bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract IA04: Relating single cell function to tissue structure in human tumors using MIBI-TOF
Authors: Angelo R. Michael
Published: December 2020

Understanding the role of distinct cellular phenotypes in tissue function, development, and pathogenesis requires tools that can rapidly and consistently quantify the expression of multiple proteins while preserving spatial information. To meet this need, we have developed Multiplexed Ion Beam Imaging by Time-Of-Flight (MIBI-TOF). MIBI-TOF uses secondary ion mass spectrometry to visualize up to 50 metal labeled antibodies at subcellular resolution simultaneously with histochemical stains and native biological elements. We have used this capability to study how single cell function and tissue structure interact at the tumor immune microenvironment, the human maternal-fetal interface, and in infectious disease. These studies have led us to develop scalable, automated, and extensible tools for image thresholding, single cell segmentation, cell clustering, and cell neighborhood analyses that can be deployed on any tissue. Through NIH HuBMAP and CIMAC initiatives, we are currently working to deploy this computational pipeline as well as preformulated antibody staining master mixes as a streamlined, end-to-end workflow for routine high dimensional tissue analysis in basic and translational research. Lastly, we are currently working to develop brighter primary ion sources and new metal reporter constructs that will permit full tissue section scanning while extending multiplexed detection to include RNA and DNA.

Citation Format: R. Michael Angelo. Relating single cell function to tissue structure in human tumors using MIBI-TOF [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr IA04.
Abstract IA05: Deciphering the immune microenvironment with spatial histology
Authors: Yuan Yinyin
Published: December 2020

Tumours are complex, evolving ecosystems with dynamic crosstalk among cancer and normal cells. Measuring spatial heterogeneity in the tumour microenvironment is critical for understanding the spatial context in which cancer develops and evolves. I will discuss quantitative spatial histology measures of immune response as a result of combining automated histology image analysis and spatial statistics. Geospatial variation in the immune microenvironment can have profound clinical implications, even in cancers with low immunogenicity, such as estrogen-receptor positive breast cancer. I will also share our recent progress on studying the geospatial complexity of tumour microenvironment in the TRACERx study of lung cancer evolution.

Citation Format: Yinyin Yuan. Deciphering the immune microenvironment with spatial histology [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr IA05.
Abstract IA13: In the light of evolution: Why do we get more cancers in old age?
Authors: Pham-Danis Catherine , Rozhok Andrii , Scarborough Hannah , Little Nathaniel , Henry Curtis , Nemkov Travis , Hansen Kirk , DeGregori James
Published: December 2020

Why do we get cancer? Why is cancer highly associated with old age? Of course, aging is associated with the accumulation of more mutations, and some of these mutations can contribute to cancer phenotypes. But we now understand that carcinogenesis is much more complex than originally appreciated. In particular, there are tissue environmental forces that both impede and promote cancer evolution. Just as organismal evolution is known to be driven by environmental changes, cellular (somatic) evolution in our bodies is similarly driven by changes in tissue environments, whether caused by the normal process of aging, by lifestyle choices or by extrinsic exposures. Environmental change promotes selection for new phenotypes that are adaptive to the new context. In our tissues, aging or insult-driven alterations in tissues drives selection for adaptive mutations, and some of these mutations can confer malignant phenotypes. We have been using mouse models of cancer initiation, mathematical models of cellular evolution, and analyses of human tissue samples to better understand the evolutionary forces that control somatic cell evolution and thus cancer risk. We have shown that aging and inflammation dependent changes in tissue environments dramatically dictate whether cancer-causing mutations are advantageous to stem cells in our tissues, starting the cells down the path to cancer. Our studies have focused on cancer initiation within the hematopoietic system and the lung. These studies have also uncovered molecular explanations for mutation-driven adaptation to aged and inflammatory tissue environments. In all, these studies indicate that strategies to prevent or treat cancers will need to incorporate interventions that alter tissue microenvironments. While we largely cannot prevent mutation accumulation through our lives, we do have the ability to manipulate tissue environments so as to change the evolutionary trajectories of cells with cancer-causing mutations.

Citation Format: Catherine Pham-Danis, Andrii Rozhok, Hannah Scarborough, Nathaniel Little, Curtis Henry, Travis Nemkov, Kirk Hansen, James DeGregori. In the light of evolution: Why do we get more cancers in old age? [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr IA13.
Abstract IA17: Measuring and modeling cancer evolution with single cell approaches
Authors: Shah Sohrab
Published: December 2020

In this talk, I will provide an overview or advances in single cell whole genome sequencing to study the properties of cancer evolution. Using recently published direct library preparation (DLP+) we used scaled timeseries analysis of model systems to derive predictive models of clone-specific fitness. We defined both genetic and pharmacologic perturbations and measured clonal population abundances at single cell resolution over granular time intervals. We then combined the statistical power of phylogenetics and population genetics to quantitate fitness coefficients of distinct clones. We show how our models are predictive through reproducibility experiments and provide a quantitative formalism to interpret the impact perturbations on fitness landscapes. We show that systemic chemotherapy can dramatically alter the fitness properties of cancer cells leading to clone-specific expansion of resistant populations and eradication of high fitness clones in the untreated context. Our results have implication for how to effectively model the impact of drug selection in pre-clinical model systems.

Citation Format: Sohrab Shah. Measuring and modeling cancer evolution with single cell approaches [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr IA17.
Abstract PO-038: DCE-MRI of tumor hypoxia in cervical carcinoma and pancreatic ductal adenocarcinoma xenografts
Authors: Gaustad Jon-Vidar , Hauge Anette , Wegner Catherine S. , Hansem Lise Mari K. , Rofstad Einar K.
Published: December 2020

Tumor hypoxia is associated with resistance to treatment, aggressive growth, and poor clinical outcome in many cancer types, and is a result of an imbalance between oxygen supply and oxygen consumption. We have previously shown that Ktrans and ve images derived by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) reflect blood perfusion and cell density which are important determinants of oxygen supply and oxygen consumption respectively. The purpose of the current study was to investigate whether Ktrans and/or ve images can be used to produce images of tumor hypoxia. Cervical carcinoma and pancreatic ductal adenocarcinoma xenografts were used as models of human cancer, and xenografted tumors were subjected to antiangiogenic treatment or left untreated. Ktrans and ve images were derived from DCE-MRI data by using Tofts standard pharmacokinetic model, and images of tumor hypoxia were produced by applying threshold values to Ktrans and/or ve. Tumor hypoxia was also assessed by immunohistochemistry by using pimonidazole as a hypoxia marker. Ktrans and ve images were highly heterogeneous. Strong correlations were found between hypoxic fractions determined by immunohistochemistry and hypoxic fractions calculated by using Ktrans but not ve images. Importantly, hypoxia images produced by using Ktrans images reflected both naturally occurring and treatment-induced hypoxia. Moreover, hypoxia images produced by combining Ktrans and ve images were not superior to the hypoxia images produced by using only Ktrans images. These observations imply that Ktrans images reflected blood perfusion and oxygen supply, and that the heterogeneity in hypoxia was caused by heterogeneity in oxygen supply rather than heterogeneity in cell density and oxygen consumption in these tumor models.

Citation Format: Jon-Vidar Gaustad, Anette Hauge, Catherine S. Wegner, Lise Mari K. Hansem, Einar K. Rofstad. DCE-MRI of tumor hypoxia in cervical carcinoma and pancreatic ductal adenocarcinoma xenografts [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-038.
Abstract PO-068: Intratumoral heterogeneity of prognostic multigene signatures for breast cancer
Authors: Hurson Amber N. , Hamilton Alina , Olsson Linnea T. , Kirk Erin L. , Calhoun Benjamin C. , Geradts Joseph , Sherman Mark E. , Troester Melissa A.
Published: December 2020

Background Multigene assays for breast cancer are becoming more commonly used for research, diagnostic, and treatment-selection purposes. These assays are commonly based on a single tumor sample, so this study assesses whether clinically-relevant multigene scores are subject to misclassification due to technical variation or intratumoral heterogeneity. Methods Using FFPE blocks, tumors from 37 patients were sampled at different pathologist-selected spatial locations, targeting regions with distinct histological appearance. A second pathologist assessed mitotic activity and presence of immune infiltration for each specimen. Gene expression was quantified using the PAM50 assay. Samples were classified with respect to intrinsic subtype (Luminal A, Luminal B, HER2-enriched, or Basal-like) and risk of recurrence with proliferation score (ROR-P, high vs. med/low). Euclidean distances between samples were calculated across the 50 genes, and the distribution of Euclidean distances were compared for samples that were concordant vs. discordant for each multigene classifier for PAM50 or ROR-P. Results Of the 37 tumors, 11 had samples with discordant PAM50 subtype and 7 had samples with discordant ROR-P group (75% and 83% agreement, respectively). The Euclidean distance between paired samples with discordant PAM50 intrinsic subtype or ROR-P score was significantly greater than that among concordant tumors. Samples discordant for ROR-P had more heterogeneity in histological characteristics, while discordance of PAM50 subtype call was generally not predicted by heterogeneity of these histological characteristics. Conclusion The concordance of PAM50 subtype calls and ROR-P, despite oversampling of heterogenous-appearing tumor regions, demonstrates reproducibility of the PAM50 classifier for breast cancer tumor intrinsic subtyping. However, assay sampling strategies for histologically heterogeneous tumors merit further consideration.

Citation Format: Amber N. Hurson, Alina Hamilton, Linnea T. Olsson, Erin L. Kirk, Benjamin C. Calhoun, Joseph Geradts, Mark E. Sherman, Melissa A. Troester. Intratumoral heterogeneity of prognostic multigene signatures for breast cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-068.
Abstract PO-105: The fibrinolytic factor tPA drives LRP1-mediated melanoma growth and metastasis
Authors: Heissig Beate , Salama Yousef , Osada Taro , Tsuda Yuko , Takahashi Satoshi , Hattori Koichi
Published: December 2020

The multifunctional endocytic receptor low-density lipoprotein receptor-related protein (LRP)1 has recently been identified as a hub within a biomarker network for multicancer clinical outcome prediction. The mechanismhowLRP1 modulates cancer progression is poorly understood. In this studywe found that LRP1 and one of its ligands, tissue plasminogen activator (tPA), are expressed inmelanoma cells and control melanoma growth and lung metastasis in vivo. Mechanistic studies were performed on 2 melanoma cancer cell lines, B16F10 and the B16F1 cells, both of which formprimary melanoma tumors, but only B16F10 cells metastasize to the lungs. Tumor-, but not niche cell–derived tPA, enhanced melanoma cell proliferation in tPA2/2 mice. Gain-of-function experiments revealed that melanoma LRP1 is critical for tumor growth, recruitment of mesenchymal stem cells into the tumor bed, and metastasis. Melanoma LRP1 was found to enhance ERK activation, resulting in increased matrix metal-loproteinase (MMP)-9 RNA, protein, and secreted activity, a well-known modulator of melanoma metastasis. Restoration of LRP1 and tPA in the less aggressive, poorly metastatic B16F1 tumor cells enhanced tumor cell proliferation and led to massive lung metastasis in murine tumor models. Antimelanoma drug treatment induced tPA and LRP1 expression. tPA or LRP1 knockdown enhanced chemosensitivity in melanoma cells. Our results identify the tPA-LRP1 pathway as a key switch that drives melanoma progression, in part by modulating the cellular composition and proteolytic makeup of the tumor niche. Targeting this pathway may be a novel treatment strategy in combination treatments for melanoma.

Citation Format: Beate Heissig, Yousef Salama, Taro Osada, Yuko Tsuda, Satoshi Takahashi, Koichi Hattori. The fibrinolytic factor tPA drives LRP1-mediated melanoma growth and metastasis [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-105.
Abstract PO-123: Distinct subpopulations of osteosarcoma cells cooperate to establish lung metastases
Authors: Reinecke James B. , Hinckley John M. , Gross Amy C. , Cam Maren , Rajan Sanjana , Roberts Ryan D.
Published: December 2020

Four decades of intense multinational efforts to improve outcomes for children and teenagers with osteosarcoma have failed. Today, we still treat patients with a regimen first developed in 1982. The same 35-40% of young people diagnosed with osteosarcoma die from their disease, almost always from complications related to lung metastasis. Believing that therapies targeting lung metastasis could dramatically improve outcomes, we have sought to understand the mechanisms that drive lung colonization in this disease. We previously found that interactions with lung epithelium cause osteosarcoma cells to produce IL6 and CXCL8 and that this activity is necessary for metastasis. Inhibiting IL6 and CXCL8 signaling prevents metastasis entirely in 85% of mice with osteosarcoma. While conducting these studies, we learned that individual tumor cells react differently to signals from lung epithelium. Nearly all the IL6 and CXCL8 produced by osteosarcoma cells come from a small subset of cells. Interactions with pulmonary epithelium cause this discrete subset of tumor cells to produce large quantities of inflammatory cytokines, become strongly p21+, and stop proliferating. Early metastatic lesions consist almost entirely of cells with this phenotype, positioning them to orchestrate the development of the metastatic niche. Thus, we call these hypo-proliferative, cytokine-producing cells that survive early attrition "anchor cells." In the initial stages of metastasis, anchor cells alter the surrounding lung tissue in ways that facilitate subsequent colonization by tumor cells with proliferating phenotypes ("growth cells"). Growth cells then divide to create expanding, clinically-relevant metastasis. Importantly, one can leverage the biology of these anchor cells to develop rational targeting strategies. Anchor cells exhibit profound sensitivity to known senolytic agents. Combining these with conventional therapies (which effectively target growth cells) can eradicate established metastatic lesions and prevent new metastases from forming. These novel findings fundamentally alter our understanding of osteosarcoma and metastasis biology and have direct implications for approaches to treatment.

Citation Format: James B. Reinecke, John M. Hinckley, Amy C. Gross, Maren Cam, Sanjana Rajan, Ryan D. Roberts. Distinct subpopulations of osteosarcoma cells cooperate to establish lung metastases [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-123.
Abstract PO-132: CaTCH - A barcode-guided CRISPRa-inducible reporter to isolate clones from heterogeneous populations
Authors: Umkehrer Christian , Holstein Felix , Formenti Laura , Jude Julian , Froussios Kimon , Neumann Tobias , Cronin Shona M. , Haas Lisa , Lipp Jesse , Burkard Thomas R. , Fellner Michaela , Wiesner Thomas , Zuber Johannes , Obenauf Anna C.
Published: December 2020

The emergence of resistant cell clones to targeted therapies poses a significant issue in the treatment of metastatic melanoma. While these founding clones are often extremely rare in a starting population, their isolation and characterization holds unique potential for understanding disease processes, uncovering novel biomarkers and developing therapeutic concepts. The functional characterization of such founder clones and comprehensive comparisons to their post-selection counterparts requires live cells. To achieve this, we developed a novel lineage tracing tool termed CaTCH (CRISPRa tracing of clones in heterogeneous cell populations). CaTCH combines precise mapping of the lineage history of millions of cells with the ability to isolate any given clone alive from a complex population based on genetic barcodes. CaTCH thereby enables the retrospective isolation and analysis of founding clones from heterogeneous cell populations prior to evolutionary selection. In first applications, we use CaTCH to provide insights into the development of resistance to targeted cancer therapies. We demonstrate that CaTCH can be used to trace and isolate a single pre-existing therapy-resistant clone from a complex cancer cell population in vitro. Furthermore, we validate the utility of CaTCH for applications in vivo by investigating the origins of resistance to clinically relevant RAF/MEK inhibition in an immunocompetent melanoma mouse model. Here we find that most clones have the capacity to acquire resistance to combined RAF/MEK inhibitor therapy, indicating that resistance to this clinically relevant regimen is a universally achievable state in this model. We envision that CaTCH will address fundamental questions in basic and translational research (e.g., how cell identity states and trajectories are determined in therapy resistance, metastasis formation, tissue development and somatic cell re-programming), potentially revealing new vulnerabilities that can serve as targets for therapies.

Citation Format: Christian Umkehrer, Felix Holstein, Laura Formenti, Julian Jude, Kimon Froussios, Tobias Neumann, Shona M. Cronin, Lisa Haas, Jesse Lipp, Thomas R. Burkard, Michaela Fellner, Thomas Wiesner, Johannes Zuber, Anna C. Obenauf. CaTCH - A barcode-guided CRISPRa-inducible reporter to isolate clones from heterogeneous populations [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-132.
Abstract PR07: A systems biology approach to reprogramming drug-resistant breast cancer stem-like cells
Authors: Worley Jeremy , Ding Hongxu , Noh Heeju , Paull Evan , Bush Erin , Dalerba Piero , Sims Peter , Dela Cruz Fil , Kung Andrew , Califano Andrea
Published: December 2020

Breast cancer stem-like cells (CSCs) are hypothesized to be a cause of poor outcome in patients, and are drug-resistant in vitro and in PDX mice. We performed plate-based single-cell RNA sequencing (scRNA-seq) on flow sorted fresh tumor samples. These data were analyzed using our metaVIPER algorithm, which infers protein activity in a manner that is robust to the effects of noise and gene dropout. metaVIPER identified known breast CSC regulators, and analysis with our OncoTreat algorithm predicted several FDA approved drugs that could reprogram the breast CSCs into a state resembling that of differentiated tumor cells. We tested two of these predictions, ivermectin and albendazole, in TNBC PDX mice, and performed scRNA-seq on fresh tumor samples after 14 days of treatment. The results were exciting, as measured by single-cell entropy or lineage marker analysis. Breast CSCs were reprogrammed as predicted, while a tumor treated with a traditional chemotherapeutic (paclitaxel) had a dramatically higher proportion of CSCs. These results suggested a therapy in which cells are cyclically reprogrammed and treated with a conventional cytotoxic drug. This reprogram-kill-repeat therapy is being tested in TNBC PDX mice. We believe that the strategy developed here will prove to be a powerful tool for understanding and manipulating cell-state in heterogeneous populations.

Citation Format: Jeremy Worley, Hongxu Ding, Heeju Noh, Evan Paull, Erin Bush, Piero Dalerba, Peter Sims, Fil Dela Cruz, Andrew Kung, Andrea Califano. A systems biology approach to reprogramming drug-resistant breast cancer stem-like cells [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PR07.
Abstract IA04: Using white privilege to help end disparities
Authors: Maues Julia
Published: December 2020

Living with metastatic breast cancer since 2013, I have become engaged in cancer advocacy and connected with other advocates all over the country and the world. This work brought me close to a number of Black women with cancer, and I saw the realities they face with the double whammy of cancer and racism. I have always considered myself an ally to people of color and am passionate about social justice causes but am not free of racial prejudice being born and raised in a systematically racist society. It wasn’t until I experienced discrimination myself as a young woman with late-stage cancer that I realized how much unlearning and learning I have ahead of me about White privilege and racism against Black people. When a Black advocate called me and others out for not including the perspective of a person of color on a panel on researcher-advocate collaborations, I (after first making the mistake of feeling attacked and defensive) realized that White advocates have an important role in addressing disparities. While racism affects Black people, it isn’t a problem created by and kept alive by Black people. It is my responsibility as a White person who aspires for an equitable society to take a stand for representation of Black and LatinX people in the space that I have an influence in. In my case that space is cancer advocacy and unfortunately there are too many Black people living with cancer. My power is my voice in cancer advocacy, so I have pledged to not participate in any advocacy initiative that doesn’t include the experience of a person of color. I encourage every White person to evaluate their privilege and take a stand in the appropriate space using the pledge at https://www.change.org/p/diversity-and-inclusion-pledge-for-women-of-color.

Citation Format: Julia Maues. Using white privilege to help end disparities [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr IA04.
Abstract IA12: Cancer in LGBT populations: Differences, disparities, and strategies for change
Authors: Baker Kellen
Published: December 2020

In discussions of cancer research, prevention, and treatment, the needs and experiences of lesbian, gay, bisexual, and transgender (LGBT) people are routinely overlooked. The American Cancer Society estimates, however, that there are more than 130,000 newly diagnosed cases of cancer and more than 45,000 cancer deaths among LGBT people in the U.S. every year. Evidence indicates that LGBT populations are disproportionately affected by specific cancers, such as anal cancer in gay and bisexual men, breast cancer in lesbian women, and viral infection–induced cancers in LGB and transgender people. The drivers of these cancer disparities include risk factors that are often more common among LGBT people, such as tobacco use, nulliparity, and HIV. These risk factors are also compounded for LGBT populations by exposure to social determinants of health that include discrimination and other minority stressors—especially for Black, Indigenous, and other LGBT people of color, who experience discrimination that targets their race or ethnicity as well as their sexual orientation and/or gender identity—lower rates of insurance and other barriers to health care services, and inaccurate assumptions among providers about cancer risk and appropriate screenings, particularly for lesbian and bisexual women and transgender people. For LGBT people who have been diagnosed with cancer, a lack of cultural responsiveness in clinical settings and social and economic challenges outside the doctor’s office can exacerbate the difficulty of navigating cancer treatment.

Because data on sexual orientation and gender identity are not routinely collected in cancer registries, clinical records, and other sources of cancer data, the full spectrum of cancer risks, prevention, treatment, outcomes, and survivorship in LGBT communities remains unexplored. LGBT people are also often rendered invisible in cancer research by data collection that does not include sexual orientation or gender identity, by study protocols that make the tacit or overt assumption that all participants are cisgender and heterosexual, and by barriers to participation such as being overlooked in recruitment or even outright excluded from consideration.

This presentation provides an overview of cancer disparities in LGBT populations; describes patient-, provider-, and structural-level barriers to effective cancer prevention and treatment; and identifies promising opportunities to expand the evidence base and address LGBT cancer disparities.

Citation Format: Kellen Baker. Cancer in LGBT populations: Differences, disparities, and strategies for change [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr IA12.
Abstract IA31: Structural Inequities, Social Determinants, and Survivorship: Opportunities and Strategies to Advance Health Equity
Authors: Alcaraz Kassandra I.
Published: December 2020

Despite considerable progress against cancer in recent decades, disparities in cancer survivorship persist. Increasingly, upstream influences are recognized as key determinants of cancer-related disparities. However, predominant strategies often neglect to consider and/or address these influences, slowing progress toward achieving cancer health equity. This presentation will discuss an integrated framework that can be used to understand and address structural and social influences on disparities in cancer survivorship. Additionally, data from diverse sources will be used to illustrate the influence of social and structural factors on cancer-related outcomes. The presentation will underscore the importance of addressing structural inequities and social determinants to help cultivate equitable outcomes among cancer survivors.

Citation Format: Kassandra I. Alcaraz. Structural Inequities, Social Determinants, and Survivorship: Opportunities and Strategies to Advance Health Equity [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr IA31.
Abstract IA34: Distinct heterogeneous subtypes of Triple-Negative Breast Cancer, associated with African Ancestry
Authors: Davis Melissa B. , Martini Rachel , Newman Lisa A. , Elemento Olivier , White Jason , Verma Akanksha , Datta Indrani , Adrianto Indra , Chen Yalei , Gardner Kevin , Kim Hyung-Gyoon , Coleman Windy D. , Eltoum Isam-Eldin , Frost Andra , Grizzle William , Sboner Andrea , Manne Upender , Yates Clayton
Published: December 2020

Triple negative breast cancers (TNBCs) are molecularly heterogeneous, and the link between their aggressiveness with African ancestry is not established. We investigated primary TNBCs for gene expression among self-reported race (SRR) groups of African American and European American women. RNA sequencing data was analyzed to measure changes in genome-wide expression, and we utilized logistic regressions to identify ancestry-associated gene expression signatures. Using SNVs identified from our RNA sequencing data, global ancestry was estimated. We identified 156 African ancestry-associated genes and found that, compared to SRR, quantitative genetic analysis was a more robust method to identify racial/ethnic-specific genes that were differentially expressed. A subset of African ancestry-specific genes that were upregulated in TNBCs of our AA patients were validated in TCGA data. In AA patients, there was a higher incidence of basal-like 2 tumors and altered TP53, NFB1, and AKT pathways. The distinct distribution of TNBC subtypes and altered oncologic pathways show that the ethnic variations in TNBCs are driven by shared genetic ancestry. Thus, to appreciate the molecular diversity of TNBCs, tumors from patients of various ancestral origins should be evaluated. We created a novel tool to determine the heterogenic status of TNBC, which accounts for proportional differences multiple cell 'subtypes'.

Citation Format: Melissa B. Davis, Rachel Martini, Lisa A. Newman, Olivier Elemento, Jason White, Akanksha Verma, Indrani Datta, Indra Adrianto, Yalei Chen, Kevin Gardner, Hyung-Gyoon Kim, Windy D. Coleman, Isam-Eldin Eltoum, Andra Frost, William Grizzle, Andrea Sboner, Upender Manne, Clayton Yates. Distinct heterogeneous subtypes of Triple-Negative Breast Cancer, associated with African Ancestry [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr IA34.
Abstract IA35: Novel biological insights into colorectal cancer from West Africa
Authors: Alatise Olusegun I. , Knapp Gregory C. , Sharma Avinash , Chatila Walid K. , Olasehinde Olalekan , Omisore Adeleye D. , Katung Aba , Olatoke Samuel A. , Kingham T.Peter
Published: December 2020

The burden of colorectal cancer (CRC) is increasing in West Africa. Understanding the molecular and clinicopathologic profile of the region’s CRC patients is vital to optimizing early detection and therapeutic regimens. Clinicopathologic data from consecutive patients from a multicenter, prospectively maintained Nigerian CRC database were compared to a contemporary cohort from Memorial Sloan Kettering Cancer Center (MSKCC). Fresh-frozen tissue from Nigerian patients was analyzed with a multigene, next-generation sequencing assay, along with immunohistochemistry and methylation analyses; data were compared to molecular data from MSKCC and The Cancer Genome Atlas (TCGA) cohorts. Adult patients with histologically confirmed colorectal adenocarcinoma enrolled in a Nigerian CRC database from April 2013-November 2018 were included. All adult patients with colorectal adenocarcinoma diagnosed from January-June 2013 were included in the MSKCC cohort. Somatic and germline next-generation sequencing of cancer-associated genes, immunohistochemistry, and methylation analyses were performed. The primary outcomes were microsatellite instability status, somatic and germline mutation frequency, and overall survival. The median age at diagnosis was 55.8 years in the Nigerian cohort (n=380) and 60.0 years in the MSKCC cohort (n=458) (p<0.001). The rate of microsatellite instability was 28.1% in the Nigerian cohort (18/64), compared to 14.2% and 8.5% in the TCGA (65/459) and MSKCC (97/1145) cohorts, respectively (p<0.001). In microsatellite-stable cases, tumors from Nigerian patients were less likely to have APC mutations (39.1% vs. 76.0% p<0.001) and WNT pathway alterations (47.8% vs. 81.9%, p<0.001), and more likely to have RAS pathway alterations (76.1% vs. 59.6%, p=0.03) compared to MSKCC patients. Overall survival was significantly longer for MSKCC vs. Nigerian patients (not reached vs. 12 months, p<0.001). The biology of CRC in Nigeria appears to be distinct from that in high-income countries, emphasizing the need for regional data to guide diagnostic and treatment approaches for patients in West Africa.

Citation Format: Olusegun I. Alatise, Gregory C. Knapp, Avinash Sharma, Walid K. Chatila, Olalekan Olasehinde, Adeleye D. Omisore, Aba Katung, Samuel A. Olatoke, T.Peter Kingham. Novel biological insights into colorectal cancer from West Africa [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr IA35.
Abstract IA36: Cancer Disparity in Sub-Sahara Africa: Challenges and Opportunities
Authors: Mohammed Bello Abdubakar
Published: December 2020

Africans are the most diverse group of people on the earth, and the continent is presently at the intersection of an epidemiological transition resulting in an increased burden of non-communicable disease, particularly cancer. This population diversity presents the scientific community with a platform to understand how best to solve deadly health problems that plague humanity. Yet, research and funding activities on cancer in sub-Saharan Africa is still nascent. Historically, cancer was first reported in Africa in the Egyptian papyrus of Imhotep (3,000–2,500 B.C), which stated treatment recommendation as “There is none.” At present, infection-related cancers account for over 25% of cancer cases in some countries in the sub-Saharan Africa region. For example, despite being fully vaccine-preventable and curable, this region has the highest incidence of cervical cancer in the world, with concomitant high mortality affecting women at their prime. Aside from infection-related cancer, breast and prostate cancers are the leading cancers for women and men, and these diseases present with an aggressive phenotype in the region. Coupled with the unfavorable biology is the late disease presentation, poor access to care infrastructure across the region, and limited human resources. For instance, apart from South Africa, Botswana, Namibia, Kenya, Gabon, Ghana and Cameroon all counties in this region have less than 1 Pathologist per 1 million people, this is coupled with the dearth of radiotherapy facilities in most countries. Furthermore, despite the genetic diversity of the African population, their inclusion in cancer genomics studies and clinical trials is limited. Thus, these social and biological determinants of health have created the ‘perfect storm’ that perpetuates cancer disparity in Sub-Saharan Africa. These unmet needs have also created opportunities for translational research that could contribute to the discovery of new knowledge and identifying new and better treatment for cancers for underrepresented populations. This presentation provides an overview of the determinants of health that have contributed to cancer disparity in Sub-Saharan African and the opportunities they present in achieving global cancer health equity.

Citation Format: Bello Abdubakar Mohammed. Cancer Disparity in Sub-Sahara Africa: Challenges and Opportunities [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr IA36.
Abstract IA42: Advances in genomic characterization of multiple myeloma and its precursor states
Authors: Bustoros Mark
Published: December 2020

Multiple myeloma (MM) is an incurable malignancy of plasma cells and the second most common adult hematologic malignancy in the USA, with an annual incidence of 6.3 new cases per 100,000 individuals. MM usually progresses from asymptomatic precursor stages, known as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). MGUS can progress into MM at a rate of 1% per year, while SMM carries a higher chance of progression of approximately 10% per year. The incidence of MGUS is about 3% of the general population aged 50 years. African Americans (AA) have a 3-fold increased prevalence of MGUS and tend to have worse MM outcomes compared to Caucasians. Some patients rapidly progress from MGUS/SMM to MM, while others remain indolent with minimal progression over their lifetime due to the significant inter-patient heterogeneity. Genomic studies are increasingly delineating the complexity of MM genomic landscape. MM genomic alterations are characterized by multiple chromosomal gains or losses, structural variations, and mutations. The full suite of MM driver events is present in most cases in the SMM stage. The most common driver events in MM are copy number alterations followed by mutations and IgH translocations; however, recent whole-genome sequencing efforts identified more structural events such as MYC translocations, chromothripsis, and chrompolexy. Recently, single-cell RNA sequencing (ScRNAseq) studies provided a better understanding of both the tumor and immune cell architecture in the bone marrow niche. Tumor cells’ ScRNAseq showed that SMM patients are indistinguishable, at the molecular level, from those with active MM and highlighted an inter and intrapatient heterogeneity. Moreover, ScRNA seq of the immune microenvironment revealed that altered immune repertoire starts as early as MGUS and evolves through SMM and MM. Few studies identified potential differences in the molecular profile between AA and Caucasian patients. However, more extensive prospective studies are needed to confirm and identify possible variations among different races and ensure better representation of minorities in MM research.

Citation Format: Mark Bustoros. Advances in genomic characterization of multiple myeloma and its precursor states [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr IA42.
Abstract IA45: Genomics contributors to tumor subtypes in African American prostate and breast cancer patients
Authors: Yates Clayton
Published: December 2020

African Americans suffer disproportionally in higher cancer incidence and worse overall survival in a number of cancer types. The reasons for the disparities are multifactorial and include differences in access to healthcare and lifestyle exposures, delayed disease diagnosis in socio-economically deprived communities, tumor biological differences, and factors related to genetics. Recent findings from multiple prostate and breast cancer genomics studies have identified subsets of ancestry associated genes that are associated with worse outcomes. Therefore, we will present an overview of these recent findings from our lab and others, specifically focusing on how these driver genes function a subset of tumors. Additionally, we will provide examples of how these ancestry-associated genes are integrated within regulatory networks, and discuss the possibility of ancestry specific subtypes promote aggressive disease in African American breast and prostate cancer patients.

Citation Format: Clayton Yates. Genomics contributors to tumor subtypes in African American prostate and breast cancer patients [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr IA45.
Abstract IA49: New Perspectives on Training Complex Communication
Authors: Kron Frederick W.
Published: December 2020

Effective, empathic communication is a cardinal skill in healthcare, and is particularly important in the setting of cancer. What may be less apparent is the complexity of empathic communication, which involves cognitive, affective and behavioral components. Current training methods do not address all these elements; this can cause mismatches in verbal, paraverbal and nonverbal communication behaviors, resulting in conversation failure and adverse outcomes. Further, traditional training methods alone do not produce conversational skill development and maintenance. Considering that problems such as implicit bias and health disparities are, to some degree, smaller conversational failures writ large, underscores the crucial need for improved communication training. Blending current methods with new technologies can fills the gap between available methods and actual training needs to produce significantly better outcomes over a variety of challenging communication topics.

Citation Format: Frederick W. Kron. New Perspectives on Training Complex Communication [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr IA49.
Abstract PO-095: Comparative analysis of breast tumor microbiome in Black non-Hispanic (BNH) and White non-Hispanic (WNH) women
Authors: Vishwanatha Jamboor K. , Thyagarajan Srikantha , Allen Michael , Zhang Yan , Phillips Nicole , Chaudhary Pankaj
Published: December 2020

Studies have demonstrated that environmental, host genetic, and socioeconomic factors influence the breast cancer prevalence landscape with a far-reaching influence on racial disparity to subtypes of breast cancer. To understand whether breast tissue harbors race-specific microbiota, we performed 16S rRNA gene-based sequencing of retrospective tumor and matched normal tissue adjacent to tumor (NAT) samples collected from Black non-Hispanic (BNH) and White non-Hispanic (WNH) women. Analysis of Triple Negative Breast cancer (TNBC) and Triple Positive Breast Cancer (TPBC) tissue for microbiota composition revealed significant differences in relative abundance of specific taxa at both phylum and genus levels between WNH and BNH women cohorts. Our main findings are that microbial diversity as measured by Shannon index was significantly lower in BNH TNBC tumor tissue as compared to matched NAT zone. In contrast, the WNH cohort had an inverse pattern for the Shannon index, when TNBC tumor tissue was compared to the matched NAT. Unweighted Principle Coordinate Analysis (PCoA) revealed a distinct clustering of tumor and NAT microbiota in both BNH and WNH cohorts.

Citation Format: Jamboor K. Vishwanatha, Srikantha Thyagarajan, Michael Allen, Yan Zhang, Nicole Phillips, Pankaj Chaudhary. Comparative analysis of breast tumor microbiome in Black non-Hispanic (BNH) and White non-Hispanic (WNH) women [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-095.
Abstract PO-159: Mediation of black/white race disparity in triple-negative breast cancer: Effect of type 2 diabetes mellitus
Authors: Dookeran Keith A.
Published: December 2020

It is theorized that the black/white race disparity in aggressive breast cancer (BC) subtype might be transmitted through social and reproductive influences. Recent studies suggest that type 2 diabetes mellitus (diabetes) may also contribute to the disparity but the role of diabetes is unclear and in need of further study. Hence, we examined to what extent the black/white race disparity in triple-negative (TN) BC might be transmitted through these influences. Our study sample is a previously reported historical cohort of 419 consecutively enrolled (331 non-Hispanic black (nHB) and 88 nH white (nHW)) women with primary BC aged 24-94 years, treated between 2000-2005 at an NCI-MBCCOP facility in Chicago, IL (Dookeran et al. 2012). US 2000 census ZIP Code Tabulation Area (ZCTA) data matched to patient address zip codes at diagnosis was used to develop a single binary measure of socioeconomic position (SEP) (> US poverty mean vs. referent of US poverty mean

Citation Format: Keith A. Dookeran. Mediation of black/white race disparity in triple-negative breast cancer: Effect of type 2 diabetes mellitus [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-159.