Incidence Of Triple-negative Breast Cancer Research Articles

Significance of LIF/LIFR Signaling in the Progression of Obesity-Driven Triple-Negative Breast Cancer.

American women with obesity have an increased incidence of triple-negative breast cancer (TNBC). The impact of obesity conditions on the tumor microenvironment is suspected to accelerate TNBC progression; however, the specific mechanism(s) remains elusive. This study explores the hypothesis that obesity upregulates leukemia inhibitory factor receptor (LIFR) oncogenic signaling in TNBC and assesses the efficacy of LIFR inhibition with EC359 in blocking TNBC progression. TNBC cell lines were co-cultured with human primary adipocytes, or adipocyte-conditioned medium, and treated with EC359. The effects of adiposity were measured using cell viability, colony formation, and invasion assays. Mechanistic studies utilized RNA-Seq, Western blotting, RT-qPCR, and reporter gene assays. The therapeutic potential of EC359 was tested using xenograft and patient-derived organoid (PDO) models. The results showed that adipose conditions increased TNBC cell proliferation and invasion, and these effects correlated with enhanced LIFR signaling. Accordingly, EC359 treatment reduced cell viability, colony formation, and invasion under adipose conditions and blocked adipose-mediated organoid growth and TNBC xenograft tumor growth. RNA-Seq analysis identified critical pathways modulated by LIF/LIFR signaling in diet-induced obesity mouse models. These findings suggest that adiposity contributes to TNBC progression via the activation of the LIF/LIFR pathway, and LIFR inhibition with EC359 represents a promising therapeutic approach for obesity-associated TNBC.

Uncovering novel pathogenic variants and pathway mutations in triple-negative breast cancer among the endogamous mizo tribe.

The incidence of triple-negative breast cancer (TNBC) in India is higher compared to Western populations. The objective of this study is to identify novel and less reported variants in TNBC in Mizoram, a state with a high cancer incidence in India. We analysed whole exome sequencing data from triple-negative breast cancer (TNBC) patients in the Mizo population to identify key and novel variants. Moreover, we analysed reported breast cancer-related genes and pathway alterations. Somatic mutation analysis revealed that TP53 was the most frequently mutated gene and TP53, CACNA1E, IGSF3, RYR1, and FAM155A as significantly mutated driver genes. Based on the ACMG guidelines, we identified a rare pathogenic germline variant of BRCA1 (p.C1697R) in 13% and a likely pathogenic frameshift insertion in RBMX (p.P106Ffs) in 73% of the patients. We also found that the ATM, STK11, and CDKN2A genes were significantly mutated in germline TNBC samples compared to healthy samples. Moreover, we identified novel somatic variants in CHEK2 (p.K182M) and NF1 (p.C245X), and novel germline variants RB1 (p.D111G), CDH1 (p.A10Gfs), CDKN2A (p.V96G), CDKN2A (p.S12Afs*22), MAP3K1 (CAAdelins0), MSH6 (p.L1226_L1230del), and PMS2 (TTCdelins0). Pathway analysis revealed that most somatic mutations were highly associated with PI3K-Akt signalling pathway and MAPK signalling pathways in TNBC. These findings identified novel variants and key genes contributing to disease development and progression. Further analysis of less studied genes, including RBMX, MRC1, ATM, CTNNB1, and CDKN2A, in TNBC may reveal new potential genes for targeted therapeutic strategies and contribute to clinical advancements in the treatment of TNBC.

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

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

An immunoinformatics approach for a potential NY-ESO-1 and WT1 based multi-epitope vaccine designing against triple-negative breast cancer

Breast cancer emerges as one of the most prevalent malignancies in women, its incidence showing a concerning upward trend. Among the diverse array of breast cancer subtypes, triple-negative breast cancer (TNBC) assumes notable significance, due to lack of estrogen, progesterone, and HER-2 receptors. More focus has to be placed on creating effective therapy due to the high prevalence and rising incidence of TNBC. Currently, conventional passive treatments have several drawbacks that have not yet been resolved. On the other hand, as innovative immunotherapy approaches, cancer vaccines have offered promising prospects in combatting advanced stages of TNBC. Therefore, the main objective of this study was to utilize WT1 and NY-ESO-1 antigenic proteins in designing a multiepitope vaccine against TNBC. Initially, to generate robust immune responses, we identified antigenic epitopes of both proteins and assessed their immunogenicity. In order to reduce junctional immunogenicity, promiscuous epitopes were joined using the suitable adjuvant (50S ribosomal L7/L12 protein) and incorporated appropriate linkers (GPGPG, AAY, and EAAAK). The best predicted 3D model was refined and validated to achieve an excellent 3D model. Molecular docking analysis and dynamic simulation were conducted to demonstrate the structural stability and integrity of the vaccine/TLR-4 complex. Finally, the vaccine was cloned into the vector pET28 (+). Thus, analysis of the constructed vaccine through immunoinformatics indicates its capability to elicit robust humoral and cellular immune responses in the targeted organism. As such, it holds promise as a therapeutic weapon against TNBC and may open doors for further research in the field.

Long-term oncologic outcomes following breast cancer surgery in adolescents and young adults: a single-center retrospective analysis.

Breast cancer (BC) in adolescents and young adults (AYAs, aged 15-39 years), remains inadequately understood. The incidence of BC in AYAs has been steadily increasing, making it the second leading cause of cancer-related mortality among females aged 0-39 globally. This study aimed to elucidate the clinical characteristics and long-term outcomes of AYAs and older adults (OAs, aged > 39 years) with BC who underwent surgery. From January 2011 to June 2017, BC patients who underwent surgery were enrolled in this study and divided into AYA group and OA group. Clinical characteristics, recurrence-free survival (RFS), and overall survival (OS) were compared between these two groups, both before and after propensity score matching (PSM). Univariate and multivariate Cox proportional hazard regression analyses were performed to assess the influence of age on OS and RFS. Compared to the OA group, the AYA group exhibited a younger age at menarche (p < 0.001), a lower prevalence of menopausal status (p < 0.001), a reduced occurrence of comorbid conditions (p < 0.001), fewer instances of undergoing mastectomy (p = 0.031), a higher incidence of Triple-Negative Breast Cancer (TNBC) (p = 0.046), and elevated Ki-67 levels (p = 0.036). In terms of prognostic outcomes, within the study cohort, AYAs had a higher mortality rate and poorer long-term survival compared to OAs, both before and after PSM. In the PSM cohort, AYAs experienced a significantly shorter median OS (p < 0.001) and RFS (p < 0.001). Young age (15-39 years) emerged as an independent risk factor for OS (HR 2.659, 95% CI 1.385-5.106, p = 0.003) and RFS (HR 3.235, 95% CI 2.085-5.022, p < 0.001) in BC patients following surgery. Significant differences were identified in the clinicopathological characteristics between AYA and OA patients with BC. In comparison to OA patients, AYA patients exhibited a less favorable long-term prognosis, with young age emerging as an independent prognostic risk factor for both OS and RFS in BC patients following surgery. Further investigations are warranted to develop age-specific therapeutic approaches for AYA BC patients.

Obesity Induces Temporally Regulated Alterations in the Extracellular Matrix That Drive Breast Tumor Invasion and Metastasis.

Obesity is associated with increased incidence and metastasis of triple-negative breast cancer, an aggressive breast cancer subtype. The extracellular matrix (ECM) is a major component of the tumor microenvironment that drives metastasis. To characterize the temporal effects of age and high-fat diet (HFD)-driven weight gain on the ECM, we injected allograft tumor cells at 4-week intervals into mammary fat pads of mice fed a control or HFD, assessing tumor growth and metastasis and evaluating the ECM composition of the mammary fat pads, lungs, and livers. Tumor growth was increased in obese mice after 12 weeks on HFD. Liver metastasis increased in obese mice only at 4 weeks, and elevated body weight correlated with increased metastasis to the lungs but not the liver. Whole decellularized ECM coupled with proteomics indicated that early stages of obesity were sufficient to induce changes in the ECM composition. Obesity led to an increased abundance of the proinvasive ECM proteins collagen IV and collagen VI in the mammary glands and enhanced the invasive capacity of cancer cells. Cells of stromal vascular fraction and adipose stem and progenitor cells were primarily responsible for secreting collagen IV and collagen VI, not adipocytes. Longer exposure to HFD increased the invasive potential of ECM isolated from the lungs and liver, with significant changes in ECM composition found in the liver with short-term HFD exposure. Together, these data suggest that changes in the breast, lungs, and liver ECM underlie some of the effects of obesity on triple-negative breast cancer incidence and metastasis. Significance: Organ-specific extracellular matrix changes in the primary tumor and metastatic microenvironment are mechanisms by which obesity contributes to breast cancer progression.

Population attributable fraction of reproductive factors in triple negative breast cancer by race.

10522 Background: Age-adjusted incidence rates of triple negative breast cancer (TNBC) are higher in African American (AA) women than in non-Hispanic White (White) women. The disproportionate incidence of TNBC in AA women partially drives the 40% higher mortality rate from breast cancer in AA women compared to White women. Several studies have identified lack of breastfeeding and younger age at first birth as risk factors for TNBC. There are large differences in breastfeeding uptake and duration in the US: only 44% of AA women breastfeed for 6 months or longer, compared to 60% of White women. To quantify the contribution of differences in breastfeeding patterns and younger age at first birth to disparities in incidence of TNBC, we calculate the population-attributable fraction (PAF), which is the proportion of the incidence of a disease that may be attributable to a particular exposure. Methods: A systematic review was performed to identify relevant case-control studies. Pooled odds ratios (ORs) for breastfeeding for &lt; 6 months and age at first birth &lt; 25 years were calculated from data extracted from studies using a common effect model. PAF was calculated using the Levin formula. Risk factor population prevalences were extracted from national surveys. Pooled ORs were used as estimates of relative risk (RR). A combined PAF was calculated using the polychoric correlation coefficient between breastfeeding duration and age at first birth to account for contributions of multiple risk factors. Results: Using race specific ORs, the PAF of breastfeeding for &lt; 6 months was 12% (95% confidence interval (CI) 5-20%) among White women and 15% (95% CI 3-26%) among AA women. The PAF of having a child before age 25 was not significantly different from zero for White women (2% (CI -6-11%)) but was significantly different from zero for AA women (21% (CI 5-25%)). The combined PAF was 27% for AA women and 17% for all women in the US. Extrapolating to the US population, we estimated that 4,850 annual cases of TNBC (2,421 among White women and 1,533 among AA women) could be attributed to breastfeeding for &lt; 6 months and age at first birth &lt; 25 years. Conclusions: Given the protective role of breastfeeding against TNBC, policy changes aimed at supporting breastfeeding, addressing structural barriers, and promoting a culture shift could reduce racial disparities in TNBC incidence in the US. [Table: see text]

Racial and ethnic disparities in hospital outcomes following hospitalizations for mastectomy for breast cancer.

e13691 Background: Racial and ethnic disparities in breast cancer (BC) treatment and survival have been well documented. White (W) and Asian (A) women are more likely to have localized BC (BC) than Black (B) or Hispanic (H) women. Furthermore, the incidence of triple negative BC is higher in B women who also have the highest death rates from BC. In this study, we aimed to identify an association between race/ethnicity and outcomes following hospitalization for mastectomy using a large national database. Methods: This study isa retrospective analysis of the National Inpatient Sample database, the largest all-payer inpatient database in the United States, of hospitalizations between 2016-2019. Patients (pts) ≥18 years of age, admitted for mastectomy for BC were included and stratified by race/ethnicity. The outcomes of the study were in-hospital mortality rate, prolonged hospital length of stay, surgical site infection, bleeding complication, cardiac complication, respiratory complication, acute kidney injury, urinary tract infection, and wound dehiscence. Hospitalizations and outcomes were identified using ICD-10 diagnosis and procedure codes. Logistic regression analysis was done to identify an association between race and outcomes. Results: A total of 302,208 pts who were hospitalized for mastectomy were included. Of these 218,092 (72.2%) pts were W, 36,242 (12.0%) were B, 25,130 (8.3%) were Hispanics, and 22,744 (7.5%) were of another race. Among B pts, adverse outcomes were significantly higher (p&lt;0.001), including in-hospital mortality rate (0.2%), prolonged hospital length of stay (64.1%), surgical site infection (0.8%), bleeding complication (4.2%), cardiac complication (0.8%), respiratory complication (0.3%), and acute kidney injury (1.4%). After adjusting for various factors including age, insurance, hospital region, hypertension, diabetes, obesity, peripheral vascular disease, alcohol use, Elixhauser comorbidity index, whether pts underwent axillary lymph node dissection and others, logistic regression was performed. This analysis identified that B pts had significantly higher odds for mortality (adjusted odds ratio [aOR], 2.99, 95% CI: 1.62-5.73), prolonged hospital length of stay (aOR, 1.32, 95% CI: 1.18-1.49), and bleeding complication (aOR, 1.28, 95% CI: 1.13-1.48). Conclusions: Results of our study show that adverse hospital outcomes following mastectomy for BC were significantly higher among Black patients. These outcomes remained significant after adjusting for clinical covariates, raising the possibility of other contributing factors to these differences in outcomes. Study limitations include the lack of information on stage at diagnosis, receptor status, and that Hispanics were categorized under race. Further studies are needed to develop effective interventions to reduce these disparities.

Associations of predictive biomarkers, MHC-I and MHC-II, with clinical and molecular features in a diverse breast cancer cohort.

517 Background: The addition of immunotherapy (IO) to chemotherapy in triple negative breast cancer (TNBC) has improved survival outcomes and recent studies have also shown improvements in pCR rates in early high-risk HR+/HER2- breast cancer. However, these improvements are not without toxicities and thus there is a critical need for biomarkers to select patients that are most likely to benefit from immunotherapy. MHC-I and tumor-specific MHC-II (tsMHC-II) expression are candidate biomarkers for predicting PD-(L)1 checkpoint inhibition benefit and have previously shown potential for predicting treatment response in multiple tumor types, including breast cancer. However, the existing data were generated from clinical trials with limited racial/ethnic diversity. Here we report associations between MHC-I and MHC-II expression and clinicopathological features in a large, racially and ethnically diverse breast cancer cohort. Methods: We performed multiplexed immunofluorescent tissue-based analysis of participants in the Carolina Breast Cancer Study (CBCS). Intrinsic subtype and P53 mutant-like status were identified using RNA-based multigene assays. To evaluate MHC-I we ranked all participants based on tumoral MHC-I intensity, with the top 33% categorized as "MHC-IHigh"; MHC-II+ expression on tumor cells was defined as ≥5% of tumor cells. Association between MHC-I/II and clinicopathological features by race was tested using Chi-square test or fisher-exact test and relative frequency difference (RFD) was calculated. Results: This study included 1630 participants (48% Black and 52% non-Black) with Stage I-III breast cancer. Black participants had a higher incidence of TNBC (25% vs. 12.5%, p=&lt;0.001) and Basal-like (29% vs. 14%, p=&lt;0.001) tumors. Basal-like and TP53 mutant tumors were more frequently observed among Black participants with HR+/HER2- tumors (11% vs. 5.5%, p=0.006 for Basal-like; 26% vs. 17%, p=0.003 for p53 mutant-like). While there was a similar distribution of tsMHC-II+ tumors between Black and non-Black participants, the relative frequency of tsMHC-II+ tumors was significantly more common in Black participants with HR+/HER2- breast cancer compared to non-Black participants (7.9% vs. 5%, p=0.04). Moreover, Black participants also were significantly more likely to have MHC-Ihigh tumors (38.9% vs. 28.4%, p=0.01), which, after IHC subtype stratification, was only significant among participants with HR+/HER2- breast cancer (28.2% vs. 22.3%, p=0.02). Conclusions: In this diverse breast cancer cohort, MHC-I and MHC-II expression, candidate predictive biomarkers of IO benefit, were more prevalent in tumors from Black women with HR+/HER2- breast cancer. These results underscore the importance of diverse and equitable clinical trial enrollment in future IO trials, especially in HR+/HER2- breast cancer.

Abstract PO5-09-08: Cancer Health Disparities among non-Hispanic African women: A systematic review of the disparities, reasons and probable intervention

Abstract Health equity places health inequities in historical and social context and calls for action to address injustice and enhance health. As an ethical and human rights value that drives us to end health inequities, health equality is defined as everyone having a fair and just opportunity to be as healthy as feasible. According to this perspective, structural discrimination and marginalization cause health disparities that can be avoided. If these issues are not resolved, social and economic injustices, bias, and unfavorable outcomes that affect all of us will continue to exist. The idea of cancer health equality recognizes that there is still considerable work to be done to change the social structures and historical momentum that have contributed to different cancer outcomes, and that this work can only succeed if it is done. In USA, non-Hispanic black women experience a complicated and multifaceted disparity in breast cancer incidence and outcome. It's possible that social, economic, and behavioral variables contribute to discrepancies. Black women are less likely to breastfeed after childbirth, statistically more likely to have diabetes, heart disease, and obesity, all of which are risk factors for breast cancer. Compared to white women, they are more likely to lack adequate health insurance or access to medical facilities, which could have an impact on screening, follow-up treatment, and therapy completion. It has become evident via more study that biology also plays a part. Black women are more likely to be diagnosed at younger ages and at higher rates with more aggressive subtypes of breast cancer, such as triple-negative breast cancer (TNBC) and inflammatory breast cancer. The National Institute on Minority Health and Health Disparities (NIMHD) established a research framework to characterize the multiple domains of influence (biological, behavioral, physical environment, sociocultural environment, and health care system) that may act across various levels of influence to impact health. A literature search was conducted using the National Library of Medicine's PubMed search engine. Triple negative breast cancer (TNBC) is a common malignancy in African American women. The incidence of TNBC is higher in women of African ancestry and is associated with overall poor prognosis. This disparity is due to the presence/absence of oncogenes/tumor suppressor genes, mutations and altered signaling pathways that might predispose premenopausal African American women to TNBC. Multiple socioeconomic factors influence the access to standard care, novel treatments and inclusion in clinical trials and contribute to overall prognoses. This review focuses on the epidemiology, molecular alterations, and treatment-related disparities in African Americans with breast cancer. This poster will elaborate the racial disparity in terms of breast cancer among the African-American women in USA, the reasons and it's effects on health equity. Citation Format: Tasnuva Khan Efa. Cancer Health Disparities among non-Hispanic African women: A systematic review of the disparities, reasons and probable intervention [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-09-08.

Abstract PO3-03-10: Race and neoadjuvant treatment of triple negative breast cancer (TNBC) in the US community oncology setting

Abstract Background: TNBC is an aggressive subtype of breast cancer with limited targeted therapies. Black women have twice the incidence of TNBC compared to White women and within TNBC, Black women have worse outcomes than White women. Differences in both tumor biology of TNBC and social determinants of health (SDOH) play a role in observed disparities. The focus of this study is to evaluate SDOH factors associated to differences in the use of neoadjuvant chemotherapy (NC) in Black and White women in the US community oncology setting. Methods: This study was a retrospective, observational, cross-sectional design and used iKnowMed SM EHR data from the The US Oncology Network. Patients diagnosed with TNBC between 03/31/2017 and 09/30/2021 with stages II-III disease of tumor size ≥ 2cm (T2 or higher) were included. The index date was date of TNBC diagnosis and records were assessed from 6 months pre- to 6 months post-diagnosis for NC initiation. Univariable and multivariable logistic regression was conducted to evaluate impact of self-reported race on NC. Age, stage, BMI, insurance, area deprivation index (ADI), size of practice represented by physician count and geographical region, were studied in their mediating and moderating effects1 on the relationship between race and NC treatment. Results: Of the 3321 patients with TNBC identified in this study, 1969 self-reported white and 494 self-reported black (80% and 20% respectively). In multivariable regression accounting for all variables, Black race (OR = 1.57, 95% CI [ 1.02, 2.44], p=0.04), younger age, more advanced stage, obesity, non-Medicaid insurance, and West region, were all found to be positively associated with use of NC. Higher physician count was nominally associated, (p = 0.07). ADI was not found to be associated to NC. Mediator and moderator analysis for the relationship between race and NC showed that only stage and ADI variable inclusion in the model are required for the positive association between black race and NC. This is driven by a significant interaction between ADI and stage (p = 0.027) which differed for Black and White women. Mainly, for Black women ADI is positively associated to NC treatment in stage IIA, but negatively associated in all other stages (interaction term, p = 0.033). For White women, ADI is negatively associated to NC treatment in all stages. Only Black women with stage IIA tend to be treated more instead of less with NC in areas of greater deprivation (greater ADI). BMI presents nominal interactions with both race and stage, where obesity was more strongly associated with NC treatment in Black women (p = 0.088) and in stage IIA (p = 0.086). All other variables presented association to NC treatment without mediation or moderation of the race effect and without detectable differences across stages. Conclusions: Black women with stage IIA appear to be a special subgroup of TNBC patients for whom treatment with NC increases with ADI. Increased ADI generally results in less standard of care treatment; this is observed in this study for White women overall and for Black women in stages &amp;gt; IIA. Black women in areas of greater deprivation with stage IIA disease, may be perceived to be presenting with more aggressive disease and thus offered NC preferentially. This result lends support to the hypothesis that young black women present with a distinct, more aggressive subtype of TNBC in the early stages. Mediator and moderator analyses are important tools in elucidating the relationships between factors underlying racial disparities in both care and outcomes. 1. Hayes AF, Rockwood NJ. Regression-based statistical mediation and moderation analysis in clinical research: Observations, recommendations, and implementation. Behav Res Ther. 2017 Nov;98:39-57. Odds ratios for multivariable analysis –insert figure image– Race, stage and ADI –insert figure image– Race and BMI in stage IIA –insert figure image– Citation Format: Paola Raska, Joseph Dye, Nicholas J Robert, Angel Kidd, Michael Danso. Race and neoadjuvant treatment of triple negative breast cancer (TNBC) in the US community oncology setting [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-03-10.

Abstract 812: Association of obesity with the early onset and diagnosis of triple negative breast cancer in black women

Abstract Breast cancer (BC) continues to be the most common cancer and the second leading cause of cancer-related death in American women. Furthermore, it affects Black women more adversely than their White counterparts, who experience an early disease onset, diagnosed more often with aggressive triple-negative breast cancer (TNBC) molecular subtype, and face greater mortality. The reasons for these disparities; however, are largely unknown. Here, using a retrospective dataset, we examined the association of body mass index (BMI) with BC early onset and diagnosis with specific molecular subtype in race-based distributions. Study cohort included 1085 BC patients, who visited University of South Alabama Health clinics between October, 2017 and March, 2022. Patients were divided into three BMI [(normal weight, NW (&amp;lt;24.9), overweight, OW (25-29.9), and obese, Ob (&amp;gt;30.0)], three age (&amp;lt;45 years, 45-65 years, &amp;gt;65 years), and four molecular subtypes [Luminal A (HR+, HER2-), Luminal B (HR+, HER2+), HER2 enriched (HR-, HER2+), and TNBC (HR-, HER2-) categories. The data show a higher prevalence of BC in Ob women (46%) than OW (27%) and NW (27%) women of all age groups and its incidence was much greater in Ob Black women (61%) than Ob White women (39%). Further, Black women had nearly twice higher diagnosis at an early age than White women. Moreover, Ob Black women had over 7- and 1.5-folds higher incidence of early onset BC than NW and OW Black women, respectively, whereas, early onset BC did not exhibit a correlative pattern in White women. Luminal A and TNBC subtypes were the most common in women with early onset BC and Black women exhibited more than twice incidence of TNBC (32%) compared to the White women (14%) of all ages. In contrast, incidence of luminal A subtype was less prevalent in Black (57.4%) than in White (72.6%) women. Interestingly, both luminal A and TNBC subtypes were also more prevalent in Ob women; however, the risk of being diagnosed with TNBC increased dramatically in Ob Black women compared to Ob White women. Together, these findings establish obesity as a major underlying cause of early onset BC and TNBC diagnosis in Black women, which could be targeted to diminish the BC disparity gaps. Citation Format: Sarabjeet Kour Sudan, Amod Sharma, Kunwar Somesh Vikramdeo, Wade Davis, Cindy Nelson, Karan Singh, Ajay Pratap Singh, Seema Singh. Association of obesity with the early onset and diagnosis of triple negative breast cancer in black women [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 812.

Abstract 6116: Rs2363956, a coding variant of ANKLE1, drives triple-negative breast cancer disparity by altering DNA damage response

Abstract African American women have a 42% higher breast cancer mortality rate than European American women and are over twice as likely to develop triple-negative breast cancer (TNBC). We have previously demonstrated that this higher incidence of TNBC is tied to ancestry-related biological determinants of TNBC tumor biology, including possible novel genetic drivers that may result in reduced treatment efficacy. Within the TCGA BRCA cohort, we have previously found that high ANKLE1 gene expression significantly improves survival in European Americans but not in African Americans. This difference may be attributed to the presence of a polymorphic variant of ANKLE1, rs2363956. The minor G allele of rs2363956 leads to a structural alteration in ANKLE1, potentially changing its functionality. Interestingly, among our International Center for the Study of Breast Cancer Subtypes (ICSBCS) patient cohort, we observed that 41-53% of European Americans with TNBC were homozygous for the G allele as compared to only ~14% of African American patients. These observations suggest that the presence of the rs2363956 polymorphic variant may drive differences between European American and African American patients. ANKLE1 is a conserved gene among eukaryotic organisms and has been reported as an endonuclease implicated in DNA damage repair. Among our patient cohort (n=62) we have observed that patients homozygous for the G allele (n=13) are enriched for COSMIC mutational signatures 2 and 13 (P≤.05 and P≤.001, respectively), that denote overactivity of APOBEC deaminases, as compared to patients homozygous for the T allele (n=19). Therefore, the increased mutational burden present in those patients caused by APOBEC overactivity may sensitize those cancer cells to chemotherapeutics or other therapies. Alternatively, the patients homozygous for the T allele may have an increased capacity for DNA damage repair that does not involve APOBEC activity. Using the MDA-MB-231 cell line, which is homozygous for the T allele, we performed an ANKLE1 knockdown with siRNA in order to examine the impact of ANKLE1 loss on DNA damage repair. Upon treatment with 25 μM, 10 μM, and 5 μM of Cisplatin we observe increased γ-H2AX and cell shrinkage in the ANKLE1 knockdowns as compared to cells treated with control siRNA, denoting increased DNA damage and apoptosis. Additionally, after knocking down ANKLE1 we observed decreased proliferation. Based on these observations, ANKLE1 is critical for DNA damage response in TNBC cells and may be implicated in the genomic stability of TNBC. The polymorphic variants observed may impact this function and in part explain why European American patients have improved survival, as compared to African American patients. Citation Format: Yanira Guerra, Rachel Martini, Olivier Elemento, Melissa B. Davis. Rs2363956, a coding variant of ANKLE1, drives triple-negative breast cancer disparity by altering DNA damage response [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 6116.

Abstract 2138: Understanding the link between breastfeeding and the risk of breast cancer through comparative analysis of the murine-based model of mammary gland involution

Abstract Introduction: A meta-analysis of 47 global epidemiological studies highlights a higher breast cancer risk in women who did not breastfeed or breastfed for a short time. Further studies showed this is especially true for triple-negative breast cancer (TNBC) patients. Premenopausal AA women (AAW) have a lower prevalence of breastfeeding and a higher incidence of TNBC and mortality. Our previous study compares short-term breastfeeding, abrupt involution (AI) with prolonged breastfeeding called gradual involution (GI), revealing that AI alone induces ductal hyperplasia four months postpartum. Our current investigation delves into early events during AI versus GI, employing a comprehensive approach encompassing histology, gene expression, and myeloid cell involvement. Methods: Utilizing FVB female mice, we conducted a comparative analysis of AI and GI. AI involved early pup removal, while GI was achieved through staggered weaning. The evaluation included analysis of histomorphology, gene/protein expression, and myeloid cell infiltration. Sequential mammary gland (MG) changes were monitored through H&amp;E staining, TUNEL assay, and DNA damage analysis. 3D-organoid cultures of luminal progenitors (LPs) were employed to assess the impact of AI versus GI. qRT-PCR, IHC, Western blot, and flow cytometry/multiplex imaging were employed for the differential expression analysis of molecular and cellular factors associated with AI/GI. Results: Our research showed that AI had early adipocyte repopulation, rapid cell death, DNA repair, and myeloid cell infiltration, resulting in a chronically inflamed microenvironment. In contrast, the GI triggers a controlled immune response and prolonged cell death, facilitating comprehensive remodeling of the MG. Our flow cytometric or multiplexing imaging analyses revealed that AI-affected glands exhibit an enrichment of CCL9-producing CD206+ M2-like macrophages and CD11b+Gr1+ myeloid-derived suppressor cells. Moreover, exogenous CCL9 treatment on LPs in 3D-organoid culture results in disorganized acinar-type organoids, mirroring morphological differences observed in LPs from AI mammary glands on day56 PPM. Further analysis of CCL9 treated organoids revealed the expansion of Esr1- LPs population in ex-vivo organoid culture which might indicate an increase in the putative cells of origin of TNBC. Conclusion: Our studies comparing AI and GI demonstrate that AI is producing a pro-tumorigenic environment in the breast. It is important to note that prolonged breastfeeding protects the breast, although this cannot be a singular risk factor for TNBC. Therefore, understanding the mechanism will lead to prevention strategies to improve outcomes for all women but, has the potential to have a significant benefit in AAW. Citation Format: Sanjay Mishra, Neelam Shinde, Maria Cuitino, Morgan Bauer, Dinesh Ahirwar, Vijaya Bharti, Kate Ormiston, Resham Mawalkar, Sara Alsammerai, Gautam Sarathy, Xiaoli Zhang, Anna Vilgelm, Ramesh Ganju, Sarmila Majumder, Bhuvaneswari Ramaswamy. Understanding the link between breastfeeding and the risk of breast cancer through comparative analysis of the murine-based model of mammary gland involution [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 2138.

Abstract A073: Prisma Health Cancer Institute: Racial Analysis in Cancer Patients Using Molecular, Clinical, and Demographic Data

Abstract Background: Racial disparities among cancer patients have become a national concern because of their effects on cancer prognosis This study aims to tackle these disparities by conducting a comprehensive examination of the racial composition and potential inequalities among cancer patients treated at the Prisma Health Cancer Institute. The findings from this study will be compared with national trends to provide insights into the impact of race on patient treatment outcomes. Factors such as cancer staging, histology, molecular characteristics, treatment, demographics, and lifestyle will be analyzed to gain a comprehensive understanding of their impact on patient treatment outcomes. The significance of this study lies in its potential to benefit the community served by the Prisma Health Cancer Institute. Armed with localized and targeted information about racial disparities, that allows the hospital to focus on ways to enhance patient care. Methods: The study includes 586 cancer patients diagnosed with breast (397) and lung (171) cancer between 2014 and 2022. Patients were categorized by race: Asians, African Americans, Hawaiian/Pacific Islanders, Latinos, Multi-Race, Whites, and patients with missing race information. Through the JMP software, the analysis of racial composition was performed in diagnosis distribution, cancer staging, cancer histology, smoking status, cancer molecular subtypes, and other factors. Results: In the studied group, African American males had a higher likelihood (3.17%) of breast cancer diagnosis compared to White males (0.84%). In addition, the African American population showed a greater proportion of stage IV lung cancer (11.11%) compared to the White population (4.63%). Our data for stage IV lung cancer and breast cancer in males were similar to national trends with African Americans having an increased probability of each of these characteristics. Notably, the incidence of triple-negative breast cancer was similar between African Americans (14.63%) and Whites (13.18%) in this cohort. Our data was different for triple-negative breast cancer because of the similarity found between the African American and the White population. Conclusion: This study provides a focused examination of patients treated at the Prisma Health Cancer Institute and their disease prognosis, shedding light on population differences in two highly lethal cancers. The research aims to improve treatment and care for minority patients. Findings contribute to a better understanding of racial disparities in cancer outcomes, potentially leading to targeted interventions. Also, with more education, this research has the potential to lead to better physician-patient interactions leading to more equitable healthcare. Citation Format: Brittany K Austin, Julie Martin, Jeff Edenfield, Anna Blenda. Prisma Health Cancer Institute: Racial Analysis in Cancer Patients Using Molecular, Clinical, and Demographic Data [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A073.

Hormone Receptors and HER2 Status of Patients with Breast Cancer in a Tertiary Center of Nepal: A Descriptive Cross-Sectional Study

Introduction: The second most prevalent cancer among women in Nepal is breast cancer. The assessment of human epidermal growth factor receptor-2 (HER2), progesterone receptor (PR), and estrogen receptor (ER) status in patients with breast cancer is currently regarded as standard practice because of its prognostic and predictive value. This study aims to find the incidence of Hormone receptor and HER2 status in patients with breast cancer. Methods: This was a descriptive observational cross-sectional study that assessed the immunohistochemistry markers of different histological types of breast cancer patients who visited a tertiary center in Nepal. Retrospective data from August 1, 2022, to July 30, 2023, were gathered from computer records of all the patients diagnosed with breast cancer who visited the Tribhuvan University Teaching Hospital (TUTH). SPSS version 26.0 was used for statistical analysis. Results: A total of 102 patients with breast cancer were included. The mean age of the patients was 50.51±12.08 years. Only one patient was male. The analysis showed that 62 (60.78%) of total patients had ER/PR positive breast cancer and 40 (39.2%) were HER2 positive with a higher number among Janajati and the age group 41-60 years. Similarly, the incidence of triple-negative breast cancer was 21 (20.59%) of all patients. Conclusion: The majority of breast cancer patients in our study were ER/PR positive, followed by HER2-positive and triple-negative cases. A higher prevalence was observed among the Janajati ethnic group and those aged 41-60 years.

Risk factors and survival of triple-negative breast cancer among breast cancer patients: Ten-year cross-sectional study in the southwestern Iranian population.

Breast cancer results from genetic and epigenetic mutations, contributing significantly to cancer-related morbidity and mortality. This study aimed to determine the prevalence and survival rates of triple-negative breast cancer (TNBC) among breast cancer patients in southwestern Iran over a ten-year period. This retrospective cross-sectional study aims to assess prognostic factors associated with survival in women diagnosed with breast cancer in Iran's southwestern region over a ten-year period (2007-2017). Data were collected from patients who visited the Clinical Oncology Department at Golestan Hospital in Ahvaz (the breast cancer center of the Southwestern country). The study enrolled women diagnosed with TNBC using a census method and data from medical records. The primary outcome (survival rates) and secondary outcomes (demographic data, diagnostic stages, and three receptors estrogen receptors [ER], progesterone receptor [PR], human epidermal growth factor receptor 2 [HER2] status) were collected. Breast cancer was diagnosed in 2641 women over ten years; TNBC was diagnosed in 227 individuals (8.59%). Statistical analysis revealed a significant correlation between negative ER status and TNBC (p > 0.05). Furthermore, the prevalence of TNBC differed significantly from that of other types of breast cancer (p = 0.0001). The variables of age, HER2, PR, and TNBC grade did not differ significantly (p > 0.05). The overall disease-free survival rate over 5 years was 88.1%, while the rate for individuals without recurrence was 77.97%. This study highlights a differentially low incidence of TNBC in the southwestern part of Iran when compared to other regions; genetic or epigenetic influences may explain this discrepancy. ER-negative status is a crucial prognostic indicator in diagnosing TNBC. The incidence of this disease is expected to rise by 100% in 2 years and 77.97% in 5 years.

A Study on the Factors and Prediction Model of Triple-Negative Breast Cancer for Public Health Promotion.

This study was conducted to identify the risk causes and predictive models based on the clinical features of patients with breast cancer classified as triple-negative breast cancer (TNBC) and non-triple-negative breast cancer (non-TNBCs) using Korean cancer statistics. A total of 2045 cases that underwent three types of hormone receptor tests were obtained from Korean cancer data in 2016. Research data were analyzed with the software SPSS Ver. 26.0. TNBC and non-TNBCs accounted for 12.4% and 87.6% of the data, respectively. Tubular and lobular tumors occurred most frequently in the external quadrant of the breast (C50.4-C50.5; 43.1%). Compared to non-TNBCs, the incidence of TNBC was the most common in patients under the age of 39 (19.5%), followed by those over the age of 70 (17.3%). Tumors larger than 2 cm accounted for 16.0%, which was higher than the number of tumors smaller than 2 cm. Cases in stage IV cancer represented 21.7% of the data. Additionally, 21.0% of the patients were in the SEER stage of distant metastasis, which was the most prevalent SEER (surveillance, epidemiology, and end outcomes) stage. Neoadjuvant therapy was administered more frequently, with a rate of 24.1%. In the logistic regression and decision-making tree model, the variables that affected TNBC were age, differentiation grade, and neoadjuvant therapy. The predictive accuracies of logistic regression and decision-making tree models were 87.8% and 87.6%, respectively. In a decision-marking tree model, the differentiation grades of TNBC affect neoadjuvant therapy, and neoadjuvant therapy affects the cancer stage. Therefore, in order to promote the health of breast cancer patients, it is urgent to apply an intensive early health check-up program for those in their 40s and 50s with a high prevalence of TNBC. For patients with breast cancer, in TNBC cases, except for poorly differentiated cases, neoadjuvant therapy must be applied first at all differentiation grades. The establishment of a policy system is necessary for the success of this process.

Does triple negative breast cancer subtype carry poorer prognosis as compared to non-triple negative breast cancer lesion - A study from a tertiary hospital

Background: The breast cancer (BC), in spite of tremendous advances has continue to remain an enigma. The major change in understanding of BC has taken place after understanding of molecular biology. Aims and Objectives: The objectives are as follows:(1) To categorize the incidence of triple negative BC (TNBC) in hospital based data. (2) To study the prognostic outcomes of TNBC. Materials and Methods: The study was an observational prospective for the period of 18th months, from February 2014 to August 2015, where total 146 cases were selected. The data regarding age, sex, tumor size, stage, grade, nodal status, Nottingham prognostic index (NPI), morphology was noted. All patients underwent immunohistochemistry (IHC) study, maintaining higher quality assurance in the same IHC laboratory. Results: Our study revealed that out of 146 patients, 71 patients are TNBC. The mean age of presentation was 54.06 years in TNBC group. About 69.0% patients presented with Grade III tumor and 74.6% patient presented with NPI ≥5.4 among TNBC. However, 56% patients presented with NPI ≥5.4 among NON TNBC. Most of the morphological variant was IDC (95.8%), 85.9% patients presented with only lymph nodes metastasis among TNBC. Conclusion: The study is tremendously significant from Indian perspective. It proofs that TNBC had the point of diagnosis, seems to be more aggressive. It suggests that Indian BC is likely to be younger at presentation as compared to its Western counterpart.

Abstract 441: Targeting MKK3-MYC complex to reduce racial survival disparity in breast cancer

Abstract Breast cancer is the most common cancer and the leading cause of cancer-related death in women. The triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer. African American women experience up to 2-fold higher incidence of TNBC as compared to White women. Moreover, African Americans die from breast cancer at up to 40% higher rate than White and Hispanic women. However, there is no therapeutic options are currently available to reduce survival disparity in breast cancer. To address this unmet medical need, we develop novel computational methods combined with experimental chemical biology and high-throughput screening (HTS) technologies. Using our specially designed bioinformatics workflow, we discovered that high expression of mitogen-activated protein kinase kinase 3 (MKK3) strongly correlates with worsened clinical outcomes in African American TNBC patients. The analysis of TNBC patient genomic profiles revealed that MKK3 promotes TNBC in part by activating the major tumor driver transcription factor MYC. MYC is a highly appealing therapeutic target in TNBC, however, no approved MYC inhibitors are available. We found that MKK3 binds and activates MYC through protein-protein interaction (PPI) in TNBC cells. Both genetic and pharmacological inhibition of the MKK3/MYC complex suppresses MYC activity and the viability of TNBC cells. Thus, MKK3/MYC interaction represents a novel vulnerability for therapeutic intervention in TNBC. By combining computational modeling with experimental HTS, we have discovered the first small molecule MKK3/MYC PPI inhibitors. For example, a quinoline derivative SGI-1027 disrupts the MKK3/MYC complex in cells and in vitro, inhibits MYC transcriptional activity, and suppresses the viability of TNBC cells. Together, our studies revealed a novel mechanism of TNBC tumorigenesis through MKK3-induced MYC activation, establish a new HTS to enable the discovery of potent and selective inhibitors to regulate MKK3/MYC complex, and may open new clinical strategies to reduce racial disparity in TNBC mortality. Acknowledgments: This work was supported in part by Mary Kay Ash Foundation Grant for Cancer Research (A.A.I.), Emory initiative on Biological Discovery through Chemical Innovation (A.A.I.), NCI’s Informatics Technology for Cancer Research (ITCR) Program (R21CA274620, A.A.I.), NCI Cancer Target Discovery and Development (CTD^2) Network (U01CA217875, H.F.), NCI Emory Lung Cancer SPORE (P50CA217691, H.F.), Career Enhancement Program (A.A.I., P50CA217691), Winship Cancer Institute (NIH 5P30CA138292).