African American Breast Cancer Research Articles

Beyond Triple-Negative: High Prevalence of Quadruple-Negative Breast Cancer in African Americans.

Quadruple-negative breast cancer (QNBC) is a triple-negative breast cancer (TNBC) subtype that lacks expression of the androgen (AR) receptor. Few studies have focused on this highly aggressive breast cancer, portending worse survival rates. We aimed to determine the following: (1) QNBC's molecular and clinical characteristics and compare them with other subtypes and (2) QNBC's association with clinicopathological factors and prognostic markers. We performed immunohistochemical evaluations of ARs on tissue tumor microarrays from FFPE tumor blocks of invasive ductal breast carcinomas in 202 African American women. Univariate analysis was performed using the chi-square test, with survival rates calculated using Kaplan-Meier curves. Overall, 75.8% of TNBCs were AR-negative. Compared to the luminal subtypes, TNBC and QNBC tumors were likely to be a higher grade (p < 0.001); HER2+/AR- and QNBCs were also larger than the other subtypes (p < 0.001). They also expressed increasing mean levels of proteins involved in invasion, such as CD44, fascin, and vimentin, as well as decreasing the expression of proteins involved in mammary differentiation, such as GATA3 and mammaglobin. We found no association between QNBC and stage, recurrence-free survival, or overall survival rates. The high prevalence of TNBC AR-negativity in these women could explain observed worse outcomes, supporting the existence of the unique QNBC subtype.

Real-world assessment of treatment-related symptoms and associated burden among African American and Caucasian patients receiving chemotherapy in the US.

11102 Background: In the treatment of breast cancer, research has identified racial differences in the ability to receive the full dose of prescribed chemotherapy which may be due in part to cancer-treatment symptom burden. In clinical trials, evaluation by race is challenging due to enrollment disparities, with African Americans (AA) accounting for 7% of trial participants, but comprising 12% of the US total population. The objective of this study is to evaluate treatment-related symptoms and treatment burden among patients treated with chemotherapy through an electronic remote symptom monitoring system, and explore whether there were any racial differences. Methods: Patients (pts) diagnosed with multiple myeloma, breast, ovarian, or lung cancer in academic cancer practices were enrolled in Carevive’s Patient Reported Outcomes Mobile Platform (Carevive PROmpt) between September 2020 and June 2023. A total of 1000 pts received chemotherapy alone or in combination. PRO-CTCAE-derived weekly surveys assessed severity, frequency, and interference for 16 symptoms: anxiety, constipation, cough, decreased appetite, diarrhea, fatigue, general pain, insomnia, mouth/throat sores, muscle pain, nausea, numbness and tingling, rash, sadness, shortness of breath, and vomiting. The GP5 assessed weekly overall burden from treatment. Results: The mean age of pts was 60.9 (SD=12.8) years, with 75% female, and 20% AA. At the time of enrollment, fatigue was reported by roughly 48% of AA and Caucasian (C) pts. Muscle pain was noted in 38% of AA pts, followed by general pain (33%), and anxiety (30%), with constipation, decreased appetite, insomnia, nausea, and numbness/tingling occurring in over 20% of pts. A different pattern was observed in C pts, with anxiety occurring in 38%, followed by cough, decreased appetite, general pain, insomnia, muscle pain, nausea, and numbness/tingling present in 20% of pts. The proportion of pts at least “somewhat” bothered by the side effects of treatment were similar (44% AA, 45% C). Conclusions: This study enabled evaluation of symptom burden in cancer in a population closer in racial representation to the real world than in clinical trials; with AA representation being three-fold that seen in clinical trials. Consistent with a qualitative study of AA breast cancer pts, fatigue was identified as the most frequent symptom among those treated with chemotherapy either alone or in combination in the real world. Racial differences in the proportions of pts reporting pain (muscle or general) and anxiety suggest that treating physicians should consider these symptoms to ensure they do not interfere with patients’ ability to receive full chemotherapy courses. Additionally, the levels of anxiety reported in patients highlights the importance of considering concomitant psycho-oncology treatments in cancer therapy.

Abstract 1014: Disparities of triple negative breast cancer in Mississippi

Abstract Background: Triple-negative breast cancer (TNBC) accounts for about 10-15% of all breast cancers nationwide with disparities of incidence and outcomes among races, geographic locations, and other factors. This study is aimed to analyze the differences in the rate of TNBC, patient conditions at time of diagnosis, and death from TNBC among women in Mississippi. Methods: A retrospective study was conducted to serially review breast cancer cases diagnosed in the University of Mississippi Medical Center during May 2016 to May 2023. The entire breast cancer population was then stratified by race. The rate of TNBC, age and BMI at time of diagnosis, the rate of expiration were compared between African American (AA) and Caucasian American (CA) women with breast cancer. Two-tailed Student’s T-test was used to calculate the difference in mean values, and Chi-Square Test was used to compare the difference in rates or percentages. The significant p value was set at p&amp;lt;0.05. Results: In total 291 women with breast cancer, AA patients were 195 (67.01%), CA patients were 88 (30.24%), and other were 8 (2.75%). The mean age of all patients was 58.3 years-old (ranged 24-97). The mean BMI was 31.19. The patients with TNBC were 109 (37.46%) in entire studied population. A total of 32 (1.6%) patients, including 14 TNBC and 18 non-TNBC were expired with an average age of 61.84 and an average survival time of 20 months from diagnosis to expiration. As compared to CA patient population, AA breast cancer patients had onset at younger age (58.08±0.88 vs. 59.18±1.36), had a higher BMI (31.79±0.62 vs. 28.25±1.05, p=0.017), higher percentage of TNBC (41.54% vs. 30.68%, p=0.082 and OR=1.605), and higher rate of expiration (11.28% vs, 9.1%). Also, as compared to CA expired patients with breast cancer, AA expired patients had higher BMI (29.57 vs. 28.61), shorter survival time (17.5 months vs. 19.4 months), and died at younger age (61.84-year old vs. 66.38-year old) with a higher proportion of TNBC subtype (54.6% vs 12.5%, p=0.045, OR=9.6). Conclusions: Breast cancer is greatly disparate racially between AA and CA and geographically between Mississippi and US national average. The disparities are manifested in the proportion of TNBC subtype, age at onset of breast cancer, BMI at time of diagnosis, and death rate. Citation Format: Navdeep Kaur, Javaria A. Khan, Jinghe Mao, Diva Melvin, Muhammad M. Hassan, Xinchun Zho. Disparities of triple negative breast cancer in Mississippi [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1014.

Abstract 5945: Exploring the antiproliferative potential of KHS101 on triple negative breast cancer cell lines

Abstract Breast cancer is the second leading cause of cancer deaths in the world. Among its subtypes, triple-negative breast cancer (TNBC) is highly aggressive, particularly affecting African American (AA) women, with limited treatment choices. HSP60 protein promotes tumorigenesis and is being studied as a possible biomarker to treat cancers such as TNBC. The small molecule KHS101 specifically binds and inhibits the mitochondrial chaperone HSP60. In this study, we hypothesized that KHS101 would inhibit the proliferation of TNBC cells and therefore may have a therapeutic potential.We studied the antiproliferative effects of KHS101 on TNBC cell lines (MDA-MB-231, MDA-MB-468, HCC1806) through MTT cell proliferation and colony forming assays at varying doses and time points (24, 48, 72, and 96 hours). We performed cell cycle analysis to understand the cell cycle response and apoptotic events in treated or control cells. Additionally, the gene expression and frequently altered pathways resulting from KHS101 treatment were analyzed by RNA sequencing of cells treated with vehicle (DMSO) or with various concentrations of KHS101(1, 2.5, 5, and 7.5 uM) for 72 hours. We analyzed the data using GraphPad Prism and Microsoft Excel, with statistical significance set at p ≤ 0.05. TNBC cell lines exhibited significant dose-response and antiproliferative effects with increased KHS101 doses and treatment durations. Notably, AA breast cancer cells (MDA-MB-468) displayed heightened cytotoxicity and reduced proliferation compared to Caucasian American (CA) breast cancer cells (MDA-MB-231 and HCC1806). Cell cycle analysis revealed G2/M phase arrest, consistent with RNA sequencing data showing downregulation of the activation of ATM/ATR response in KHS101-treated cell lines compared to the controls. Gene set enrichment analysis indicated downregulation of the cell cycle control genes in MDA-MB-231 cells after 72 hours of KHS101 treatment (7.5 µM). Reactome pathway analysis in KHS101-treated MDA-MB-231 cells showed upregulation of IFN-gamma signaling and degradation of extracellular matrix. Similarly, Kegg pathway analysis showed upregulation in cell adhesion molecules, cytokine-cytokine receptor interaction, antigen processing and presentation, and Natural Killer cell-mediated cytotoxicity in KHS101-treated cancer cells compared to the controls. KHS101 demonstrates varying cytotoxic effects on TNBC cells, with potential implications for antitumor immune responses. Our findings highlight the distinct susceptibility of AA breast cancer cells and suggest KHS101 as a promising avenue for further research in understanding its mechanism of action and validating therapeutic potential in TNBC. Citation Format: Reshma Gurung, Alehegne W. Yirsaw, Muhammad G. Khodary, Temesgen Samuel, Maninder Sandey, Clayton C. Yates, Deepa Bedi. Exploring the antiproliferative potential of KHS101 on triple negative breast cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5945.

THU486 Identification Of Metabolic And Molecular Mechanisms Driving Estrogen Receptor Positive Breast Cancer Disparities Using A Machine-Learning Pipeline

Abstract Disclosure: A. Santaliz Casiano: None. D. Mehta: None. H. Patel: None. G. Rauscher: None. J. Kim: None. J.M. Frasor: None. K. Hoskins: None. Background: African American (AA) women in the United States have a 40% higher breast cancer mortality rate compared with Non-Hispanic White (NHW) women. The survival disparity is particularly striking among ER+ breast cancer cases. The purpose of this study is to examine whether there are racial differences in metabolic pathways typically activated in patients with ER+ positive breast cancer. Methods: We collected pretreatment plasma from AA and NHW ER+ breast cancer cases and cancer-free controls to conduct an untargeted metabolomics analysis using gas chromatography mass spectrometry (GC-MS) to identify metabolites that may be altered in the different racial groups. Statistical methods combined with multiple feature selection and prediction models were employed to identify race-specific altered metabolic signatures. This was followed by the identification of altered metabolic pathways with a focus in AA patients with breast cancer. The clinical relevance of the identified pathways was further examined in PanCancer Atlas breast cancer data set from TCGA. Results: We identified differential metabolic signatures between NHW and AA patients. In AA patients, we observed changes in metabolites associated with amino acid metabolism, while fatty acid metabolism was significantly enriched in NHW patients. By mapping these metabolites to potential epigenetic regulatory mechanisms, this study identified significant association with regulators of metabolism such as methionine adenosyltransferase 1A (MAT1A), DNA Methyltransferases and Histone methyltransferases for AA individuals, and Fatty acid Synthase (FASN) and Monoacylglycerol lipase (MGL) for NHW individuals. Specific gene NELFE with histone methyltransferase activity was associated with poor survival exclusively for AA individuals. Conclusion: We employed a comprehensive and novel approach that integrates multiple machine learning methods and statistical methods, coupled with human functional pathway analyses. The metabolic profile of plasma samples identified may help elucidate underlying molecular drivers of disproportionately aggressive ER+ tumor biology in AA women, and may ultimately lead to identification of novel therapeutic targets. To our knowledge, this is a novel finding that describes a link between metabolic alterations and epigenetic regulation in AA breast cancer, and underscores the need for detailed investigations into the biological underpinnings of breast cancer health disparities. Presentation: Thursday, June 15, 2023

Identification of metabolic pathways contributing to ER+ breast cancer disparities using a machine-learning pipeline

African American (AA) women in the United States have a 40% higher breast cancer mortality rate than Non-Hispanic White (NHW) women. The survival disparity is particularly striking among (estrogen receptor positive) ER+ breast cancer cases. The purpose of this study is to examine whether there are racial differences in metabolic pathways typically activated in patients with ER+ breast cancer. We collected pretreatment plasma from AA and NHW ER+ breast cancer cases (AA n = 48, NHW n = 54) and cancer-free controls (AA n = 100, NHW n = 48) to conduct an untargeted metabolomics analysis using gas chromatography mass spectrometry (GC–MS) to identify metabolites that may be altered in the different racial groups. Unpaired t-test combined with multiple feature selection and prediction models were employed to identify race-specific altered metabolic signatures. This was followed by the identification of altered metabolic pathways with a focus in AA patients with breast cancer. The clinical relevance of the identified pathways was further examined in PanCancer Atlas breast cancer data set from The Cancer Genome Atlas Program (TCGA). We identified differential metabolic signatures between NHW and AA patients. In AA patients, we observed decreased circulating levels of amino acids compared to healthy controls, while fatty acids were significantly higher in NHW patients. By mapping these metabolites to potential epigenetic regulatory mechanisms, this study identified significant associations with regulators of metabolism such as methionine adenosyltransferase 1A (MAT1A), DNA Methyltransferases and Histone methyltransferases for AA individuals, and Fatty acid Synthase (FASN) and Monoacylglycerol lipase (MGL) for NHW individuals. Specific gene Negative Elongation Factor Complex E (NELFE) with histone methyltransferase activity, was associated with poor survival exclusively for AA individuals. We employed a comprehensive and novel approach that integrates multiple machine learning and statistical methods, coupled with human functional pathway analyses. The metabolic profile of plasma samples identified may help elucidate underlying molecular drivers of disproportionately aggressive ER+ tumor biology in AA women. It may ultimately lead to the identification of novel therapeutic targets. To our knowledge, this is a novel finding that describes a link between metabolic alterations and epigenetic regulation in AA breast cancer and underscores the need for detailed investigations into the biological underpinnings of breast cancer health disparities.

Examining experiences of African American patients with breast cancer in a multidisciplinary survivorship clinic.

e18621 Background: Breast cancer (BC) is the most commonly diagnosed cancer in women. More effective therapies have led to improved survival rates, yet, the survival benefit is not shared across all patient (pt) populations, with worse breast cancer outcomes among African American (AA) pts. The American College of Surgeons has mandated that accredited sites have a cancer survivorship program. At the Cardinal Bernardin Cancer Center (CBCC), there remain disparities in access and utilization of the survivorship clinic, especially by AA BC survivors. Of the 385 new BC analytic cases CBCC treated between March 1, 2020, and March 1, 2021, 72 of these were AA pts. Unfortunately, less than 10% of AA BC pts who received curative intent therapy attended the CBCC Survivorship Clinic. As part of the "Bringing Quality Care Training to Komen’s African American Health Equity Initiative" in collaboration with ASCO, CBCC remodeled its survivorship program into a multidisciplinary clinic staffed by medical oncology, oncologic psychology, genetic counselor, nutritionist and social worker in order to provide comprehensive care to pts following diagnosis and treatment. Methods: The CBCC team performed the following: construction of a process map outlining the current pathway for referring pts to the survivorship clinic; creation of a fishbone cause and effect diagram highlighting factors contributing to poor utilization of the clinic; implementation of faculty surveys to assess reasons for lack of referral to survivorship clinic; development of pt experience surveys; and identification of countermeasures. Tumor registry identified BC pts by stage, race, and ethnicity. Results: Review of the CBCC BC registry showed a low attrition rate among 72 AA pts, with only 1.4% (n = 1) of AA pts diagnosed at CBCC treated elsewhere. AA pts made up a disproportionate number of stage IV diagnoses comprising 40% (n = 8). Surveys demonstrated the following reasons for poor utilization of the survivorship clinic by faculty in order of descending importance: providers felt they were providing survivorship care to their pts; pts declined referral due to appointment fatigue; lack of understanding to make referral; no outcomes data to support survivorship clinics; pt misunderstanding the purpose; fear of losing the pt; pt financial burden. Pt surveys (n = 20) showed high pt satisfaction, with an average rating of 4.8 out of 5 for overall care. Conclusions: Lack of utilization of the cancer survivorship clinic among AA BC pts leads to inefficient application of resources, decreased survivorship care, reduced pt experience, and diminished opportunity for survivorship education and increased health literacy. Paths for the future include increased faculty and pt education, faculty engagement, designated scheduler for survivorship clinic, and increased promotional and marketing work.

Addressing the clinical trial selection process to improve representation by African American patients with breast cancer in cancer clinical trials.

e18620 Background: Breast cancer (BC) is the most commonly diagnosed cancer in women. Despite overall improvements in BC outcomes, African American (AA) women are 41% more likely to die from BC. Causation of the disparity gap is multifactorial including less access to quality treatment, such as clinical trials (CTs). AA patients (pts) account for 12% of new BC cases in the United States, but constituted only 3% of the participants in the BC CTs that led to U.S. Food and Drug Administration approvals from 2008-2018. Lack of diverse participation on CTs does not allow the broad applicability of the results. As part of the "Bringing Quality Care Training to Komen’s African American Health Equity Initiative" in collaboration with ASCO, the Cardinal Bernardin Cancer Center (CBCC) examined the process for CT selection in order to increase opportunities for AA BC pts to participate in CTs. Methods: The CBCC team, comprised of social worker, breast program coordinator, medical oncology, and director of outreach developed process maps for CT selection, analyzed the BC CT content, and identified gaps relative to the pt population for industry and cooperative group CTs. The team surveyed faculty on reasons for not enrolling pts in CTs and assessed the demographics of the CT participants. Tumor registry identified BC pts by sex, race, ethnicity, phenotype and stage. Results: The CBCC treated 283 new BC cases in 2021. AA patients made up 15% (n = 22), 18% (n = 9), and 23% (n = 5) of stages I, II/III, and IV respectively. Fifteen percent were triple negative BC. Review of Velos demonstrated that CBCC enrolled 13 BC pts onto 2 BC drug CTs in 2021. We projected the need for CT selection based upon stage at diagnoses and tumor biology. We identified the following gaps in the breast oncology CT portfolio: non-competing neo-adjuvant CTs; adjuvant endocrine, HER2-targeted and triple negative CTs; and metastatic endocrine and HER2-targeted CTs. Faculty surveys demonstrated perceptions for not enrolling pts in CTs including low health literacy amongst pts, pt ineligibility, lack of institutional support, pt mistrust, language barriers, lack of time, and pt co-morbidities. Overall, pts were more likely to participate in cancer CTs if they were non-Hispanic white, privately insured, married and 60-69 years old. Conclusions: CTs lead to treatment advancements at faster rates with concurrent mortality reductions in the cancer population. It is necessary to increase representation in CT to address health equity. This requires intentional detail to the CT development and implementation process. Our study identified a number of factors, including structural, clinical, and attitudinal barriers on the part of the physician that impair enrollment. Institutions need to construct CT portfolios to ensure that it reflects the pt population that it serves. Further studies need to include the pt experience in CT participation.

Immune Profile of Exosomes in African American Breast Cancer Patients Is Mediated by Kaiso/THBS1/CD47 Signaling

African American (AA) women with breast cancer are more likely to have higher inflammation and a stronger overall immune response, which correlate with poorer outcomes. In this report, we applied the nanostring immune panel to identify differences in inflammatory and immune gene expression by race. We observed a higher expression of multiple cytokines in AA patients compared to EA patients, with high expression of CD47, TGFB1, and NFKB1 associated with the transcriptional repressor Kaiso. To investigate the mechanism associated with this expression pattern, we observed that Kaiso depletion results in decreased expression of CD47, and its ligand SIRPA. Furthermore, Kaiso appears to directly bind to the methylated sequences of the THBS1 promotor and repress gene expression. Similarly, Kaiso depletion attenuated tumor formation in athymic nude mice, and these Kaiso-depleted xenograft tissues showed significantly higher phagocytosis and increased infiltration of M1 macrophages. In vitro validation using MCF7 and THP1 macrophages treated with Kaiso-depleted exosomes showed a reduced expression of immune-related markers (CD47 and SIRPA) and macrophage polarization towards the M1 phenotype compared to MCF7 cells treated with exosomes isolated from high-Kaiso cells. Lastly, analysis of TCGA breast cancer patient data demonstrates that this gene signature is most prominent in the basal-like subtype, which is more frequently observed in AA breast cancer patients.

Abstract 1937: Racial differences of epigenome in normal breast tissue reveal biological pathways implicated in racial disparities in breast cancer

Abstract Racial disparity in breast cancer is well recognized. Compared to European American (EA) women, African American (AA) women are more often diagnosed with breast cancer at younger ages, have a more advanced or aggressive disease, and have poorer outcomes. Increasing evidence suggests that biological differences between EA and AA women, particularly differences in epigenetic changes of DNA methylation (DNAm), may contribute to the observed cancer disparity. We hypothesize that racial differences in DNAm in normal breast tissue may reflect distinct genomic susceptibility to breast cancer in different racial groups. Therefore, we investigated epigenome-wide differences of DNAm in normal breast tissue between 178 EA and 272 AA women using the Illumina TruSeq Methyl Capture EPIC library and NGS technology. We identified 17,340 differentially methylated CpG loci (DMLs) between EA and AA women, of which 7,744 were hypermethylated in AA women and 9,596 were hypermethylated in EA women. Pathway analyses of genes annotated to these racial DMLs suggested enrichment of biological processes including cell movement, cell motility, and cell migration, features that are likely linked to the aggressiveness and metastatic potentials of tumor cells. We further examined racial differences in DNAm of breast cancer-related candidate genes and GWAS-identified breast cancer risk loci. Approximately 30% of candidate genes were found to have racial differences in DNAm at more than three CpG sites and these candidate genes were enriched for pathways related to response to stimulus and anatomic structure development. Most interestingly, racial DMLs were found to be enriched for breast cancer risk loci that are associated with risk of estrogen-receptor negative (ER-) breast cancer, treatment response to aromatase inhibitor, and breast cancer-specific morality, phenotypes of which we observed differences between EA and AA breast cancer patients. Our results suggest that racial differences in DNAm in normal breast tissue may induce different biological processes that lead to distinct clinical features of breast tumors observed in EA and AA women and provide an epigenetic mechanism underlying the observed racial disparities. Further research is need to validate the findings of this study. Citation Format: Nan Lin, James Castle, Jinpeng Liu, Chunyan He. Racial differences of epigenome in normal breast tissue reveal biological pathways implicated in racial disparities in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1937.

Abstract P3-01-15: Real-world effectiveness of palbociclib plus aromatase inhibitors (AI) in African American (AA) patients with metastatic breast cancer (MBC)

Abstract Background: Randomized clinical trials and a growing body of real-world evidence have demonstrated clinical benefit of cyclin dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy for HR+/HER2- (MBC). In the National Comprehensive Cancer Network (NCCN) guidelines, CDK4/6i + AI or Fulvestrant is recognized as a preferred regimen for HR+/HER2- MBC. Disparities in survival and clinical outcomes between AA and white breast cancer patients are well documented, but AA patients were not well represented in CDK4/6i randomized clinical trials. We compared real-world progression free survival (rwPFS) and overall survival (OS) of palbociclib plus AI (PB+AI) vs AI alone in AA patients with HR+/HER2- MBC in US clinical practices. Methods: The Flatiron Health longitudinal database contains electronic health records from &amp;gt;280 cancer clinics representing &amp;gt; 2.4 million actively treated cancer patients in the US. We conducted a retrospective analysis of 270 AA patients from the Flatiron database with HR+/HER2- MBC who started PB+AI or AI as first-line therapy between February 2015 and March 2020, Patients were evaluated from start of PB+AI or AI to September 30, 2020 (Data cutoff date), death, or last visit, whichever came first. OS was defined as months from start of PB+AI or AI to death. Patients were censored at the end of the study if they were living. rwPFS was defined as months from start of PB+AI or AI to death or disease progression, evaluated based on clinical assessment or radiographic scan/tissue biopsy. Cox proportional-hazards models were used to estimate the relative effectiveness of PB+AI vs AI without and with adjustment of baseline demographics and clinical characteristics. Results: Of the 270 eligible patients, 127 (47.0%) were treated with PB+AI and 143 (53.0%) were treated with AI. Median age was 64.0 years in PB+AI patients and 68.0 years in AI patients, respectively. Median follow-up was 24.0 months for PB+AI and 18.2 months for AI treated patients. Compared with AI patients, those treated with PB+AI were more likely to have de novo MBC (48.6% vs 30.8%) and to have ≥2 metastatic sites (41.7% vs 29.4%). Of the PB+AI patients, 82.7% started PB at 125mg/day and 30.7% experienced dose adjustment. Median OS was not reached (NR, 95%CI=(38.2-NR)) in PB+AI patients vs 28.2 months (95%CI=19.2-52.8) in AI patients (HR=0.46, 95%CI=0.31-0.68, p =&amp;lt; 0.001; adjusted HR=0.56, 95%CI=0.36-0.89, p=0.013). Median rwPFS was 18.0 months (95%CI = 12.4 – 26.7) in PB+AI patients and 10.5 months (95%CI=7.0-13.4) in AI patients (HR=0.63, 95%CI=0.44-0.88, p &amp;lt; 0.007; Adjusted HR=0.74, 95%CI=0.47-1.17, p =0.199). Conclusions: This comparative analysis of palbociclib plus AI vs AI alone provides evidence that first-line palbociclib in combination with endocrine is associated with improved effectiveness for AA patients with HR+/HER2- MBC in the real-world setting. Additonal studies with larger cohorts are needed to provide additional evidence of outcomes and safety for AA patients in routine clinical practice. Table. Patient characteristics and effectiveness outcomes Citation Format: Hope Rugo, Xianchen Liu, Benjamin Li, Lynn McRoy, Connie Chen, Rachel M. Layman, Adam M. Brufsky. Real-world effectiveness of palbociclib plus aromatase inhibitors (AI) in African American (AA) patients with metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-01-15.

Genetic variants of glucose metabolism and exposure to smoking in African American breast cancer.

Insulin resistance (IR) is a well-established risk factor for breast cancer (BC) development in African American (AA) postmenopausal women. While obesity and IR are more prevalent in AA than in white women, they are under-represented in genome-wide studies for systemic regulation of IR. By examining 780 genome-wide IR single-nucleotide polymorphisms (SNPs) available in our data, we tested 4689 AA women in a Random Survival Forest framework. With 37 BC-associated lifestyle factors, we conducted a gene-environment interaction analysis to estimate risk prediction for BC with the most influential genetic and behavioral factors and evaluated their combined and joint effects on BC risk. By accounting for variations of individual SNPs in BC in the prediction model, we detected four fasting glucose-associated SNPs in PCSK1, SPC25, ADCY5, and MTNR1B and three lifestyle factors (smoking, oral contraceptive use, and age at menopause) as the most predictive markers for BC risk. Our joint analysis of risk genotypes and lifestyle with smoking revealed a synergistic effect on the increased risk of BC, particularly estrogen/progesterone positive (ER/PR+) BC, in a gene-lifestyle dose-dependent manner. The joint effect of smoking was more substantial in women with prolonged exposure to cigarette smoking and female hormones. The top genome-wide association-SNPs associated with metabolic biomarkers in combination with lifestyles synergistically increase the predictability of invasive ER/PR+ BC risk among AA women. Our findings highlight generically targeted preventive interventions for women who carry particular risk genotypes and lifestyles.

Abstract C020: Identification of metabolic and molecular mechanisms contributing to ER+ cancer disparities using a machine-learning pipeline

Abstract Background: African American (AA) women are less likely to develop breast cancer but when they do, their mortality rates are 40% higher compared to Non-Hispanic White (NHW) women. This disparity is particularly striking among ER+ breast cancer cases. The purpose of this study is to examine whether there are racial differences in metabolic and molecular pathways typically activated in patients with ER+ positive breast cancer. Methods: We collected plasma from AA and NHW cases and controls to conduct an untargeted metabolomics analysis using gas chromatography-mass spectrometry (GC-MS) to identify metabolites that are possibly altered in the different race groups. Statistical methods combined with multiple feature selection and prediction models were employed to identify race-specific altered metabolic signatures. This was followed by the identification of altered metabolic pathways with a focus on AA patients with breast cancer. The clinical significance of the findings was further examined in the PanCancer Atlas breast cancer data set. Results: We identified differential metabolic signatures between NHW and AA patients. In AA patients, we observed disturbed amino acid metabolism, while fatty acid metabolism was significant in NHW patients. By mapping these metabolites to genes, this study identified significant relations with regulators of metabolism such as methionine adenosyltransferase 1A (MAT1A), DNA Methyltransferases, Histone methyltransferases for AA individuals, and Fatty acid Synthase (FASN) and Monoacylglycerol lipase (MGL) for NHW individuals. Specific histone methyltransferase NELFE was overexpressed and associated with poor survival exclusively in AA individuals. Conclusion: We employ a comprehensive and novel approach that integrates multiple machine learning methods, and statistical methods, coupled with human functional pathway analyses. This metabolic profile of serum samples might be used to assess risk progression in AA individuals with ER+ breast cancer. To our knowledge, this is a novel finding that describes metabolic alterations in AA breast cancer and emphasizes a potential biological basis for breast cancer health disparities. Citation Format: Ashlie Santaliz Casiano, Zeynep Madak-Erdogan, Dhruv Meta, Jonna Frasor, Garth Rauscher, Kent Hoskins. Identification of metabolic and molecular mechanisms contributing to ER+ cancer disparities using a machine-learning pipeline [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C020.

Abstract B119: Effect of a smart pill bottle and text messaging-based intervention on medication adherence and side effect management in African American women with breast cancer new to endocrine therapy

Abstract Background For women with hormone receptor-positive breast cancer (BCa), approximately 75-80% of all BCa cases, long-term use of endocrine therapy has been demonstrated to improve disease free survival. However, data reported that non-adherence rates range from 28% to 59%, and African American (AA) women had lower odds of being adherent to endocrine therapy than other racial/ethnic groups, suggesting that medication adherence might be an important level for targeting racial disparities in AA BCa outcomes. Emerging adherence-promoting interventions using technologies to provide at-home medication management support, however, few studies have formally assessed their effects in minority groups. The objective of this study was to evaluate the impact of an interactive text messaging (TXT) intervention and a smart pill bottle (SPB) on adherence to endocrine therapy and symptom management among AA women with early stage BCa. Method This prospective and random assignment study recruited 48 AA women with early stage ER+ or PR+ BCa who completed active treatments and were new to endocrine therapy. Participants were randomized to 1:1: between the txt2adhere and control groups. The txt2adhere group received interactive text messages three times a week, that were culturally tailored addressing barriers on the cognitive, affective interpersonal and symptom levels. The intervention group also received a SPB with light and chimes reminders. The control group received an identical SPB with all alerts deactivated. Patient adherence was calculated by % days adherent over the study time. The study was 3 months and patient-reported outcomes were collected at 1-month, 2-month and 3-month. A post-intervention interview was conducted to understand participant’s satisfaction and feedback. Results Forty-eight women were enrolled with 22 randomized in the txt2adhere group and 26 in the control group; 4 patients in the txt2adhere and 3 in the control were lost of follow up. Participants are in average 57 years old; 71% had an annual household income of $45K and lower; and 67% had a stage I BCa. Overall, the txt2adhere group has a 91% adherence rate at the end of 3-month study compared with 89% in the control group. Post-intervention interviews revealed the utility and feasible of the intervention, areas for TXT content improvement in symptom management such as joint pain and hot flashes were also identified. Conclusion In this study, a culturally-sensitive TXT intervention equipped with a SPB were associated with increased medication adherence, which need to be tested in a fully powered study. This pilot provides preliminary data on the feasibility of adherence technology used in an underserved AA population. Citation Format: Kuang-Yi Wen, Suzanne Miller, Aruna Padmanabhan, Rita Smith, Emmanuel Lapitan, Lori Goldstein. Effect of a smart pill bottle and text messaging-based intervention on medication adherence and side effect management in African American women with breast cancer new to endocrine therapy [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr B119.

Utilizing Social Media Advertisements and Participant Social Networks to Recruit African American Breast Cancer Survivors: Design and Rationale.

PurposeOur objective is to pilot an advertisement-driven sampling procedure among African American (AA) breast cancer survivors living in Maryland. These pilot study methods will inform a future population-based study of AA breast cancer survivors at high risk of poor outcomes due to biological differences and social inequities.MethodsThis cross-sectional study utilizes an innovative, social media-based advertisement campaign with an associated social media study page to recruit 100 AA breast cancer survivors. Participants are biologically female, aged 18 and older, identify as AA/Black, have a diagnosis of breast cancer, and reside in Maryland. A preset “Audience” was created via Meta (formerly Facebook) to automatically target potential interest in the online study via geolocation and public social media interests (estimated range = 101,000 women). Eligible participants complete an online survey including demographic and clinical characteristics, cancer screening, healthcare access, and utilization, COVID-19 impact, quality of doctor-patient communication, and preferences for future study participation.ResultsRecruitment began on 5 January 2022 and remains ongoing. As of 7 June 2002: 124 completed the screener, 110/124 (88.7%) consented passively, 24/110 (21.8%) started but did not complete survey, 86/110 (78.1%) completed the survey.ConclusionsResults from this study will inform a statewide multilevel prospective population-based study to improve health behaviors, disease management, and self-efficacy of chronic disease management among AA breast cancer survivors.

Abstract 474: Integrating imaging and multi-omics data to elucidate racial differences in breast tumor biology to optimize precision oncology approaches and patient outcome

Abstract Background: Racial disparities in breast cancer incidence and clinical outcome have been well characterized. In particular, African American (AA) patients have higher mortality rates than other racial groups. Research into these racial disparities has primarily focused on socioeconomic determinants, with some studies exploring potential molecular determinants and limited biological differences found between AA and Caucasian patient tumors. Tumor intrinsic and extrinsic factors that promote racial differences in breast cancer development and patient outcome are not fully understood and strategies to address this are scarce. As a result, we have developed a platform that combines patient-specific imaging and multi-omics data to elucidate how biological differences integrate to promote racial disparities in tumor behavior and patient outcome. Methods: Imaging and transcriptomic data from over 500 patients were integrated within the SimBioSys TumoScope biophysical modeling software to understand racial differences in tumor biology and coordinated tumor behavior. Results: AA patients have tumors that display higher growth rates, characteristically have higher adipose tissue around the tumor, higher spatial variation in drug secretion, lower spatial variation in blood flow/and increased tumor stiffness. Conclusion: Using a transdisciplinary approach, our results show that metabolic and structural tumor features are associated with the disproportionately poor survival rates observed in AA breast cancer patients. By characterizing racial-specific tumor intrinsic and extrinsic biological factors and their potential interactions, strategies may emerge to personalize clinical management based on racial differences. In this way, precision oncology approaches can be applied to increase life-expectancy for racial minorities with breast cancer. Citation Format: Nicole Liadis, Tyler Earnest, Eduardo Braun, Anu Antony, Lance Munn, Michael Hallock, Daniel Cook, The SimBioSys Team. Integrating imaging and multi-omics data to elucidate racial differences in breast tumor biology to optimize precision oncology approaches and patient outcome [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 474.

Using a multimodal approach to elucidate racial disparities in breast cancer biology by integrating tumor imaging and -omics data.

e12541 Background: Race-related differences in breast cancer incidence and clinical outcome have been well documented, with many studies focusing on socioeconomic determinants contributing to African American (AA) breast cancer patients having higher mortality rates. Far less is understood about the underlying biological differences in tumors between AA and Caucasian patients. In recent years, there have been more and more individual accounts identifying specific somatic mutations or observed breast tumor behaviors associated with racial disparities in breast cancer. Understanding how these specific observations coincide to give rise to alternative tumor biology in AA women, remains a challenge. Given the multifactorial nature of cancer, we have developed a platform that integrates the combinatorial phenotypic, molecular, and biological hallmarks of cancer. Our technology combines imaging and multi-omics data, providing a systematic approach for understanding race-specific biological differences and how they contribute to patient survival. Methods: Imaging and transcriptomic data from 1108 patients were integrated within the SimBioSys TumoScope biophysical modeling software to understand racial differences in tumor biology, coordinated tumor behavior, and corresponding patient outcome. Results: AA patients have tumors that display higher growth rates, characteristically have higher adipose tissue around the tumor, higher spatial variation in drug/ nutrient delivery, and increased tumor stiffness. We also identified biological features, including tumor/gland density and intertumoral heterogeneity that are prognostic for overall survival even when accounting for race and cancer subtype. Conclusions: Our results outline characteristic biological features that along with race and FDA breast cancer subtype may promote the disproportionately poor survival rates observed in AA breast cancer patients. This is the first study demonstrating a systematic approach being used to elucidate race-specific biological difference that may coordinate to impact patient survival. Our findings emphasize the importance of accounting for racial disparities and patient-specific biology to develop tailored intervention strategies and personalize race-specific clinical management of breast cancer.

Abstract P3-14-06: A transdisciplinary approach for characterizing racial differences in the biology of breast cancer by integrating imaging and -omics data

Abstract Background: Racial disparities in breast cancer incidence and clinical outcome have become increasingly recognized. In particular, African American (AA) patients have higher mortality rates than other racial groups. Research into these racial disparities has primarily focused on socioeconomic determinants, with some studies exploring molecular determinants. Biologically, few differences in genetics or transcriptomics have been found to be due to race. Understanding racial differences in breast cancer development as they relate to patient outcomes requires a comprehensive approach, integrating tumor intrinsic and extrinsic factors. We have developed a platform that combines patient-specific imaging and -omics data to elucidate how biological differences are integrated to cause racial differences in tumor behavior and disparities in patient outcome. Methods: Imaging and transcriptomic data from over 500 patients were integrated within the SimBioSys TumorScope biophysical modeling software to understand how racial differences in tumor biology are coordinated to determine tumor behavior. Specifically, we used artificial intelligence to automatically segment tumors from patient MRIs, and construct 3D models of patient tumors and the surrounding microenvironment. We then used these segmentations to identify radiological differences between AA and Caucasian patients. Simultaneously, we used patient-specific mathematical models of tumor metabolism constructed from RNA-seq data to determine racial differences in tumor metabolism. Results: We profiled structural differences in 266 tumors (181 Caucasian and 85 AA) and metabolic differences in 552 tumors (422 Caucasian and 130 AA). In our patient cohort, AA tumors were smaller (AA/Caucasian volume = 0.573, p = 0.004), more spherical (AA/Caucasian sphericity = 1.12, p = 0.0046), had lower spatial variation in tumor stiffness (AA/Caucasian Contrast GLRLM Gray Level Non-uniformity = 0.63, p = 0.0004), and had higher vascular perfusion than Caucasian tumors (AA/Caucasian vascular shell density = 1.43, p = 0.0015). In addition, AA tumors had increased levels in several features which may contribute to decreased response to therapy, including a higher spatial heterogeneity in drug delivery and secretion (AA/Caucasian WIS std = 2.2, p = 5.9x10-9, WOS std = 11.5, p &amp;lt; 10-10) and higher levels of adipose surrounding the tumor (AA/Caucasian adipose shell density = 1.13, p = 0.0024). Metabolically, we found that tumors from AA patients have increased sphingolipid metabolism (AA/Caucasian fold change (FC) = 1.4, p = 0.04) and pyruvate metabolism (FC = 1.03, p = 0.03); and decreased starch and sucrose metabolism (FC = 0.89, p = 0.03), fatty acid metabolism (average FC = 0.83, p = 0.04), glycerolipid metabolism (FC = 0.70, p = 0.025), and acylglyceride metabolism (FC = 0.69, p = 0.025). Furthermore, we found that these metabolic features integrate in such a way that tumors from AA patients had an increased specific growth rate (FC = 1.52, p = 0.014), compared to Caucasian patients (even when correcting for PAM50 subtype). Conclusion: Taken together, these results indicate that tumors of AA patients have a more aggressive phenotype (high growth rate) and potentially a lower response to chemotherapeutic drugs (high spatial heterogeneity of drug delivery and secretion and high surrounding adipose). These features likely work together to contribute to the disproportionately poor survival rates repeatedly observed in AA breast cancer patients. By characterizing racial-specific tumor intrinsic and extrinsic biological factor and their potential interactions, TumorScope simulation platform can assist in finding strategies that may improve clinical management, life-expectancy, and overall outcomes of racial minorities with breast cancer. Citation Format: Nicole Liadis, Tyler Earnest, Eduardo Bruan, Anu Antony, Michael Hallock, Daniel Cook. A transdisciplinary approach for characterizing racial differences in the biology of breast cancer by integrating imaging and -omics data [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-14-06.

Abstract PO-179: Analysis of long-term exposures to cigarette smoking and female hormones jointly with risk alleles of glucose metabolism in African American hormone receptor positive breast cancer

Abstract Background: Breast cancer (BC) is the most common cancer diagnosis and cause of death related to cancer in women in the United States and worldwide and more than 80% of new cases and deaths occur in postmenopausal women ages 50 years and older. Whereas African American (AA) women have a lower BC incidence rate than white women (e.g., 126.7 vs. 130.8 cases per 100,000 during 2012–2016), AA women's incidence rates have more rapidly increased than those in white women (0.9% vs. 0.4% per year), contributing to a convergence in BC incidence rates in 2016. BC is also the top leading cause of cancer incidence and mortality in AA women. Glucose intolerance/insulin resistance (IR) is a well-established risk factor for invasive BC development in AA postmenopausal women. While obesity and IR are more prevalent in AA than white women, they are under-represented in genome-wide studies for systemic regulation of IR and the association with BC risk. Methods: By examining 780 genome-wide IR single-nucleotide polymorphisms (SNPs) available in the Women's Health Initiative Database for Genotypes and Phenotypes (WHI dbGaP) SNP Health Association Resource (SHARe), we tested 4,689 AA women for potential causal pathways of genetically determined IR and BC risk in a Mendelian randomization (MR) framework. By incorporating 37 BC-associated lifestyle factors, we further conducted a gene–environment interaction analysis to estimate risk prediction for the most influential genetic and lifestyle factors and evaluated their combined and joint effects on BC risk. Results: Our MR results analyzing 38 index SNPs were mixed. By accounting for variations of individual SNPs in BC risk in the prediction model, we detected 4 fasting glucose–associated SNPs in PCSK1, SPC25, ADCY5, and MTNR1B and 3 lifestyle factors (smoking, oral contraceptive use, and age at menopause) as the most predictive markers for BC risk. Our joint analysis of risk genotypes and lifestyles with smoking revealed a synergistic effect on increased risk of BC, particularly ER/PR+ BC, in a gene–lifestyle dose-dependent manner. The joint effect of smoking on ER/PR+ BC was more profound in women who had long-term exposure to cigarette smoking and a prolonged exposure to female hormones. Conclusion: Our finding may improve the prediction accuracy in BC subtypes and highlight genetically targeted preventive interventions (e.g., smoking cessation) for AA postmenopausal women who carry particular risk genotypes. Citation Format: Su Yon Jung, Jeanette C. Papp, Eric M. Sobel, Matteo Pellegrini, Herbert Yu. Analysis of long-term exposures to cigarette smoking and female hormones jointly with risk alleles of glucose metabolism in African American hormone receptor positive breast cancer [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-179.

Abstract PO-096: Caloric restriction may decrease health disparity in AA breast cancer patients due to significant downregulation of the IGF-1R pathway in a window-of-opportunity clinical trial

Abstract Introduction: Health disparities in breast cancer outcomes exist for African American (AA) women who are noted to present with more aggressive cancer with worse survival. Although the underlying reason for this disparity is not apparent, it is likely multifactorial. Interestingly, type 1 insulin-like growth factor receptor (IGF-1R) expression, which plays a critical role in cell growth, survival, and migration, is higher in normal breast tissue in AA women as compared to Caucasian women. Although this has been well established, interventional studies to modulate this pathway have not been performed. We sought to determine if a dietary intervention of caloric restriction could play a role in modulating the IGF-1R pathway to help address the disparities seen in AA breast cancer patients. Methods: On an IRB approved clinical trial, patients were enrolled in a window-of-opportunity clinical trial to assess the effect of caloric restriction, or a 25% reduction of calories from the patients' baseline, on biomarkers in the tumor and blood. Patients recorded their baseline caloric intake for 3-5 days and were then instructed on a target calorie intake for the remainder of the diet. The patients remained on the dietary intervention for 2-12 weeks. Participants had anthropometric evaluation, blood draws to evaluate serum cytokines, tissue collection, and quality of life surveys collected at baseline and completion of diet which was the morning of surgery. Results: We enrolled 19 breast cancer patients between the years 2016 and 2018. The average age of the patients at the time of enrollment was 58 years old with 47% AA and 53% Caucasian. The patients were on the trial for an average of 19 days. Patients lost an average of 4.91 lbs during the trial, with AA patients losing an average of 5.18 lbs and Caucasians losing an average of 4.68 lbs. To determine the importance of IGF-1R in the disparities seen in AA women, we looked at two hundred cytokines from serum samples in patients who underwent caloric restriction. Analysis of the cytokine array data showed that nine cytokines involved in regulating or modulation by the IGF-1R pathway were significantly (p&amp;lt;0.05) downregulated in AA women post-diet. Compared to Caucasian women, AA women showed a significant decrease in IL-12p40 (~51%), VCAM1 (16.8%), IL-2 (28.72%), IL-2Rb (40.81%), CCL28 (36%), ERBB3 (26.6%), PAI-1 (9.4%), Axl (36%) and PDGF-AB (12%). Conclusion: These results demonstrate that caloric restriction significantly downregulated members of the IGF-1R pathway in the AA community. Since this pathway is notably dysregulated in AA patients, an integrated approach, one incorporating dietary changes to alter key pro-survival pathways, should be further investigated to narrow the disparity in breast cancer outcomes in AA patients. Citation Format: Samantha Okere, Anuradha A. Shastri, Kamryn Hines, Pramila Anne, Rita Murphy, Tiziana DeAngelis, Adam Berger, Alliric Willis, Melissa Lazar, Edith Mitchell, Nicole Simone. Caloric restriction may decrease health disparity in AA breast cancer patients due to significant downregulation of the IGF-1R pathway in a window-of-opportunity clinical trial [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-096.