American Cancer Patients Research Articles

Abstract PO-147: Kidney iron overload in African American renal cancer patients with the ferroportin Q248H mutation

Abstract Iron plays a role in cellular replication, metabolism, and growth. Although iron is needed, the imbalance of iron in the body can result in adverse health effects, including cancer. Interestingly, cancer cells have frequently been observed to express increased levels or activity of proteins that are associated with iron metabolism. Ferroportin (FPN), the only known mammalian cell iron exporter, is essential for iron homeostasis. Germline mutations in FPN occur more frequently in African and African American populations. A glutamine to histidine amino acid substitution at position 248 (Q248H) is the first and most prevalent gain-of-function mutation observed in FPN, with an allele frequency range of 2.2% to 13.4% in African and African Americans. However, it is unknown whether FPN Q248H is involved in cancer-associated reprogramming of iron metabolism, especially in individuals of African descent where the FPN Q248H mutation is enriched. The Q248H mutation traditionally renders FPN resistant to degradation. As a result, iron release is increased and aberrant uptake of iron across epithelial barriers of tissues can occur to cause iron overload, a risk factor for cancer. We hypothesize that patients with FPN Q248H have improper regulation of iron and thus increased unbound iron that will result in subsequent systemic and kidney-specific iron overload. We leveraged the repository of kidney cancer patients and banked samples of the Urologic Oncology Branch at the NIH to determine the association of FPN Q248H with kidney cancer. In our study, Black males with kidney cancer that expressed FPN Q248H had earlier onset of cancer compared to those without the variant. There were higher iron levels (p<0.01) and transferrin saturation (p=0.01), a measure for blood iron transport, in serum form Black males with FPN Q248H compared to Black males without. Additionally, serum levels of the iron storage protein ferritin were elevated in association with FPN Q248H. In the kidney, both normal and tumor tissue had distinct levels of iron, as well as protein expression of ferritin and FPN between patients with and without FPN Q248H. In all, these results highlight a potential novel mechanism for global iron-associated cancer risk populations. This work will provide a foundation for future studies that include pre-cancer individuals and other cancer outcomes where the relationship between FPN Q248H and iron overload can be further examined to expand our knowledge of cancer risk. Citation Format: Samira Brooks, Cathy Vocke, Deliang Zhang, Victor Gordeuk, Tracey Rouault, Marston Linehan. Kidney iron overload in African American renal cancer patients with the ferroportin Q248H mutation [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-147.

"I'm Dealing With That": Illness Concerns of African American and White Cancer Patients While Undergoing Active Cancer Treatments.

National oncology guidelines recommend early integration of palliative care for patients with cancer. However, drivers for this integration remain understudied. Understanding illness concerns at the time of cancer treatment may help facilitate integration earlier in the cancer illness trajectory. To describe cancer patients' concerns while undergoing cancer treatment, and determine if concerns differ among African Americans and Whites. A 1-time, semi-structured qualitative interview was conducted with a purposive subsample of cancer patients participating in a larger study of illness concerns. Eligible patients were undergoing cancer treatments and had self-reported moderate-to-severe pain in the last week. Analysis encompassed a qualitative descriptive approach with inductive thematic analysis. Participants (16 African American, 16 White) had a median age of 53 and were predominantly females (72%) with stage III/IV cancer (53%). Illness concerns were largely consistent across participants and converged on 3 themes: symptom experience (pain, options to manage pain), cancer care delivery (communication, care coordination and care transitions), and practical concerns (access to community and health system resources, financial toxicity). The findings extend the scope of factors that could be utilized to integrate palliative care earlier in the cancer illness trajectory, moving beyond the symptoms- and prognosis-based triggers that typify current referrals to also consider diverse logistical concerns. Using this larger set of concerns aids anticipatory risk mitigation and planning (e.g. care transitions, financial toxicity), helps patients receive a larger complement of support services, and builds cancer patients' capacity toward a more patient-centered treatment and care experience.

Racial disparities in performance status among cancer patients at a community oncology practice.

132 Background: Performance status is used to characterize patient ability to tolerate chemotherapy and as a selection criterion for clinical research. Poor performance status can exclude patients from clinical trial participation. Further, African American cancer patients are underrepresented in cancer clinical trials. The study purpose was to document performance status at the initial patient visit to a community oncology practice and to explore racial disparities between White and Black patients. Methods: This study used a retrospective, observational design with ePRO collected via the Patient Care Monitor™ (PCM). All study data were collected as part of routine clinical care at a community oncology practice during 1/2019–11/2019. An Eastern Cooperative Oncology Group (ECOG) score was automatically calculated after patients at an initial clinic visit completed a 1-item question that assessed performance status via e-tablet. Results: 6,613 patients completed the PCM survey (mean age 59; 33% male/67% female; 55.4% White, 38% Black). Cancer type was known for a subset of patients (22% breast, 9% hematologic, 4% lung, 5% colorectal, 3% prostate, 11% other types). The average ECOG score for the total sample was 0.97. 50% indicated they were able to complete their normal daily activities without any restriction; 26.9% were able to complete their normal daily activities and some light work. In contrast, 10.3% indicated they could take care of themselves, but could not work and are in bed/chair less than half the day. 10.3% could take care of themselves sometimes but could not work and are in bed/chair more than half the day. 4.5% indicated they could not take care of themselves and were in bed/chair almost always. When assessing racial differences between those self-identifying as White or Black/African American, average ECOG score was higher in Black patients [Mean(SD) = 1.03(1.24)] when compared to White patients [Mean(SD) = 0.93(1.14)] (p = 0.003). We observed a higher percentage of Black patients reported not being able to take care of themselves (51.9% Black v. 41.0% White). In contrast, a higher percentage of White patients reported being able to complete all daily activities without restriction (38.3% Black v. 54.5% White). Conclusions: This study shows significant racial disparities in performance status among patients seen at a community oncology practice with Black patients exhibiting significant worse performance status than White patients. These findings have implications for disparities in treatment outcomes and racially biased access to clinic trials.

Immune-Related Gene Expression and Cytokine Secretion Is Reduced Among African American Colon Cancer Patients.

Background: Colorectal cancer is the third most deadly cancer among African Americans (AA). When compared to Caucasian Americans (CA), AA present with more advanced disease and lower survival rates. Here, we investigated if differences in tumor immunology could be contributive to disparities observed between these populations.Methods: We examined gene expression of tumor and non-tumor adjacent tissues from AA and CA by whole transcriptome sequencing, and generated scores for immune cell populations by NanoString. In addition, we utilized “The Cancer Genome Atlas” (TCGA) database from AA and CA as a validation cohort. Finally, we measured the secretion of cytokines characteristic of effector T helper cell (Th) subsets by ELISA using plasma from each AA and CA participant.Results: Colon tumors from AA patients showed significant fold-change increase in gene expression when compared to CA for FOXP3 (6.22 vs. 3.22), IL1B (103 vs. 11.4) and IL8 (220 vs. 28.9) (p < 0.05). In contrast, among CA we observed statistically higher gene expression of markers associated with antitumor activity such as GZMB (Granzyme B), IFNG and the immunotherapy targets PDL1 (CD274) and CTLA4 (p < 0.05). TCGA data validated our observed higher gene expression of GZMB and PDL1 in CA patients when compared to AA. Notably, our observations on immune cell populations show that AA tumors have significantly higher number of exhausted CD8+ cells (p < 0.01), mast cells (p < 0.02) and increased T regulatory cells when compared to CA. AA colon cancer patients differed from CA in cytokine production patterns in plasma (i.e., reduced IL-12).Conclusions: Our study demonstrates significant differences of the immunological profiles of colon tumors from AA compared to CA that suggest a deficiency of appropriate immune defense mechanisms in terms of gene expression, recruitment of immune cells and systemic secretion of cytokines. As such, these immune differences could be mitigated through population-specific therapeutic approaches.

High expression of MKK3 is associated with worse clinical outcomes in African American breast cancer patients

BackgroundAfrican American women experience a twofold higher incidence of triple-negative breast cancer (TNBC) and are 40% more likely to die from breast cancer than women of other ethnicities. However, the molecular bases for the survival disparity in breast cancer remain unclear, and no race-specific therapeutic targets have been proposed. To address this knowledge gap, we performed a systematic analysis of the relationship between gene mRNA expression and clinical outcomes determined for The Cancer Genome Atlas (TCGA) breast cancer patient cohort.MethodsThe systematic differential analysis of mRNA expression integrated with the analysis of clinical outcomes was performed for 1055 samples from the breast invasive carcinoma TCGA PanCancer cohorts. A deep learning fully-convolutional model was used to determine the association between gene expression and tumor features based on breast cancer patient histopathological images.ResultsWe found that more than 30% of all protein-coding genes are differentially expressed in White and African American breast cancer patients. We have determined a set of 32 genes whose overexpression in African American patients strongly correlates with decreased survival of African American but not White breast cancer patients. Among those genes, the overexpression of mitogen-activated protein kinase kinase 3 (MKK3) has one of the most dramatic and race-specific negative impacts on the survival of African American patients, specifically with triple-negative breast cancer. We found that MKK3 can promote the TNBC tumorigenesis in African American patients in part by activating of the epithelial-to-mesenchymal transition induced by master regulator MYC.ConclusionsThe poor clinical outcomes in African American women with breast cancer can be associated with the abnormal elevation of individual gene expression. Such genes, including those identified and prioritized in this study, could represent new targets for therapeutic intervention. A strong correlation between MKK3 overexpression, activation of its binding partner and major oncogene MYC, and worsened clinical outcomes suggests the MKK3-MYC protein–protein interaction as a new promising target to reduce racial disparity in breast cancer survival.

Abstract 1673: Conservation of copy number profiles during engraftment and passaging of patient-derived cancer xenografts

Abstract Patient-derived xenografts (PDXs) are resected human tumors engrafted into mice for preclinical studies and therapeutic testing. It has been proposed that the mouse host affects tumor evolution during PDX engraftment and propagation, which could impact the capacity of PDXs for faithful modeling of patient treatment response. Such results contrast with reports that have observed genomic fidelity of PDX models with respect to the originating patient tumors and from early to late passages by direct DNA measurements (DNA sequencing or SNP arrays). Here we resolve these contradicting observations by systematically evaluating CNA changes and the genes they affect during engraftment and passaging in a large, internationally collected set of PDX models, comparing both RNA and DNA-based approaches. The data collected, as part of the U.S. National Cancer Institute (NCI) PDXNet (PDX Development and Trial Centers Research Network) Consortium and EurOPDX consortium, comprises 1548 patient (PT) and PDX datasets (1451 unique samples) from 509 models derived from American, European and Asian cancer patients, spanning across 16 tumor types. By assessing copy number changes by pairwise (PT-PDX or PDX-PDX) correlation and residual analysis to control for systematic biases, our study demonstrates that prior reports of systematic copy number divergence between PTs and PDXs are incorrect, and confirms the high retention of copy number during PDX engraftment and passaging. Moreover, only a small proportion of models show large CNA discordance between the samples, suggesting that the variations observed in PDX are mainly due to rare clonal selection of individual tumors rather than murine pressures. This large scale data analysis also reveals several other findings that clarify the evolutionary process in PDXs. We do observe larger deviations between PT-PDX than in PDX-PDX comparisons, likely due to dilution of PT signal by human stromal cells. Interestingly, we found that a major contributor to the differences between PDX samples is lineage-specific drift associated with splitting of tumors into fragments during PDX propagation. We observed no significant enrichment of cancer-related genes in PDX-specific CNAs across models, suggesting the lack of systematic copy number evolution driven by the PDX mouse host. Moreover, CNA differences between patient and PDX tumors were comparable to variations in multi-region tumor samples or intra-patient samples. Thus concerns about the genetic stability of the PDX system are likely to be less important than the spatial heterogeneity of solid tumors themselves. This result is consistent with our results on lineage effects during passaging, which indicate that intratumoral spatial evolution is the major reason for genetic drift. Our in-depth tracking of CNAs throughout PDX engraftment and passaging confirms that tumors engrafted and passaged in PDX models maintain a high degree of molecular fidelity to the original patient tumors and their suitability for pre-clinical drug testing. This work also finely enumerates the copy number profiles in hundreds of publicly available models, which will enable researchers to assess the suitability of each for individualized treatment studies. Citation Format: Xing Yi Woo, Jessica Giordano, Anuj Srivastava, Zi-Ming Zhao, Michael W. Lloyd, Roebi de Bruijn, Yun-Suhk Suh, Jong-Il Kim, Han-Kwang Yang, Charles Lee, Dennis A. Dean, Brandi Davis-Dusenbery, Yvonne A. Evrard, James H. Doroshow, Alana L. Welm, Bryan Welm, Michael T. Lewis, Bingliang Fang, Jack A. Roth, Funda Meric-Bernstam, Meenhard Herlyn, Michael Davies, Li Ding, Shunqiang Li, Ramaswamy Govindan, Claudio Isella, Jeffrey A. Moscow, Livio Trusolino, Annette Byrne, Jos Jonkers, Carol J. Bult, Enzo Medico, Jeffrey H. Chuang, PDXNET consortium &amp; EurOPDX consortium. Conservation of copy number profiles during engraftment and passaging of patient-derived cancer xenografts [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1673.

Comparing Perceptions and Decisional Conflict Towards Participation in Cancer Clinical Trials Among African American Patients Who Have and Have Not Participated

Despite efforts to increase the diversity of cancer clinical trial participants, African Americans are still underrepresented. While perceptions of participation have been studied, the objective of this study was to compare perceptions and decisional conflict towards clinical trials among African American cancer patients who have and have not participated in clinical trials to identify key areas for intervention. Post hoc analysis also looked at whether they had been asked to participate and how that group differed from those who did. Forty-one African American cancer patients were surveyed at two urban cancer centers and asked to agree/disagree to statements related to clinical trials perceptions (facilitators, barriers, beliefs, values, support, and helpfulness), and complete the O'Connor Decisional Conflict Scale. Independent-samples t tests compared participants by clinical trials participation status; 41% had participated in a clinical trial. Results revealed significant perceptual differences among the groups in three main areas: helpfulness of clinical trials, facilitators to participate in clinical trials, and barriers to participating in clinical trials. Post hoc analysis indicated that those who were not asked about clinical trials and had not participated differed significantly in all areas compared with participants. Additionally, clinical trial participants reported significantly lower decisional conflict in most items compared with both those who had and had not be asked to participate. These differences can give practitioners clues as to how to bridge the gap from non-participator to participator. Messages could then be infused in the clinician-patient dyad when introducing and discussing clinical trials, potentially providing a more effective strategy for communicating with African American patients.

Leukocyte telomere length is associated with aggressive prostate cancer in localized African American prostate cancer patients.

Telomeres play important roles in cancer initiation and progression. Leukocyte telomere length (LTL) has been associated with the risk and prognosis of several cancers, but its association with prostate cancer (PCa) prognosis in African Americans (AAs) has not been reported. In this study, we measured relative LTL from 317 AA PCa patients and assessed its associations with aggressive disease characteristics at diagnosis and biochemical recurrence (BCR) after radical prostatectomy and radiotherapy. LTL was shorter in patients with higher Gleason scores (GS) at diagnosis. Dichotomized into short and long LTL groups, patients with short LTL exhibited a 1.91-fold (95% confidence interval, CI, 1.14-3.20, P = 0.013) increased risk of being diagnosed with high-risk disease (GS =7 [4 + 3] and GS ≥8) than those with long LTL in multivariable logistic regression analysis. Moreover, shorter LTL was significantly associated with an increased risk of BCR (hazard ratio = 1.68, 95% CI, 1.18-11.44, P = 0.024) compared with longer LTL in localized patients receiving prostatectomy or radiotherapy in multivariable Cox analysis. Kaplan-Meier survival analysis showed patients with short LTL had significantly shorter BCR-free survival time than patients with long LTL (Log rank P = 0.011). In conclusion, our results showed for the first time that LTL was shorter in PCa patients with higher GS and short LTL was associated with worse prognosis in AA PCa patients receiving prostatectomy or radiotherapy.

Factors Associated with Depression in African American Patients Being Treated for Cancer Pain

BackgroundAmong cancer patients in the United States, African American cancer patients have the highest mortality rate and shortest survival rate. Although depression is known as a predictor of mortality in cancer and a potential barrier to health care utilization, research on depression in African American patients is limited. Cancer pain can interfere with an individual’s ability to cope with depression. AimsTo identify factors that are associated with a positive screening of depressive symptoms assessed by the PHQ-8 in African American patients treated for cancer pain. DesignSecondary data analysis of a cross-sectional study of opioid adherence. SettingMedical oncology, palliative care, and radiation oncology clinics in Atlanta, Georgia. Participants/SubjectsAfrican American patients with cancer pain in the parent study. MethodsIndependent samples t-test was used to assess variable correlations with and without depressive symptoms. Adjusted logistic regression was conducted to identify factors that were associated with presence of depressive symptoms. ResultsMean patient age was 55.6 years, and nearly 38% had a PHQ-8 score of >10 indicating presence of moderate to severe depressive symptoms. Participants with depressive symptoms had significantly higher means for anxiety and pain interference with mood than those without depressive symptoms. Factors that were significantly associated with depressive symptoms were anxiety, pain interfering with mood, and lack of involvement with a religious congregation. ConclusionsThe findings of this study help to identify African American cancer patients at risk for depression and demonstrates the need for increased screening for depression in this underserved population.

Abstract B084: Dysregulation of the AR-Nrdp1-ErbB3 axis occurs in African American prostate cancer patients and is associated with worse outcomes

Abstract Background: We previously showed that Nrdp1, an E3 ubiquitin ligase, is transcriptionally regulated by the androgen receptor (AR) in prostate cancer (CaP) cells and that Nrdp1 can post-translationally regulate ErbB3 (an EGFR family member) levels via ubiquitination and subsequent proteasomal degradation. Increased levels of ErbB3 are associated with worse CaP patient outcome. The goal of the current study was to determine whether dysregulation of the AR-Nrdp1-ErbB3 axis contributes to prostate cancer health disparities for African American (AA) men, and to identify the underlying mechanisms involved. Methods: Expression levels and localization of AR, Nrdp1, and ErbB3 were assessed in a total of 208 CaP patient samples (50 African American (AA) and 158 Caucasian (CA) CaP patients) and two cell lines (LNCaP (CA) and MDAPCa2b (AA)). Expression levels and localization of these molecules were determined by immunohistochemistry (IHC) and subcellular fractionation and western blot. A combination of knockdown (siRNA), forced overexpression (Nrdp1-FLAG construct), and treatment with enzalutamide or synthetic androgen (R1881) experiments were employed to investigate the relationship between AR, Nrdp1, and ErbB3 expression levels and localization and to identify differences in AA and CA cell lines. Immunoprecipitation allowed for investigation of the mechanisms which facilitate nuclear transport of Nrdp1. Results: A statistically significant negative association between cytoplasmic levels of AR (AR C) and nuclear Nrdp1 (Nrdp1 N) exists in both Caucasian (CA) and African American (AA) prostate cancer (CaP) patients, but this association was stronger in AA patients compared to CA patients (Spearman correlation coefficient of -0.62 for AA patients, and -0.36 for CA patients). Increased nuclear Nrdp1 expression levels were associated with increased 5-year survival rates, and reduced nuclear Nrdp1 expression levels predicted biochemical recurrence (AUC 0.63). Dysregulation of the AR-Nrdp1-ErbB3 axis in AA CaP cells was also observed in cell line studies; AA CaP cells expressed significantly lower levels of both total and nuclear Nrdp1 compared to their CA CaP counterparts. Manipulation of AR expression levels and localization via knockdown and inhibition with enzalutamide had a lesser impact on Nrdp1 expression levels and localization in AA versus CA CaP cells. Immunoprecipitation studies demonstrated that Nrdp1 can bind to AR in CA CaP cells but not AA CaP cells. Conclusions: Our combined data indicate that dysregulation of the AR-Nrdp1-ErbB3 axis occurs to a larger extent in AA than CA CaP cells and that this can contribute to worse patient outcomes. Our data also indicate that lack of binding between AR and Nrdp1 in AA CaP cells may account for the lower levels of nuclear Nrdp1 observed in AA CaP cells. Further understanding of the mechanisms which regulate Nrdp1 levels and localization may allow for the development of treatments which help abrogate cancer health disparities. Note: This abstract was not presented at the conference. Citation Format: Anhao Sam, Elizabeth Browning, Shawna Evans, Thomas Steele, Paramita Ghosh, Ruth Vinall. Dysregulation of the AR-Nrdp1-ErbB3 axis occurs in African American prostate cancer patients and is associated with worse outcomes [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B084.

Abstract B075: Defining germline mutations of DNA damage repair genes in African American prostate cancer patients

Abstract Background: DNA damage repair genes (DDRGs) play a critical role in protecting genome integrity and have been implicated in several cancer types. In the context of prostate cancer (CaP) emerging data provide potential role of this pathway in aggressive disease. It has also been recently demonstrated that PARP inhibitors can extend overall survival in metastatic patients with DDRG mutations. However, the association and therapeutic stratification based on inherited mutations of DDRGs remains to be defined in African American (AA) CaP patients. Our objective was to assess the frequency and association with disease aggressiveness of all known DDRGs in blood derived genomic DNAs of AA and Caucasian American (CA) CaP patients archived at the DOD Center for Prostate Disease Research and assess how this information can refine patient stratification for specific targeted therapeutic options. Method: Germline mutations in all DDRGs was evaluated by whole genome sequence (WGS) analysis of archived blood DNA samples from 600 CaP patients (300 AA and 300 CA) who underwent primary treatment at Walter Reed National Military Medical Center (WRNMMC) over the past 20 years. These patients had equal access Department of Defense healthcare system with up to 20 years of follow-up time. Following quality control steps to assess DNA quantity by Qubit assay and DNA quality by Bioanalyzer assay, DNA samples were used to generate PCR-free libraries for WGS using the NovaSeq (Illumina) platform. Out of the 600 libraries we generated, 14 dropped out, achieving a success rate of 97.6%. The successful libraries had an excellent quality based on DNA library metrics (yield and fragment length). Whole genome sequencing depth of the samples exceeded 37x on average and about 4 million SNPs were identified in the samples. Patient genotypes were projected onto principal components from reference populations. Sample ancestries were predicted by using the “Peddy” program, which uses a machine learning model trained on individuals of diverse ancestries from the 1000 Genomes Project reference panel. Due to mismatched ancestry, 33 samples were excluded from further analyses. An additional 17 samples were excluded due to higher than minimal noise level based on analyses using “ContEst” tool from Broad GATK package and Illumina noise percent values. Results: Interrogation of an inclusive DDRG set of 180 genes predicted to have non-silent effects on the protein sequence (e.g. missense, nonsense, frameshift) for germline mutations in this cohort revealed several known and novel mutations. The analysis has not been finalized yet. Mutation data will be assessed for association with the extensive available clinical and pathological data, including disease progression (metastasis), family history and African ancestry. Novel mutations, anticipated especially in the understudied AA context, will be analyzed for functional impact. Citation Format: Kevin Babcock, Xijun Zhang, Matthew Wilkerson, Clifton L. Dalgard, Shyh-Han Tan, Lakshmi Ravindranath, Yongmei Chen, Jennifer Cullen, Shiv Srivastava, Inger L. Rosner, Gyorgy Petrovics. Defining germline mutations of DNA damage repair genes in African American prostate cancer patients [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B075.

Abstract B042: Loss of nuclear alpha catenin contributes to chemoresistance and aggressive disease in African American triple-negative breast cancer patients

Abstract Triple-negative breast cancer (TNBC) is a particularly aggressive, difficult-to-treat subtype of the disease. A well-documented health disparity exists within TNBC: African American (AA) women are more likely to be diagnosed with and die from the disease. Our group reported homozygous deletions in the CTNNA1 gene, which encodes the protein alpha catenin, in AA TNBC. We have undertaken a basic and translational research study to understand the mechanistic role and clinical impact of alpha catenin loss in TNBC, particularly in AA patients. To validate our findings of alpha catenin loss in TNBC, we analyzed over 600 breast cancer patient samples by immunohistochemistry. We found that alpha catenin protein loss was inversely correlated with survival in TNBC. Moreover, loss was observed more frequently in tumors from AA patients. Interestingly, both nuclear and cytosolic alpha catenin adhered to this pattern. While its cytosolic role has been well studied, little is known about nuclear alpha catenin and its role in disease. To understand the nuclear function of alpha catenin, we developed several isogenic cell line pairs. Using CRISPR/Cas9-mediated gene editing, we generated CTNNA1 knockout (KO) BT-549 and MB-MDA-436 cell lines. We also reintroduced CTNNA1 into MDA-MB-468 cells—a line derived from an AA woman with an endogenous deletion in CTNNA1. Using these models, we found that alpha catenin KO cells demonstrated greater capacity for anchorage-independent growth. Loss of alpha catenin also resulted in decreased sensitivity to DNA-damaging chemotherapies including platinum salts (cisplatin, carboplatin), topoisomerase poisons (doxorubicin, etoposide), and the PARP inhibitor olaparib. This is clinically relevant as doxorubicin, carboplatin, and olaparib are approved for treatment of TNBC patients. To identify binding partners, we performed co-immunoprecipitation of alpha catenin from nuclear lysates, followed by mass spectrometry. We found that nuclear alpha catenin can interact directly with ATR, a kinase critical to the DNA damage response (DDR). ATR mediates both the repair of DNA lesions and the G2/M cell cycle checkpoint, which ensures that only cells with undamaged DNA may enter mitosis. We further found that alpha catenin KO cells were more sensitive to inhibitors of ATR, as well as to inhibitors of the G2/M checkpoint proteins Chk1 and Wee1. Tellingly, the KO cells were less sensitive to inhibitors of ATM or DNA-PK, two regulators of alternate DDR pathways. This suggests that nuclear alpha catenin likely plays a specific role in ATR-directed processes. In our study, we have identified nuclear alpha catenin as a tumor suppressor that affects TNBC's susceptibility to chemotherapy by playing a role in the DDR and the G2/M checkpoint. Our data suggest that loss of alpha catenin is more common in AA patients, and is associated with poor prognosis. Therefore, CTNNA1 status may be important in determining appropriate therapeutic strategies in a subset of patients. Citation Format: Rania Bassiouni, Victoria Dirgo, Krystine Mansfield, Ritin Sharma, Lee D. Gibbs, Patrick Pirrotte, Nasreen Vohra, Kevin Gardner, John D. Carpten. Loss of nuclear alpha catenin contributes to chemoresistance and aggressive disease in African American triple-negative breast cancer patients [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr B042.

Abstract D078: Unlocking the vault: Can 2nd opinions by Comprehensive Cancer Center breast oncologists improve treatment quality for African Americans?

Abstract Research increasingly points to inadequate treatment as a factor in the excess breast cancer mortality experienced by African Americans. Likely causes include lack of guideline-concordant care, underuse of medical advances, and limited opportunities to participate in clinical trials and genetic counseling. African Americans are disproportionately affected because they are more likely to receive care in low-resource settings. Importantly, emerging research shows that NCI-designated Comprehensive Cancer Centers (CCCs) have the best cancer outcomes compared with other clinical settings - yet African Americans and Latinx are under-represented as patients in CCCs. It is as if the leading cancer clinicians and the resources at their disposal are locked in a vault inaccessible to those with the greatest need. We used ethnographic methods to explore the feasibility of and extent to which the simple mechanism of a CCC 2nd opinion can improve the quality of treatment offered to African American breast cancer patients receiving care in a range of other institutions. Through community outreach, 14 patients were recruited and 17 CCC consultations were conducted at no charge. Each visit was observed and audio-taped to capture the consulting oncologist’s recommendations. Patients were interviewed 3 weeks after the consultation and again up to 1 year later to document the impact of the consultation on their treatment. Consulting oncologists were also interviewed. Our findings reveal a variety of ways in which the CCC 2nd opinion substantially improved the quality of treatment for African American breast cancer patients. In all cases CCC clinicians offered important recommendations, from complete revision of a treatment plan to adding/changing medications, modifying the plan for monitoring, and/or improving management of side effects. Patients reported that all major recommendations were implemented by their treating clinicians. In one dramatic case, chemotherapy was failing to slow the growth a young public hospital patient’s stage 3 tumor associated with a P53 mutation. The CCC clinician recommended and advocated for an entirely different treatment. In remission two years later, the patient has had another child. To our knowledge, this is the first study to explore the CCC consultation as an intervention to reduce mortality disparities. It appears highly feasible to target CCC 2nd opinions to vulnerable patients at relatively low cost to the CCC. Many CCC clinicians are eager to see high-risk under-represented patients, and go beyond the consultation by communicating with treating clinicians and seeing patients more than once. Patients readily recognized the expertise of CCC clinicians and were deeply grateful for the opportunity. Based on this pilot study, the 2nd opinion concept warrants further testing via a randomized trial. Comprehensive Cancer Centers can and must take greater responsibility for disparities in their region through innovations that extend their expertise beyond their walls. Citation Format: Rena J Pasick, Brittany Campbell, Hope S Rugo, Christen Dillard, Marion Harris, Galen Joseph. Unlocking the vault: Can 2nd opinions by Comprehensive Cancer Center breast oncologists improve treatment quality for African Americans? [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D078.

Abstract A006: Can expert second opinions reduce treatment disparities for African American breast cancer patients? An exploratory study

Abstract Purpose: The excess breast cancer mortality among African Americans is well documented, and insufficient treatment quality in low-resource settings is a key cause. The second opinion could connect patients with the best available medical knowledge. We explored the extent to which treatment plans can be improved through consultations at NCI-designated Comprehensive Cancer Centers (CCC) that deliver the latest treatments, and to describe the experience of patients and consulting clinicians. Methods: Eligible patients, those who self-identify as African American and have concerns about breast cancer, were recruited from communities and clinics. The research grant covered the cost of consultations. Ethnographic methods (audio-recorded observations and in-depth interviews) were used to ascertain consultation impacts. Data sources were transcripts from consultations; post-consult patient interviews, once following the consultation and again after treatment decisions were made; and one clinician interview per consultation. Standard grounded theory analytic methods were used. Results: A total of 17 consultations were conducted with 14 female patients ages 32-71. Treating health care institutions were public hospitals, an integrated health care delivery system, an academic medical center, private not-for-profit community hospitals, and a private cancer center. Patients sought consults for concerns such as the possibility that a breast change was cancer, diagnosis of lobular carcinoma in situ (LCIS), treatment plans for invasive breast cancers at every stage, management of metastases, and prevention of recurrence. Some changes were recommended in every case, from simple routine procedures to major transformations. For example: An LCIS patient was advised to start an aromatase inhibitor, have yearly mammograms and MRIs, and to change her diet.A patient with advanced disease was advised to add CDK 4/6 inhibitor to her treatment.Whether and how to administer complex intrathecal chemotherapy (injection into the space between the thin layers of tissue that cover the brain and spinal cord) was discussed for a young patient with brain metastases.A clinical trial and genetic testing were recommended to a Stage IV breast cancer patient. Overall consulting doctors' proposals were adopted. Patients learned about their cancer, the benefits and limitations of their current treatment, and about clinical trials. They appreciated confirmation that they were receiving quality care or recommended changes. CCC clinicians were eager to help patients with the greatest needs. Conclusions: Second opinion consultations can open communication channels between leading cancer experts and oncologists in low-resource settings, increasing prospects for equal treatment. Citation Format: Brittany Campbell, Marion Harris, Hope Rugo, Galen Joseph, Rena Pasick. Can expert second opinions reduce treatment disparities for African American breast cancer patients? An exploratory study [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr A006.

Abstract B055: Characterization of immune cell subsets from tissue expression profiles in African American triple-negative breast cancer patients

Abstract Triple-negative breast cancer (TNBC) is more frequent and aggressive in African American women and women of African descent. The heterogeneity of TNBC has become a challenge in today's clinical practice, and significant research efforts have been deployed to better understand the molecular nature of TNBC. Clinically, the heterogeneous nature of TNBC has not been accounted for, hence leading to therapy resistance, metastasis, and relapse. TNBC has been associated with an elevation of immune infiltrates, which suggests that some patients may benefit from immune-based therapies. In this study, we used analytical tools that perform cell type enrichment analysis and provide an estimation of the abundances of immune cell types in a mixed cell population using gene expression data to compare the differences among immune cell types between African and Caucasian American breast cancer patient samples. Here, we examined RNA-sequencing data from 1,215 patients from two breast cancer cohorts including The Cancer Genome Atlas, which consists of 32 African American and 64 Caucasian TNBC samples, and data from 130 breast cancer cases with extensive clinical annotation collected and accrued from rural regions of eastern North Carolina in collaboration with Noreen Vohra at the Brody School of Medicine at East Carolina University. This cohort contained data from 23 African American TNBC samples and 25 Caucasian TNBC samples. Results revealed that tumor-associated macrophages and T cells were significantly represented among TNBC patients in both datasets with uncommitted macrophages (M0), M2-like macrophages, and CD4 memory resting cells as the predominant populations. Additionally, known antitumor immune cells, such as CD8 T cells and NK cells, were under-represented among TNBC patients. Although expression of immune cells and immune cell subsets was represented in our datasets, we did not find any significant difference between African American and Caucasian TNBC patients. We plan to present analyses from this data stratifying cases by mutational burden and expression of immune checkpoint markers. Our findings suggest that TNBC patients could possibly benefit from immunotherapies and their therapy could be personalized to their immune profile. Therefore, immune profiling may unlock new therapeutic opportunities for African American TNBC patients. Citation Format: Lee D. Gibbs, Jung Byun, Tingfen Yan, Anna Napoles, Eliseo Pere-Stables, Troy McEachron, Nasreen Vohra, John D. Carpten, Kevin Gardner. Characterization of immune cell subsets from tissue expression profiles in African American triple-negative breast cancer patients [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr B055.

Abstract B083: Dysregulation of the AR-Nrdp1-ErbB3 axis occurs in African American prostate cancer patients and is associated with worse outcomes

Abstract Background: We previously showed that Nrdp1, an E3 ubiquitin ligase, is transcriptionally regulated by the androgen receptor (AR) in prostate cancer (CaP) cells and that Nrdp1 can post-translationally regulate ErbB3 (an EGFR family member) levels via ubiquitination and subsequent proteasomal degradation. Increased levels of ErbB3 are associated with worse CaP patient outcome. The goal of the current study was to determine whether dysregulation of the AR-Nrdp1-ErbB3 axis contributes to prostate cancer health disparities for African American (AA) men, and to identify the underlying mechanisms involved. Methods: Expression levels and localization of AR, Nrdp1, and ErbB3 were assessed in a total of 208 CaP patient samples (50 African American (AA) and 158 Caucasian (CA) CaP patients) and two cell lines (LNCaP (CA) and MDAPCa2b (AA)). Expression levels and localization of these molecules were determined by immunohistochemistry (IHC) and subcellular fractionation and western blot. A combination of knockdown (siRNA), forced overexpression (Nrdp1-FLAG construct), and treatment with enzalutamide or synthetic androgen (R1881) experiments were employed to investigate the relationship between AR, Nrdp1, and ErbB3 expression levels and localization and to identify differences in AA and CA cell lines. Immunoprecipitation allowed for investigation of the mechanisms which facilitate nuclear transport of Nrdp1. Results: A statistically significant negative association between cytoplasmic levels of AR (AR C) and nuclear Nrdp1 (Nrdp1 N) exists in both Caucasian (CA) and African American (AA) prostate cancer (CaP) patients, but this association was stronger in AA patients compared to CA patients (Spearman correlation coefficient of -0.62 for AA patients, and -0.36 for CA patients). Increased nuclear Nrdp1 expression levels were associated with increased 5-year survival rates, and reduced nuclear Nrdp1 expression levels predicted biochemical recurrence (AUC 0.63). Dysregulation of the AR-Nrdp1-ErbB3 axis in AA CaP cells was also observed in cell line studies; AA CaP cells expressed significantly lower levels of both total and nuclear Nrdp1 compared to their CA CaP counterparts. Manipulation of AR expression levels and localization via knockdown and inhibition with enzalutamide had a lesser impact on Nrdp1 expression levels and localization in AA versus CA CaP cells. Immunoprecipitation studies demonstrated that Nrdp1 can bind to AR in CA CaP cells but not AA CaP cells. Conclusions: Our combined data indicate that dysregulation of the AR-Nrdp1-ErbB3 axis occurs to a larger extent in AA than CA CaP cells and that this can contribute to worse patient outcomes. Our data also indicate that lack of binding between AR and Nrdp1 in AA CaP cells may account for the lower levels of nuclear Nrdp1 observed in AA CaP cells. Further understanding of the mechanisms which regulate Nrdp1 levels and localization may allow for the development of treatments which help abrogate cancer health disparities. Citation Format: Anhao Sam, Shawna Evans, Elizabeth Browning, Sheryl Krig, Neelu Batra, Thomas Steele, Salma Siddqui, Paramita Ghosh, Ruth Vinall. Dysregulation of the AR-Nrdp1-ErbB3 axis occurs in African American prostate cancer patients and is associated with worse outcomes [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B083.

Abstract A053: Watchful Living: A pilot lifestyle intervention for African American and Hispanic prostate cancer patients on active surveillance and their partners

Abstract Background: Prostate cancer is the most commonly diagnosed cancer in both African American and Hispanic men. Prostate cancer mortality rate is 2.4 times higher among African American men than that among non-Hispanic white men. Further, Hispanic prostate cancer patients report poorer quality of life than their non-Hispanic white counterparts. Active surveillance is a safe treatment option for low-risk prostate cancer patients in which patients' conditions are actively monitored, and preliminary studies have shown that lifestyle interventions have a promise to reduce disease progression and improve quality of life for active surveillance patients. However, none have specifically targeted African American or Hispanic men. Also, none have included partners, who are the main source of support for prostate cancer patients. Objective: This ongoing study seeks to pilot test a lifestyle intervention, Watchful Living, for African American and Hispanic men on active surveillance and their partners. The primary aim is to determine the feasibility of recruiting and implementing Watchful Living. Secondary aims are to: 1) evaluate the preliminary efficacy of the intervention in improving diet, physical activity, quality of life, and inflammation and 2) conduct a process evaluation of the intervention. Methods: We will adapt an existing, evidence-based intervention. Our intervention adaptation process is based on the Intervention Mapping Adapt and typology of adaptation, which were specifically developed for racial/ethnic minorities. First, we will conduct a needs assessment (in-depth interview) with prostate cancer patients and their partners. Participants will be asked about their physical activity and eating behaviors, impacts of cancer, determinants of lifestyle behavior changes, social support for lifestyle behaviors from partners, and their interests in lifestyle behaviors program. All feedback will be used to revise existing intervention materials and components before implementation, to ensure that the intervention is responsive to dyads' needs and culturally relevant. Second, we will conduct an RCT in which 30 dyads will be assigned to intervention group and 10 dyads will be assigned to control group. Intervention group will receive biweekly telephone coaching calls and two nutrition counseling sessions over 6 months. Participants will be assessed at baseline, month 3, and month 6, and blood will also be collected at month 3 and 6. Finally, we will conduct a process evaluation to examine thoughts about strengths, weaknesses, and needed improvements; perceptions about outcomes and impact; and overall reactions to and satisfaction with the intervention. Results: This is an ongoing study and results are not yet available. Discussion: Recruiting minority prostate cancer patients and their partners is challenging and requires extensive planning and collaboration. Building teamwork with multiple hospitals and multidisciplinary teams probably may be a key to succeed. Citation Format: Dalnim Cho, Karen Basen-Engquist, Richard Simpson, Hilary Ma, Curtis Pettaway, Yisheng Li, Steven Canfield, Cindy Carmack, John Davis, Jeffrey Jones, Lorna H. McNeill. Watchful Living: A pilot lifestyle intervention for African American and Hispanic prostate cancer patients on active surveillance and their partners [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr A053.

Abstract B017: Role of CYP3A5 in modulating androgen receptor signaling and its relevance in African American prostate cancer patients

Abstract Introduction: African-American men (AA) often present with aggressive castration-resistant prostate cancer (CRPC), due to highly active androgen receptor (AR). AR is a ligand-activated transcription factor that promotes expression of genes responsible for cell proliferation and growth. Previously, we have shown that CYP3A5 promotes AR nuclear translocation and activation leading to increased prostate cancer (PC) growth. 73% of AAs carrying wild-type CYP3A5 (*1/*1) express full-length functional CYP3A5, whereas 95% of Caucasians carry mutant (*3/*3) variant producing truncated nonfunctional protein. Difference in CYP3A5 expression leads to highly active AR and aggressive disease in AAs. Additionally, most of the PC patients are prescribed concomitant medications to manage age-related comorbidities. Many of these drugs are known modulators of CYP3A5; modulation of CYP3A5 may alter efficacy of ADT in these patients. Our work is focused on characterizing the effect of CYP3A5 modulating drugs on AR signaling in AAs. Methods: q-RT-PCR based profiler assay was used to study effect of CYP3A5 modulation on AR-regulated genes using cDNA from nontarget (NT) and CYP3A5 siRNA treated cells. Confocal microscopy and cell fractionation assays were performed to evaluate and confirm the effect of CYP3A5 modulating drugs on AR nuclear translocation. Genes shortlisted from q-PCR based profiler assays were analyzed for change of expression in response to CYP3A5 modulating drugs. MDAPCA2b (AA origin, *1/*3) and LNCaP (Caucasian, *3/*3) cell lines were used for above experiments. Results: CYP3A5 siRNA pool treatment downregulates AR regulated genes identified using q-PCR based profiler assay, performed with cDNA from CYP3A5 siRNA pool and NT treated MDAPCA2b cells. These downregulated genes include SCL45A3, FKBP5, NCAPD3, MYC, MME, ELL2, PIK3R3, HPRT1 and SPDEF with p-value of ≤0.005. These genes are known to regulate AR nuclear translocation, cell cycle progression, and cell growth. CYP3A5 siRNA treated MDACPA2b/ LNCaP cells showed decreased AR nuclear translocation and PSA production. Commonly prescribed drugs that are either CYP inhibitors (amiodarone, ritonavir) or inducers (phenytoin, rifampicin) were tested for their ability to alter AR signaling. The results show that the CYP inducers promoted AR nuclear migration and downstream signaling whereas CYP3A5 inhibitors blocked it. Further, CYP3A5 siRNA treated MDAPCa2b cells do not show any increase in AR nuclear migration with phenytoin treatment (CYP3A inducer), confirming that the activation of AR activity is specific to changes in CYP3A5 activity. Conclusions: Concomitantly prescribed CYP3A5 modulating drugs can alter downstream AR signaling, cell growth, and ADT efficacy in men, more so in AAs expressing wild-type CYP3A5. We propose to further characterize drug-induced CYP3A5 modulation of AR signaling to develop a guideline for physicians coprescribing CYP3A5 modulating drugs to treat comorbidities in elderly patients undergoing ADT. Citation Format: Priyatham Gorjala, Oscar B. Goodman Jr, Ranjana Mitra. Role of CYP3A5 in modulating androgen receptor signaling and its relevance in African American prostate cancer patients [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr B017.

Abstract B062: Kaiso influences immune signaling of breast cancer exosomes

Abstract Introduction: Exosomes are communication vesicles act as mediator of intracellular transfer of genetic information, act an important role in intercommunication between tumor cells and immune cells. However, the mechanism underlining this cell-cell communication is not well understanding, particularly in African American breast cancer patients. Recently, our lab has demonstrated that Kaiso, a novel bi-modal transcription factor is highly expressed in African American breast cancer and notably, high Kaiso expression correlates with breast cancer aggressiveness and the disparity in survival outcomes of breast cancer patients of African American compared to European American patients. However, the differential expression and biological consequences of Kaiso in immune signaling of breast cancer exosomes has not been studied yet. Herein we demonstrate the biological role of Kaiso in immune signaling in breast cancer exosomes. Methods: In this study we utilized Nanostring immune profiling technology along with multiple in vitro and in vivo assays were used to study the role of Kaiso in breast cancer immune escape. Results: Nanostring pan cancer immune profiling demonstrated that European American breast cancer exosomes exhibited higher expression of TILs markers, T cell activation markers and CD8+T Cells markers compared to African American, while we observed an increase in the expression of the anti-phagocytic molecule CD47 in breast cancer patient exosomes of African American compared to European American patients. In addition to that CD47 and SIRP-α (Signal Regulatory Protein) are highly expressed in Kaiso-scrambled MDA-MB-231 cells (sh-Scr) and exosomes, whereas THBS1, which is a regulator of CD47 expression and is regarded as angiogenesis inhibitor is significantly increased in sh-Kaiso MDA-231 cells and exosomes. Additionally, we observed that Kaiso directly binds methylated sequences in the promoter region of CD47 and THBS1 by ChIP assay. Furthermore, in vivo sh-Kaiso cells injected into athymic mice exhibited delayed tumor formation after four weeks with smaller tumor size as compared to sh-SCR cells, and we observed higher expression of THBS1 with lower expression of CD47 and SIRP-α molecules by IHC and exosomes isolated from invivo tumors, indicating that Kaiso is associated with macrophage mediated immune escape. Conclusion: These findings demonstrate the important role of kaiso in immune signaling through exosomes which may be related with more aggressive cancer phenotype in breast cancer specially in African Americans. Citation Format: Shakir U Ahmed, Brittany Davis, Benjamin Adu Addai, Balasubramanyanam Karanam, Melissa Davis, William Grizzle, Honghe Wang, Clayton C Yates. Kaiso influences immune signaling of breast cancer exosomes [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B062.

Abstract A092: DNA repair proficiency predicts disparities in triple negative breast cancer outcomes

Abstract Breast cancer remains as one of the most lethal type of gynecological cancers in women. Among various subtypes, triple negative breast cancer (TNBC) is the most aggressive and difficult to treat subtype due to limited therapeutic options. African American women have higher death rate from breast cancer than women of other racial and ethnic groups. Additionally, the incidence of germline BRCA1 mutations is much lower among African American women diagnosed with TNBC, than the women of the other races or ethnicities. Mechanistically, increased DNA repair and cell cycle checkpoint activation remain as the foremost reasons behind TNBC tumor resistance to chemotherapy and recurrence. We used a CHK1 inhibitor prexasertib to inhibit cell cycle checkpoint activation in TNBC cells. Interestingly, we found that prexasertib treatment promotes both proteasome-mediated degradation of BRCA1 and RAD51 proteins and affects their transcript levels. Analysis of DNA repair efficiency in prexasertib treated TNBC cells revealed reduction in homologous recombination efficiency compared to control cells. Based on these results, we hypothesized that prexasertib treatment induced homologous recombination deficiency (HRD) should cause synergistic lethality when combined with PARP inhibitors (PARPi) in TNBC cells. As predicted, combined treatment of TNBC cells with prexasertib and PARPi olaparib resulted in increased DNA strand breaks, gH2AX foci and nuclear disintegration, an indicator of mitotic catastrophe. Similarly, these drug combinations also caused synergistic lethality in multiple TNBC cell lines when compared to single drug-treatments, as indicated by combination index (CI) values. Since RAD51 is the downstream effector repair protein in FA-BRCA pathway-mediated HR, we evaluated TCGA data for RAD51 gene expression using UALCAN portal. Computational analysis revealed that RAD51 overexpression in breast tumors compared to normal breast tissues, in particular, TNBC subtype showed highest RAD51 expression compared to other subtypes of breast cancer. Overall, these data show RAD51 as a poor prognostic marker for breast cancer patients. Interestingly, there was a discrepancy in RAD51 expression levels in distinct racial groups, where African American and Asian breast cancer patients showed high RAD51 expression compared to Caucasian breast cancer patients. Consistent with these observations, African American and Asian TNBC patients show decreased survival probability. Based on these data, RAD51 could be a biomarker for aggressive TNBC and racial disparity in breast cancer therapeutic outcomes. As positive correlation exists between RAD51 and CHEK1 expression in breast cancer, in-vitro preclinical data presented here provides additional mechanistic insights for further evaluation of the rational combination of prexasertib and olaparib for improved prognosis and to reduce racial disparity in TNBC. Citation Format: Chinnadurai Mani, Jonnalagadda Shirisha, Awasthi Sanjay, Manne Upender, Palle Komaraiah. DNA repair proficiency predicts disparities in triple negative breast cancer outcomes [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr A092.