Nikita Wright

Multi-institutional study of nuclear KIFC1 as a biomarker of poor prognosis in African American women with triple-negative breast cancer

Nuclear KIFC1 (nKIFC1) predicts worse outcomes in breast cancer, but its prognostic value within racially distinct triple-negative breast cancer (TNBC) patients is unknown. Thus, nKIFC1 expression was assessed by immunohistochemistry in 163 African American (AA) and 144 White TNBC tissue microarrays (TMAs) pooled from four hospitals. nKIFC1 correlated significantly with Ki67 in White TNBCs but not in AA TNBCs, suggesting that nKIFC1 is not merely a surrogate for proliferation in AA TNBCs. High nKIFC1 weighted index (WI) was associated with significantly worse overall survival (OS), progression-free survival (PFS), and distant metastasis-free survival (DMFS) (Hazard Ratios [HRs] = 3.5, 3.1, and 3.8, respectively; P = 0.01, 0.009, and 0.007, respectively) in multivariable Cox models in AA TNBCs but not White TNBCs. Furthermore, KIFC1 knockdown more severely impaired migration in AA TNBC cells than White TNBC cells. Collectively, these data suggest that nKIFC1 WI an independent biomarker of poor prognosis in AA TNBC patients, potentially due to the necessity of KIFC1 for migration in AA TNBC cells.

Distinctions in Breast Tumor Recurrence Patterns Post-Therapy among Racially Distinct Populations

Background Clinical studies have revealed a higher risk of breast tumor recurrence in African-American (AA) patients compared to European-American (EA) patients, contributing to the alarming inequality in clinical outcomes among the ethnic groups. However, distinctions in recurrence patterns upon receiving hormone, radiation, and/or chemotherapy between the races remain poorly characterized. Methods We compared patterns and rates (per 1000 cancer patients per 1 year) of recurrence following each form of treatment between AA (n = 1850) and EA breast cancer patients (n = 7931) from a cohort of patients (n = 10504) treated between 2005–2015 at Northside Hospital in Atlanta, GA. Results Among patients who received any combination of adjuvant therapy, AA displayed higher overall rates of recurrence than EA (p = 0.015; HR: 1.699; CI: 1.108–2.606). Furthermore, recurrence rates were higher in AA than EA among stage I (p = 0.031; HR: 1.736; CI: 1.052–2.864) and T1 classified patients (p = 0.003; HR: 2.009; CI: 1.263–3.197). Interestingly, among patients who received neoadjuvant chemotherapy, AA displayed higher rates of local recurrence than EA (p = 0.024; HR: 7.134; CI: 1.295–39.313). Conclusion Our analysis revealed higher incidence rates of recurrence in AA compared to EA among patients that received any combination of adjuvant therapy. Moreover, our data demonstrates an increased risk of tumor recurrence in AA than EA among patients diagnosed with minimally invasive disease. This is the first clinical study to suggest that neoadjuvant chemotherapy improves breast cancer recurrence rates and patterns in AA.

Panoptic Overview of Triple-Negative Breast Cancer in Nigeria: Current Challenges and Promising Global Initiatives

Purpose Triple-negative breast cancer (TNBC) is the most deadly form of breast cancer (BC) today. TNBC treatment is fraught with challenges because of the extensive interpatient heterogeneity in clinical behavior and scarcity of stratifying biomarkers and actionable targets. Women of African ancestry face a disproportionate burden resulting from this disease, which affects them earlier and more aggressively and has a higher propensity to spread and resist conventional treatments. A much higher proportion of Nigerian patients with BC have TNBC compared with patients with BC in the United States and Europe. Methods This article spotlights Nigeria as an example of a nation wherein genetic and nongenetic spheres of influence intersect to affect the prevalence of this disease, the scale of its challenge, and its toll. Results Studies have illuminated the inherently different tumor biology of Nigerian TNBCs, which show distinct genetic variants and gene expression patterns compared with European or European-American TNBCs. Parallels are apparent between TNBC phenotypes among African Americans and Nigerians, implicating the common thread of shared genetic ancestry between these populations. Reproductive, lifestyle, socioeconomic, and cultural factors also shape TNBC outcomes in Nigeria, as do resource constraints in Nigerian health care and research sectors. Conclusion Increasing our understanding of how these factors contribute to poorer outcomes among Nigerian women may uncover valuable insights and strategies in alleviating the TNBC burden in many countries of the world and help reduce the racial disparity in BC-related outcomes here in the United States. Importantly, this review also highlights collaborative global and local initiatives that converge expertise and resources to advance research on effective management of TNBC in diverse populations.

Abstract PR06: Differences in tumor-infiltrating lymphocytes between racially distinct triple-negative breast tumors

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype that lacks hormone receptors [estrogen receptor (ER), progesterone receptor (PR)] and overexpression of human epidermal growth factor receptor 2 (HER2/neu). The disease is characterized by an aggressive clinical disease course, and a high risk of disease progression within 5 years of diagnosis. There are currently no targeted treatments available for TNBC, and surgery and chemotherapy are the mainstay of TNBC treatment. TNBC afflicts African-American (AA) women at a 2-3 times higher rate than European-American (EA) women. AAs also present with more aggressive clinicopathologic characteristics such as higher grade and stage at diagnosis, and experience poorer clinical outcomes than EAs among TNBC patients. Furthermore, AAs harbor more aggressive TNBC subtypes such as a basal-like phenotype and quadruple-negative [androgen receptor (AR)-negative TNBC] breast cancer than EA TNBC patients. This disparate burden underscores an urgent need to identify distinctions in inherent tumor biology between racially distinct TNBCs. Tumor-infiltrating lymphocytes (TILs) are implicated in killing tumor cells and thus have been associated with better clinical outcomes and response to neoadjuvant chemotherapy. Studies have also reported that TILs are associated with more aggressive clinicopathologic characteristics such as such as higher grade, stage, Ki67, TNBC status, and increased lymph node metastasis. In formalin-fixed, paraffin-embedded resection samples from TNBC patients who received adjuvant chemotherapy at Emory Hospital in Atlanta, GA, we compared overall (intratumoral and peripheral) TIL counts between AA and EA patients (n=121). We observed a trend of more TILs among AA (n=87) compared to EA (n=34) TNBC patients (p=0.02). Among early-stage (I-II) TNBC patients, we found that AAs (n=71) harbored significantly more TILs than EAs (n=32) (p=0.019) but not among late-stage (III-IV) patients (p=0.86). Among early-stage AA TNBC patients, more TILs negatively correlated with younger age at diagnosis (ρ=-0.25; p=0.03) and positively correlated with intramammary lymph node involvement (ρ=0.36; p=0.002). Furthermore, TILs correlated negatively with AR expression (ρ=-0.25; p=0.04) and positively with BRCA1-associated protein (ρ=0.3; p=0.02) and programmed cell death protein 1 (ρ=0.56; p Citation Format: Nikita Wright, Chaeyun Lee, Wei Guanhao, Uma Krishnamurti, Xiaoxian Li, Padmashree C. G. Rida, Remus Osan, Ritu Aneja. Differences in tumor-infiltrating lymphocytes between racially distinct triple-negative breast tumors [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr PR06.

Abstract B13: A novel metric illuminates disparities in cell cycling kinetics between ethnically-distinct breast tumors and enhances prediction of metastatic risk

Breast tumors in African-Americans (AAs) exhibit higher recurrence rates and faster kinetic progression to metastasis than those in European-Americans (EAs). This results in a stark ethnic disparity in breast cancer outcomes. Hence, enhancing understanding of cell cycle kinetics within breast tumors may illuminate hitherto overlooked and fundamental tumor biological characteristics of breast tumors underpinning racial differences in metastatic propensities. Current clinico-pathological prognostic markers that evaluate cell proliferation in breast carcinomas include mitotic index (MI) and Ki67 proliferation index (KI). However, as autonomous prognosticators measured on distinct scales, MI and KI lack the ability to capture information about the cycling kinetics of proliferating tumor cells-a key driver of intratumoral heterogeneity; this diminishes and undermines their prognostic accuracy. We performed a three-color immunofluorescence staining on paraffin-embedded AA (n=83) and EA (n=151) breast tumor tissue specimens from Northside Hospital to integrate mitotic cells and cycling cells into the same measurement scale. Phospho histone H3 was used as a mitotic marker and Ki-67 as a cell proliferation marker. Stained samples were examined in confocal microscopy to determine the proportion of mitotic cells among Ki-67 positive proliferative cells to yield the Mitosis:Proliferation (M:P) Ratio, a measure of the turnover rate of proliferating tumor cells. We observed higher M:P ratio in AA compared to grade-matched and stage-matched EA tumor tissue specimens. AA displayed significantly higher M:P ratio than EA among early stage tumors (p=0.015). Furthermore, among the clinico-pathological parameters, age, race, grade, stage, and receptor status, a multivariate analysis revealed that race was the only variable that exhibited a significant confounding influence on M:P ratio (p=0.042). A higher M:P Ratio likely reflects an increased mitotic propensity and higher risk of developing intratumoral heterogeneity and producing aggressive clones; thus, a higher M:P ratio may underlie the observed greater metastatic propensity exhibited in AA compared to EA patients. Thus, our novel metric provides new insights into the KI-MI relationship in tumors, exposes previously unrecognized differences in cycling kinetics among early stage AA and EA breast tumors, and proffers additional metastatic risk predictive information currently unavailable in the clinic. Citation Format: Nikita Wright, Sergey Klimov, Mildred Jones, Guilherme H. Cantuaria, Padmashree C. G. Rida, Ritu Aneja. A novel metric illuminates disparities in cell cycling kinetics between ethnically-distinct breast tumors and enhances prediction of metastatic risk. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr B13.

Abstract A02: Breast cancer recurrence patterns among ethnically distinct populations: A single institution large cohort study

African-American (AA) women with breast cancer have worse overall survival compared with European-American (EA) women with breast cancer for reasons that are incompletely understood. A primary risk factor for breast cancer-specific mortality is disease recurrence, yet racial distinctions in recurrence patterns remain poorly characterized. Evaluation of the risk of recurrence upon initial diagnosis is crucial for clinicians to customize an optimal treatment plan. Prognostic factors associated with recurrence include lymph node involvement, larger tumor size, earlier age at diagnosis, and triple-negative receptor status. These poor prognostic indicators have been associated with AA race. In this study, we examined rates and patterns of recurrence in a large cohort of breast cancer patients (n=10504) treated from 2005-2015 at Northside Hospital in Atlanta, GA. We observed that AA breast cancer patients (n=1850) exhibited a higher frequency of recurrences than EA breast cancer patients (n=7931) (p=0.047). Moreover, AA breast cancer patients exhibited a trend towards regional and distant recurrences, which are more fatal, whereas EA breast cancer patients displayed a higher inclination towards local recurrences that show a better prognosis. However, while these trends were robust, they did not achieve significance perhaps owing to the small number of patients in recurrence location subcategories. Importantly, overall survival was worse among AA patients with distant recurrences (n=26) than EA breast cancer patients with distant recurrences (n=80) (p=0.01). Furthermore, among patients who underwent lymph node surgery, regional recurrence was more likely among AAs (n=1030) than EAs (n=5252) (p=0.045). Among patients who received radiation, there was a non-significant trend towards AAs (n=874) exhibiting a greater propensity toward disease recurrence than EAs (n=3734). This study illuminates striking differences in recurrence patterns among AA and EA breast cancer patients by exposing that AA patients are more likely to experience more aggressive non-local recurrences, and are at a greater risk of mortality from distant recurrences. Collectively, these findings help to explain the accelerated progression of the disease and lower survival rates in AA breast cancer patients compared with their EA counterparts, underscoring the urgent need for clinicians to consider race in screening programs and when devising treatment plans. Citation Format: Nikita Wright, Pranay Neema, Remus Osan, Jun Xia, Stephen Wells, Josef G. Venable, Mildred Jones, Padmashree Rida, Ritu Aneja, Guilherme Cantuaria. Breast cancer recurrence patterns among ethnically distinct populations: A single institution large cohort study. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr A02.

Abstract P5-10-15: Empowering the Nottingham Grading System: An integrated Ki67-mitosis classifier yields a better patient stratification tool

Therapeutic decision-making for personalized management of breast cancer relies on patient stratification based on the risk conferred by clinicopathologic factors, such as stage, Ki67 Index (KI) and tumor histological grade. The most widely used histologic grading system for breast cancer, the Nottingham Grading System (NGS) provides prognostic information about breast tumor samples by combining analysis of the extent of glandular differentiation, nuclear pleomorphism and mitotic activity present in the tumor sample. In the NGS, the mitotic Index (MI) is defined as the number of mitotic cells per ten high-power fields. KI is a universal prognostic indicator but is not part of the NGS. Although the NGS has been widely used owing to its reproducibility and significant prognostic value, its accuracy in predicting disease prognosis and aggressiveness is limited. Our earlier work has demonstrated that by rationally integrating KI and MI into a new metric called the Ki67-Adjusted Mitotic Score (KAMS), which is a measure of the proportion of mitotic cells amongst Ki67-positive cells, we are able to glean a new layer of prognostic information about metastatic risk. We found that for Nottingham Grade II and III patients, high KAMS values predicted relatively better overall survival (OS) than low KAMS values. We therefore asked if the incorporation of a KAMS-based classifier subsequent to conventional Nottingham classification, would improve patient stratification to enable their funneling towards more optimal treatment choices. Ideal KAMS thresholds were established by analyzing the KAMS-stratified survival groups and selecting the thresholds which created the widest survival stratification that was additionally confirmed to be statistically significant via a Log-Rank test. For Nottingham Grade II and III patients, an above-threshold KAMS value was deemed as low-risk and a below-threshold KAMS value was deemed as high-risk for the purpose of grade adjustment. Grade adjustments were based solely on the patients’ KAMS values. Thus the adjusted Nottingham Grade I consisted of the original Nottingham Grade I patients along with KAMS determined low-risk original Nottingham Grade II patients. Adjusted Nottingham Grade II patients were composed of KAMS determined high-risk patients originally in Nottingham Grade II along with KAMS determined low-risk original Nottingham Grade III patients. Finally, the adjusted Nottingham Grade III was made up exclusively of high-risk patients from the original Nottingham Grade III. We found that the adjusted system represents a wider separation between OS curves with adjusted Grade I (n = 774) OS being 95.48%, adjusted grade II (n = 727) OS at 87.62%, and adjusted Grade III (n = 110) having an OS of 78.18%. Overall survival groups between adjusted grade I and II and I and III (p Citation Format: Vaishali Pannu, Padmashree CG Rida, Sergey Klimov, Nikita Wright, Guilherme Cantuaria, Michelle Reid, Ritu Aneja. Empowering the Nottingham Grading System: An integrated Ki67-mitosis classifier yields a better patient stratification tool [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-10-15.

Abstract PR13: Disparities in centrosomal profiles: Prediction of metastatic risk in African American and European American breast cancer patients

Centrosome amplification has long been established as a hallmark of cancer. More than 80% of invasive breast tumors display this cellular trait. Centrosomal aberrations underlie chromosome instability (CIN) thus corroborating the extensive clonal intratumoral heterogeneity existent within breast lesions that fuels tumor evolution. Sub-clonal heterogeneity drives emergence of aggressive clones with a propensity to migrate and invade, resulting in tumor dissemination and metastases. Thus, centrosome amplification is a critical driver of tumor progression and metastases. Although numerous studies have linked centrosomal overload to tumor aggressiveness, no studies have yet quantified this cell-biological feature to establish a well-defined relationship between the severity and extent of centrosome amplification and tumor aggressiveness. Utilizing an innovative and rationally-guided approach, we have derived an algorithm that allows the precise quantitation of the frequency and severity of both structural and numerical aberrations in supernumerary centrosomes present in clinical samples. Our novel method thus uncovers previously unrecognized differences in the centrosomal profiles of grade-matched breast tumors from African-American (AA) (n=71) and European American (EA) (n=104) women. Our data demonstrate that AA breast tumors exhibit higher numeral, structural and total centrosome amplification scores than grade-matched EA tumors. Interestingly, tumors displaying lymph node and distant metastasis exhibited higher structural amplification than grade-matched non-metastatic tumors. Hence, our novel quantification tool offers valuable information that can potentially predict the risk of AA breast tumors rapidly progressing to metastatic disease and uncovers a hitherto unappreciated organelle-specific disparity marker among racially distinct breast tumors. This abstract was also presented as Poster B6. Citation Format: Nikita Wright, Vaishali Pannu, Padmashree Rida, Karuna Mittal, Sergey Klimov, Farida N. Yada, Michelle D. Reid, Guilherme Cantuaria, Ritu Aneja. Disparities in centrosomal profiles: Prediction of metastatic risk in African American and European American breast cancer patients. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr PR13.