Relative Frequency Differences Research Articles

Characterizing Cancer Burden in the American Indian Population in North Carolina.

The American Indian (AI) population in North Carolina has limited access to the Indian Health Service. Consequently, cancer burden and disparities may differ from national estimates. We describe the AI cancer population and examine AI-White disparities in cancer incidence and mortality. We identified cancer cases diagnosed among adult AI and White populations between 2014-2018 from the North Carolina Central Cancer Registry. We estimated incidence and mortality rate ratios (IRR; MRR) by race. Additionally, between the AI and White populations, we estimated relative frequency differences (RRFs, with 95% confidence limits [CL]) of clinical and sociodemographic characteristics. Lastly, we evaluated the geographic distribution of incident diagnoses among AI populations. Our analytic sample included 2,161 AI and 204,613 White individuals with cancer. Compared to the White population, the AI population was more likely to live in rural areas (48% vs 25%; RRF:1.89;CL:1.81,1.97) and to have Medicaid (18% vs 7%; RRF:2.49;CL:2.27,2.71). Among the AI population, the highest age-standardized incidence rates were female breast, followed by prostate and lung and bronchus. Liver cancer incidence was significantly higher among the AI population than White population (IRR:1.27;CL:1.01,1.59). AI patients had higher mortality rates for prostate (MRR:1.72;CL:1.09,2.70), stomach (MRR:1.82;CL:1.15,2.86), and liver (MRR:1.70;CL:1.25,2.33) cancers compared to White patients. To reduce prostate, stomach, and liver cancer disparities among AI populations in North Carolina, multi-modal interventions targeting risk factors and increasing screening and treatment are needed. This study identifies cancer disparities that can inform targeted interventions to improve outcomes among AI populations in North Carolina.

Doppler-dependent fluorescence spectroscopy of Yb atomic gas for trapped-ion experiments

An ion trap-based Quantum system has been one of the leading architectures toward building a scalable and practical quantum computer. The trapped ion system also has been used for precision experiments such as quantum sensing, metrology, and atomic clock. For the ion-trap experiment, searching resonant frequencies of atomic isotopes are essential for selectively ionization and trapping a specific isotope. In this work, we set up an Yb fluorescence spectroscopy for detecting 399 nm photons of 1S0 → 1P1 transition of the Yb gas from a heated oven. We observed the relative frequency differences between the Yb isotopes and calibrated an optical wavemeter comparing with previous literatures. In addition, we obtain characteristic properties of the atomic oven such as gas’ velocity and density distribution at different oven temperatures. Our experiment can offer a relatively simple and cost-efficient apparatus of spectroscopy and can be useful for designing trap devices in the trapped-ion experiment.

Socioeconomic status, access to care, risk factor patterns, and stage at diagnosis for head and neck cancer among black and white patients.

Little is known about how factors combine to influence progression of squamous cell carcinoma of the head and neck (HNSCC). We aimed to evaluate multidimensional influences of factors associated with HNSCC stage by race. Using retrospective data, patients with similar socioeconomic status (SES), access to care (travel time/distance), and behavioral risk factors (tobacco/alcohol use and dental care) were grouped by latent class analysis. Relative frequency differences (RFD) were calculated to evaluate latent classes by stage, race, and p16 status. We identified three latent classes. Advanced T-stage was higher for black (RFD=+20.2%; 95% CI: -4.6 to 44.9) than white patients (RFD=+10.7%; 95% CI: 2.1-19.3) in the low-SES/high-access/high-behavioral risk class and higher for both black (RFD=+29.6%; 95% CI: 4.7-54.5) and white patients (RFD=+23.9%; 95% CI: 15.2-32.6) in the low-SES/low-access/high-behavioral risk class. Results suggest that SES, access to care, and behavioral risk factors combine to underly the association with advanced T-stage. Additionally, differences by race warrant further investigation.

Breast cancer treatment patterns by age and time since last pregnancy in the Carolina Breast Cancer Study Phase III.

To describe breast cancer treatment patterns among premenopausal women by age and time since last pregnancy. Data were analyzed from 1179 women diagnosed with premenopausal breast cancer in the Carolina Breast Cancer Study. Of these, 160 had a recent pregnancy (within 5years of cancer diagnosis). Relative frequency differences (RFDs) and 95% confidence intervals (CIs) were used to compare cancer stage, treatment modality received, treatment initiation delay (> 30days), and prolonged treatment duration (> 2 to > 8months depending on the treatment received) by age and recency of pregnancy. Recently postpartum women were significantly more likely to have stage III disease [RFD (95% CI) 12.2% (3.6%, 20.8%)] and to receive more aggressive treatment compared to nulliparous women. After adjustment for age, race and standard clinical tumor characteristics, recently postpartum women were significantly less likely to have delayed treatment initiation [RFD (95% CI) -11.2% (-21.4%, -1.0%)] and prolonged treatment duration [RFD (95% CI) -17.5% (-28.0%, -7.1%)] and were more likely to have mastectomy [RFD (95% CI) 14.9% (4.8%, 25.0%)] compared to nulliparous. Similarly, younger women (< 40years of age) were significantly less likely to experience prolonged treatment duration [RFD (95% CI) -5.6% (-11.1%, -0.0%)] and more likely to undergo mastectomy [RFD (95% CI) 10.6% (5.2%, 16.0%)] compared to the study population as a whole. These results suggest that recently postpartum and younger women often received prompt and aggressive breast cancer treatment. Higher mortality and recurrence among recently pregnant women are unlikely to be related to undertreatment.

Hepatocyte growth factor pathway expression in breast cancer by race and subtype

BackgroundAfrican American women have the highest risk of breast cancer mortality compared to other racial groups. Differences in tumor characteristics have been implicated as a possible cause; however, the tumor microenvironment may also contribute to this disparity in mortality. Hepatocyte growth factor (HGF) is a stroma-derived marker of the tumor microenvironment that may affect tumor progression differentially by race.ObjectiveTo examine whether an HGF gene expression signature is differentially expressed by race and tumor characteristics.MethodsInvasive breast tumors from 1957 patients were assessed for a 38-gene RNA-based HGF gene expression signature. Participants were black (n = 1033) and non-black (n = 924) women from the population-based Carolina Breast Cancer Study (1993–2013). Generalized linear models were used to estimate the relative frequency differences (RFD) in HGF status by race, clinical, and demographic factors.ResultsThirty-two percent of tumors were positive for the HGF signature. Black women were more likely [42% vs. 21%; RFD = + 19.93% (95% CI 16.00, 23.87)] to have HGF-positive tumors compared to non-black women. Triple-negative patients had a higher frequency of HGF positivity [82% vs. 13% in non-triple-negative; RFD = + 65.85% (95% CI 61.71, 69.98)], and HGF positivity was a defining feature of basal-like subtype [92% vs. 8% in non-basal; RFD = + 81.84% (95% CI 78.84, 84.83)]. HGF positivity was associated with younger age, stage, higher grade, and high genomic risk of recurrence (ROR-PT) score.ConclusionHGF expression is a defining feature of basal-like tumors, and its association with black race and young women suggests it may be a candidate pathway for understanding breast cancer disparities.

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 &lt; 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]

Abstract SS1-05: Racial differences in breast cancer immune microenvironments

Abstract Background: Black women suffer 40% higher mortality from breast cancer (BC) compared to non-Hispanic white women, and the underlying causes of these disparities remain uncertain. Growing evidence supports the importance of the immune microenvironment in BC survival, but immune response differences by race are poorly understood. We sought to characterize the immune microenvironment of BC to evaluate how phenotypes of immune response vary across race and tumor intrinsic subtype to impact clinical outcomes. Methods: We leveraged the Carolina Breast Cancer Study (CBCS), a large population-based study that oversampled young (≤50) and black women with invasive breast cancer and collected tumor tissue on &amp;gt;95% of participants. We curated a 48-gene panel representative of 13 individual immune cell types, and performed NanoString gene expression profiling on tissue from 1957 BC patients, including 1033 (53%) Black and 924 (47%) Non-Black women. Consensus clustering was used to identify phenotypes of immune response, and individual immune cell scores were calculated as the median expression of cell-type markers. Immune phenotypes and cell-type scores were compared against validated protein markers and H&amp;E-based quantification of TILs from corresponding tissue microarrays (TMAs). We estimated associations of immune classes with BC intrinsic subtype, ROR-PT scores (calculated as low, medium and high), age and race using relative frequency differences (RFDs), adjusting for age and tumor stage. Cell type scores were compared by race using Welch’s t-tests and adjusted for multiple comparisons with the Benjamani-Hochberg procedure. Results: We identified three BC immune phenotypes primarily defined by features related to an Adaptive-enriched, Innate-enriched, or a Quiet immune microenvironment. These expression-based groups correlated with histological evidence of immune cells from corresponding TMAs. Similarly, expression-based cell scores correlated strongly with protein-based quantification of immune cells from corresponding TMAs (e.g. B-cell score vs. CD19 immunofluorescence, rho=0.75; ICOS RNA counts vs. protein; Rho=0.76). Both Adaptive-enriched and Innate-enriched tumors were associated with high ROR-PT scores [RFD for Adaptive-enriched vs. Quiet: 24.1% (95% CI 19.3-28.8); Innate-enriched vs. Quiet RFD: 13.1 (95% CI 9.1-17); frequencies: 37.2%, 26.2% and 10% for Adaptive, Innate and Quiet, respectively], the basal-like intrinsic subtype [RFD for Adaptive-enriched vs. Quiet: 19.4% (95% CI 14.3-24.6); Innate-enriched vs. Quiet RFD: 9.8 (95% CI 5.6-14.1); frequencies: 43.4%, 27.4% and 8.9% respectively] and Black race [RFD for Adaptive-enriched vs. Quiet: 16.1% (95% CI 10.3-21.9); Innate-enriched vs. Quiet RFD: 9.5 (95% CI 3.9-15); frequencies 60.5%, 53.5% and 42.5% respectively]. After adjusting for tumor subtype, the Adaptive-enriched class remained associated with Black race (RFD for Adaptive-Enriched vs Quiet: 7.5% (95% CI 1.4-13.6). Conversely, tumors in the immune-quiet group were primarily non-basal (90%) with low ROR-PT scores (86.7%). Within the Adaptive-enriched class, Black women displayed decreased CD8 T cell scores (p=0.05) but increased T-reg cell scores (p=0.02) relative to Non-Black women. Conclusion: Immune response appears to be intricately related to race and tumor subtype, with black women having strong associations with adaptive-enriched and innate-enriched immune microenvironments. Differences in CD8 T cell and Treg expression suggest that even within broad classes of immune response, racial differences in specific cell-type distributions exist. Immune response differences may be targetable to improve treatment response, and therefore it is important to identify race- and subtype-specific differences in immune microenvironments. Citation Format: Alina M Hamilton, Linnea T Olsson, Benjamin C Calhoun, Katherine A Hoadley, Melissa A Troester. Racial differences in breast cancer immune microenvironments [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SS1-05.

Abstract PD11-06: Associations between obesity and metastasis in the Carolina breast cancer study

Abstract Background. Metastatic disease accounts for the majority of breast cancer-specific mortality, and identifying women who are most at risk for metastasis remains an important challenge. Genomic risk scores are valuable tools in assessing risk of recurrence but have rarely been applied to assess risk of distant metastasis in large, diverse population-based cohorts. Such cohorts can identify important modifiers of the relationship between tumor genomics and metastasis. In particular, obesity at diagnosis has been implicated as a risk factor for breast cancer metastasis. Waist-to-hip ratio (WHR), as a measure of central adiposity, appears to increase risk of breast cancer mortality. It is important to understand how obesity impacts risk of metastasis and modifies other known prognostic factors. Methods. Data from the Carolina Breast Cancer Study, a prospective cohort of women with incident breast cancer that oversampled young women and black women such that each represented 50% of the study population, were used to study metastasis within five years of follow up (n=239 incident metastases in 2767 eligible participants with stage I-III disease). PAM50-derived risk-of-recurrence (ROR-PT) scores were measured using a research version of the 50-gene assay, and represent a multigene classifier incorporating tumor subtype, size, and proliferation score. Women with de novo metastasis (identified at diagnosis, n=109) were excluded, as incident and de novo metastases have different prognosis. Obesity was defined by WHR (&amp;gt; 0.85). Absolute risk within strata and risk differences between strata were calculated using the Kaplan-Meier estimator; models were adjusted with inverse probability weights conditional on grade, stage, age, and race, where appropriate. To examine the association between obesity and site or multiplicity of metastasis, relative frequency differences were estimated using generalized linear models. Results. The overall risk of metastasis in CBCS differed significantly by race (11.2% in Black women and 6.8% in non-Black women and was associated with higher ROR-PT score (19.8% in high ROR-PT vs. 6.5% in low or medium ROR-PT). 48.2% of women were classified as obese by WHR. Women with high WHR had a significantly higher absolute risk of metastasis (11.2%, 95% CI: 9.4, 13.0) relative to those with lower WHR (6.9, 95% CI: 5.6, 8.2). However, the effects of WHR on risk seemed to be isolated to those with high risk tumors. Non-obese and obese women with low-to-medium ROR-PT scores had similar risk of metastasis [RDLowMed (95% CI) = 1.5% (-1.5, 4.4)], while obese women with high ROR-PT scores had substantially higher risk of metastasis than non-obese women [RDHigh (95% CI) = 13.1% (4.3, 21.9); 26.2% vs. 13.1%]. Considering site of metastasis, more metastases were observed among women with high WHR at every site except brain. More occurrences of multiple metastases were also observed among obese women. Conclusions. Consistent with previous studies, we observed racial disparities in metastasis, with Black women having higher 5-year metastatic risk and with women with high ROR-PT scores also having higher risk. Obesity, herein measured by WHR, is an important predictor of metastatic risk and may modify the relationship between genomic risk scores and risk of metastasis. Citation Format: Linnea T Olsson, Andrea Walens, Alina M Hamilton, Halei C Benefield, Kevin P Williams, Jodie M Fleming, Stephen D Hursting, Melissa A Troester. Associations between obesity and metastasis in the Carolina breast cancer study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD11-06.

Abstract PS19-03: Dna repair imbalance and immune response in breast cancer mortality disparities

Abstract Background: Black breast cancer patients have p53 loss in 60% of their tumors, compared to 35% p53 loss in white breast cancer patients. The tumor suppressor p53 has pleiotropic effects on DNA repair, as it regulates both error prone and error-free DNA repair pathways. These effects on DNA repair represent molecular vulnerabilities that influence chemotherapy response, both directly and indirectly through the activation of immune responses. While studies have begun to elucidate DNA repair imbalance and immune response in human cancer, little is known about how these pathways differ by race. Methods: To study DNA repair and immune response in breast cancer, we performed gene expression analysis on FFPE samples from the Carolina Breast Cancer Study (CBCS), a large population-based study that oversampled black and younger women. We curated a list of DNA repair genes representing regulators of error prone and error free DNA repair. Pathways included Nucleotide Excision Repair (NER), Fanconi Anemia (FA), Mismatch repair (MMR), Base Excision Repair (BER), Homologous Recombination (HR), Translesion Synthesis (TLS), Alternative End Joining (AEJ), Checkpoint, and APOBEC. In addition, we developed a 50-gene immune panel representing 12 individual immune cell types (B cells, T cells, Treg cells, T help cells, T follicular helper cells, CD8 T cells, NK cells, Eosinophils, Neutrophils, M1 &amp; M2 Macrophages) and both adaptive and innate arms of the immune system. A total of 1464 patients (53% black, 53% under 50) were included in the current analysis. We used consensus clustering to identify groups of patients based on DNA repair gene expression and used linear regression to estimate the relative frequency differences between these classes and demographic and clinical characteristics. Results: We found that breast cancers grouped into four clusters based on DNA repair gene expression. One cluster, ‘Repair High’, represented 32% of the tumors, and had high expression of NER, NHEJ, HR, and FA genes, suggesting a broad DNA repair response. Another group, ‘HR/FA High’ represented 23% of the tumors and was enriched for high expression of HR and FA genes. An “APOBEC High” group consisted of 32% of the tumors and was enriched for high expression of APOBEC family genes (APOBEC3D, APOBEC1, APOBEC3A, APOBEC3H, APOBEC3B). Finally, 13% of tumors, had a ‘Heterogeneous Repair’ pattern of high expression of HR, NHEJ, and FA genes, but lower expression of NER genes. The HR/FA and Heterogeneous Repair groups were enriched for TP53 mutant-like tumors (93% vs. 5% and 61% vs. 38% Mutant vs. Wildtype respectively). In addition, the Heterogeneous Repair group was enriched for Hormone Receptor positive samples ([RFD] 8.2% (0.613, 15.3), 77% vs. 23% in positive vs. negative respectively), while the HR/FA High group was significantly enriched for TNBC ([RFD] HR/FA: 51.2% (45.1, 57.1), 75% vs. 25% TNBC vs. non-TNBC respectively). The Repair High group was the only group enriched for non-black race ([RFD]: 10.4% (4.0, 16.7), 42% vs. 58% in blacks vs. non-blacks respectively). Finally, DNA repair classes were associated with immune scores, with the APOBEC High tumors having a significantly higher Eosinophil score (p = 0.021) and Neutrophil score (p = 0.007) compared to the other four groups. Conclusion: DNA repair expression is highly variable across breast tumors and may depend upon TP53 status, tumor subtype, and race. Differential immune marker expression by DNA repair group suggests some DNA repair groups may have differential response to immune-targeted therapies. DNA repair, immune response, and race are inter-related in breast cancer and unraveling and ultimately targeting breast cancer disparities may require coordinated evaluation of these pathways. Citation Format: Andrea Walens, Alina M Hamilton, Markia A Smith, Xiaohua Gao, Erin L Kirk, Stephen D Hursting, Katherine A Hoadley, Cyrus Vaziri, Melissa A Troester. Dna repair imbalance and immune response in breast cancer mortality disparities [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS19-03.

Abstract 1184: Association of immune microenvironment and race in the Carolina Breast Cancer Study

Abstract Background: High levels of tumor infiltrating lymphocytes have been associated with favorable prognosis in triple negative and HER2-positive breast cancer (BC), especially in tumors with high mutation burden. Recently, our group showed that TP53 functional defects are strongly associated with black race in the Carolina Breast Cancer Study (CBCS). However, the immune microenvironment has been inconsistently associated with racial disparities in BC. Methods: To characterize immune phenotypes in BC, we curated a 50-gene NanoString immune panel and validated the gene set using RNA sequencing data from The Cancer Genome Atlas (TCGA). We applied the NanoString panel in the CBCS and estimated associations with immune infiltrates, BC intrinsic subtype, proliferation scores, p53 mutation signature and race using relative frequency differences (RFDs) as the measure of association. Results: Our 50-gene immune panel produced sample groupings in TCGA similar to that observed with the deconvolution algorithm, CIBERSORT. In CBCS (n=1208), we identified three immune groups primarily defined by features related to either adaptive immunity, innate immunity, or a quiet immune environment. Confirming that our expression-based groups reflect the tumor immune microenvironment, these immune groups correlated with histological evidence of immune cells from H&amp;E slides in both TCGA and CBCS. The adaptive-enriched group was strongly associated with young age (≤50 years), high tumor grade, higher proliferation scores and the basal-like intrinsic subtype. TP53 mutant-like status was strongly associated with the adaptive-enriched immune group (RFD: 25.3%, p&amp;lt;0.0001), adjusting for age, race, and stage. Conversely, tumors in the innate and immune-quiet groups were primarily luminal (67.7%) and TP53 WT-like (60.2%). Black race was associated with the adaptive-enriched immune phenotype, even after adjusting for age and tumor stage (RFD: 7.6%, p=0.031). Conclusions: Our immune panel defines groups of BCs according to type of immune infiltration. Consistent with previous literature, we show that adaptive immunity is associated with aggressive breast tumors in CBCS. In addition, our data suggest an immunomodulatory effect of TP53 functional status–a variable we have previously associated with race in the CBCS. We provide evidence for a role of the immune microenvironment in racial disparities of BC. Further characterization of individual immune cell populations by race could reveal potential targets for BC intervention strategies that improve survivorship disparities. Citation Format: Alina M. Hamilton, Linnea T. Olsson, Benjamin C. Calhoun, Katherine A. Hoadley, Melissa A. Troester. Association of immune microenvironment and race in the Carolina Breast Cancer Study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1184.

Abstract C045: Outcomes of hormone-receptor positive, HER2-negative breast cancers by race and tumor biologic features

Abstract Background: Black women have higher breast cancer mortality than white women, particularly within the hormone receptor positive, human epidermal growth factor receptor 2 negative (HR+/HER2-) clinical subtype. Interactions between tumor biology and treatment factors are complex and racial disparities in early events (such as 5-year recurrence risk) are not well characterized. Methods: Using data from the Carolina Breast Cancer Study (Phase 3, 2008-2013), a large population-based study enrolling 50% black and 50% white women from 44 counties in North Carolina, we estimated associations between race and recurrence among non-metastatic HR+/HER2- tumors, overall and within subgroups defined by PAM50 Risk of Recurrence score (ROR-PT, calculated from subtype, proliferation level, and tumor size), PAM50 intrinsic subtype, and tumor grade. We also compared treatment patterns by race among HR+/HER2- patients with high-risk disease. Relative frequency differences (RFD), interpretable as the percentage difference between index and referent groups, were estimated using multivariable linear regression. Recurrence risk was estimated using survival curves standardized for age and stage and inverse probability-weighted Cox models. Results: Among 1,775 eligible women, black women had higher recurrence risk relative to white women (crude hazard ratio: 1.8, 95% confidence interval [CI]: 1.3, 2.5), which remained elevated after standardizing for age and clinical covariates (hazard ratio: 1.4, CI: 1.0, 1.9). In stratified analyses, racial disparities persisted among women with high ROR-PT score (5-year standardized recurrence risk 18.9% in black vs. 12.5% in white women) and in high grade patients (5-year standardized recurrence risk 16.6% in black vs. 12.0% in white women). Black women with high grade tumors were significantly less likely to initiate endocrine therapy (RFD: -8.4%, CI: -15.9, -1.0) and experienced treatment delay more often than white women (RFD: +10.4%, CI: 1.8, 19.0). Conclusions: Racial disparities in HR+/HER2- breast cancer recurrence persist within high-risk subgroups. Efforts to identify treatment inequities and other causes of variation in cancer treatment are critical to reducing outcome disparities. Note: This abstract was not presented at the conference. Citation Format: H. Shelton Earp, Andrew F Olshan, Lisa A Carey, Charles M Perou, Melissa A Troester, Halei C. Benefield, Katherine E Reeder-Hayes, Hazel B Nichols, Benjamin C Calhoun, Michael I Love, Xuezheng Sun, Erin L Kirk, Joseph Geradts, Katherine A Hoadley, Stephen R Cole. Outcomes of hormone-receptor positive, HER2-negative breast cancers by race and tumor biologic features [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C045.

A cladistic approach for generic delimitation of Paracloeodes Day, Rivudiva Lugo-Ortiz &amp; McCafferty, and Varipes Lugo-Ortiz &amp; McCafferty (Ephemeroptera: Baetidae)

The taxonomic knowledge of Baetidae has been greatly improved in the last decades in South America. Despite the advances, there are problems that need to be addressed. One of these problems is doubt concerning the systematics of species assigned to the genera Paracloeodes Day, Rivudiva Lugo-Ortiz &amp; McCafferty, and Varipes Lugo-Ortiz &amp; McCafferty, and the evolution of long setae on femora. In the present paper, the monophyly of these three genera is tested using a cladistic approach. The matrix included 53 species and 151 morphological characters: 127 for nymphs and 24 for adults. The dataset was analyzed under equal and implied weights with nine values of k. Group support was estimated with relative Bremer and frequency differences. The results corroborate (i) the paraphyly of Paracloeodes and Varipes, which become monophyletic without P. caldensis + V. singuil, proposed as a new genus Rhopyscelis gen. n., (ii) the long setae on femora as an independent acquisition between Rhopyscelis gen. n. + Varipes and Rivudiva, (iii) the transversal rows of setae on femora as an independent acquisition between Rhopyscelis gen. n. + Varipes and Rivudiva, (iv) the spine on subgenital plate as an independent acquisition between Paracloeodes, Rivudiva and Gen. A.

Borderline Estrogen Receptor-Positive Breast Cancers in Black and White Women.

Some breast tumors expressing greater than 1% and less than 10% estrogen receptor (ER) positivity (ER-borderline) are clinically aggressive; others exhibit luminal biology. Prior ER-borderline studies included few black participants. Using the Carolina Breast Cancer Study (phase I: 1993-1996; 2: 1996-2001; 3: 2008-2013), a population-based study that oversampled black women, we compared ER-borderline (n = 217) to ER-positive (n = 1885) and ER-negative (n = 757) tumors. PAM50 subtype and risk of recurrence score (ROR-PT, incorporates subtype, proliferation, tumor size) were measured. Relative frequency differences (RFD) were estimated using multivariable linear regression. Disease-free interval (DFI) was evaluated by ER category and endocrine therapy receipt, overall and by race, using Kaplan Meier and Cox models. Statistical tests were two-sided. ER-borderlines were more frequently basal-like (RFD = +37.7%, 95% confidence interval [CI] = 27.1% to 48.4%) and high ROR-PT (RFD = +52.4%, 95% CI = 36.8% to 68.0%) relative to ER-positives. Having a high ROR-PT ER-borderline tumor was statistically significantly associated with black race (RFD = +26.2%, 95% CI = 9.0% to 43.3%). Compared to ER-positives, DFI of ER-borderlines treated with endocrine therapy was poorer but not statistically significantly different (hazard ratio [HR] = 2.03, 95% CI = 0.89% to 4.65%), whereas DFI was statistically significantly worse for ER-borderlines without endocrine therapy (HR = 3.33, 95% CI = 1.84% to 6.02%). However, black women with ER-borderline had worse DFI compared to ER-positives, even when treated with endocrine therapy (HR = 2.77, 95% CI = 1.09% to 7.04%). ER-borderline tumors were genomically heterogeneous, with survival outcomes that differed by endocrine therapy receipt and race. Black race predicted high-risk ER-borderlines and may be associated with poorer endocrine therapy response.

Probing the shape of the mixing profile and of the thermal structure at the convective core boundary through asteroseismology

Aims. We investigate from a theoretical perspective if space asteroseismology can be used to distinguish between different thermal structures and shapes of the near-core mixing profiles for different types of coherent oscillation modes in massive stars with convective cores; we also examine whether this capacity depends on the evolutionary stage of the models along the main sequence. Methods. We computed 1D stellar structure and evolution models for four different prescriptions of the mixing and temperature gradient in the near-core region. We investigated their effect on the frequencies of dipole prograde gravity modes in slowly pulsating B stars and in β Cep stars as well as pressure modes in β Cep stars. Results. A comparison between the mode frequencies of the different models at various stages during the main sequence evolution reveals that they are more sensitive to a change in temperature gradient than to the exact shape of the mixing profile in the near-core region. Depending on the duration of the observed light curve, we can distinguish between either just the temperature gradient, or also between the shapes of the mixing coefficient. The relative frequency differences are in general larger for more evolved models and are largest for the higher frequency pressure modes in β Cep stars. Conclusions. In order to unravel the core boundary mixing and thermal structure of the near-core region, we must have asteroseismic masses and radii with ∼1% relative precision for hundreds of stars.

Abstract P1-09-05: Clinical and genomic characteristics of borderline ER-positive breast cancers

Abstract Background: Though current guidelines classify breast tumors with ≥1% estrogen receptor (ER) positivity by immunohistochemistry as ER positive, “borderline” tumors expressing ≥1 – &amp;lt;10% positivity have biological similarities to ER negative tumors in prior studies. We sought to describe molecular features of ER-borderline breast cancer in a diverse cohort of incident cases and identify characteristics associated with high-risk borderline tumors. Methods: We used the Carolina Breast Cancer Study, a large population-based study that oversampled young and black women in 44 counties of North Carolina, to study characteristics of ER-borderline cases compared to other ER-positive and ER-negative tumors. Gene expression of ESR1, PAM50 subtype, and risk of recurrence score (ROR-PT, calculated from subtype, proliferation level, and tumor size; categorized as low, medium, high) were quantified using RNA counting methods, with finite mixture modeling to establish a cutoff for ESR1-high vs. -low tumors. The relative frequency differences of clinical and genomic features of borderline vs. positive/negative tumors were estimated using linear regression, adjusted for age and race. Recurrence risk was evaluated by ER status, with and without receipt of endocrine therapy using Kaplan-Meier curves and Cox proportional hazards models. Results: Of 2,859 eligible patients, 8% (n=217) were ER borderline, 26% (n=757) were ER negative and 66% were ER positive. Compared to other ER positive tumors (which were 5% basal-like, 89% luminal, 8% high ROR-PT, 16% ESR1-low), borderlines (40% basal-like, 42% luminal, 26% high ROR-PT, 71% ESR1-low) had a higher relative frequency of basal-like subtype (+37.7%, 95% CI 27.1, 48.4), high ROR-PT (+52.4%, 95% CI 36.8, 68.0), and ESR1-low status (+26.3%, 95% CI 20.2, 32.5). In log-rank analysis, recurrence risk in borderlines was not significantly different from ER negatives. However, after adjusting for patient and tumor factors, recurrence risk in borderlines treated without endocrine therapy was the highest of all subtypes (HR 2.9, 95% CI 1.6, 5.0) and persisted after further adjusting for ROR-PT. Results are summarized in Table 1. Frequency of high ROR-PT was 22% among white women with borderline tumors but was significantly more common among black women with borderline tumors (+26.0%, 95% CI 7.1, 45.0). Among borderlines, high grade was associated with basal-like subtype (+43.4%, 95% CI 18.7, 68.0; reference = non-basal subtype, 52% high grade). Table 1:Recurrence-free survival by ER subtype and endocrine therapy receipt Hazard Ratio (HR) Model 1HR Model 2ER PositiveREFREFER Borderline, no endocrine therapy2.9 (1.6, 5.0)2.3 (1.1, 4.9)ER Borderline, endocrine therapy1.5 (0.7, 3.2)1.5 (0.6, 3.7)ER Negative1.8 (1.3, 2.6)1.5 (0.9, 2.4)Adjusted for (1) age, race, stage, grade, year of diagnosis, (2) variables in (1) and ROR-PT Conclusion: Consistent with prior studies, borderline tumors demonstrated characteristics that were intermediate between other ER positive and negative tumors, with heterogeneity of genomic features. Given the higher recurrence risk among borderlines, identifying aggressive borderline tumors is important. Black women and those with high tumor grade may benefit from further genomic assessment to guide treatment decisions. Citation Format: Benefield HC, Allott EH, Sun X, Reeder-Hayes KE, Troester MA. Clinical and genomic characteristics of borderline ER-positive breast cancers [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-09-05.

Differences in race, molecular and tumor characteristics among women diagnosed with invasive ductal and lobular breast carcinomas.

The dominant invasive breast cancer histologic subtype, ductal carcinoma, shows intrinsic subtype diversity. However, lobular breast cancers are predominantly Luminal A. Both histologic subtypes show distinct relationships with patient and tumor characteristics, but it is unclear if these associations remain after accounting for intrinsic subtype. Generalized linear models were used to estimate relative frequency differences (RFDs) and 95% confidence intervals (95% CIs) for the associations between age, race, tumor characteristics, immunohistochemistry (IHC) and RNA-based intrinsic subtype, TP53 status, and histologic subtype in the Carolina Breast Cancer Study (CBCS, n = 3,182) and The Cancer Genome Atlas (TCGA, n = 808). Relative to ductal tumors, lobular tumors were significantly more likely to be Luminal A [CBCS RNA RFD: 44.9%, 95% CI (39.6, 50.1); TCGA: RFD: 50.5%, 95% CI (43.9, 57.1)], were less frequent among young (≤ 50years) and black women, were larger in size, low grade, lessfrequently had TP53 pathway defects, and were diagnosed at later stages. These associations persisted among Luminal A tumors (n = 242). While histology is strongly associated with molecular characteristics, histologic associations with age, race, size, grade, and stage persisted after restricting to Luminal A subtype. Histology may continue to be clinically relevant among Luminal A breast cancers.

TP53 protein levels, RNA-based pathway assessment, and race among invasive breast cancer cases

Mutations in tumor suppressor TP53 have been inconsistently linked to breast cancer risk factors and survival. Immunohistochemistry (IHC) staining, a primary clinical means of TP53 mutation determination, only detects mutations that facilitate protein accumulation (e.g., missense mutations). RNA-based pathway methods capture functional status and may aid in understanding the role of TP53 function in racial disparities of breast cancer. TP53 status was assessed among invasive breast cancer cases from the Carolina Breast Cancer Study (CBCS) (2008–2013) using IHC and an established RNA-based TP53 signature (CBCS and The Cancer Genome Atlas (TCGA)). Frequency of TP53 status (IHC, RNA-based) was estimated in association with tumor characteristics, PAM50 intrinsic subtype, age, and race using relative frequency differences (RFDs) and 95% confidence intervals (95% CI) as the measure of association. Approximately 60% of basal-like tumors were TP53 protein positive (IHC), while nearly 100% were TP53 mutant-like (RNA). Luminal A tumors had low frequency of TP53 positivity (IHC: 7.9%) and mutant-like status (RNA: 1.7%). Mutant-like TP53 (RNA) was strongly associated with age ≤50 years, high tumor grade, advanced stage of disease, large tumor size, and basal-like and HER2 intrinsic subtypes. Black race was strongly associated with TP53 mutant-like status (RNA) (RFD: 24.8%, 95% CI: 20.5, 29.0) even after adjusting for age, grade, stage (RFD: 11.3%; 95% CI: 7.6, 15.0). Associations were attenuated and non-significant when measured by IHC. IHC-based TP53 status is an insensitive measurement of TP53 functional status. RNA-based methods suggest a role for TP53 in tumor prognostic features and racial disparities.

Phylogeny of Callibaetis (Ephemeroptera: Baetidae) based on morphology of nymphs and adults

Callibaetis is considered to be one of the most problematic genera among mayflies by a series of taxonomic inaccuracies that have accumulated over the last two centuries. Despite these taxonomic problems, two independent hypotheses of species groups have been proposed. In the first hypothesis, three species groups for North America were proposed, and in the second, three species groups were proposed for South American. In these hypotheses, the generic delimitation and monophyly of Callibaetis have not been evaluated under a cladistic framework. Taking this into account, the objectives of this study were to verify the monophyly of Callibaetis and whether the groups of species proposed for the genus are corroborated as natural. The matrix included 128 morphological characters and one habitat character, 119 discrete characters were compiled (101 of nymphs and 18 of adults), and six imaginal characters are related to pigmentation pattern. Continuous characters were ratios and were represented by 10 characters (nine for nymphs and one for adults). The data set was analysed under implied weights. Group support was estimated with relative Bremer support and frequency differences. The results corroborated the monophyletic nature of Callibaetis and the generic status of Callibaetoides; however, the groups proposed for North and South American Callibaetis species were not corroborated. Our study indicated four groups of species for the genus, which we proposed as subgenera: Callibaetis, Abaetetuba subgen. n. Aiso subgen. n. and Cunhaporanga subgen. n.

Does plural dominance play a role in spoken picture naming? A comparison of unimpaired and impaired speakers

Abstract This study investigates the effect of frequency on plural processing. In particular it explores the effect of relative frequency differences between plurals and their singular forms on the representation of plurals. This paper reports data from a group of thirty-eight unimpaired speakers and compares their spoken picture naming of single and multiple objects to that of two people with acquired language impairments (aphasia). For both participant groups (unimpaired and impaired), we observed two key findings for picture naming: first, plurals that are lower in frequency than their singulars (singular-dominant plurals) are responded to more slowly or with more errors compared to their singulars. Second, for plurals that are higher in frequency than their singulars (plural-dominant plurals), no difference in reaction time or error rate was detected between singulars and plurals. By capitalising on patterns observed in both unimpaired and impaired language processing, this study suggests that plural-dominant plurals are stored differently from singular-dominant plurals.

Clinical and genetic evaluation of DYT1 and DYT6 primary dystonia in China

Dystonia is defined as the presence of sustained involuntary muscle contractions, often leading to abnormal posture and movement. DYT1 is caused by a mutation in the TOR1A gene, whilst mutations in THAP1 gene have been identified as responsible for DYT6. The relative frequency and phenotype differences between DYT1 and DYT6 amongst Chinese primary dystonia patients have not been well-characterized. One hundred eleven unrelated Chinese patients with primary dystonia were screened for mutations in TOR1A and THAP1 genes, and correlate this with clinical presentation. Exon 5 of TOR1A and all three exons and exon-intron conjunctions in THAP1 were screened by direct sequencing. Three subjects were found to have the GAG deletion in the TOR1A gene, and two patients were detected with THAP1 gene mutations/variations (c.224A>T, c.449A>C). The overall mutation frequency was 4.5% in this cohort with TOR1A mutations found in 2.7% and THAP1 mutations found in 1.8%. No mutations were detected in the controls composed of 100 normal Chinese subjects. The clinical presentations of the DYT1 cases included onset in the limbs that could progress to the generalized dystonia within several years but without cranial involvement. Whilst in the DYT6 cases, the onset was cranial or cervical and progresses very slowly. The major clinical differences between DYT1 and DYT6 dystonia in China were the cranial involvement in DYT6 and progress to general dystonia within several years in DYT1.