Investigating survivin as a novel target in black women with breast cancer.

594 Background: Black women with breast cancer have higher mortality than White women. Differences in tumor biology contribute to racial disparities in breast cancer outcomes. BIRC5 gene encodes survivin, an inhibitor of apoptosis protein, and an independent marker of poor prognosis in breast cancer. Cancer patients have anti-survivin antibodies and circulating survivin-specific T cells, suggesting that survivin may be targetable. Several ongoing antibody-mediated, vaccine strategies that target survivin are being developed. Nevertheless, most survivin studies were conducted in cohorts of White women. To date, the prevalence and/or role of survivin expression in breast tumors from Black women has not been studied. Methods: Associations between BIRC5 expression, clinicopathological and molecular features were measured in the population-based Carolina Breast Cancer Study (CBCS) and The Cancer Genome Atlas (TCGA) breast cancer cohort. Gene expression was measured by Nanostring RNA counting and split into BIRC5 high (4th quartile) and low categories based on log2 gene expression values. Relative frequency differences (RFD) for the association between BIRC5 high and clinicopathologic features were estimated. RNA based p53 mutant status and homologous recombination deficiency (HRD) status were included in RFD analysis. Receiver operating characteristic (ROC) curves were used to illustrate the potential of BIRC5 expression to distinguish patients who achieved pathological complete response (pCR) after receiving neoadjuvant chemotherapy in CBCS (133 Black, 49 non-Black). Results: BIRC5 gene expression was significantly increased in tumors from 966 Black patients compared to 1,497 non-Black (p < 0.00001), adjusting for stage and subtype. BIRC5 high tumors were significantly more expressed in higher stage and basal-like breast cancer subtypes. BIRC5 high tumors were also significantly enriched for expression of genes involved in p53 loss and HRD. Furthermore, in an analysis of 182 CBCS patients, BIRC5 gene expression alone predicted pCR with similar overall AUC to ROR-PT multigene signatures (AUC 0.62 vs 0.64). Conclusions: Our study shows that survivin expression is particularly high in breast tumors from Black women. This was associated with more aggressive clinicopathological features in addition to p53 mutant and HRD status. Black women with breast cancer represent an area of unmet clinical need and could potentially benefit from anti-survivin targetable treatment strategies. Further studies are needed to help close this gap which constitutes the largest disparity among cancer-specific diseases.[Table: see text]

Download Full-text

Whole-genome analysis of Nigerian patients with breast cancer reveals ethnic-driven somatic evolution and distinct genomic subtypes

10.1101/2020.10.28.359240 ◽

2020 ◽

Author(s):

Naser Ansari-Pour ◽

Yonglan Zheng ◽

Jason J. Pitt ◽

Stefan Dentro ◽

Toshio F. Yoshimatsu ◽

...

Keyword(s):

Breast Cancer ◽

Black Women ◽

White Women ◽

African Ancestry ◽

Clinical Intervention ◽

The Cancer Genome Atlas ◽

European Ancestry ◽

Precision Oncology ◽

Whole Genome Analysis ◽

Somatic Evolution

AbstractBlack women of African ancestry experience more aggressive breast cancer with higher mortality rates than White women of European ancestry. Although inter-ethnic germline variation is known, differential somatic evolution has not been investigated in detail. Analysis of deep whole genomes of 97 breast tumors, with RNA-seq in a subset, from indigenous African patients in Nigeria in comparison to The Cancer Genome Atlas (n=76) revealed a higher rate of genomic instability and increased intra-tumoral heterogeneity as well as a unique genomic subtype defined by early clonal GATA3 mutations and a 10.5-year younger age at diagnosis. We also found evidence for non-coding mutations in two novel drivers (ZNF217 and SYPL1) and a novel INDEL signature strongly associated with African ancestry proportion. This comprehensive analysis of an understudied population underscores the need to incorporate diversity of genomes as a key parameter in fundamental research with potential to tailor clinical intervention and promote equity in precision oncology care.

Download Full-text

Whole-genome analysis of Nigerian patients with breast cancer reveals ethnic-driven somatic evolution and distinct genomic subtypes

Nature Communications ◽

10.1038/s41467-021-27079-w ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Naser Ansari-Pour ◽

Yonglan Zheng ◽

Toshio F. Yoshimatsu ◽

Ayodele Sanni ◽

Mustapha Ajani ◽

...

Keyword(s):

Breast Cancer ◽

Black Women ◽

White Women ◽

African Ancestry ◽

The Cancer Genome Atlas ◽

European Ancestry ◽

Breast Cancers ◽

Whole Genome Analysis ◽

Somatic Evolution ◽

Germline Variation

AbstractBlack women across the African diaspora experience more aggressive breast cancer with higher mortality rates than white women of European ancestry. Although inter-ethnic germline variation is known, differential somatic evolution has not been investigated in detail. Analysis of deep whole genomes of 97 breast cancers, with RNA-seq in a subset, from women in Nigeria in comparison with The Cancer Genome Atlas (n = 76) reveal a higher rate of genomic instability and increased intra-tumoral heterogeneity as well as a unique genomic subtype defined by early clonal GATA3 mutations with a 10.5-year younger age at diagnosis. We also find non-coding mutations in bona fide drivers (ZNF217 and SYPL1) and a previously unreported INDEL signature strongly associated with African ancestry proportion, underscoring the need to expand inclusion of diverse populations in biomedical research. Finally, we demonstrate that characterizing tumors for homologous recombination deficiency has significant clinical relevance in stratifying patients for potentially life-saving therapies.

Download Full-text

Changes in black-white disparity in receipt of guideline concordant treatment for women with early-stage breast tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e19089 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e19089-e19089

Author(s):

Hasan Nadeem ◽

John Romley ◽

Shaneda Warren-Andersen

Keyword(s):

Breast Cancer ◽

Radiation Therapy ◽

Black Women ◽

White Women ◽

Treatment Guidelines ◽

Early Stage ◽

Breast Tumors ◽

Breast Conserving Surgery ◽

Black And White ◽

Period 2

e19089 Background: Racial disparities are well documented in the treatment of women with breast cancer. Whereas clinical treatment guidelines are established for early stage breast tumors, disparities in guideline-concordant (GC) treatment may influence variation in breast cancer outcomes. As such, we investigated differences in the receipt of GC treatment for black and white women with early-stage breast cancer between 2008 and 2016. Methods: We evaluated the Surveillance, Epidemiology, and End Results Registry (SEER) Incidence database for black and white women aged 20-64 years with stage I / stage II breast tumors. Primary analyses investigated associations between race and receipt of GC treatment in three chronological periods. Potential driving factors for trends in receipt of guideline-concordant treatment were also assessed. Results: Among 145,561 women diagnosed with early stage breast tumors, overall receipt of GC care decreased from 84.58% in 2008 to 83.89% in 2016. In period 1 (2008-2010), there was a prominent disparity between black and white women (81.89% black vs 86.24% white; p < 0.001). By period 3 (2014-2016), GC care increased for black women (84.29%) but decreased for white women (84.82%), eliminating the disparity (p = 0.276). Multivariate logistic regression on changes in the black-white disparity across the study period showed increased receipt of GC treatment for black women relative to white women in period 2 (2011-2013, odds ratio [OR], 1.202; 95% confidence interval [CI], 1.075 – 1.344) and period 3 (OR, 1.376; 95% CI, 1.212 – 1.505). For black women undergoing breast conserving surgery, administration of radiation therapy increased from 44.01% in period 1 to 50.64% in period 3 (p < 0.001) and was a prominent driver for increased GC care. Conclusions: Overall receipt of guideline-concordant treatment decreased from 2008-2016. Black women experienced a substantial increase in receipt of guideline-concordant care in period 2 (2011-2013) and period 3 (2014-2016) relative to white women. Delivery and completion of radiation therapy with breast conserving surgery increased the likelihood of receipt of guideline-concordant treatment.

Download Full-text

Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer

npj Breast Cancer ◽

10.1038/s41523-020-00208-2 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Francesco Schettini ◽

Nuria Chic ◽

Fara Brasó-Maristany ◽

Laia Paré ◽

Tomás Pascual ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Overall Survival ◽

High Activity ◽

Triple Negative ◽

Her2 Expression ◽

Drug Conjugates ◽

Molecular Features ◽

Biological Heterogeneity ◽

Antibody Drug

AbstractNovel antibody-drug conjugates against HER2 are showing high activity in HER2-negative breast cancer (BC) with low HER2 expression (i.e., 1+ or 2+ and lack of ERBB2 amplification). However, the clinical and molecular features of HER2-low BC are yet to be elucidated. Here, we collected retrospective clinicopathological and PAM50 data from 3,689 patients with HER2-negative disease and made the following observations. First, the proportion of HER2-low was higher in HR-positive disease (65.4%) than triple-negative BC (TNBC, 36.6%). Second, within HR-positive disease, ERBB2 and luminal-related genes were more expressed in HER2-low than HER2 0. In contrast, no gene was found differentially expressed in TNBC according to HER2 expression. Third, within HER2-low, ERBB2 levels were higher in HR-positive disease than TNBC. Fourth, HER2-low was not associated with overall survival in HR-positive disease and TNBC. Finally, the reproducibility of HER2-low among pathologists was suboptimal. This study emphasizes the large biological heterogeneity of HER2-low BC, and the need to implement reproducible and sensitive assays to measure low HER2 expression.

Download Full-text

The BIRC Family Genes Expression in Patients with Triple Negative Breast Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22041820 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1820

Author(s):

Anna Makuch-Kocka ◽

Janusz Kocki ◽

Anna Brzozowska ◽

Jacek Bogucki ◽

Przemysław Kołodziej ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Clinical Data ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Lymphatic Vessels ◽

The Cancer Genome Atlas ◽

Expression Level ◽

Cancer Tissue ◽

Expression Levels

The BIRC (baculoviral IAP repeat-containing; BIRC) family genes encode for Inhibitor of Apoptosis (IAP) proteins. The dysregulation of the expression levels of the genes in question in cancer tissue as compared to normal tissue suggests that the apoptosis process in cancer cells was disturbed, which may be associated with the development and chemoresistance of triple negative breast cancer (TNBC). In our study, we determined the expression level of eight genes from the BIRC family using the Real-Time PCR method in patients with TNBC and compared the obtained results with clinical data. Additionally, using bioinformatics tools (Ualcan and The Breast Cancer Gene-Expression Miner v4.5 (bc-GenExMiner v4.5)), we compared our data with the data in the Cancer Genome Atlas (TCGA) database. We observed diverse expression pattern among the studied genes in breast cancer tissue. Comparing the expression level of the studied genes with the clinical data, we found that in patients diagnosed with breast cancer under the age of 50, the expression levels of all studied genes were higher compared to patients diagnosed after the age of 50. We observed that in patients with invasion of neoplastic cells into lymphatic vessels and fat tissue, the expression levels of BIRC family genes were lower compared to patients in whom these features were not noted. Statistically significant differences in gene expression were also noted in patients classified into three groups depending on the basis of the Scarff-Bloom and Richardson (SBR) Grading System.

Download Full-text

Immune microenvironment and intrinsic subtyping in hormone receptor-positive/HER2-negative breast cancer

npj Breast Cancer ◽

10.1038/s41523-021-00223-x ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Gaia Griguolo ◽

Maria Vittoria Dieci ◽

Laia Paré ◽

Federica Miglietta ◽

Daniele Giulio Generali ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Gene Expression Data ◽

Hormone Receptor ◽

Tumor Biology ◽

Expression Data ◽

Immune Microenvironment ◽

Immune Infiltrate ◽

Hormone Receptor Positive ◽

Her2 Breast Cancer

AbstractLittle is known regarding the interaction between immune microenvironment and tumor biology in hormone receptor (HR)+/HER2− breast cancer (BC). We here assess pretreatment gene-expression data from 66 HR+/HER2− early BCs from the LETLOB trial and show that non-luminal tumors (HER2-enriched, Basal-like) present higher tumor-infiltrating lymphocyte levels than luminal tumors. Moreover, significant differences in immune infiltrate composition, assessed by CIBERSORT, were observed: non-luminal tumors showed a more proinflammatory antitumor immune infiltrate composition than luminal ones.

Download Full-text

Distant metastases after diagnosis: Racial disparities in breast cancer outcomes.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.1084 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 1084-1084

Author(s):

Julia Blanter ◽

Ilana Ramer ◽

Justina Ray ◽

Emily J. Gallagher ◽

Nina A. Bickell ◽

...

Keyword(s):

Breast Cancer ◽

Multivariate Analysis ◽

Black Women ◽

Racial Disparities ◽

Late Stage ◽

White Women ◽

Univariate Analysis ◽

Distant Metastases ◽

Stage At Diagnosis

1084 Background: Black women diagnosed with breast cancer are more likely to have a poor prognosis, regardless of breast cancer subtype. Despite having a lower incidence rate of breast cancer when compared to white women, black women have the highest breast cancer death rate of all racial and ethnic groups, a characteristic often attributed to late stage at diagnosis. Distant metastases are considered the leading cause of death from breast cancer. We performed a follow up study of women with breast cancer in the Mount Sinai Health System (MSHS) to determine differences in distant metastases rates among black versus white women. Methods: Women were initially recruited as part of an NIH funded cross-sectional study from 2013-2020 to examine the link between insulin resistance (IR) and breast cancer prognosis. Women self-identified as black or white race. Data was collected via retrospective analysis of electronic medical records (EMR) between September 2020-January 2021. Distant metastases at diagnosis was defined as evidence of metastases in a secondary organ (not lymph node). Stage at diagnosis was recorded for all patients. Distant metastases after diagnosis was defined as evidence of metastases at any time after initiation of treatment. Univariate analysis was performed using Fisher’s exact test, multivariate analysis was performed by binary logistic regression, and results expressed as odds ratio (OR) and 95% confidence interval (CI). A p value <0.05 was considered statistically significant. Results: We identified 441 women enrolled in the IR study within the MSHS (340 white women, 101 black women). Median follow up time for all women was 2.95 years (median = 3.12 years for white and 2.51 years for black women (p=0.017)). Among these patients, 11 developed distant metastases after diagnosis: 4 (1.2%) white and 7 (6.9%) black (p=0.004). Multivariate analysis adjusting for age, race and stage at diagnosis revealed that black women were more likely to have distant metastasis (OR 5.8, CI 1.3-25.2), as were younger women (OR for age (years) 0.9, CI 0.9-1.0), and those with more advanced stage at diagnosis. Conclusions: Black women demonstrated a far higher percentage of distant metastases after diagnosis even when accounting for age and stage. These findings suggest that racial disparities still exist in the development of distant metastases, independent from a late-stage diagnosis. The source of existing disparities needs to be further understood and may be found in surveillance, treatment differences, or follow up.

Download Full-text

Geographical disparities of incidence and prevalence of triple-negative breast cancers: Multistate study data analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e12599 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e12599-e12599

Author(s):

Hyein Jeon ◽

Myeong Lee ◽

Mohammed Jaloudi

Keyword(s):

Breast Cancer ◽

Black Women ◽

Significant Relationship ◽

White Women ◽

Triple Negative ◽

The State ◽

Luminal A ◽

Black Females ◽

Black And White ◽

State Effect

e12599 Background: Higher prevalence of triple negative breast cancer (TNBC) in black women with associated poor outcomes due to various disparities is well documented within a single state. We examine multiple states to better understand the state effect on such differences in incidence and prevalence of TNBC in black women. Methods: Female patients of ages 19 years old and above with breast cancer from the Surveillance, Epidemiology and End Results (SEER) Program across 13 states (608 counties) from 2015 (n = 66,444) and 2016 (n = 66,122) were examined. The relationships between the proportion of black and white women and the rate of patients with different tumor subtypes (luminal A, luminal B, HR-HER2+, and triple negative) were examined at the county level using ordinary least-square regression models. In parallel, due to consideration of various state-specific healthcare policies, socio-cultural norms, and socio-economic disparities, multi-level regression models were applied to examine the nested, random effect of each state on TNBC prevalence in each county. Bonferroni correction was applied to reduce the Type I error caused by repeated use of the same variables in multiple tests. Results: The baseline breast cancer rates between black and white women were similar in the population (0.171% for black and 0.168% for white). Consistent to previous studies, we demonstrate a significant positive correlation (p < 0.001) in TNBC in black females in both years. Surprisingly, when accounted for the random effects on states, 38.2% (2015) and 34.3% (2016) increase in incidence of TNBC in black females were seen, suggestive of state-specific disparity affecting race-specific health. In 2015, other subtypes of breast cancer in both black and white females did not result in significant relationship. Interestingly, in 2016, there was a significant relationship seen between the TNBC rate in white females and the white female population rate only after adjusting for the state effect (p = 0.026). This indicates the impact of non-biological factors such as state-wide health policies. Additionally, HR-HER2+ black females had a significant relationship against respective population rate only after adjusting for the state effect as well (p = 0.0394). For luminal A white females, a 15% decrease in incidence was seen after adjusting for state effect (p = 0.0424). Conclusions: This is the first known across-state examination of breast cancer subtypes by race with random effects on state. This study shows the role of state-specific factors affecting incidence in black and white females and potentially indicates the importance of state-level management for breast cancer on health disparities in addition to race-driven effects. Further studies are needed to elucidate comparable differences between states affecting the rates of various subtypes of breast cancer and thus health outcomes.

Download Full-text

Insulin Resistance and Inflammation in Black Women with and without Breast Cancer: Cause for Concern

Ethnicity & Disease ◽

10.18865/ed.26.4.513 ◽

2016 ◽

Vol 26 (4) ◽

pp. 513 ◽

Cited By ~ 2

Author(s):

Kathleen A. Griffith ◽

Seon Yoon Chung ◽

Shijun Zhu ◽

Alice S. Ryan

Keyword(s):

Breast Cancer ◽

Insulin Resistance ◽

Black Women ◽

White Women ◽

Cancer Recurrence ◽

Control Group ◽

Study Objective ◽

Increased Risk ◽

Tnf Α ◽

History Of

Objective: After chemotherapy for breast cancer, Black women gain more weight and have an increased mortality rate compared with White women. Our study objective was to compare biomarkers associated with obesity in Black women with and without a history of breast cancer.Design: Case-controlSetting: Academic/federal institutionParticipants: Black women with a history of breast cancer (cases) and age-matched controls.Methods: We compared insulin resistance, inflammation, and lipids in overweight and obese Black women with a history of breast cancer (n=19), age similar controls (n=25), and older controls (n=32). Groups did not differ on mean body mass index (BMI), which was 35.4 kg/m2, 36.0 kg/m2, and 33.0 kg/m2, respectively.Main Outcome Measures: Insulin resistance (HOMA-IR); inflammation (TNF-α, IL-1b, IL-6, IL-8, CRP); lipids (cholesterol, triglycerides).Results: Cases had 1.6 and 1.38 times higher HOMA-IR values compared with age similar and older controls, respectively (P≤.001 for both). TNF-α and IL-1b were significantly higher in cases compared with both control groups (P<.001 for both). IL-6 was also higher in cases compared with age-similar controls (P=.007), and IL-8 was lower in cases compared with older controls (P<.05). Lipids did not differ between cases and either control group.Conclusions: Black women with breast cancer were significantly more insulin resistant with increased inflammation compared not only with age similar controls but with women who were, on average, a decade older. These biomarkers of insulin resistance and inflammation may be associated with increased risk of breast cancer recurrence and require ongoing evaluation, especially given the relatively abnormal findings compared with the controls in this underserved group. Ethn Dis. 2016;26(4):513-520; doi:10.18865/ed.26.4.513

Download Full-text

Integrative transcriptome data mining for identification of core lncRNAs in breast cancer

PeerJ ◽

10.7717/peerj.7821 ◽

2019 ◽

Vol 7 ◽

pp. e7821 ◽

Cited By ~ 7

Author(s):

Xiaoming Zhang ◽

Jing Zhuang ◽

Lijuan Liu ◽

Zhengguo He ◽

Cun Liu ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Prognostic Value ◽

Early Stage ◽

Expression Profiles ◽

Diagnostic Value ◽

The Cancer Genome Atlas ◽

Functional Enrichment ◽

Differentially Expressed ◽

Data Set

Background Cumulative evidence suggests that long non-coding RNAs (lncRNAs) play an important role in tumorigenesis. This study aims to identify lncRNAs that can serve as new biomarkers for breast cancer diagnosis or screening. Methods First, the linear fitting method was used to identify differentially expressed genes from the breast cancer RNA expression profiles in The Cancer Genome Atlas (TCGA). Next, the diagnostic value of all differentially expressed lncRNAs was evaluated using a receiver operating characteristic (ROC) curve. Then, the top ten lncRNAs with the highest diagnostic value were selected as core genes for clinical characteristics and prognosis analysis. Furthermore, core lncRNA-mRNA co-expression networks based on weighted gene co-expression network analysis (WGCNA) were constructed, and functional enrichment analysis was performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID). The differential expression level and diagnostic value of core lncRNAs were further evaluated by using independent data set from Gene Expression Omnibus (GEO). Finally, the expression status and prognostic value of core lncRNAs in various tumors were analyzed based on Gene Expression Profiling Interactive Analysis (GEPIA). Results Seven core lncRNAs (LINC00478, PGM5-AS1, AL035610.1, MIR143HG, RP11-175K6.1, AC005550.4, and MIR497HG) have good single-factor diagnostic value for breast cancer. AC093850.2 has a prognostic value for breast cancer. AC005550.4 and MIR497HG can better distinguish breast cancer patients in early-stage from the advanced-stage. Low expression of MAGI2-AS3, LINC00478, AL035610.1, MIR143HG, and MIR145 may be associated with lymph node metastasis in breast cancer. Conclusion Our study provides candidate biomarkers for the diagnosis and prognosis of breast cancer, as well as a bioinformatics basis for the further elucidation of the molecular pathological mechanism of breast cancer.

Download Full-text