A novel role for KIFC1-MYH9 interaction in triple-negative breast cancer aggressiveness and racial disparity.

African American (AA) women are twice as likely to develop triple-negative breast cancer (TNBC) as women of European descent. Additionally, AA women with TNBC present a much more aggressive disease course than their European American (EA) counterparts. Thus, there is an unmet clinical need to identify race-specific biomarkers and improve survival outcomes in AA patients with TNBC. The minus-end directed microtubule motor protein kinesin family member C1 (KIFC1) promotes centrosome clustering and chromosomal instability and is often overexpressed in TNBC. Previous findings suggest that KIFC1 plays a role in cell proliferation and migration in TNBC cells from AAs and that the levels of nuclear KIFC1 (nKIFC1) are particularly high in AA patients with TNBC. The nuclear localization of KIFC1 in interphase may underlie its previously unrecognized race-specific association. In this study, we found that in TNBC cells derived from AAs, nKIFC1 interacted with the tumor suppressor myosin heavy chain 9 (MYH9) over EA cells. Treatment of AA TNBC cells with commercial inhibitors of KIFC1 and MYH9 disrupted the interaction between KIFC1 and MYH9. To characterize the racial differences in the KIFC1-MYH9-MYC axis in TNBC, we established homozygous KIFC1 knockout (KO) TNBC cell lines. KIFC1 KO significantly inhibited proliferation, migration, and invasion in AA TNBC cells but not in EA TNBC cells. RNA sequencing analysis showed significant downregulation of genes involved in cell migration, invasion, and metastasis upon KIFC1 KO in TNBC cell lines from AAs compared to those from EAs. These data indicate that mechanistically, the role of nKIFC1 in driving TNBC progression and metastasis is stronger in AA patients than in EA patients, and that KIFC1 may be a critical therapeutic target for AA patients with TNBC.

Racial disparities in outcomes of patients with stage I-III triple-negative breast cancer after adjuvant chemotherapy: a post-hoc analysis of the E5103 randomized trial.

PURPOSE: Breast cancer mortality is higher in Black women than other racial groups. This difference has been partially attributed to a higher proportion of triple-negative breast cancer (TNBC). However, it is uncertain if survival disparities exist in racially diverse TNBC patients receiving similar treatments. Here, we examine racial differences in disease-related outcomes in TNBC patients treated on the E5103 clinical trial. METHODS: From 2007 to 2011, 4,994 patients with stage I-III HER2-negative breast cancer were randomized to adjuvant chemotherapy with or without bevacizumab. This analysis was limited to the subset of 1,742 TNBC patients with known self-reported race. Unadjusted Kaplan-Meier curves and adjusted Cox-Proportional Hazards models were used to determine breast cancer events and survival outcomes. RESULTS: Of the analysis population, 51 (2.9%) were Asian, 269 (15.4%) Black, and 1422 (81.6%) White. Median age was 51 years. Patient characteristics, treatment arm, and local therapies were similar across racial groups. White women were more commonly node-negative (56% vs. 49% and 44% in Asian and Black women, respectively; p < 0.01). At a median follow-up of 46 months, unadjusted Kaplan-Meier locoregional and distant recurrence, and disease-free and overall survival, did not differ significantly by race. In Cox models adjusted for patient and tumor characteristics and treatment arm, race was not associated with any disease event. Larger tumor size and nodal involvement were consistently associated with breast cancer events. CONCLUSION: This clinical trial population of similarly treated TNBC patients showed no racial differences in breast cancer outcomes. Disease extent, rather than race, was associated with disease events.

Racial disparities in breast cancer risk factors and risk management.

Racial disparities in breast cancer outcomes are well described across the spectrum of screening, diagnosis, treatment, and survivorship. Breast cancer mortality is markedly elevated for Non-Hispanic Black women compared with other racial and ethnic groups, with multifactorial causes. Here, we aim to reduce this burden by identifying disparities in breast cancer risk factors, risk assessment, and risk management before breast cancer is diagnosed. We describe a reproductive profile and modifiable risk factors specific to the development of triple-negative breast cancer. We also propose that screening strategies should be both risk- and race-based, given the prevalence of early-onset triple-negative breast cancer in young Black women. We emphasize the importance of early risk assessment and identification of patients at hereditary and familial risk and discuss indications for a high-risk referral. We discuss the subtleties following genetic testing and highlight "uncertain" genetic testing results and risk estimation challenges in women who test negative. We trace aspects of the obesity epidemic in the Black community to infant feeding patterns and emphasize healthy eating and activity. Finally, we discuss building an environment of trust to foster adherence to recommendations, follow-up care, and participation in clinical trials. Addressing relevant social determinants of health; educating patients and clinicians on factors impacting disparities in outcomes; and encouraging participation in targeted, culturally sensitive research are essential to best serve all communities.

Targeted genotyping for recurring variants in cancer susceptibility genes in non-Ashkenazi Jewish patients with breast cancer diagnosed ≥50 years.

PURPOSE: Several recurring pathogenic variants (PVs) in BRCA1/BRCA2 and additional cancer susceptibility genes are described in the ethnically diverse Israeli population. Since 2019, testing for these recurring PVs is reimbursed unselectively for all patients with breast cancer (BC) in Israel. The aim was to evaluate the yield of genotyping for these PVs in non-Ashkenazi Jewish (AJ) patients with BC diagnosed ≥age 50 years. METHODS: Clinical and genotyping data of all patients with BC undergoing oncogenetic counseling at the Oncology Institute at Sheba Medical Center from June 2017 to December 2023 were reviewed. RESULTS: Of 2706 patients with BC (mean age at diagnosis, 54 years; range, 20-92 years) counseled, 515 patients of non-AJ (all four grandparents) descent, diagnosed ≥age 50 years of age were genotyped, 55 with triple-negative BC (TNBC) and 460 with non-TNBC. One of the recurring PVs in BRCA1/BRCA2 were detected in 12.7% (7/55) of TNBC patients and 0.65% (3/460) of non-TNBC. One patient with non-TNBC had PMS2 PV. Low-penetrance variants were found in 2.5% of genotyped TNBC and in 3.7% of patients with non-TNBC, including CHEK2 c.499G>A (n = 3), APC c.3920T > A (n = 4), and heterozygous MUTYH c.1187G>A (n = 5). Following first-pass genotyping, 146 patients performed multigene panel testing, none carried a BRCA1/BRCA2 PV, and only 5/127 non-TNBC (3.9%) harbored PVs in CHEK2 (n = 2, c.846+1G>C and c.592+3A>T), ATM c.103C>T (n = 2), and NBN c.966C>G (n = 1). CONCLUSIONS: The observed low rates of PV detection in non-AJ non-TNBC cases ≥age 50 years at diagnosis, mostly for clinically insignificant variants, questions the justification of unselected genotyping in this subset of patients.

Germline pathogenic variants associated with triple-negative breast cancer in US Hispanic and Guatemalan women using hospital and community-based recruitment strategies.

PURPOSE: Recruit and sequence breast cancer subjects in Guatemalan and US Hispanic populations. Identify optimum strategies to recruit Latin American and Hispanic women into genetic studies of breast cancer. METHODS: We used targeted gene sequencing to identify pathogenic variants in 19 familial breast cancer susceptibility genes in DNA from unselected Hispanic breast cancer cases in the US and Guatemala. Recruitment across the US was achieved through community-based strategies. In addition, we obtained patients receiving cancer treatment at major hospitals in Texas and Guatemala. RESULTS: We recruited 287 Hispanic US women, 38 (13%) from community-based and 249 (87%) from hospital-based strategies. In addition, we ascertained 801 Guatemalan women using hospital-based recruitment. In our experience, a hospital-based approach was more efficient than community-based recruitment. In this study, we sequenced 103 US and 137 Guatemalan women and found 11 and 10 pathogenic variants, respectively. The most frequently mutated genes were BRCA1, BRCA2, CHEK2, and ATM. In addition, an analysis of 287 US Hispanic patients with pathology reports showed a significantly higher percentage of triple-negative disease in patients with pathogenic variants (41% vs. 15%). Finally, an analysis of mammography usage in 801 Guatemalan patients found reduced screening in women with a lower socioeconomic status (p < 0.001). CONCLUSION: Guatemalan and US Hispanic women have rates of hereditary breast cancer pathogenic variants similar to other populations and are more likely to have early age at diagnosis, a family history, and a more aggressive disease. Patient recruitment was higher using hospital-based versus community enrollment. This data supports genetic testing in breast cancer patients to reduce breast cancer mortality in Hispanic women.

Racial/Ethnic Disparities in Pathologic Complete Response and Overall Survival in Patients With Triple-Negative Breast Cancer Treated With Neoadjuvant Chemotherapy.

PURPOSE: Black women have higher rates of death from triple-negative breast cancer (TNBC) than White women. We hypothesized that pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) and overall survival (OS) may vary by race/ethnicity in patients with TNBC. METHODS: We identified women 18 years and older with stage I-III TNBC who received NAC followed by surgery from the National Cancer Database (2010-2019). We excluded patients without race/ethnicity or pathology data. Primary outcomes were pCR rates and OS on the basis of race/ethnicity. RESULTS: Forty thousand eight hundred ninety women with TNBC met inclusion criteria (median age [IQR], 53 [44-61] years): 26,150 Non-Hispanic White (64%, NHW), 9,672 Non-Hispanic Black (23.7%, NHB), 3,267 Hispanic (8%), 1,368 Non-Hispanic Asian (3.3%, NHA), and 433 Non-Hispanic Other (1.1%, NHO) patients. Overall, 29.8% demonstrated pCR (NHW: 30.5%, NHB: 27%, Hispanic: 32.6%, NHA: 28.8%, NHO: 29.8%). Unadjusted OS was significantly higher for those with pCR compared with those with residual disease (5-year OS, 0.917 [95% CI, 0.911 to 0.923] v 0.667 [95% CI, 0.661 to 0.673], log-rank P < .001), and this association persisted after adjustment for demographic and tumor factors. The effect of achieving pCR on OS did not differ by race/ethnicity (interaction P = .10). However, NHB patients were less likely (odds ratio [OR], 0.89 [95% CI, 0.83 to 0.95], P = .001) and Hispanic patients were more likely (OR, 1.19 [95% CI, 1.08 to 1.31], P = .001) to achieve pCR than NHW patients. After adjustment for patient and disease factors, including achievement of pCR, Hispanic (hazard ratio [HR], 0.76 [95% CI, 0.69 to 0.85], P < .001) and NHA (HR, 0.64 [95% CI, 0.55 to 0.75], P < .001) race/ethnicity remained associated with OS. CONCLUSION: Odds of achieving pCR and OS in patients with TNBC appear to be associated with race/ethnicity. Additional research is necessary to understand how race/ethnicity is associated with rates of pCR and OS, whether related to socioeconomic factors or biologic variables, or both.

Native American ancestry and breast cancer risk in Colombian and Mexican women: ruling out potential confounding through ancestry-informative markers.

BACKGROUND: Latin American and Hispanic women are less likely to develop breast cancer (BC) than women of European descent. Observational studies have found an inverse relationship between the individual proportion of Native American ancestry and BC risk. Here, we use ancestry-informative markers to rule out potential confounding of this relationship, estimating the confounder-free effect of Native American ancestry on BC risk. METHODS AND STUDY POPULATION: We used the informativeness for assignment measure to select robust instrumental variables for the individual proportion of Native American ancestry. We then conducted separate Mendelian randomization (MR) analyses based on 1401 Colombian women, most of them from the central Andean regions of Cundinamarca and Huila, and 1366 Mexican women from Mexico City, Monterrey and Veracruz, supplemented by sensitivity and stratified analyses. RESULTS: The proportion of Colombian Native American ancestry showed a putatively causal protective effect on BC risk (inverse variance-weighted odds ratio [OR] = 0.974 per 1% increase in ancestry proportion, 95% confidence interval [CI] 0.970-0.978, p = 3.1 × 10-40). The corresponding OR for Mexican Native American ancestry was 0.988 (95% CI 0.987-0.990, p = 1.4 × 10-44). Stratified analyses revealed a stronger association between Native American ancestry and familial BC (Colombian women: OR = 0.958, 95% CI 0.952-0.964; Mexican women: OR = 0.973, 95% CI 0.969-0.978), and stronger protective effects on oestrogen receptor (ER)-positive BC than on ER-negative and triple-negative BC. CONCLUSIONS: The present results point to an unconfounded protective effect of Native American ancestry on BC risk in both Colombian and Mexican women which appears to be stronger for familial and ER-positive BC. These findings provide a rationale for personalised prevention programmes that take genetic ancestry into account, as well as for future admixture mapping studies.

Molecular profiling of a real-world breast cancer cohort with genetically inferred ancestries reveals actionable tumor biology differences between European ancestry and African ancestry patient populations.

BACKGROUND: Endocrine-resistant HR+/HER2- breast cancer (BC) and triple-negative BC (TNBC) are of interest for molecularly informed treatment due to their aggressive natures and limited treatment profiles. Patients of African Ancestry (AA) experience higher rates of TNBC and mortality than European Ancestry (EA) patients, despite lower overall BC incidence. Here, we compare the molecular landscapes of AA and EA patients with HR+/HER2- BC and TNBC in a real-world cohort to promote equity in precision oncology by illuminating the heterogeneity of potentially druggable genomic and transcriptomic pathways. METHODS: De-identified records from patients with TNBC or HR+/HER2- BC in the Tempus Database were randomly selected (N = 5000), with most having stage IV disease. Mutations, gene expression, and transcriptional signatures were evaluated from next-generation sequencing data. Genetic ancestry was estimated from DNA-seq. Differences in mutational prevalence, gene expression, and transcriptional signatures between AA and EA were compared. EA patients were used as the reference population for log fold-changes (logFC) in expression. RESULTS: After applying inclusion criteria, 3433 samples were evaluated (n = 623 AA and n = 2810 EA). Observed patterns of dysregulated pathways demonstrated significant heterogeneity among the two groups. Notably, PIK3CA mutations were significantly lower in AA HR+/HER2- tumors (AA = 34% vs. EA = 42%, P < 0.05) and the overall cohort (AA = 28% vs. EA = 37%, P = 2.08e-05). Conversely, KMT2C mutation was significantly more frequent in AA than EA TNBC (23% vs. 12%, P < 0.05) and HR+/HER2- (24% vs. 15%, P = 3e-03) tumors. Across all subtypes and stages, over 8000 genes were differentially expressed between the two ancestral groups including RPL10 (logFC = 2.26, P = 1.70e-162), HSPA1A (logFC = - 2.73, P = 2.43e-49), ATRX (logFC = - 1.93, P = 5.89e-83), and NUTM2F (logFC = 2.28, P = 3.22e-196). Ten differentially expressed gene sets were identified among stage IV HR+/HER2- tumors, of which four were considered relevant to BC treatment and were significantly enriched in EA: ERBB2_UP.V1_UP (P = 3.95e-06), LTE2_UP.V1_UP (P = 2.90e-05), HALLMARK_FATTY_ACID_METABOLISM (P = 0.0073), and HALLMARK_ANDROGEN_RESPONSE (P = 0.0074). CONCLUSIONS: We observed significant differences in mutational spectra, gene expression, and relevant transcriptional signatures between patients with genetically determined African and European ancestries, particularly within the HR+/HER2- BC and TNBC subtypes. These findings could guide future development of treatment strategies by providing opportunities for biomarker-informed research and, ultimately, clinical decisions for precision oncology care in diverse populations.

State Variation in Racial and Ethnic Disparities in Incidence of Triple-Negative Breast Cancer Among US Women.

Importance: There are few data on state variation in racial and ethnic disparities in incidence of triple-negative breast cancer (TNBC) in the US, limiting the ability to inform state-level health policy developments toward breast cancer equity. Objective: To quantify between and within racial and ethnic disparities in TNBC incidence rates (IRs) among US women across states. Design, Setting, and Participants: This cohort study using population-based cancer registry data included data for all women with TNBC diagnosed from January 1, 2015, to December 31, 2019, identified in the US Cancer Statistics Public Use Research Database. Data were analyzed from July through November 2022. Exposures: State and race and ethnicity (Hispanic, non-Hispanic American Indian or Alaska Native, non-Hispanic Asian or Pacific Islander, non-Hispanic Black, or non-Hispanic White) abstracted from medical records. Main Outcomes and Measures: The main outcomes were diagnosis of TNBC, age-standardized IR per 100 000 women, state-specific incidence rate ratios (IRRs) using the rate among White women in each state as a reference for between-population disparities, and state-specific IRRs using the race and ethnicity-specific national rate as a reference for within-population disparities. Results: The study included data for 133 579 women; 768 (0.6%) were American Indian or Alaska Native; 4969 (3.7%), Asian or Pacific Islander; 28 710 (21.5%), Black; 12 937 (9.7%), Hispanic; and 86 195 (64.5%), White. The TNBC IR was highest among Black women (25.2 per 100 000 women), followed by White (12.9 per 100 000 women), American Indian or Alaska Native (11.2 per 100 000 women), Hispanic (11.1 per 100 000 women), and Asian or Pacific Islander (9.0 per 100 000 women) women. Racial and ethnic group-specific and state-specific rates substantially varied, ranging from less than 7 per 100 000 women among Asian or Pacific Islander women in Oregon and Pennsylvania to greater than 29 per 100 000 women among Black women in Delaware, Missouri, Louisiana, and Mississippi. Compared with White women, IRRs were statistically significantly higher in 38 of 38 states among Black women, ranging from 1.38 (95% CI, 1.10-1.70; IR, 17.4 per 100 000 women) in Colorado to 2.32 (95% CI, 1.90-2.81; IR, 32.0 per 100 000 women) in Delaware; lower in 22 of 22 states among Asian or Pacific Islander women, varying from 0.50 (95% CI, 0.34-0.70; IR, 5.7 per 100 000 women) in Oregon to 0.82 (95% CI, 0.75-0.90; IR, 10.5 per 100 000 women) in New York; and did not differ among Hispanic and American Indian or Alaska Native women in 22 of 35 states and 5 of 8 states, respectively. State variations within each racial and ethnic population were smaller but still substantial. For example, among White women, compared with the national rate, IRRs varied from 0.72 (95% CI, 0.66-0.78; IR, 9.2 per 100 000 women) in Utah to 1.18 (95% CI, 1.11-1.25; IR, 15.2 per 100 000 women) in Iowa, 1.15 (95% CI, 1.07-1.24; IR, 14.8 per 100 000 women) in Mississippi, and 1.15 (95% CI, 1.07-1.24; IR, 14.8 per 100 000 women) in West Virginia. Conclusions and Relevance: In this cohort study, there were substantial state variations in racial and ethnic disparities in TNBC incidence, with Black women in Delaware, Missouri, Louisiana, and Mississippi having the highest rates among all states and racial and ethnic populations. The findings suggest that more research is needed to identify factors contributing to the substantial geographic variations in racial and ethnic disparities in TNBC incidence to develop effective preventive measures and that social determinants of health contribute to the geographic disparities in TNBC risk.

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.

Chemokine receptors differentially expressed by race category and molecular subtype in the breast cancer TCGA cohort.

Racial disparities in mortality due to metastasis remain significant among breast cancer patients. Chemokine receptors contribute to breast tumors and metastatic outcome. We explored for significant differences in chemokine receptor expression in breast tumors from Black, Asian, and White patients in The Cancer Genome Atlas. We show that despite sharing the same molecular subtype, expression of the chemokine receptors ACKR1, CCR3, CCR6, CCRL1, CCRL2, CXCR1, CXCR2, CXCR4, CXCR6, and CXC3CR1 was significantly different depending on racial group. For patients with triple negative breast cancer, CCR3 was higher in Black versus White and CCRL2 was higher in Asian versus White. In luminal A tumors, ACKR1 was lower in Asian versus White, CCR3 was higher in Black versus White, and CCR6 and CXC3CR1 were lower in Black versus White. In luminal B tumors, CCRL2 was lower in Black versus White, CXCR1 and CXC3CR1 were lower in Asian versus White, and CXCR2 was lower in Black and Asian versus White. In HER2 enriched tumors, CCR3 was higher in Black versus White and CXCR4 lower in Asian versus White. CCR3, CCR6, and CXCR6 associated with worse patient survival. These findings can inform improved treatment strategies to decrease racial disparities in breast cancer burden.

Translational Epidemiology: An Integrative Approach to Determine the Interplay Between Genetic Ancestry and Neighborhood Socioeconomic Status on Triple Negative Breast Cancer.

OBJECTIVE: To investigate the impact of global and local genetic ancestry and neighborhood socioeconomic status (nSES), on breast cancer (BC) subtype, and gene expression. BACKGROUND: Higher rates of aggressive BC subtypes [triple negative breast cancer (TNBC)] and worse overall BC survival are seen in black women [Hispanic Black (HB) and non-Hispanic Black (NHB)] and women from low nSES. However, the complex relationship between genetic ancestry, nSES, and BC subtype etiology remains unknown. METHODS: Genomic analysis was performed on the peripheral blood from a cohort of 308 stage I to IV non-Hispanic White (NHW), Hispanic White (HW), HB, and NHB women with BC. Patient and tumor characteristics were collected. Global and local ancestral estimates were calculated. Multinomial logistic regression was performed to determine associations between age, stage, genetic ancestry, and nSES on rates of TNBC compared to estrogen receptor (ER+)/epidermal growth factor receptor 2 (HER2-), ER+/HER2+, and ER-/HER2+ disease. RESULTS: Among 308 women, we identified a significant association between increasing West African (WA) ancestry and odds of TNBC [odds ratio (OR): 1.06, 95% confidence interval (95% CI): 1.001-1.126, P =0.046] as well as an inverse relationship between higher nSES and TNBC (OR: 0.343, 95% CI: 0.151-0.781, P =0.011). WA ancestry remained significantly associated with TNBC when adjusting for patient age and tumor stage, but not when adjusting for nSES (OR: 1.049, 95% CI: -0.987-1.116, P =0.120). Local ancestry analysis, however, still revealed nSES-independent enriched WA ancestral segment centered at χ 2 =42004914 ( p =3.70×10 -5 ) in patients with TNBC. CONCLUSIONS: In this translational epidemiologic study of genetic ancestry and nSES on BC subtype, we discovered associations between increasing WA ancestry, low nSES, and higher rates of TNBC compared to other BC subtypes. Moreover, on admixture mapping, specific chromosomal segments were associated with WA ancestry and TNBC, independent of nSES. However, on multinomial logistic regression adjusting for WA ancestry, women from low nSES were more likely to have TNBC, independent of genetic ancestry. These findings highlight the complex nature of TNBC and the importance of studying potential gene-environment interactions as drivers of TNBC.

Clinical genomic profiling to identify actionable alterations for very early relapsed triple-negative breast cancer patients in the Chinese population.

BACKGROUND: Triple-negative breast cancer (TNBC) represents about 19% of all breast cancer cases in the Chinese population. Lack of targeted therapy contributes to the poorer outcomes compared with other breast cancer subtypes. Comprehensive genomic profiling helps to explore the clinically relevant genomic alterations (CRGAs) and potential therapeutic targets in very-early-relapsed TNBC patients. METHODS: Formalin-fixed paraffin-embedded (FFPE) tumour tissue specimens from 23 patients with very-early-relapsed TNBC and 13 patients with disease-free survival (DFS) more than 36 months were tested by FoundationOne CDx (F1CDx) in 324 genes and select gene rearrangements, along with genomic signatures including microsatellite instability (MSI) and tumour mutational burden (TMB). RESULTS: In total, 137 CRGAs were detected in the 23 very-early-relapsed TNBC patients, averaging six alterations per sample. The mean TMB was 4 Muts/Mb, which was higher than that in non-recurrence patients, and is statistically significant. The top-ranked altered genes were TP53 (83%), PTEN (35%), RB1 (30%), PIK3CA (26%) and BRCA1 (22%). RB1 mutation carriers had shorter DFS. Notably, 100% of these patients had at least one CRGA, and 87% of patients had at least one actionable alteration. In pathway analysis, patients who carried a mutation in the cell cycle pathway were more likely to experience very early recurrence. Strikingly, we detected one patient with ERBB2 amplification and one patient with ERBB2 exon20 insertion, both of which were missed by immunohistochemistry (IHC). We also detected novel alterations of ROS1-EPHA7 fusion for the first time, which has not been reported in breast cancer before. CONCLUSIONS: The comprehensive genomic profiling can identify novel treatment targets and address the limited options in TNBC patients. Therefore, incorporating F1CDx into TNBC may shed light on novel therapeutic opportunities for these very-early-relapsed TNBC patients.

Genetic Mutations Associated with Hormone-Positive Breast Cancer in a Small Cohort of Ethiopian Women.

In Ethiopia, a breast cancer diagnosis is associated with a prognosis significantly worse than that of Europe and the US. Further, patients presenting with breast cancer in Ethiopia are far younger, on average, and patients are typically diagnosed at very late stages, relative to breast cancer patients of European descent. Emerging data suggest that a large proportion of Ethiopian patients have hormone-positive (ER+) breast cancer. This is surprising given (1) that patients have late-stage breast cancer at the time of diagnosis, (2) that African Americans with breast cancer frequently have triple negative breast cancer (TNBC), and (3) these patients typically receive chemotherapy, not hormone-targeting drugs. To further examine the similarity of Ethiopian breast tumors to those of African Americans or of those of European descent, we sequenced matched tumor and normal adjacent tissue from Ethiopian patients from a small pilot collection. We identified mutations in 615 genes across all three patients, unique to the tumor tissue. Across this analysis, we found far more mutations shared between Ethiopian patient tissue and that from white patients (103) than we did comparing to African Americans (3). Several mutations were found in extracellular matrix encoding genes with known roles in tumor cell growth and metastasis. We suggest future mechanistic studies on this disease focus on these genes first, toward finding new treatment strategies for breast cancer patients in Ethiopia.

Frequency and spectrum of mutations across 94 cancer predisposition genes in African American women with invasive breast cancer.

African American women are at increased risk of being diagnosed at a young age and/or with triple negative breast cancer, both factors which are included in current guidelines for identifying women who may benefit from genetic testing. Commercial breast cancer predisposition genetic panels, based largely on data derived from women of European ancestry, may not capture the full spectrum of cancer predisposition genes associated with breast cancer in African American women. Between 2001 and 2018, 488 unselected African American women with invasive breast cancer enrolled in the Clinical Breast Care Project. National Comprehensive Cancer Network (NCCN) Hereditary Cancer testing criteria version 1.2020 were applied to determine genetic risk. Targeted sequencing was performed using the TruSight Cancer panel and variants classified using the ClinVar database. Using NCCN criteria, 64.1% of African American women would be eligible for genetic testing. Fifty pathogenic or likely pathogenic mutations were detected in 19 genes with the highest frequencies in BRCA2 (29.4%) and BRCA1 (15.7%). Mutation frequencies in test-eligible and test-ineligible women were 13.1% and 3.5%, respectively. One-third of women harbored variants that could not be classified. While these data do not suggest a need to expand current commercial gene panels, NCCN criteria would fail to identify 12.5% of African American women with mutations in hereditary cancer predisposing genes.

Epidemiology of Basal-like and Luminal Breast Cancers among Black Women in the AMBER Consortium.

BACKGROUND: Evidence suggests etiologic heterogeneity among breast cancer subtypes. Previous studies with six-marker IHC classification of intrinsic subtypes included small numbers of black women. METHODS: Using centralized laboratory results for estrogen receptor (ER), progesterone receptor, HER2, proliferation marker, Ki-67, EGFR, and cytokeratin (CK)5/6, we estimated case-only and case-control ORs for established breast cancer risk factors among cases (n = 2,354) and controls (n = 2,932) in the African American Breast Cancer Epidemiology and Risk (AMBER) consortium. ORs were estimated by ER status and intrinsic subtype using adjusted logistic regression. RESULTS: Case-only analyses by ER status showed etiologic heterogeneity by age at menarche, parity (vs. nulliparity), and age at first birth. In case-control analyses for intrinsic subtype, increased body mass index and waist-to-hip ratio (WHR) were associated with increased risk of luminal A subtype, whereas older age at menarche and parity, regardless of breastfeeding, were associated with reduced risk. For basal-like cancers, parity without breastfeeding and increasing WHR were associated with increased risk, whereas breastfeeding and age ≥25 years at first birth were associated with reduced risk among parous women. Basal-like and ER-/HER2+ subtypes had earlier age-at-incidence distribution relative to luminal subtypes. CONCLUSIONS: Breast cancer subtypes showed distinct etiologic profiles in the AMBER consortium, a study of more than 5,000 black women with centrally assessed tumor biospecimens. IMPACT: Among black women, high WHR and parity without breastfeeding are emerging as important intervention points to reduce the incidence of basal-like breast cancer.

Are There Regional Differences in Triple Negative Breast Cancer among Non-Hispanic Black Women?

BACKGROUND: Non-Hispanic black women (NHB) are diagnosed with triple negative breast cancer (TNBC) more often than other ethnic or racial groups in the United States (US). This study describes regional differences in TNBC incidence among NHB women in the US from 2011 to 2015. METHODS: We analyzed data from the United States Cancer Statistics (USCS) that includes incidence data from the Centers for Disease Control and Prevention's National Program of Cancer Registries (NPCR) and the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) programs. RESULTS: Compared to the incidence rate for NHB women in the South, rates were significantly lower in the Northeast (22.6 per 100,000), higher in the Midwest (25.5 per 100,000) and similar in the West. These regional differences might be explained by genetic admixture among people with different geographic ancestral origins. CONCLUSIONS: Results from this study highlight the need to extend etiological research and evidence-based cancer prevention and control efforts to women at high risk of this disease in order to decrease cancer disparities.

Patterns of Failure in Triple Negative Breast Cancer Patients in an Urban, Predominately Black Population.

Triple negative breast cancers (TNBC) behave more aggressively than hormone-receptor positive breast cancers. They are also known preferentially to affect young black women, often leading to poorer outcomes compared with those for white women. We sought to evaluate the comprehensive patterns of failure associated with treatment for TNBC at an urban institution with a predominantly black population and to assess the impact of social determinants of health on treatment failure. A retrospective review of TNBC patients treated from 2005 to 2015 was conducted. Detailed patient, tumor, and treatment characteristics and information on patterns of failure were included. With a median follow-up of 46 months, 32 (16%) documented failures occurred. Locoregional failures comprised 84% of failure patterns whether isolated or in combination with distant failure. Treatment failure was associated with insurance type and smoking status, as well as several tumor characteristics. On multivariate analysis, pathologic nodal staging was the most significant predictor of treatment failure. In contrast to previous studies, we found that black women had higher overall survival than white women, but race was not associated with differences in recurrence patterns or with likelihood of treatment failure. Regardless of race, of the patients who recurred, 53% failed in distant and locoregional sites simultaneously, with an additional 34% failing locally only. These results highlight the need for aggressive local therapies in high-risk patients and suggest a need for improved follow-up focusing on detecting locoregional failures. Multidisciplinary care is essential in the management of these patients at time of failure.

Racial/Ethnic Disparities in All-Cause Mortality among Patients Diagnosed with Triple-Negative Breast Cancer.

It is unclear whether racial/ethnic disparities in triple-negative breast cancer (TNBC) mortality remain after accounting for clinical characteristics, treatment, and access-to-care-related factors. In this study, women with a primary diagnosis of TNBC during 2010-2014 were identified from the National Cancer Database. Hazard ratios (HR) and 95% confidence intervals (CI) for 3- and 5-year all-cause mortality associated with race/ethnicity were estimated using Cox proportional hazards models with stepwise adjustments for age, clinical characteristics, treatment, and access-to-care-related factors. Of 78,708 patients, non-Hispanic (NH) black women had the lowest 3-year overall survival rates (79.4%), followed by NH-whites (83.1%), Hispanics (86.0%), and Asians (87.1%). After adjustment for clinical characteristics, NH-blacks had a 12% higher risk of dying 3 years post-diagnosis (HR, 1.12; 95% CI, 1.07-1.17), whereas Hispanics and Asians had a 24% (HR, 0.76; 95% CI, 0.70-0.83) and 17% (HR, 0.83; 95% CI, 0.73-0.94) lower risk than their NH-white counterparts. The black-white disparity became non-significant after combined adjustment for treatment and access-to-care-related factors (HR, 1.04; 95% CI, 0.99-1.09), whereas the white-Hispanic and white-Asian differences remained. Stratified analyses revealed that among women aged less than or equal to 50 with stage III cancer, the elevated risk among NH-blacks persisted (HR, 1.20; 95% CI, 1.04-1.39) after full adjustments. Similar results were seen for 5-year mortality. Overall, clinical characteristics, treatment, and access-to-care-related factors accounted for most of the white-black differences in all-cause mortality of TNBC but explained little about Hispanic- and Asian-white differences. SIGNIFICANCE: These findings highlight the need for equal healthcare to mitigate the black-white disparity and for investigations of contributors beyond healthcare for lower mortality among Asians and Hispanics.

Association between tumor mutation profile and clinical outcomes among Hispanic Latina women with triple-negative breast cancer.

Triple-negative breast cancer (TNBC) represents 15%-20% of all breast cancer types. It is more common among African American (AA) and Hispanic-Latina (HL) women. The biology of TNBC in HL women has been poorly characterized, but some data suggest that the molecular drivers of breast cancer might differ. There are no clinical tools to aid medical oncologists with decisions regarding appropriate individualized therapy, and no way to predict long-term outcomes. The aim of this study was to characterize individual patient gene mutation profiles and to identify the relationship with clinical outcomes. We collected formalin-fixed paraffin-embedded tumors (FFPE) from women with TNBC. We analyzed the gene mutation profiles of the collected tumors and compared the results with individual patient's clinical histories and outcomes. Of 25 patients with TNBC, 24 (96%) identified as HL. Twenty-one (84%) had stage III-IV disease. The most commonly mutated genes were TP53, NOTCH1, NOTCH2, NOTCH3, AKT, MEP3K, PIK3CA, and EGFR. Compared with other international cancer databases, our study demonstrated statistically significant higher frequencies of these genes among HL women. Additionally, a worse clinical course was observed among patients whose tumors had mutations in NOTCH genes and PIK3CA. This study is the first to identify the most common genetic alterations among HL women with TNBC. Our data strongly support the notion that molecular drivers of breast cancer could differ in HL women compared with other ethnic backgrounds. Therefore, a deeper understanding of the biological mechanisms behind NOTCH gene and PIK3CA mutations may lead to a new treatment approach.