI, 3.88- 3.96] vs. 2.96 [95% CI, 2.93- 2.99]). African American patients had the highest AAMR (5.85 [95% CI, 5.75- 5.96]). The Midwest region had the highest AAMR (3.83 [95% CI, 3.78- 3.89]). The AAMR was higher in the rural areas than in the urban regions (3.77 [95% CI, 3.71- 3.83] vs. 3.23 [95% CI, 3.20- 3.25]). Most patients died in hospices or nursing homes (29,000, 35.2%). Our study showed a significant increase in heart failure AAMR in patients with comorbid chronic kidney disease in recent eras. Further effort is needed to optimize cardioprotective agents for this population and to address demographic discrepancies at the policy level.

Association between race, post operative outcomes and costs for inpatient and outpatient total joint arthroplasty

Background: While factors like readmissions and costs have been compared between care settings for total joint arthroplasty, little research has analyzed readmission and cost differentials stratified by patient characteristics within each care setting. This study will unveil such differences with regard to race and co-morbidity status. Methods: Retrospective binary-logistic-regression and OLS regression were employed on de-identified inpatient and outpatient orthopedic surgical data gathered from an academic medical center from 2016-2020. Data elements included surgical setting, covariates (age, gender, race, obesity, smoking status), Elixhauser comorbidity indices, surgical times, and cost. Results: African American (AA) inpatients had significantly greater odds of return to hospital (7 day, 30 day, 90 day) when compared to Caucasian inpatients (P&lt;0.01-0.05). AA inpatients less than 65 yr old had significantly increased odds of returning to the hospital and getting readmitted (7 day, 30 day) when compared to AA inpatients older than 65 and all Caucasian inpatients (P&lt;0.05). Asian inpatients had significantly greater odds of 90 day return (P&lt;0.05). AA outpatients had significantly greater odds of 30 day return when compared to Caucasian outpatients. Age and time spent in the OR directly correlated with increased costs (P&lt;0.05, P&lt;0.01). Increased comorbidities correlated with increased costs only for inpatients (P&lt;0.05). Conclusion: All AA patients, but specifically those less than 65 yr of age, experience increased readmissions and returns to hospital following the same procedure when compared to their Caucasian counterparts. Medicaid patients experience greater costs, Medicare-Managed patients experienced decreased costs. Co-morbidites were directly related to costs in the inpatient setting.

Abstract 34: Elevation of Plasma anti-Endothelin A Receptor Autoantibodies in Lupus Subjects Correlates with Plasma Vascular Adhesion Molecule-1 Independent of Blood Pressure

Systemic Lupus Erythematosus (SLE) is an autoimmune disease that is characterized by deposition of autoantibodies and their immune complexes, resulting in inflammation, and end-organ damage to the kidney and vasculature. SLE disproportionally affects women to men (9:1 ratio), with a high prevalence in African American women and patients often have cardiovascular complications including hypertension (HTN). The activation of the endothelin (ET) system has been implicated in numerous pathological disease states including HTN, SLE, and diabetes. Recently, dual ET receptor antagonism was approved for treatment of patients with uncontrolled hypertension. Studies have demonstrated the presence of biologically active endothelin A receptor autoantibodies (ETAR-AAs) in systemic sclerosis and cystic fibrosis patients. Few studies have investigated the role of the synergistic interplay of SLE and HTN on ETAR-AAs. We hypothesized that women with SLE and HTN would have elevated plasma ETAR-AAs compared to control or SLE only subjects. To investigate this, we recruited non-SLE non-HTN controls (n=10), non-SLE HTN (n=10), SLE non-HTN (n=8), and SLE-HTN (n=10) female human subjects and analyzed clinical characteristics, plasma ETAR-AAs, soluble vascular adhesion molecule-1 (sVCAM-1) and soluble intracellular adhesion molecule-1 (sICAM-1). Plasma ETAR-AAs did not significantly correlate with either age (r=-0.1375; p=0.4453) or body mass index (r=-0.3149; p=0.0743). When subjects were categorized by SLE or HTN diagnosis, we found that subjects with SLE had a profound increase in ETAR-AAs compared to non-SLE controls (p&lt;0.0001) while the levels were similar between HTN and non-HTN controls (p=0.7626). Next, we stratified subjects by blood pressure status and found a significant elevation in plasma ETAR-AAs in SLE non-HTN over non-SLE HTN subjects (p=0.0121), while SLE-HTN subjects had significant elevations in ETAR-AAs compared to both non-SLE non-HTN (p=0.0183) and non-SLE HTN (p=0.0014) subjects. We correlated plasma levels of ETAR-AA with sVCAM-1 and sICAM-1 and found that plasma ETAR-AAs were positively associated with plasma sVCAM-1 (r=0.4288; p=0.0114) and sICAM-1 (r=0.3812; p=0.0286). These data indicate that irrespective of blood pressure status, elevated plasma ETAR-AAs are associated with markers of vascular dysfunction in SLE subjects. Further investigation of cell-specific ETAR-AA and ETAR signaling should be performed in murine models and human subjects with SLE.