Incidence Of Triple-negative Breast Cancer Research Articles

Abstract P6-05-09: Cardiovascular Risk Evaluation for Breast Cancer Survivors: A Pilot Study

Abstract Introduction: Breast cancer (BC) is the most common cancer in women in the United States (US). With advances in screening and treatment, there are increasing numbers of BC survivors. Preexisting or emerging cardiovascular (CV) risk factors and some cancer therapies put BC survivors at risk for long-term CV disease (CVD). ASCO clinical practice guidelines for prevention and monitoring of cardiac dysfunction recommend treatment of CV risk factors in cancer survivors, however, the application of these guidelines in clinical practice presents several challenges. In this pilot study, we describe the feasibility of performing CVD risk assessment in a cohort of BC survivors in a single institution in an urban area that serves mostly Black/African American (AA) populations. Methods: We identified patients with early-stage BC treated between 2015 and 2022. Patients underwent CVD risk assessment including vital signs, hemoglobin A1c, lipid panel, transthoracic echocardiogram (TTE), 6-minute walk test (6MWT), troponin T, and B-type natriuretic peptide (NT-ProBNP). The primary objective of the study was to describe the feasibility of performing a CVD risk assessment. Results: Out of 69 eligible patients who were approached for the study, 50 were enrolled and completed the CVD risk assessment (72%). Among 19 patients who did not enroll or complete the risk assessment, time constraints to complete the work up was the predominant factor. The median age was 60.5 years (SD = 13.65; range 34-86), 76% self-identified as Black/AA, 14% as White, and 95% as Non-Hispanic. Half of the patients had hormone-receptor-positive BC, 34% human epidermal growth factor receptor 2 (HER2) positive disease (and received HER2-targeted therapies), and 28% triple-negative breast cancer (TNBC). In terms of treatment, 34% received anthracycline-containing regimens. CVD risk assessment results are shown in Table 1. Twenty-four (48%) of the patients had metabolic syndrome defined as the presence of 3 out of 5 CV risk factors (waist circumference, hypertension, low HDL, high triglycerides, insulin resistance). Although all patients had an ejection fraction (EF) above 55%, 7 patients (14%) had an abnormal global longitudinal strain (GLS). The median number of meters in the 6MWT was 369 (SD 94.46, range 67-531); 74% of patients walked a shorter distance than predicted by age and body mass index, indicating significant physical impairment. All patients had a troponin T value below the 99th percentile. The most frequent modifiable CVD-risk factors included obesity and hypertension. Conclusion: Performing a low-cost CVD risk assessment in a population of mostly Black/AA BC survivors was feasible in this pilot study. We identified a high prevalence of CVD risk factors, with 48% of patients meeting metabolic syndrome criteria and the majority of patients demonstrated a very high level of functional impairment measured by 6MWT. Our findings underscore the importance of survivorship care focused on CVD risk in BC survivors. Limitations include the small sample size, single-institution study, and lack of CV and BC-related outcomes. The higher incidence of TNBC could be explained by a selection bias of patients receiving cytotoxic chemotherapy and the higher incidence of TNBC in the Black/AA population. Future research will focus on implementing this assessment in the survivorship clinic and establishing interventions to decrease CVD risk in cancer survivors. Table 1. Clinical Measurements & Outcomes (n=50). Citation Format: Ilana Schlam, Dipanjan Debnath, Christopher Gallagher, Asma A. Dilawari, Shruti R. Tiwari, Malate Aschalew, Hiwot Guebre-Xabiher, Stacy Malloy, Kristi Graves, Ana Barac, Ami Chitalia. Cardiovascular Risk Evaluation for Breast Cancer Survivors: A Pilot Study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-05-09.

Abstract P4-03-24: State variation in racial and ethnic disparities in triple-negative breast cancer rates: NPCR-SEER incidence data, 2015-2019

Abstract Background: Triple-negative breast cancer (TNBC) (i.e., estrogen receptor-negative, progesterone receptor-negative, and human epidermal growth factor receptor type 2-negative) is an aggressive subtype of breast cancer, more frequently diagnosed among non-Hispanic Black women than other racial/ethnic groups in the United States. TNBC risk also varies by location, but limited data exist for state-level variation in the racial/ethnic disparities in TNBC risk. Methods: Data for TNBC diagnosed at all ages during 2015-2019 were obtained from the National Program of Cancer Registries and Surveillance, Epidemiology & End Results for racial/ethnic groups classified as non-Hispanic American Indian/Alaska Native (AIAN), non-Hispanic Asian or Pacific Islander (API), non-Hispanic Black (Black), Hispanic, or non-Hispanic White (White). State-specific incidence rates were available for 8, 23, and 36 states for AIAN, API, and Hispanic women, respectively, and 38 states and Washington, D.C. for Black women and 50 states and Washington, D.C. (hereafter referred to collectively as “states”) for White women. State-specific rates were compared within and between racial/ethnic groups using incidence rate ratios (IRR). Results: Nationally, the age-standardized incidence rate of TNBC was the highest among Black women (25.1 per 100,000), followed by White (12.9 per 100,000), AIAN (11.1 per 100,000), Hispanic (11.1 per 100,000), and API (9.0 per 100,000) women. The highest state-specific rates were found among Black women in Delaware, Missouri, and Louisiana (>30 per 100,000) and the lowest rates were among API women in Oregon and Pennsylvania (< 7 per 100,000). State variations within a population were relatively larger among AIAN (2.8-fold) and Hispanic (2.3-fold) women, and smaller among White women (1.65-fold). Compared with White women, Black women had a higher rate of TNBC in all 39/39 states with the greatest IRRs in Delaware (2.31, 95%CI=1.90-2.81), Missouri (2.28, 95%CI=2.08-2.50), and Louisiana (2.20, 95%CI=2.02-2.38) and the lowest IRRs in Minnesota (1.38, 95%CI=1.12-1.68) and Colorado (1.38, 95%CI=1.12-1.68). In contrast, API women had a lower rate than White women in 22/23 states, except for Nevada, with the lowest IRR in Oregon (0.50, 95%CI=0.34-0.70) and the highest IRR in New York (0.82, 95%CI=0.75-0.90). The rate among Hispanic compared with White women did not differ statistically significantly in 23/36 states but was lower in 12/36 states, with the lowest IRR in Ohio (0.57, 95%CI=0.43-0.74), and higher in Massachusetts (1.21, 95%CI=1.04-1.39). The rate among AIAN compared with White women did not differ in 5/8 states but was lower in Arizona (0.53, 95%CI=0.38-0.73) and North Carolina (0.68, 95%CI=0.46-0.96), and higher in Oklahoma (1.30, 95%CI=1.09-1.54). Conclusions: State variations in TNBC incidence rates both within and between populations are substantial, signifying the important role of potentially modifiable risk factors in determining the risk of TNBC by state and race/ethnicity. This finding highlights the need for more research to identify factors contributing to these variations to develop more effective preventive measures. Meanwhile, to mitigate the impact of the disproportionate burden of TNBC across states and racial/ethnic groups, universal access to screening modalities and timely, guideline-concordant treatments is essential. Citation Format: Hyuna Sung, Daniel Wiese, Ismail Jatoi, Ahmedin Jemal. State variation in racial and ethnic disparities in triple-negative breast cancer rates: NPCR-SEER incidence data, 2015-2019 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-24.

Association of Neighborhood-Level Household Income With 21-Gene Recurrence Score and Survival Among Patients With Estrogen Receptor–Positive Breast Cancer

While low income has been associated with a higher incidence of triple-negative breast cancer, its association with 21-gene recurrence score (RS) among patients with estrogen receptor (ER)-positive breast cancer remains unclear. To evaluate the association of household income with RS and overall survival (OS) among patients with ER-positive breast cancer. This cohort study used data from the National Cancer Database. Eligible participants included women diagnosed between 2010 and 2018 with ER-positive, pT1-3N0-1aM0 breast cancer who received surgery followed by adjuvant endocrine therapy with or without chemotherapy. Data analysis was performed from July 2022 to September 2022. Low vs high neighborhood-level household income levels defined as below vs above the median household income of $50 353 based on each patient's zip code. RS (a score ranged from 0 to 100 based on gene expression signatures indicating the risk of distant metastasis, with RS of 25 or below indicating non-high risk and RS above 25 indicating high risk) and OS. Among 119 478 women (median [IQR] age, 60 [52-67] years; 4737 [4.0%] Asian and Pacific Islander, 9226 [7.7%] Black, 7245 [6.1%] Hispanic, 98 270 [82.2%] non-Hispanic White), 82 198 (68.8%) and 37 280 (31.2%) patients had high and low income, respectively. Logistic multivariable analysis (MVA) showed that, compared with high income, low income was associated with higher RS (adjusted odds ratio [aOR], 1.11; 95% CI, 1.06-1.16). Cox MVA showed that low income was also associated with worse OS (adjusted hazards ratio [aHR], 1.18; 95% CI, 1.11-1.25). Interaction term analysis showed a statistically significant interaction between income levels and RS (interaction P < .001). On subgroup analysis, significant findings were noted among those with RS below 26 (aHR, 1.21; 95% CI, 1.13-1.29), while there was no significant OS difference between income levels among others with RS of 26 or higher (aHR, 1.08; 95% CI, 0.96-1.22). Our study suggested that low household income was independently associated with higher 21-gene recurrence scores and significantly worse survival outcomes among those with scores below 26, but not 26 or higher. Further studies are warranted to investigate the association between socioeconomic determinants of health and intrinsic tumor biology among patients with breast cancer.

Identifying Biomarkers Using Support Vector Machine to Understand the Racial Disparity in Triple-Negative Breast Cancer.

With the properties of aggressive cancer and heterogeneous tumor biology, triple-negative breast cancer (TNBC) is a type of breast cancer known for its poor clinical outcome. The lack of estrogen, progesterone, and human epidermal growth factor receptor in the tumors of TNBC leads to fewer treatment options in clinics. The incidence of TNBC is higher in African American (AA) women compared with European American (EA) women with worse clinical outcomes. The significant factors responsible for the racial disparity in TNBC are socioeconomic lifestyle and tumor biology. The current study considered the open-source gene expression data of triple-negative breast cancer samples' racial information. We implemented a state-of-the-art classification Support Vector Machine (SVM) method with a recurrent feature elimination approach to the gene expression data to identify significant biomarkers deregulated in AA women and EA women. We also included Spearman's rho and Ward's linkage method in our feature selection workflow. Our proposed method generates 24 features/genes that can classify the AA and EA samples 98% accurately. We also performed the Kaplan-Meier analysis and log-rank test on the 24 features/genes. We only discussed the correlation between deregulated expression and cancer progression with a poor survival rate of 2 genes, KLK10 and LRRC37A2, out of 24 genes. We believe that further improvement of our method with a higher number of RNA-seq gene expression data will more accurately provide insight into racial disparity in TNBC.

Abstract A069: The impact of race and glycemic control on triple negative breast cancer in type 2 diabetics

Abstract Although the association between type 2 diabetes (T2D) and breast cancer is well established, the relationship between glycemic control and breast cancer by hormone receptor subtype is poorly understood. We sought to investigate the relationship between glycemic control and the incidence of triple negative breast cancer (TNBC) among patients with T2D. Furthermore, we hoped to elucidate whether this hypothesized risk was further moderated by demographic factors, such as patient race. METHODS: A retrospective cohort study evaluating 1,679 patients with T2D diagnosed with breast cancer between 2010-2020 was conducted. Data including tumor hormone receptor status, Hgb A1c measured within 3 months of cancer diagnosis date, and patient race were ascertained via chart review. Tumor subtype was categorized as either hormone receptor-positive (ER+, PR+ or both) or triple-negative (ER/PR- and HER2/neu-). Based on Hgb A1c measurements, subjects were assigned to one of three categories of glycemic control: well-controlled (Hgb A1c less than 7.0), moderately controlled (Hgb A1c 7.0-9.4), or poorly controlled (Hgb A1c greater than or equal to 9.5) T2D. RESULTS: Accounting for all study subjects, the incidence of TNBC increased with worsening glycemic control (12.7% vs 15.2% vs 21.8%, P=0.040). Among non-Hispanic White patients, a significant increase in the incidence of TNBC with worsening glycemic control was also observed (9.2% vs 13.2% vs 21.9%, P=.010). Among Black patients, the incidence of TNBC did not significantly change across the three levels of glycemic control (17.6% vs 17.6% vs 22.7%, P=.700). Comparing the incidence rates of breast cancer by subtype between non-Hispanic White and Black patients across the three categories of glycemic control, a significant difference was only observed among patients with well-controlled T2D (17.6% of Black patients with TNBC versus 9.2% of non-Hispanic White patients, P&amp;lt;.001; 87.4% of non-Hispanic White patients with hormone receptor positive breast cancer versus 75.6% of Black patients, P&amp;lt;.001). CONCLUSION: Poor glycemic control is associated with a higher incidence of TNBC in patients with T2D overall. A significant increase in the incidence of TNBC with lesser degrees of glycemic control was only observed in the population of non-Hispanic white patients. Although previous studies have shown that Black patients are 2-3 times more likely to develop TNBC than their non-Hispanic White counterparts, a statistically significant racial difference in the rates of breast cancer by subtype was only noted among those with well-controlled T2D. Together our data not only suggests that T2D may serve as a modifiable risk factor for the development of TNBC, but also that the risk conferred by poor glycemic control may bear more significance for non-Hispanic White patients than Black patients. Citation Format: Madison E. Miller, Myah Bell, Priscella Holland, Vanessa Ibrahim, Gordon Jacobsen, Monique Swain. The impact of race and glycemic control on triple negative breast cancer in type 2 diabetics [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr A069.

Associations between quantitative measures of TDLU involution and breast tumor molecular subtypes among breast cancer cases in the Black Women’s Health Study: a case–case analysis

BackgroundTerminal duct lobular units (TDLUs) are the structures in the breast that give rise to most breast cancers. Previous work has shown that TDLU involution is inversely associated with TDLU metrics, such as TDLU count/100mm2, TDLU span (µm), and number of acini/TDLU, and that these metrics may be elevated in the normal breast tissue of women diagnosed with triple-negative (TN) compared with luminal A breast tumors. It is unknown whether this relationship exists in Black women, who have the highest incidence of TN breast cancer and the highest overall breast cancer mortality rate. We examined relationships between TDLU metrics and breast cancer molecular subtype among breast cancer cases in the Black Women’s Health Study (BWHS).MethodsWe assessed quantitative TDLU metrics (TDLU count/100mm2, TDLU span (µm), and number of acini/TDLU) in digitized 247 hematoxylin and eosin-stained adjacent normal tissue sections from 223 BWHS breast cancer cases, including 65 triple negative (TN) cancers (estrogen receptor (ER) negative, progesterone receptor (PR) negative, human epidermal growth factor-2 (HER2) negative) and 158 luminal A cancers (ER positive, HER2 negative). We evaluated associations of least square mean TDLU metrics adjusted for age and body mass index (BMI) with patient and clinical characteristics. In logistic regression models, we evaluated associations between TDLU metrics and breast cancer subtype, adjusting for age, BMI, and tumor size.ResultsOlder age and higher BMI were associated with lower TDLU metrics and larger tumor size and lymph node invasion with higher TDLU metrics. The odds of TN compared with luminal A breast cancer increased with increasing tertiles of TDLU metrics, with odds ratios (95% confidence intervals) for tertile 3 versus tertile 1 of 2.18 (0.99, 4.79), 2.77 (1.07, 7.16), and 1.77 (0.79, 3.98) for TDLU count, TDLU span, and acini count/TDLU, respectively.ConclusionAssociations of TDLU metrics with breast cancer subtypes in the BWHS are consistent with previous studies of White and Asian women, demonstrating reduced TDLU involution in TN compared with luminal A breast cancers. Further investigation is needed to understand the factors that influence TDLU involution and the mechanisms that mediate TDLU involution and breast cancer subtype.

Racial and regional disparities of triple negative breast cancer incidence rates in the United States: An analysis of 2011-2019 NPCR and SEER incidence data.

Triple negative breast cancer (TNBC) is a more aggressive subtype resistant to conventional treatments with a poorer prognosis. This study was to update the status of TNBC and the temporal changes of its incidence rate in the US. Women diagnosed with breast cancer during 2011-2019 were obtained from the National Program of Cancer Registries (NPCR) and Surveillance, Epidemiology and End Results (SEER) Program SEER*Stat Database which covers the entire population of the US. The TNBC incidence and its temporal trends by race, age, region (state) and disease stage were determined during the period. A total of 238,848 (or 8.8%) TNBC women were diagnosed during the study period. TNBC occurred disproportionally higher in women of Non-Hispanic Black, younger ages, with cancer at a distant stage or poorly/undifferentiated. The age adjusted incidence rate (AAIR) for TNBC in all races decreased from 14.8 per 100,000 in 2011 to 14.0 in 2019 (annual percentage change (APC) = -0.6, P = 0.024). Incidence rates of TNBC significantly decreased with APCs of -0.8 in Non-Hispanic White women, -1.3 in West and -0.7 in Northeastern regions. Women with TNBC at the age of 35-49, 50-59, and 60-69 years, and the disease at the regional stage displayed significantly decreased trends. Among state levels, Mississippi (20.6) and Louisiana (18.9) had the highest, while Utah (9.1) and Montana (9.6) had the lowest AAIRs in 2019. New Hampshire and Indiana had significant and highest decreases, while Louisiana and Arkansas had significant and largest increases in AAIR. In individual races, TNBC displayed disparities in temporal trends among age groups, regions and disease stages. Surprisingly, Non-Hispanic White and Hispanic TNBC women (0-34 years), and Non-Hispanic Black women (≥70 years) during the entire period, as well as Asian or Pacific Islander women in the South region had increased trends between 2011 and 2017. Our study demonstrates an overall decreased trend of TNBC incidence in the past decade. Its incidence displayed disparities among races, age groups, regions and disease stages. Special attention is needed for a heavy burden in Non-Hispanic Black and increased trends in certain groups.

Racial differences in anthropometric measures as risk factors for triple-negative breast cancer.

The incidence of triple-negative breast cancer (TNBC) is higher in Black women compared to White women which is not explained by racial differences in body mass index (BMI). As BMI has limitations as an anthropometric measure, we used different anthropometric measures to examine associations with TNBC by race. Of 161,808 postmenopausal participants in Women's Health Initiative, eligible were a subsample of 121,744 White and Black postmenopausal women enrolled from 1993 to 1998, 50-79years of age with anthropometric measures who were followed for breast cancer incidence until March 2019. At entry, BMI, waist circumference (WC), and waist-hip ratio (WHR) were measured using standardized methods. Breast cancers were verified by central medical record review. Associations between anthropometric measures and triple-negative breast cancer risk were examined using Cox proportional hazards regression models. After 17.6years (median) follow-up, there were 87 Black women and 529 White women with incident triple-negative breast cancer. Overall, there were no significant associations between anthropometric measures and risk of triple-negative breast cancer. However, compared to White women with normal BMI, White women with obesity (BMI ≥ 30) (HR 0.76, 95% CI 0.60, 0.96) were significantly associated with a lower risk of triple-negative breast cancer. And larger waist circumference (HR per centimeter 0.99, 95% CI 0.99, 1.00) was significantly associated with a lower risk of triple-negative breast cancer among White women. Overall, among postmenopausal women, anthropometric measures were not associated with risk of TNBC. The association among White women with larger waist circumference and women with obesity with a lower risk of triple-negative breast cancer needs further confirmation.

African Ancestry-Associated Gene Expression Profiles in Triple-Negative Breast Cancer Underlie Altered Tumor Biology and Clinical Outcome in Women of African Descent.

Our comprehensive ancestry quantification process revealed that ancestry-associated gene expression profiles in TNBC include population-level distinctions in immunologic landscapes. These differences may explain some differences in race-group clinical outcomes. This study shows the first definitive link between African ancestry and the TNBC immunologic landscape, from an African-enriched international multiethnic cohort. See related commentary by Hamilton et al., p. 2496. This article is highlighted in the In This Issue feature, p. 2483.

Abstract 2525: Understanding triple-negative breast cancer immune microenvironment by disease stages, obesity, and race

Abstract Background: Triple-negative breast cancer (TNBC) is a molecularly heterogeneous group of clinically aggressive malignancies. There are well-recognized health disparities in TNBC outcomes, and the risk of TNBC is higher among African-Americans (AA). It is unclear whether immunological features of the tumor microenvironment (TME) associated with disease stage, socioeconomic factors, or comorbidities such as obesity may affect tumor immunity. The incidence of TNBC and obesity in Louisiana is among the highest in the nation, and we have documented disparities in incidence linked to race and disparities in mortality linked to social determinants of health. Recent studies described immunologic characteristics of the TNBC TME. However, the possible association of immunogenomic portraits of TNBCs with race, comorbidities or socioeconomic factors remains understudied. Methods: We studied the expression of immunity-associated genes in clinically annotated TNBCs from Louisiana AA and European-American (EA) patients with or without obesity. Primary invasive breast cancer cases with confirmed TNBC diagnosis were identified by the Louisiana Tumor Registry (LTR). Sections of FFPE tissue containing ≥ 50% tumor were identified and processed for RNA-Sequencing [(n = 256; White women:125 (Lean: 50 and Obese:75) and Black women:131 (Lean:28 and Obese: 103)] at Translational Genomic Core, LSUHSC. Categorical outcomes were compared via Chi-squared tests, and survival was compared via log-rank tests. Spearman correlation analysis was used to determine associations between CIBERSORT cell populations and stage of disease at diagnosis. Results: We found that race was associated with the stage of TNBC, and AA patients were more often diagnosed with a later stage of TNBC (p=0.0447). However, race was not associated with survival (p=0.4673). Obesity was not associated with stage at diagnosis (p=0.7256). Stage at diagnosis was the strongest determinant of survival (p&amp;lt;0.0001). We utilized CIBERSORT analysis to identify and quantify immune cell populations within the TME. Later stage at diagnosis was associated with increased T follicular helper cells (p=0.0038), M1 macrophages (p= 0.0032), and activated mast cells (p=0.0487). Conversely, later stage of disease was associated with decreased resting mast cells (p=0.0004) and monocytes (p=0.0455). Immunosuppressive Treg cells were positively associated with stage at diagnosis in AA patients (p=0.0273) but not in EA patients (p=0.9141). Conclusions: Stage at diagnosis was the strongest determinant of survival and was associated with significant differences in TME immune cell populations. Stage, race and obesity were associated with the presence of immunosuppressive Treg cells. If confirmed, these findings may help understand the variability in immunotherapy responses in TNBC. Citation Format: Fokhrul Hossain, Denise Danos, Jovanny Zabaleta, Jiande Wu, Mary Anne Lynch, Luis Del Valle, Xiao-Cheng Wu, Augusto Ochoa, Chindo Hicks, Lucio Miele. Understanding triple-negative breast cancer immune microenvironment by disease stages, obesity, and race [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2525.

Triple negative breast cancer presentation in Afro-Caribbean women in New York City.

e18726 Background: In the United States, triple negative breast cancer (TNBC) accounts for 10-15% of all breast cancers. It also has a higher incidence and worse prognosis in black women. There is paucity of information on the incidence and presentation of breast cancer in black women from the Caribbean. The clinical and pathologic profile of TNBC in this immigrant underrepresented patient group is described here. Methods: This is a retrospective study performed at Kings County Hospital (KCH), a safety net hospital in Central Brooklyn, New York City with a predominantly Afro-Caribbean patient population. Data from patients diagnosed with breast cancer from 2015-2018 were collected from the institution’s tumor registry and the clinical and pathologic data of these patients were collected and analyzed with descriptive statistics and chi square testing. Results: Of the total 299 female patients with a breast cancer diagnosis, 60 patients (20%) had TNBC with median age 57 and Nottingham grade 3 in 90% (54) of the patients. At presentation, 43% (26) presented with localized disease, 55% (33) with lymph node involvement (regional), and 2% (1) with distant metastasis. When stratified by menopausal status, 46 patients (77 %) were post-menopausal and remainder pre-menopausal. Premenopausal women presented with higher rates of regional disease at 64% with compared to 50% in the postmenopausal women (p = 0.5444). BMI was similar in both groups (p = 0.9879). Of the 37 patients with documented country of origin, 84% (31) were from the Caribbean, and 27% of these patients identified as medical tourists from the Caribbean. 25% (15) of all patients reported 1st or 2nd degree relative with breast cancer and 18% (11) reported a first degree relative with malignancy other that breast cancer. 100% of patients younger than 44 years reported a family history of cancer. Genetic testing information was unavailable to these patients. Of the twenty patients (33%) that received neoadjuvant chemotherapy with standard treatment, two achieved complete response, 15 partial response, and 3 without response to treatment. Conclusions: In our study of African-Caribbean patients with breast cancer, the incidence of TNBC was high at 20% with most presenting with high-grade tumors, regional lymph node involvement, and young age at diagnosis. Notably this represents a high-risk cohort with significant family history of breast and other cancers suggestive of inherited or familial cancers. Response to standard neoadjuvant chemotherapy was less than expected, encouraging the need to consider neoadjuvant immunotherapy in these patients.

Ambient air emissions of endocrine-disrupting metals and the incidence of hormone receptor- and HER2-dependent female breast cancer in USA.

Limited evidence exists on the relationship between exposure to endocrine-disrupting metals in ambient air and hormone receptor- and HER2-dependent breast cancer. This study investigates the association between ambient air emissions of endocrine-disrupting metals and the incidence of female breast cancer of different receptor status. County-level data from the US national datasets were analyzed for the association between emissions of various metals including arsenic, cadmium, chromium VI, lead, and mercury, and the annual age-adjusted incidence of hormone receptor-dependent breast cancer for 1990-2016 and HER2-dependent breast cancer for 2010-2016 using adjusted linear regression models. Lead emissions showed the strongest association among the metals examined with the incidence of different receptor status breast cancers, including ER-positive, ER-negative, PR-negative, HER2-negative, and Triple-negative breast cancers, with the adjusted β ranging from 917.26 for ER-negative to 3182.37 for HER2-negative breast cancer. Arsenic and mercury showed significant associations with the incidence of ER-positive, ER-negative, PR-positive, and PR-negative breast cancers. However, cadmium emissions were only significantly associated with ER-negative breast cancer. Moreover, chromium was not associated with any subtypes of breast cancer. Among all of the metals, only lead and mercury emissions showed significant associations with HER2-negative and Triple-negative breast cancer incidence. The results from this study suggest that increased exposure to endocrine-disrupting metals, especially lead, in ambient air could be associated with an increased incidence of female breast cancers with various receptor status in the US. Prospective studies are warranted to further explore this relationship.

Clinical-pathologic characteristics and response to neoadjuvant chemotherapy in triple-negative low Ki-67 proliferation (TNLP) breast cancers

Triple-negative breast cancers (TNBCs) often have a high Ki-67 proliferation index and respond favorably to neoadjuvant chemotherapy (NACT) with pathologic complete response (pCR) resulting in ~40% of cases. Nevertheless, morbidity/mortality remain high, mostly due to recurrence in patients with residual disease. In contrast, the incidence and clinical features of TNBC with low proliferation (TNLP), defined as TNBC with a Ki-67 index of ≤30% remains unknown. We report 70 cases of TNLP identified at our center from 2008 to 2018, including 18 treated with NACT. TNLP tumors represent <1% of all breast cancers, and ~5–10% of TNBCs. Ninety percent of carcinomas were grade I/II and 70% were either pure apocrine or showed apocrine differentiation. Fifty cases had available immunohistochemistry results; 80%, 84%, 22%, and 20% were positive for AR, INPP4B, nestin, and SOX10, respectively. With a median follow-up of 72 months, 14% experienced recurrence, and 11% died of breast cancer. The tumor stage was prognostic. Among 39 stage-I patients, 18 (46%) received chemotherapy, but this did not impact survival. There was a trend for improved recurrence-free survival with chemotherapy in stage-II patients. Of the 18 patients treated with NACT, 2 (11%) showed pCR; these were notable for either high stromal TILs or a high mitotic count despite a low Ki-67 index. TNLPs are enriched in low to intermediate-grade carcinomas with apocrine features. Due to overall good prognosis of stage-I TNLP and the lack of clear benefit of chemotherapy, de-escalation of chemotherapy may be considered in select patients with stage-I TNLP.

Abstract P2-09-08: Impact of race on clinical outcomes among patients with advanced triple negative breast cancer (TNBC) and Germline BRCA1/2 mutation(s) (gBRCA1/2mut): Results from a US real-world study

Abstract Background: Racial disparities among patients with breast cancer in the United States are well documented, with Black patients having a 40% higher mortality than White patients. Socioeconomic status, tumor biology differences, and treatment access are known contributing factors. Additionally, despite having a higher incidence of TNBC, Black patients are substantially less likely to receive gBRCA1/2mut testing than White patients. TNBC is an aggressive subtype, accounting for 15% of all breast cancers diagnosed in the United States. TNBC disproportionately affects BRCA mutation carriers and Black women. With the advent of poly ADP-ribose polymerases inhibitors (PARPi), gBRCA1/2mut are considered actionable biomarkers. Limited data are available on the impact of race on clinical outcomes among patients with gBRCA1/2-mutated advanced TNBC in the United States. Methods: US oncologists retrospectively reviewed patient charts (July 2019-June 2020) of a quasirandom selection of patients aged ≥18 years with gBRCA1/2-mutated advanced TNBC who received ≥1 cytotoxic chemotherapy (CT) regimen for advanced TNBC between Jan 2013-April 2018. Patients were categorized into 2 mutually exclusive cohorts of White and Black (based on self-identification). Descriptive analysis was performed for treatment patterns for the first 2 lines of therapy (LOT). Clinical outcomes (progression-free survival [PFS] by LOT and survival rates) were estimated with the Kaplan-Meier method. A log-rank test was used to assess differences in PFS and survival rates between White and Black patients. Results: Among 182 patients with gBRCA1/2-mutated advanced TNBC, 99.5% were women and 76.4% were White. The median age was 57.2 years (range, 48.7-64.7 years), and 30.2% had no known family history of BRCA-related cancer. Treatments for White patients with advanced TNBC included first-line (n=139) nonplatinum-based CT (61.9%) and platinum-based CT (38.1%) and second-line (n=90) PARPi (40.0%), nonplatinum-based CT (43.3%), platinum-based CT (11.1%), and other (5.6%). Treatments for Black patients with advanced TNBC included first-line (n=43) nonplatinum-based CT (60.5%) and platinum-based CT (39.5%) and second-line (n=19) PARPi (47.4%), nonplatinum-based CT (31.6%), platinum-based CT (10.5%), and other (10.5%). Across treatment types, no significant difference in 2-year survival rates was observed between White and Black patients (73.8% vs 73.2%, P=0.89). Median PFS rates by LOT were not statistically different across White and Black patients (Table 1). Conclusion: In this real-world study, no significant differences in clinical outcomes were observed between White and Black patients with gBRCA1/2-mutated advanced TNBC. This observation may be because this sample reflects a select patient population with a known genetic test result of a gBRCA1/2mut who were treated by oncologists that understood the value of genetic testing, and provided appropriate treatment options. The findings suggest that when all patients are provided with equitable care (inclusive of genetic testing), racial disparities in breast cancer may be minimized. Further trials are needed to validate these findings. Funding: Pfizer Inc Table 1.PFS (Months) by LOT and Race Among Patients With gBRCA1/2-Mutated Advanced TNBCWhite PatientsBlack PatientsP ValueFirst-line, n 13642PFS, median (95% CI)10.7 (9.3−12.6)15.6 (9.7−NE)0.078Second-line, n 5310PFS, median (95% CI)7.2 (5.9−11.4)9.2 (2.8−NE)0.406NE=not estimatable. Citation Format: Kristen Whitaker, Rohan Parikh, Elizabeth Esterberg, Bhakti Arondekar, Abigail Hitchens, Lillian Shahied Arruda, Alexander Niyazov, Elias Obeid. Impact of race on clinical outcomes among patients with advanced triple negative breast cancer (TNBC) and Germline BRCA1/2 mutation(s) (gBRCA1/2mut): Results from a US real-world study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-09-08.

Structural Racism and Triple-Negative Breast Cancer Among Black and White Women in the United States.

Purpose: To determine the associations between state-level indicators of structural racism and incidence of triple-negative breast cancer (TNBC) among black and white women diagnosed with breast cancer.Methods: Black and white women diagnosed with breast cancer between 2010 and 2016 were identified from 12 states represented in the Surveillance, Epidemiology, and End Results (SEER18) program. State-level disparities were measured by black to white rate ratios in educational attainment, political participation, incarceration, and unemployment; and dichotomized to “high” or “low” structural racism using the median rate ratio of the 12 states. Logistic regression was used to examine the associations between indicators of structural racism and TNBC among black and white women.Results: Living in states with high levels of structural racism in the domains of educational attainment, judicial treatment, and political participation were generally associated with greater odds of TNBC among black and white women. The increased odds of TNBC was greater for black women living in states with high levels of racial disparities than white women. Among black women diagnosed with breast cancer, the odds ratio (OR) of being diagnosed with TNBC comparing women living in states with high disparities in educational attainment versus those with low disparities was 1.50 (95% confidence interval [CI]: 1.27–1.77). For white women, the OR for educational attainment was 1.17 (95% CI: 1.10–1.23).Conclusion: Results from this study support the notion that racial health disparities need to be contextualized. Further research should address mechanisms through which structural racism influences health disparities.

Scoping Review: Relationship between Overweight and Obesity with Triple Negative Breast Cancer in Woman

Breast cancer is still one of the main problems for global public health. Breast cancer has several pathological characteristics, including triple negative breast cancer (TNBC) characterized by negative ER, PR, HER2 results and has a poor prognosis. Risk factors for TNBC are closely related to Body Mass Index (BMI) as an individual description of obesity. It is known in women, overweight and obesity can trigger breast cancer. This study aims to analyze the relationship between overweight and obesity based on BMI with the incidence of TNBC in women. This study used a scoping review to analyze scientific writings from three data sources, they are PubMed, ScienceDirect and SpringerLink. In the initial search, 797 articles were generated, then adjusted according to the inclusion, exclusion and eligibility criteria to produce 5 articles summarized in the PRISMA diagram. Of the five articles that were predominantly conducted in Asia, four articles stated that women with a BMI ≥25 kg/m2 had a higher risk of TNBC. One article stated that the risk factors for TNBC can be assessed from waist circumference other than BMI. In addition, there is one article that mentioned the opposite, there is no relationship between BMI at the age of 25-54 years and TNBC. The conclusion of this study is that obesity have a relationship with the incidence of TNBC in women.

Propolin G-Suppressed Epithelial-to-Mesenchymal Transition in Triple-Negative Breast Cancer Cells via Glycogen Synthase Kinase 3β-Mediated Snail and HDAC6-Regulated Vimentin Degradation.

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer with a poor prognosis. The incidence and mortality rate of TNBC are frequently found in younger women. Due to the absence of a good therapeutic strategy, effective remedies for inhibiting TNBC have been developed for improving the cure rate. Epithelial-to-mesenchymal transition (EMT) is a critical mechanism to regulate cancer cell motility and invasion. Furthermore, ectopic expression of EMT molecules correlates with the metastasis and poor prognosis of TNBC. Targeting EMT might be a strategy for the therapy and prevention of TNBC. Propolin G, an active c-prenylflavanone in Taiwanese propolis, has been shown to possess anti-cancer activity in many cancers. However, the anti-metastasis activity of propolin G on TNBC is still unclear. The present study showed that the migration and invasion activities of TNBC cells was suppressed by propolin G. Down-regulated expression of Snail and vimentin and up-regulated expression of E-cadherin were dose- and time-dependently observed in propolin G-treated MDA-MB-231 cells. Propolin G inhibited Snail and vimentin expressions via the signaling pathways associated with post-translational modification. The activation of glycogen synthase kinase 3β (GSK-3β) by propolin G resulted in increasing GSK-3β interaction with Snail. Consequently, the nuclear localization and stability of Snail was disrupted resulting in promoting the degradation. Propolin G-inhibited Snail expression and the activities of migration and invasion were reversed by GSK-3β inhibitor pretreatment. Meanwhile, the outcomes also revealed that histone deacetylase 6 (HDAC6) activity was dose-dependently suppressed by propolin G. Correspondently, the amounts of acetyl-α-tubulin, a down-stream substrate of HDAC6, were increased. Dissociation of HDAC6/Hsp90 with vimentin leading to increased vimentin acetylation and degradation was perceived in the cells with the addition of propolin G. Moreover, up-regulated expression of acetyl-α-tubulin by propolin G was attenuated by HDAC6 overexpression. On the contrary, down-regulated expression of vimentin, cell migration and invasion by propolin G were overturned by HDAC6 overexpression. Conclusively, restraint cell migration and invasion of TNBC by propolin G were activated by the expression of GSK-3β-suppressed Snail and the interruption of HDAC6-mediated vimentin protein stability. Aiming at EMT, propolin G might be a potential candidate for TNBC therapy.

Abstract PO-099: African American women with breast cancer have unique molecular features and reduced clinical trial enrollment

Abstract Introduction: African American (AA) women have a lower incidence of breast cancer (BC), however experience higher rates of more aggressive subtypes, mortality, and worse outcomes compared to Caucasian (C) women. Data also points to disparities among treatment access and response in AA women. Most existing genetic research and clinical trials have been conducted with majority C women, thus our existing knowledge about molecular profiles and effective treatments may not be accurate for AA women. The aim of this study is to uncover the biological and social factors related to treatment that may be causing this disparity in BC outcomes between AA and C women. Materials and Methods: Data from Surveillance, Epidemiology, and End Results (SEER) and The Cancer Genome Atlas Program (TCGA) was analyzed for differences in etiology, incidence, and prevalence of BC between AA and C. Prevalence of molecular aberrations and subtypes of BC were assessed to gain insight into potential causes of this disparity. FDA's Drug Trials Snapshots data was assessed for clinical trial enrollment by race. Results: SEER data from 2000-2018 reveals AA patients have higher incidences of TNBC and HER2 enriched BC compared to C, with luminal A incidence being higher in C patients. Within all subtypes of BC, 5-year survival rates were significantly lower for AA compared to C. TCGA data found 2282 genes that were significantly differentially altered in C vs. AA subgroups. Among the most commonly altered and significantly different genes, CSMD1 and TP53 were more prevalent among AA (19.78% AA vs. 10.79% in C for CSMD1, and 40.09% AA vs. 28.58% C for TP53), and PIK3CA among C (36.28% (C) vs. 22.47% (AA)). Survival analysis revealed AA women with PIK3CA alterations had lower rates of disease-free survival compared to C women. Clinical trials for oncology drugs approved in 2020 enrolled 5% AAs, with AAs also being underrepresented for BC specific drugs. The recent NCT02492711 trial of MARGENZA, for metastatic HER2 positive BC, had 5% AA compared to 80% C, the NCT01631552 trial of TRODELVY, for metastatic triple negative BC (TNBC), had 7% AA vs. 76% C, and the NCT02614794 trial of TUKYSA, for advanced HER2+ BC, had 9% AA vs. 73% C. Conclusion: Most existing treatments are for luminal A BC; with fewer approved drugs for subtypes more common among AA women, including the more aggressive TNBC. Recent data indicates that AA women continue to be underrepresented in clinical trials, despite having higher incidence of both HER2 and TNBC, resulting in a poor understanding of effective treatment for this subgroup. These factors may perpetuate disparities in outcomes for AA women with BC. Additionally, TCGA data uncovered underlying molecular differences in BC between AA and C women, some that are actionable. Disparities are multifactorial and can include both biological and socioeconomic factors. Thus, as we move towards more personalized medicine, it is increasingly important to improve representation of AA women in precision oncology trials. Citation Format: Genevra Magliocco, Roy Khalife, Anthony Magliocco. African American women with breast cancer have unique molecular features and reduced clinical trial enrollment [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-099.

YB1 Is a Major Contributor to Health Disparities in Triple Negative Breast Cancer.

Simple SummaryTriple negative breast cancer (TNBC) is a devastating disease that affects many women, due to the lack of FDA-approved targeted therapy. In the absence of cell surface receptors ER, PR, and Her2 that can be targeted with hormonal and antibody treatments, cytotoxic chemotherapy remains the major course of treatment, with a dismal response and rapid recurrence due to the acquisition of resistance. TNBC is also twice as more prevalent in African American (AA) when compared to Caucasian American (CA) women. This study investigated the role of the YB1 gene in the disparities in TNBC between AA and CA women. We found that YB1 is highly expressed in TNBC tumors of AA origin when compared to CAs. Increased expression levels and activity of YB1 correlates with poor disease outcomes, resistance to chemotherapy, and the activation of the cancer stem cell (CSC) phenotype, with higher levels in AA than in CA TNBC tumors. More importantly, we found that the targeted inhibition of the expression and activity of YB1 significantly inhibited the oncogenic behavior of AA tumors through sensitization to chemotherapy and inhibition of CSCs. Our study is the first to show that YB1 activity may be a major biological contributor to the health disparities in TNBC, and that development of therapies that specifically target YB1 could reduce these disparities.Triple negative breast cancer (TNBC) is the most aggressive amongst all breast cancer (BC) subtypes. While TNBC tumors represent less than 20% of all BC subtypes, they are responsible for the most BC-related deaths. More significantly, when considering TNBC incidence across all racial/ethnic groups, TNBC accounts for less than 20% of all BCs. However, in non-Hispanic black women, the incidence rate of TNBC is more than 40%, which may be a contributing factor to the higher BC-related death rate in this population. These disparities remain strong even after accounting for differences in socioeconomic status, healthcare access, and lifestyle factors. Increased evidence now points to biological mechanisms that are intrinsic to the tumor that contribute to disparate TNBC disease burdens. Here, we show that YB1, a multifunction gene, plays a major role in the TNBC disparities between African American (AA) and Caucasian American (CA) women. We show in three independent TNBC tumors cohorts, that YB1 is significantly highly expressed in AA TNBC tumors when compared to CAs, and that increased levels of YB1 correlate with poor survival of AA patients with TNBC. We used a combination of genetic manipulation of YB1 and chemotherapy treatment, both in vitro and in animal models of TNBC to show that YB1 oncogenic activity is more enhanced in TNBC cell lines of AA origin, by increasing their tumorigenic and aggressive behaviors, trough the activation of cancer stem cell phenotype and resistance to chemotherapeutic treatments.

LncRNA SNHG11 aggravates cell proliferation and migration in triple-negative breast cancer via sponging miR-2355-5p and targeting CBX5.

Triple-negative breast cancer (TNBC) is one of the most common malignances worldwide. Concurrently, the incidence of TNBC has continued to rise in recent years. It is reported that long non-coding RNAs (lncRNAs) are involved in biological processes in numerous cancers including TNBC. Small nucleolar RNA host gene 11 (SNHG11) has already been studied and reported in some cancers. However, the role of SNHG11 in TNBC remains unknown. RT-qPCR was used to measure gene expression in the current study. CCK-8, colony formation, flow cytometry, Transwell and western blotting experiments were also performed to determine the biological function of SNHG11 in TNBC cells. Luciferase reporter and RIP assays were performed to measure relationship between genes. In the present study, the results indicated SNHG11 was highly expressed in TNBC tissues and cell lines. Moreover, SNHG11 aggravated cell proliferation and migration, and whereas it attenuated cell apoptosis in TNBC. Furthermore, SNHG11 sponged microRNA 2355-5p (miR-2355-5p) in TNBC. Silencing SNHG11 increased miR-2355-5p expression. In addition, chromobox 5 (CBX5) was identified to be targeted by miR-2355-5p in TNBC. It was also suggested that CBX5 silencing suppressed cell proliferation and migration. Furthermore, overexpressed CBX5 recovered the inhibitive influence of SNHG11 silencing on proliferative and migrative abilities of TNBC cells. Overall, SNHG11 acted as a tumor promoter in TNBC and regulated TNBC cell growth by modulating the miR-2355-5p/CBX5 axis, which indicated that it may be used as a biomarker for TNBC treatment.