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Background: Despite increased incidence of contralateral prophylactic mastectomy (CPM), there is insufficient evidence that it improves survival in women at average risk for breast cancer. In addition to BRCA1/2 mutation carriers, patients with estrogen-receptor negative tumors have been examined as a subgroup that may seek to benefit from CPM. In this study, we sought to investigate whether CPM improves survival in patients with triple negative breast cancer (TNBC).Study Design: Survival outcomes were evaluated for all TNBC patients from a multi-institutional database from 1999-2018 at New York Presbyterian - Weill Cornell Medical Center and Henry Ford Health System. Median follow-up time was 44.4 months.Results: 802 TNBC patients were evaluated. The median age was 57 years. 17% patients underwent CPM. Factors associated with CPM were White American race, younger age, presence of lymphovascular invasion (LVI), lack of mammography screen-detection, mastectomy surgery, postoperative adjuvant radiotherapy, and having had genetic testing. A borderline significant trend was observed in improved overall survival among patients undergoing CPM versus those not having CPM (5-year OS 95.1% vs. 85.0%; p = 0.05). Subset analysis of patients younger than 50 years of age at diagnosis demonstrated no improvement in overall survival for patients undergoing CPM versus those that declined CPM (94.3% v. 88.7%; p = 0.21). Conclusion: Our data demonstrate a trend in improved 5-year overall survival in TNBC patients undergoing CPM. However, in patients younger than 50 years at diagnosis, CPM did not confer a survival advantage. Citation Format: Genevieve A Fasano, Solange Bayard, Yalei Chen, Jennifer Marti, Rache Simmons, Alexander Swistel, Jessica Bensenhaver, S David Nathanson, Lindsay Petersen, Erica Proctor, Melissa Davis, Lisa Newman. Does contralateral prophylactic mastectomy improve survival in triple negative breast cancer? [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-20-08.

Purpose / Objectives: In patients with macromastia, breast conservation surgery (BCS) followed by radiation therapy (RT) for the treatment of breast cancer may be associated with a different complication profile than those without macromastia. General complications of BCS followed by RT includes seroma, infection, wound complications, cosmetic deformity, asymmetry, acute versus long term arm and/or breast lymphedema. Oncoplastic reduction mammoplasty (ORM) aims to reduce breast volume while excising the tumor bed and its margins. Since breast volume was found to be a risk factor for chronic breast lymphedema, this study was performed to determine the impact of ORM on chronic breast lymphedema as well as other complications compared to BCS without ORM. Materials / Methods: We performed a retrospective chart review on patients who underwent lumpectomy with RT from 2014 to 2018. Chronic breast lymphedema (CBL) was defined as swelling that persisted >1 year post-RT. Breast volumes (BV) were determined by contoured breast volumes or, if unavailable, estimated by the 95% isodose volumes from the RT treatment planning system. Univariate analysis was used to evaluate various patient factors and treatment outcomes in women with BV ≥1300 cc compared to 1300 cc are at increased risk for developing several complications regardless of the presence of ORM. Those who had ORM experienced an increase in wound complications but having undergone ORM appeared to eliminate the increased risk of CBL associated with macromastia. This suggests that ORM should be considered at the time of BCS to reduce their future risk of CBL as there is no cure for this disease. Citation Format: Jenna Nicole Luker, Cara Canella, Sanjay Rama, Kelley Park, Renee Barry, Saheli Ghosh, Simeng Zhu, Yalei Chen, Jessica Bensenhaver, Eleanor Walker, Kenneth Levin, Maristella Evangelista, Dunya Atisha. The effect of oncoplastic reduction on the incidence of post-operative breast lymphedema in breast cancer patients undergoing lumpectomy [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 PS1-49.

Purpose/Objective(s):Unlike temporary breast edema caused by post-lumpectomy radiation therapy (RT), the edema that persists beyond one year is not well defined and difficult to treat. The aim of this study is to define the incidence and risk factors for the development of chronic breast lymphedema in women undergoing lumpectomy with RT at a large metropolitan cancer center. Materials/Methods:A retrospective chart review was performed on all patients who underwent lumpectomy from 2014 to 2018. Women who did not undergo RT at our institution and those with stage IV disease were excluded from the analysis. Patient demographics, comorbidities, operative data, RT data and postoperative complications were obtained. Chronic breast lymphedema (CBL) was defined as edema that persisted beyond one year post completion of radiation therapy. Breast volumes were determined by contoured breast volumes or, if unavailable, estimated by the 95% isodose volumes from the RT treatment planning system. Using a density curve, the distribution of breast volumes was plotted for patients with and patients without CBL. Univariate analysis was used to evaluate factors associated with CBL. Multivariate regression analysis was used to evaluate factors associated with the risk of CBL while accounting for potential confounding variables as defined by the univariate analysis. Results:A total of 1173 patients were included for analysis. Seventy-four (6.3%) patients developed breast lymphedema beyond one year. For the entire cohort, mean age was 63 years old (SD=11.17), mean BMI was 31.15 kg/m2 (SD=7.17), mean breast volume was 1198.54 cm3 (SD=645.82 cm3), mean total radiation was 59.18 Gy (SD=16.76), and 139 (11.8%) patients underwent ALND. Compared to the cohort that did not develop CBL (n=1099), the CBL cohort (n=74) had a higher median BMI (33.23 kg/m2 vs. 29.81 kg/m2, P Conclusion:Chronic breast lymphedema presents a clinical concern for women undergoing lumpectomy with postoperative radiation, particularly in women with larger breasts. Further studies should focus on preventative strategies, as well as the psychosocial and economic impact of this morbidity. Citation Format: Sanjay Rama, Cara Canella, Jenna Luker, Kelley Park, Renee Barry, Saheli Ghosh, Simeng Zhu, Yalei Chen, Jessica Bensenhaver, Eleanor Walker, Kenneth Levin, Dunya Atisha, Maristella Evangelista. Factors associated with chronic breast lymphedema after adjuvant radiation in women undergoing breast conservation therapy [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 PS1-12.

DARC/ACKR1 erythrocyte expression, also known as the “Duffy blood group,” is understood to sequester pro-inflammatory chemokines and thereby regulate circulating gradients that direct immune cell infiltration. We hypothesize that this function also determines immune cell landscapes in the tumor microenvironment. Due to evolutionary selection pressures of malaria, individuals with sub-Saharan African ancestry typically carry the Duffy-null allele (rs4849887) and this lack of DARC/ACKR1 expression gives immunity to malaria while also allowing chronically high inflammation levels. Over 68% of African Americans (AA) have been found to have the Duffy-null genotype, compared to a rare 1-3% in European American individuals and we have shown it increases predisposition for Triple-Negative Breast Cancer (TNBC). In addition, we are currently studying if Duffy-null may contribute to higher breast cancer mortality that disproportionately affects AA women. This may be in part due to the role that low-DARC/ACKR1 expression plays in chronic inflammation, altering levels of several chemokines that modulate the migration and differentiation of specific immune cells. This role will impact tumor immune cell infiltration as well as the immune cell population composition overall, depending upon levels of DARC/ACKR1. Using RNA sequencing, our initial results indicated that for breast cancer tumors with high DARC/ACKR1 expression there was a higher estimated presence of CD8+ T cells, CD4+ T cells, regulatory T cells, follicular helper T cells, and memory B cells. Whereas with low DARC/ACKR1 expression, there was markedly less expression of resting dendritic cells and memory B cells. Therefore, in order to ascertain the influence DARC status has on spatial deposition and functional status of immune cell landscapes across the tumor microenvironment, we performed imaging mass cytometry on primary TNBC tumors. The panel contained tumor, structural, and immune markers, and was used to characterize the spatial differences between samples that had been verified to be DARC-high or DARC-low through immunohistochemistry. Our imaging analyses indicated that high DARC/ACKR1 expression correlates with infiltration of monocytes, macrophages, and cytotoxic T cells into the solid tumor microenvironment. Conversely, tumors with low DARC/ACKR1 expression showed monocytes and cytotoxic T cells contained in the tumor stroma. Using single-cell phenotyping, we were also able to identify distinct cell populations between DARC-high and -low. The tSNE analysis and heatmaps performed using Histology Topography Cytometry Analysis Toolbox (histoCAT), allowed us to visualize the spatial distribution of these cell populations, indicating an immune-suppressive tumor microenvironment in DARC-low tumors. These differences may be implicated in the causality of tumor progression as well as how to approach treatment given the cell heterogeneity of TNBC. This work provides greater context on the role that Duffy-null plays in chronic inflammation on the tumor microenvironment. Citation Format: Yanira Guerra, Rachel Martini, Jessica Bensenhaver, Yalei Chen, Joseph K. Oppong, Ishmael Kyei, Frances S. Aitpillah, Michael O. Adinku, Joseph K. Oppong, Ernest K. Adjei, Aisha Jibril, Baffour Awuah, Mahteme Bekele, Engida Abebe, Kwasi Ankomah, Ernest B. Osei-Bonsu, Kofi K. Gyan, Clayton Yates, Kim Blenman, Olivier Elemento, Lisa Newman, Melissa B. Davis. The role of African Duffy-null allele related inflammation on the tumor microenvironment [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-141.

Introduction In sub-Saharan Africa, breast cancer (BC) is the leading cancer in women and the second cause of cancer mortality. In order to reduce the burden of BC in women with African ancestry there is a need for a structured, coordinated effort to address gaps in our understanding of the factors associated with the disease that influence tumor initiation, progression, and outcomes. To address this need ‘Precision Medicine for African Breast Cancer (PMABC)’ a comprehensive partnership housed at the Henry Ford Cancer Institute was created with the aim of bringing together African researchers to study African BC. We are currently composed of nine leading institutions spanning West and East Africa and two institutions in the United States. Objectives The broad aim of PMABC is to bring together researchers and institutions across sub-Saharan Africa to partner with foreign institutions and funding agencies to study and identify new and improved methods of screening, diagnosing, and treating BC in Africans to improve the overall outcome. Among the aims of PMABC are: • Registry: Create a national BC registry building on data from participating institutions which comprise at least 80% of all BC cases seen in the respective country • Standardization of pathology protocol and reporting: harmonize the pathology reporting scheme and ensure its conformity to international standards Standardization of treatment protocols: Study and compare treatment protocols with international standards and make recommendations • Biorepository: Create a national repository of patient samples to be used in genetic and biological studies • Study African tumor biology: Build the capacity to be able to study African tumors locally and participate in clinical trials • Patient follow up and survival studies: study and obtain data on patient outcomes Achievements We currently have ethical approval and have begun work in nine institutions across West and East Africa. • Creation of a national database in Ghana that currently consists of over 7000 patients. The data is being analyzed to determine risk factors and the distribution of BC by subtypes • We are setting up two research labs in Ghana to train local researchers for basic and translational research • We have a biorepository of over 2000 patient samples that is available for collaborative studies • We have developed tumor models from continental African breast tumors • Building partnership with international organizations, pharmaceutical companies, and funding agencies to study African BC Conclusion PMABC serves as an umbrella institution to coordinate the work between these researchers and to provide resources for the institutions to provide a high level of BC research and treatment. We are aiming to partner with countries across Africa to translate the model created by PMABC in order fulfill the need for further BC research and standardization of data collection and treatment. PMABC is made possible because of the dedication and passion of our collaborating researchers. Citation Format: Sabrina I. Fossi, Sylvester Antwi, Kwabena Agbedinu, Kafui Akakpo, Samuel Mensah, Nelson Affram, Mohammed Sheriff, Foster Amponsah, Jacqueline Asibey, Osei Collins, Alex Mremi, Livingstone Aduse-Poku, Kurt Fernando, Haythem Ali, Eleanor Walker, Jessica Bensenhaver, Evelyn M. Jiagge. Precision medicine for African breast cancer: Bringing African researchers together to study African breast cancer [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-189.

The Duffy Antigen Receptor for Chemokines (DARC/ACKR1) is an atypical chemokine receptor which promiscuously binds chemokines of both CC and CXC chemokine families. DARC/ACKR1 maintains homeostatic levels of chemokines in circulation through its expression on erythrocytes, and in tissues participates in chemokine transport, where chemokines are transported across the cell layer to help establish chemokine gradients. Establishment of these chemokine gradients is essential for proper immune cell trafficking. In our recent study, we have shown that DARC/ACKR1 is expressed on the tumor epithelium, and through in silico analysis of data from the Cancer Genome Atlas (TCGA), that higher DARC/ACKR1 expression is positively and significantly correlated with tumor-associated leukocyte abundance when using CIBERSORT deconvolution methods. Specifically, higher DARC/ACKR1 expression was linked with increases in B cell, T cell, monocyte and macrophage populations. Higher DARC/ACKR1 expression is also significantly associated with better survival outcomes, across all breast cancer molecular subtypes. To further evaluate DARC/ACKR1 expression and influences on the breast TME, we have employed multiple approaches to characterize how DARC/ACKR1 impacts immune cell recruitment and subsequent infiltration into the tumor. In our patient cohort, we have recently completed Hyperion imaging mass cytometry staining of tumors that have been scored by IHC as DARC/ACKR1 high or low expressing. We used a panel of approximately 30 markers, including structural, immune, and other markers of interest. Following imaging, we have used cell segmentation software to quantify marker expression on a cell-by-cell basis. Using this method, we are able to conduct single-cell analyses of our markers of interest, while also retaining the spatial composition of the cells. We have used the tSNE algorithm to identify cell populations that cluster uniquely within DARC/ACKR1 high or low tumor expressing groups, specifically identifying different clusters of immune cell populations, which show different spatial expression patterns in our comparison groups. In addition to investigations of immune cell recruitment to the TME, we have also developed a novel DARC/ACKR1 breast cancer transgenic mouse model to study how disease progression may differ with differing DARC/ACKR1 phenotypes. Briefly, DARC -/- female mice were crossed with the male C3(1)Tag +/0 breast cancer transgenic mouse to generate DARC +/-, C3(1)Tag +/0 male mice. These males were subsequently backcrossed to DARC -/- females, to generate the target DARC/ACKR1 +/- or -/-, C3(1)Tag+ mice. These mice show evidence of early disease beginning at 3.5 months of age, and progress to advanced disease by 5 months of age. We have collected tumor tissue and blood specimens from mice ranging from 3.5 to 7 months of age, to characterize disease progression over time between our DARC/ACKR1 expressing and non-expressing groups. We have observed differences in tumors characteristics between our DARC/ACKR1 expressing groups, and upon histological and immunofluorescent evaluation, we have begun to observe differences in immune cell recruitment, following similar patterns to what we observed in our in silico and patient cohort analyses. Citation Format: Rachel Martini, Brittany Jenkins, Dorrah Deeb, Hiranmayi Ravichandran, Paula Ginter, Esther Cheng, Syed Hoda, Dhananjay Chitale, Haythem Ali, Eleanor Walker, Jessica Bensenhaver, Olivier Elemento, Nancy Manley, Lisa Newman, Melissa Davis. Breast tumor expression of DARC/ACKR1 and impacts on disease progression and immune cell recruitment in the tumor microenvironment [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 4975.

This abstract was withdrawn by the authors.

Background: Population-based incidence rates of breast cancers that are negative for the estrogen receptor (ER), progesterone receptor (PR), HER2/neu triple-negative breast cancer (TNBC) are higher among African American (AA) compared to White American (WA) women, and several studies suggest that TNBC prevalence is increased among selected populations of African patients. The colonial-era transatlantic slave trade resulted in shared ancestry between contemporary AA and Gh populations. The extent to which associations between TNBC are related to East African versus West African ancestry, and whether these associations extend to expression of additional hormone receptors such as androgen receptor (AR) and stem cell markers such as ALDH1, is uncertain, but this research may explain breast cancer disparities between domestic communities within the United States as well as between international population subsets. Methods: We utilized immunohistochemistry to evaluate ER, PR, HER2/neu, AR and ALDH1 expression among White American (n=153), African American (n=76), Ethiopian (Eth)/East African (n=90), and Ghanaian (Gh)/West African (n=286) breast cancers through an IRB-approved international research program. Results: Mean age at breast cancer diagnosis was 43, 49, 60, and 57 years for the Eth, Gh, AA, and WA patients, respectively. Frequency of TNBC was significantly higher for the AA and Gh patients (41% and 54%, respectively) compared to the WA and Eth patients (23% and 15%, respectively; p Conclusions: Extent of African ancestry appears to be associated with particular breast cancer phenotypes. West African ancestry correlates with increased risk of TNBC and breast cancers that are positive for ALDH1. Citation Format: Evelyn M. Jiagge, Aisha Jibri, Jessica Bensenhaver, Max Wicha, Baffour Awuah, Sofia Merajver, Lisa Newman. Androgen receptor and ALDH1 expression among internationally diverse patient populations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1639.

TNBC is the only subtype of breast cancer for which there are no approved targeted therapies. In the US, its incidence is highest in women with African ancestry (AA); in western sub-Saharan Africa, single-institution studies show that TNBC constitutes 40- 80% of all breast cancers. Given the Caucasian/AA survival disparity in breast cancer, there is an urgent need to find actionable targets in TNBC of all ethnicities, but especially in TNBC in AA, which are suspected to be more aggressive. Breast cancer stem cells, the small population of cells that have been shown to mediate breast tumor initiation, metastasis, and resistance to conventional therapy have also been reported to mediate the heterogeneity of TNBC and are especially abundant in TNBC in AA women. Here, we sought to better understand the biology of TNBC by finding genes and pathways that are differentially expressed in the stem cell population of patient derived xenografts (PDX) from TNBC from Ghanaian (G), AA and Caucasian (C) women and the effect of these differentially expressed genes on the stem cell phenotype in these primary tumors. We isolated the ALDH+ and the CD44+/CD24- stem cell populations from the bulk cells from 15 PDXs using flow cytometry. We performed RNA sequencing (Illumina HiSeq platform) on the isolated populations and bulk cells (45). Comprehensive bioinformatics analyses led to the identificationof highly significantly differentially expressed genes and pathways between the cell populations. By principal component analysis, the tumors were very heterogeneous. However, the ALDH+ cells separated out from the CD44+/CD24- and the bulk cells. We identified 14 genes that were simultaneously differentially expressed between the ALDH+ vs the CD44+/CD24- as well as ALDH+ VS bulk (p-value Citation Format: Evelyn M. Jiagge, Shukmei Wong, Rabia Gilani, Sean Mcdermott, Lisa Newman, Jessica Bensenhaver, Max Wicha, John Carpten, Sofia Merajver. Aldh expressing stem cells mediate tumor initiation and metastasis in triple negative breast cancers across different ethnicities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3371. doi:10.1158/1538-7445.AM2017-3371

In the US where extensive studies have been conducted, African-American(AA) women have poorer survival from breast cancer (BC) even after adjusting for stage, age, treatment and co-morbid conditions. Since survival in BC is mainly dependent on the appearance and robustness of metastasis, we have hypothesized that BC occurring in women with African ancestry have a greater metastatic potential. With the growing evidence that BC tumor initiation, metastases and recurrence is driven by stem-like cancer cells, we further hypothesize that BC in women of African descent has aggressive phenotypic characteristics that result from the integration of signaling alterations and metabolic adaptations in their cancer stem cells. Rodent xenograft models are powerful tools for studying tumor biology and treatment response to novel agents, but they are challenging to develop in the laboratory. Here we describe the first-ever creation of a library of xenografts from a series of patients affected with triple negative breast cancer (TNBC) from sub-Saharan Africa, based upon a unique international collaboration; we also report on studies that are being conducted on the xenografts to understand the stem cell biology of aggressive African breast cancers. Methods: Our research team explored several different strategies for obtaining fresh tumor specimens from Ghanaian patients with aggressive TNBC tumors, undergoing surgery in Kumasi, Ghana, and rapidly transporting these tissues for implantation into immunocompromised mice in the United States. Xenograft tumors were also developed from AA and Caucasian American (CA) patients undergoing surgery in the United States. The whole genome expression patterns of the bulk tumor as well as the stem cell compartments were compared for AA, Ghanaian and CA TNBC. Single cells from the tumors were grown in suspension and in attachment plates. Results: Successful xenografts were created by harvesting fresh tissue from patients undergoing surgery in Ghana, slow freezing tumor pieces at -80o C and transporting it on dry ice by air to the United States within 24-36 hours to implant into nod scid gamma mice. Currently we have successful growth, as follows: 12 tumors from 4 patients growing in 10 mice. We have successful growth of tumorspheres and cell lines from single cells separated from the xenografts, as additional resources for biological studies of signaling and metastases. In a preliminary study, we have performed a gene array expression study of AA and White American triple negative and estrogen positive cell lines that show significantly different gene expression patterns, with the cell lines of high African ancestry segregating from Caucasian cell lines . Conclusions: The study of aggressive breast cancers in African populations is feasible through the creation of xenografts from fresh tumor tissue harvested from the treating facilities and transported to laboratories in the United States. International collaborations are critical for this process and should thus be encouraged, to create the appropriate resources worldwide to improve our understanding of aggressive BC subtypes.. Moreover, we are finding common expression patterns in TNBC of African extraction. This will help advance our understanding of the survival disparities. To this end, we will be able to test the observed differences in the new tumorspheres and cell lines developed directly from patients. Citation Format: Evelyn M. Jiagge, Jessica Bensenhaver, Sean McDermott, Awuah Baffour, Max Wicha, Lisa A. Newman, Sofia Merajver. Differences in breast cancer stem cell signaling and metabolic integration associated with African versus European ancestry. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr PL03-03. doi:10.1158/1538-7755.DISP13-PL03-03