bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P2-17-02: Locoregional therapy targeted at the primary tumour improves overall survival in patients presenting with de novo stage IV metastatic breast cancer: A systematic review and meta-analysis of real-world data with 201598 patients
Authors: Tayeh Salim , Gera Ritika , Chehade Hiba El Hage , Wazir Umar , Kasem Abdul , Mokbel Kefah
Published: March 2020

Background: De novo stage IV metastatic breast cancer is a complex disease that is traditionally treated using systemic therapy. There is mounting evidence that locoregional therapy (LRT), defined as resection of the primary tumour and/or localised radiotherapy, could be associated with survival improvements. We aimed to conduct a meta-analysis to inform decision making.

Methods: Using the PubMed, Cochrane and Ovid SP databases, a literature review and meta-analysis was undertaken to assess whether LRT of the primary tumour in metastatic breast cancer prolongs survival.

Results: 48 studies met the criteria for analysing the efficacy of all locoregional treatments (radiotherapy and/or surgery) and 44 studies were suitable for the analysis of surgery-only treatment of the primary. Studies were analysed for the impact of LRT on survival. All LRT resulted in a significant 32.9% reduction in mortality with LRT (N=48; HR=0.671: 95% CI 0.624-0.721). Primary resection alone resulted in a significant 36.9% mortality (N=44; HR=0.631: 95% CI 0.591-0.674).

Conclusions: This is the largest meta-analysis regarding this question to date. LRT seems to improve overall survival in stage IV disease at initial diagnosis and should be considered in selected patients after a multidisciplinary discussion.

Citation Format: Salim Tayeh, Ritika Gera, Hiba El Hage Chehade, Umar Wazir, Abdul Kasem, Kefah Mokbel. Locoregional therapy targeted at the primary tumour improves overall survival in patients presenting with de novo stage IV metastatic breast cancer: A systematic review and meta-analysis of real-world data with 201598 patients [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-17-02.
Abstract P2-19-02: Circulating osteocalcin-positive cells as a novel diagnostic biomarker for bone metastasis in breast cancer patients
Authors: Cho Sun Wook W , Lee Kyung-Hun , Kim Tae-Yong , Park Serk In , Im Seock-Ah
Published: March 2020

Purpose: Diagnosis of bone metastasis (BM) in breast cancer relies on structural changes of bone. We investigated whether circulating osteocalcin-positivecells (cOC) could detect the incipient and/or progressive BM earlier than image-based diagnostics.

Experimental design: Metastatic breast cancer patients with or without bone metastasis (designated BM+ or BM-) were enrolled and cOC were quantified at baseline by flow cytometry. The progression of BM was evaluated after 18 months. Murine BM models were established by intra-tibial or -cardiac injection of MDA-MB-231 or 4T1 breast cancer cells.

Results: In the baseline analysis, cOC was significantly higher in BM+ than BM- group. In the 18-month follow-up study of BM+ patients (n=63), baseline cOC was significantly associated with BM disease progression. Among BM- patients (n=33), three patients developed new bone metastasis within 18 months and were found to have had higher cOC at baseline. The patients with higher cOC showed shortened BM progression-free survival, compared with those with lower cOC (cutoff=0.045%; P<.001; HR 4.79; 95% CI 2.17-10.56). In murine intra-tibial injection models, cOC significantly increased at an early time-point, even when micro-metastases were evident only by histologic examination but undetectable by bioluminescence imaging. Additionally, in an intra-cardiac injection model, the mice with higher cOC developed BM at an earlier time point, compared with the mice with lower cOC.

Conclusions: cOC is increased in the early phase of breast cancer BM and predict the disease progression. cOC can be a novel biomarker for early diagnosis and progression of BM.

Citation Format: Sun Wook W Cho, Kyung-Hun Lee, Tae-Yong Kim, Serk In Park, Seock-Ah Im. Circulating osteocalcin-positive cells as a novel diagnostic biomarker for bone metastasis in breast cancer patients [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-19-02.
Abstract P3-01-14: N-Myc and STAT interactor regulates STAT5a in mammary development and metastasis
Authors: Samant Rajeev Sharad , Alsheikh Heba A , Metge Brandon J , Chen Dongquan , Wei Shi , Shevde Lalita A
Published: March 2020

Delicate balance between cellular plasticity and differentiation is critically maintained during mammary development. Disruption of this balance leads to breast cancer initiation and metastatic progression. Recent findings from our lab have revealed that N-Myc and STAT Interactor (NMI) protein is decreased in 70% of primary patient specimens with metastatic breast cancer. Mammary specific Nmi knock out mouse model revealed that conditional Nmi loss disrupts luminal differentiation in the mammary gland affecting alveologenesis and prompted the progression of tumors with aggressive metastatic characteristics.

Our studies showed that Nmi is induced at the onset of pregnancy and its expression remains throughout lactation. Furthermore, prolactin stimulation and differentiation of HC11 murine mammary epithelial cells is accompanied by up-regulation of Nmi. STAT5a is one of the downstream effector of prolactin and is essential for differentiation of secretory alveolar epithelium. However, functional relationship of NMI and STAT5a was not known.

Here we present our finding that NMI and STAT5a expression has a direct relationship in normal mammary development as well as in breast primary and metastatic tumor specimens. We demonstrate that loss of Nmi in vivo caused a decrease in STAT5a activity and a subsequent transcriptomic shift in mammary epithelial and breast cancer cells. Detailed examination of STAT5a mammary specific controlled genetic program in the context of transcription profiles of NMI knockout and overexpressing cell lines as well as mammary tumors revealed ISG20, interferon stimulated exonuclease gene 20, as a unique negatively regulated transcript. Here we show that expression of ISG20 is kept in check by NMI by miR17-92 cluster and that ISG20 has a positive influence on tumor progression and metastasis.

Citation Format: Rajeev Sharad Samant, Heba A Alsheikh, Brandon J Metge, Dongquan Chen, Shi Wei, Lalita A Shevde. N-Myc and STAT interactor regulates STAT5a in mammary development and metastasis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-01-14.
Abstract P3-01-16: Utilizing a decellularized patient-derived xenograft tumor model for the evaluation of triple negative breast cancer
Authors: Wright Maryl , Matossian Margarite , King Connor , Nguyen Khoa , Elliott Steven , Alzoubi Madlin , Martin Elizabeth , Collins-Burow Bridgette , Burow Matthew
Published: March 2020

Triple negative breast cancer (TNBC) is an aggressive and heterogeneous disease with poorer prognoses compared to other breast cancer (BC) subtypes. This is due, in part, to the lack of clinically approved targeted therapeutics. The mechanisms underlying the process of recurrence in TNBC remain elusive. Traditional 2D BC models do not accurately mimic the cell-matrix interactions and extracellular matrix (ECM) composition that are vital to maintaining the tumor microenvironment and are unique to individual patient tumors. Here we introduce and utilize our novel decellularized patient-derived xenograft (PDX) TNBC model, TU-BcX-4IC (“4IC”), to address this knowledge discrepancy. In this study, we seeded TU-BcX-4IC PDX-derived cells onto TU-BcX-4IC PDX decellularized tumor scaffold (“4IC + 4IC scaffold”) and implanted our model into SCID/beige mice. Concordantly, mice were inoculated with TU-BcX-4IC cells mixed with Matrigel and PBS (“4IC + Matrigel”), or PBS alone (“4IC + PBS”). We demonstrate that our decellularized model, along with the injected cells, can form tumors in vivo. We also show that the “4IC + 4IC scaffold” model retains aberrant mitotic figures seen in the original 4IC PDX. However, due to inconsistent tumor growth in the experimental group, optimization of cell seeding onto our decellularized scaffold model is needed to produce consistent tumor propagation in vivo. We compared the number and area of metastases in the lungs and livers excised from the mice. The area and number of lung metastases were lower in mice implanted with “4IC + 4IC scaffold,” albeit not significantly. There was little difference in the area of liver metastases in all groups. The number of liver metastases was lower in the “4IC + Matrigel” and “4IC + 4IC scaffold” groups; however, there was no significance. All groups had a greater propensity to metastasize to the livers. We also compared differences in human and mouse ECM gene expression amongst all groups. Our decellularized scaffold model can be used as a platform to evaluate ECM onco-architecture and composition. The data presented here will help enhance our understanding of the breast tumor microenvironment and elucidate the mechanisms underlying tumorigenesis and recurrence in TNBC.

Citation Format: Maryl Wright, Margarite Matossian, Connor King, Khoa Nguyen, Steven Elliott, Madlin Alzoubi, Elizabeth Martin, Bridgette Collins-Burow, Matthew Burow. Utilizing a decellularized patient-derived xenograft tumor model for the evaluation of triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-01-16.
Abstract P3-01-21: Functional duality of NUAK2 in breast cancer metastases
Authors: Jia Wang , Jingyan XUE , Jianjing Hou , Bingqiu Xiu , Lun Li , Yayun Chi , Jiong Wu
Published: March 2020

Background: Breast cancer patients with lymph nodes metastasis were proven to have more aggressive biologically phenotypes. This study was aimed to find different biomarker ectopic expression between breast cancer patients' metastatic lymph nodes and primary cancer, and to explore the potential molecular mechanisms.

Method: From our previous research, we selected the pairing samples from primary breast cancer with their early stage lymph node metastasis to carry out differential gene expression profiling. Genes with high expression level in sentinel lymph node metastasis were obtained. Then according to the findings of CRISPR/Cas9 screening and the results in relevant literature and online public database, we decided to investigate the role of NUAK2 in our further research. In vitro and in vivo analyses were carried out to determine the potential mechanisms of NUAK2 in lymph node metastases and prognosis. Results NUAK2 belongs to the AMP-activated protein kinase (AMPK) family, with its members controling protein metabolism, polarity, and overall cellular homeostasis actin cytoskeleton organization. The effect of NUAK2 variant expression in breast cancer metastases remains unknown. In this study, it was found that the expression level of NUAK2 was significantly higher in 5 paired metastatic lymph node than that in primary cancer, using Affymetrix GeneChip® Human Transcriptome Array 2.0. From online public database, higher NUAK2 expression level was markedly associated with better metastasis-free survival in breast cancer patients. The effects of NUAK2 on proliferation were investigated by CCK-8 and IncuCyte ZOOM™ assay, respectively. The results demonstrated that knockdown NUAK2 was able to significantly inhibit the proliferation of breast cancer cells. However, for cancer metastases, it was demonstrated that knock-down of NUAK2 significantly accelerated the migration of breast cancer cells, while overexpression of NUAK2 notably inhibited breast cancer cell migration. When promoting proliferation of breast cancer cells, NUAK2 might involve signal pathways of cell cycle. As for the anti-metastasis function, it would regulate cell adhesion, cell motility and microenvironment.

Conclusion: Our in vitro study demonstrated that NUAK2 has shown reverse effects of tumor cell proliferation and invasion. The interaction of NUAK2 and cancer cells could be an important role in cell proliferation involved in cell cycle signal pathway, and modulate cell mobility by inducing cell-cell detachment. Its molecular mechanism of dual effect in breast cancer need further investigation.

Citation Format: Wang Jia, XUE Jingyan, Hou Jianjing, Xiu Bingqiu, Li Lun, Chi Yayun, Wu Jiong. Functional duality of NUAK2 in breast cancer metastases [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-01-21.
Abstract P3-01-27: Ectonucleotidase ATP hydrolysis facilitates breast cancer bone metastasis
Authors: Shropshire Daniel B , Benavides Jaime , Jiang Jean X
Published: March 2020

Bone is the most common site for breast cancer metastasis. Osteocytes are the most abundant bone cell and can signal nearby cells by releasing ATP through connexin 43 hemichannels. We previously found that this signaling pathway hindered breast cancer growth in bone. In this study, we investigated the role of purinergic signaling on breast cancer bone metastasis in patient samples. Surprisingly, no ATP receptors were differentially expressed in bone metastases compared to other sites. However, enzymes that degrade ATP into adenosine (CD39/ENTPD1 and CD73/NT5E) were upregulated, as was the ADORA3 adenosine receptor (Limma, p=0.037, 0.016, 0.0019, respectively). We next investigated whether this expression signature in primary tumors predicts bone metastasis. In primary ER+ breast cancer, which predominately metastasizes to bone, high expression of these genes is correlated with lower distant metastasis-free survival (HR = 1.97, 1.49, 2.03, logrank p=0.0017, 0.0004, 0.0012). Moreover, this expression pattern is correlated with a bone metastasis signature (Spearman R=0.28, p=1.2 × 10−20). In a pharmacologic screen of 750 cancer cell lines, breast cancer lines and especially ER+ ones, are uniquely sensitive to a pan-adenosine receptor inhibitor (Limma, p=2.9 × 10−5) and ADORA3/2B inhibitor (p=5.4 × 10−5). Our findings suggest that an expression program to convert ATP to adenosine facilitates bone metastasis and begins in the primary tumor. ADORA3 inhibition is proposed as a pharmacologic strategy for preventing or treating bone metastasis. Furthermore, bone metastases should be analyzed in anti-CD39 and CD73 clinical trials.

Citation Format: Daniel B Shropshire, Jaime Benavides, Jean X Jiang. Ectonucleotidase ATP hydrolysis facilitates breast cancer bone metastasis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-01-27.
Abstract P3-02-12: CAV1, MCT1, and MCT4 expression in ductal carcinoma in situ of the breast and its association with clinicopathologic features
Authors: Lee Ji Shin , Kim Nah Ihm , Park Min Ho
Published: March 2020

Background: Multicompartment tumor metabolism and metabolic coupling are markers of aggressive tumor behavior, clinically manifested as disease recurrence and progression. Loss of caveolin-1(CAV1) in stromal cells and upregulation of monocarboxylate transporters (MCTs), especially MCT1 and MCT4, in both stromal and cancer cells have been identified as playing an important role in the metabolic coupling necessary for release and uptake of metabolites. However, this phenomenon has only scarcely been described in ductal carcinoma in situ (DCIS) of the breast. The purpose of this study was to investigate the role of CAV1, MCT1, and MCT4 in DCIS carcinogenesis and its association with clinicopathologic factors.

Materials and methods: CAV1, MCT1, and MCT4 expression was examined in 9 pairs of DCIS tissues and matched normal adjacent tissues at mRNA and protein levels by qRT-PCR, RNAscope in situ hybridization (ISH) and immunohistochemistry. Immunohistochemical staining of CAV1, MCT1, and MCT4 was done in 79 DCIS samples with known hormone receptor (HR) and human epidermal growth factor 2 (HER2) expression using tissue microarray.

Results: CAV1 mRNA expression by qRT-PCR analysis was significantly decreased in DCIS tissues compared to their corresponding normal tissues. On the other hand, MCT1 and MCT4 mRNA expression in DCIS tissues were increased compared with corresponding normal tissues and the difference was statistically significant in MCT1. Compared with their corresponding normal tissues, DCIS tissues showed decreased stromal CAV1 mRNA and protein expression and increased epithelial MCT1 and MCT4 mRNA and protein expression by ISH and immunohistochemistry. Low stromal CAV1, high epithelial MCT1, and high epithelial MCT4 expressions were observed in 29 (36.7%), 51 (64.6%) and 15 (18.9%) cases with DCIS, respectively. Low stromal CAV1 expression was significantly associated with high nuclear grade (P < 0.05). High epithelial MCT4 expression was associated with larger tumor size and HER2 positivity (P < 0.05 and P < 0.05, respectively). Although not statistically significant, low stromal CAV1 and high epithelial MCT4 expression tended to be associated with recurrence of DCIS. No associations were observed between stromal CAV1 expression and epithelial MCT 1 or MCT4 expression.

Conclusions: These results suggested that changes in CAV1, MCT1, and MCT4 are associated with carcinogenesis of DCIS, and further studies are needed for their clinical usefulness.

Keywords: Ductal carcinoma in situ; CAV1; MCT1; MCT4; Metabolism

Citation Format: Ji Shin Lee, Nah Ihm Kim, Min Ho Park. CAV1, MCT1, and MCT4 expression in ductal carcinoma in situ of the breast and its association with clinicopathologic features [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-02-12.
Abstract P3-02-15: Integrin a2 promotes stemness and lung metastasis in triple negative breast cancer
Authors: Adorno-Cruz Valery , Hoffmann Andrew , Liu Xia , Keri Ruth , Liu Huiping
Published: March 2020

Accumulating evidence demonstrates that cancer plasticity and stem cell properties (stemness) drive both tumorigenesis and metastasis, and how to eliminate metastasis remains one of the biggest challenges in the clinic. Here we report that the integrin receptor CD49b-encoding ITGA2 is an oncogenic target of miR-206 regulating cancer stemness and metastasis through pathways linked to lipid metabolism and cell cycle regulation in metastatic triple negative breast cancer (TNBC). ITGA2 knockdown suppressed self-renewal related mammosphere formation and pluripotency marker expression, inhibited cell cycling, compromised migration and invasion, and therefore decreased lung metastasis of TNBC. RNA sequencing analyses revealed that ITGA2 knockdown inhibits newly identified pathways such as lipid metabolism and protein kinase activity. ACLY-encoded ATP citrate lyase is one of the top targets in CD49b promoting lipid biosynthesis and self-renewal of breast cancer cells. Overexpression of CCND1 rescues the phenotype of ITGA2 knockdown-induced cell cycle arrest. High expression levels of the ITGA2/ACLY/CCND1 axis are associated with an unfavorable relapse-free survival of patients with high grade breast cancer, in both basal-like and other subtypes. This study identifies ITGA2 as a potential therapeutic target of TNBC stemness, metabolism, and metastasis.

Citation Format: Valery Adorno-Cruz, Andrew Hoffmann, Xia Liu, Ruth Keri, Huiping Liu. Integrin a2 promotes stemness and lung metastasis in triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-02-15.
Abstract P3-03-01: Double PIK3CA mutations in cis drive oncogene addiction and enhance sensitivity to PI3K alpha inhibitors in breast cancer
Authors: Vasan Neil , Razavi Pedram , Johnson Jared L , Shao Hong , Wilson Timothy , Schimmoller Frauke , Shah Hardik , Antoine Alesia , Ladewig Erik , Gorelick Alexander , Lin Ting-Yu , Toska Eneda , Xu Guotai , Kazmi Abiha , Chang Matthew T , Taylor Barry S. , Dickler Maura N. , Jhaveri Komal , Chandarlapaty Sarat , Rabadan Raul , Reznik Ed , Smith Melissa L , Sebra Robert , Friedman Lori , Cantley Lewis C , Scaltriti Maurizio , Baselga José
Published: March 2020

Activating mutations in PIK3CA, the gene coding for the catalytic subunit (p110α) of phosphoinositide-3-kinase (PI3K), are the most frequent oncogenic alterations in estrogen receptor-positive (ER+) breast cancer and are also prevalent in other tumor types. PI3Kα inhibitors including alpelisib have recently been shown to be clinically active in ER+ PIK3CA mutant breast cancer. To characterize determinants of sensitivity to these agents, we undertook a comprehensive analysis of PIK3CA mutant cancer genomes and observed the presence of double PIK3CA mutations in 12-15% of breast cancer and other tumor types. These double PIK3CA mutations are clonal, located in cis on the same allele, and are composed of a single hotspot mutation combined with a recurrent second-site mutation. Double PIK3CA mutations in cis result in increased PI3K activity and downstream signaling together with enhanced cell proliferation and tumor growth compared to single hotspot mutations. The biochemical mechanisms underlying this increased oncogenicity include increased disruption of p110α binding to the inhibitory subunit p85α, which relieves its catalytic inhibition, and increased membrane lipid binding. Finally, these double PIK3CA mutations predict for increased sensitivity to PI3Kα inhibitors compared to single hotspot mutations (e.g. E545K or H1047R) in experimental models and in patients with ER+ PIK3CA mutant metastatic breast cancer from the SANDPIPER randomized phase III clinical trial. These findings implicate double PIK3CA mutations in cis as a novel mechanism of oncogene addiction relative to single hotspot mutations, providing a rationale to develop PI3Kα inhibitors for the therapy of double PIK3CA mutant cancers.

Citation Format: Neil Vasan, Pedram Razavi, Jared L Johnson, Hong Shao, Timothy Wilson, Frauke Schimmoller, Hardik Shah, Alesia Antoine, Erik Ladewig, Alexander Gorelick, Ting-Yu Lin, Eneda Toska, Guotai Xu, Abiha Kazmi, Matthew T Chang, Barry S. Taylor, Maura N. Dickler, Komal Jhaveri, Sarat Chandarlapaty, Raul Rabadan, Ed Reznik, Melissa L Smith, Robert Sebra, Lori Friedman, Lewis C Cantley, Maurizio Scaltriti, José Baselga. Double PIK3CA mutations in cis drive oncogene addiction and enhance sensitivity to PI3K alpha inhibitors in breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-03-01.
Abstract P3-03-12: Obesity promotes the activation of genes and pathways in tumor associated breast fat
Authors: Infante Niel , Coad James , Primerano Don , Denvir James , Vona-Davis Linda
Published: March 2020

Tumor-associated adipocytes play an active role in breast tumor progression. Moreover, obesity has been established as a risk factor in cancer-related mortality. The altered expression of genes and signaling pathways in breast adipose as a result of obesity may create a more favorable microenvironment for tumor progression. To this end, we analyzed transcriptome profiles of human adipose tissue from lean and obese women with invasive breast cancer using RNA sequencing (n=10/group). Within individuals, adipose tissue was sampled proximal and distal (2 cm) to the breast tumor. A heat map of normalized expression values was generated with unsupervised clustering for the most informative genes. A cluster heat map was obtained by the analysis of the express of 35 DEGs with the most significant differences (adjusted p-value P< 0.01 and fold change > 2) recorded. Starting with a list of genes marked as significant in the analysis of lean vs obese, we queried the STRING database. Using ClusterMaker2 and MCL clustering, we performed enrichment analysis and found KEGG pathway hsa05224 breast cancer was enriched with an FDR of 2.7e-40. Using KEGGParser, we over-layed fold changes from lean vs obese data. In examining obese women, there were 16 Hallmark pathways that were statistically significant (adjusted p-value P< 0.10); whereas a subset of these (11 pathways) were significant in lean women. Pathways that were significant in both lean and obese individuals were pathways that regulate EMT, adipogenesis and TGF-β signaling. EMT transcription factors and TGF-β signaling are known to regulate cancer adipogenesis. The results underscore the link between obesity and altered gene expression in mammary fat associated with breast cancer. (Supported by NIH P20GM103434 and NIGMS U54GM104942)

Citation Format: Niel Infante, James Coad, Don Primerano, James Denvir, Linda Vona-Davis. Obesity promotes the activation of genes and pathways in tumor associated breast fat [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-03-12.
Abstract P3-05-05: Imipramine, an FDA approved anti-depressant, suppresses triple negative breast cancer growth and progression through inhibition of FOXM1 and DNA repair pathways
Authors: Timilsina Santosh , Rajamanickam Subapriya , Jatoi Ismail , Chen Yidong , Vadlamudi Ratna , Kaklamani Virginia , Rao Manjeet K
Published: March 2020

Triple Negative Breast Cancer (TNBC) is an aggressive subtype of breast cancer that lacks effective targeted therapies with the main therapeutic option being cytotoxic chemotherapies, which have toxic side effects on patient’s health. Less toxic alternatives that could target key pathways that are altered in TNBCs could lead to better outcomes for the patients. Important distinguishing traits of TNBCs is the high amounts of genomic instability and high number of alterations in key proteins in DNA repair and cell proliferation that helps the cancer grow, survive and progress. Previous findings from our lab indicate that Imipramine Blue, a derivative of anti-depressant imipramine, is a potent inhibitor of proliferation and DNA repair pathways in TNBC. Therefore, we tested the therapeutic efficacy of Imipramine on TNBCs using various in vitro assays for viability, migration, invasion as well as in vivo xenograft assays for tumor growth. Our results demonstrate that Imipramine inhibits cancer cell viability and progression in vitro. Similarly, in vivo xenograft assays showed reduced tumor growth in pre-clinical models upon imipramine treatment. Importantly, at the molecular level, Imipramine treatment suppressed key players in both cell proliferation, and DNA repair pathways, including FOXM1; a proto-oncogene that is a master regulator of both cell proliferation and DNA Repair pathways. These findings suggest that Imipramine may be a potential therapeutic option for TNBC patients. A clinical trial is ongoing to test the efficacy of Imipramine in Triple Negative Breast Cancer patients.

Citation Format: Santosh Timilsina, Subapriya Rajamanickam, Ismail Jatoi, Yidong Chen, Ratna Vadlamudi, Virginia Kaklamani, Manjeet K Rao. Imipramine, an FDA approved anti-depressant, suppresses triple negative breast cancer growth and progression through inhibition of FOXM1 and DNA repair pathways [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-05-05.
Abstract P3-06-12: Autophagy-mediated survival mechanism to c-Src inhibitor therapy in triple negative breast cancer
Authors: Jung Kwanghwa , Park Junhyoung , Sirupangi Tirupataiah , Jia Dongya , Gandhi Nishant , Pudakalakatti Shivanand , Elswood Jessica , Porter Weston , Putluri Nagireddy , Zhang Xiang H.-F , Chen Xi , Bhattacharya Pratip K. , Creighton Chad J. , Lewis Michael T. , Rosen Jeffrey M. , Wong Lee-Jun C. , Das Gokul M. , Osborne C. Kent , Rimawi Mothaffar F , Kaipparettu Benny Abraham
Published: March 2020

c-Src (Src) is a proto-oncogene involved in signaling that culminates in the control of multiple biological functions. Src is also one of the most frequently upregulated pathways in triple negative breast cancer (TNBC). Dysregulation of Src has been detected in TNBC and is strongly associated with tumor metastasis and poor prognosis. However, even after promising preclinical studies, Src inhibitors did not show major clinical advantage in unselected TNBC populations. We have previously published that metastatic TNBC has high energy-dependency to mitochondrial fatty acid beta-oxidation (FAO) and FAO activates Src by inducing autophosphorylation at Y419. However, our recent analysis suggests that as observed with the Src inhibitors, TNBC tumors treated with FAO inhibitors also develop drug-resistance and exhibit continuous tumor growth. Evaluation of their drug resistance mechanism revealed that while short-term inhibition of FAO or Src induces autophagic and apoptotic cell deaths, long-term inhibition results in autophagy-mediated drug resistance and survival. Further analyses suggest that FAO/Src inhibitors promote interferon regulatory factor 1 (IRF1) expression and activate mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway via the induction of cellular reactive oxygen species (ROS) in TNBC. Activated MEK/ERK then suppresses IRF1 expression and induces survival pathways for drug resistance and tumor survival. Validation of in vitro findings using in vivo TNBC models confirmed that combination of FAO/Src inhibitors with MEK/ERK inhibitor or ROS scavenger provide significant benefit to overcome the therapeutic resistance of TNBC. These findings open-up new therapeutic opportunities to manage TNBC patients with currently non-targetable metastatic tumors.

Citation Format: Kwanghwa Jung, Junhyoung Park, Tirupataiah Sirupangi, Dongya Jia, Nishant Gandhi, Shivanand Pudakalakatti, Jessica Elswood, Weston Porter, Nagireddy Putluri, Xiang H.-F Zhang, Xi Chen, Pratip K. Bhattacharya, Chad J. Creighton, Michael T. Lewis, Jeffrey M. Rosen, Lee-Jun C. Wong, Gokul M. Das, C. Kent Osborne, Mothaffar F Rimawi, Benny Abraham Kaipparettu. Autophagy-mediated survival mechanism to c-Src inhibitor therapy in triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-06-12.
Abstract P3-06-14: Inhibition of PRKCQ enhances chemosensitivity of triple negative breast cancer by regulating EMT and Bim
Authors: Irie Hanna Yoko , Byerly Jessica H. , Port Elisa R.
Published: March 2020

Background/Rationale: While some patients with triple negative breast cancer (TNBC) achieve long-term remission with standard-of-care chemotherapy, many have cancers that are chemotherapy resistant, putting them at risk for metastatic recurrence. There is also a lack of targeted therapies for TNBC, highlighting the need for novel therapeutic strategies for this subtype. PRKCQ, a member of the novel protein kinase C family, is preferentially expressed in TNBC compared to other breast cancer subtypes and we previously reported that PRKCQ expression is sufficient to promote oncogenic activities (growth-factor independent growth, anoikis resistance and migration). In addition, PRKCQ suppression inhibits growth of TNBC tumor xenografts. We sought to determine if PRKCQ expression modulation impacts sensitivity of triple negative breast cancer cells to standard of care chemotherapy and whether PRKCQ inhibition could be a strategy to enhance chemosensitivity of drug-resistant TNBC. Methods: We determined the effects of modulating PRKCQ expression, using PRKCQ cDNA or shRNA vectors, on sensitivity of TNBC cells to the apoptotic effects of standard-of-care chemotherapy, including those cancers that are relatively chemotherapy resistant at baseline. We also determined the mechanisms by which PRKCQ regulates sensitivity to chemotherapy. Results: Increased PRKCQ expression in non-transformed MCF-10A breast epithelial cells promotes resistance to the apoptosis-inducing effects of Doxorubicin or Paclitaxel treatment. These effects are dependent on PRKCQ kinase activity as a catalytically inactive PRKCQ failed to promote resistance. Downregulation of PRKCQ or inhibition of its kinase activity enhanced sensitivity of TNBC cells to chemotherapy. PRKCQ impacts chemotherapy sensitivity of TNBC by regulating epithelial-mesenchymal transition (EMT) and expression of Bim, a pro-apoptotic Bcl2 family protein. Conclusions. PRKCQ promotes resistance of TNBC to standard of care chemotherapies by promoting EMT and suppressing pro-apoptotic Bim. Inhibiting PRKCQ expression or activity sensitizes TNBC cells to chemotherapy and could be an effective strategy to overcome chemotherapy resistance of a subset of triple negative breast cancers, thereby improving patient outcomes.

Citation Format: Hanna Yoko Irie, Jessica H. Byerly, Elisa R. Port. Inhibition of PRKCQ enhances chemosensitivity of triple negative breast cancer by regulating EMT and Bim [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-06-14.
Abstract P3-07-11: BRCA mutations and association with discordance in a large oncotype database
Authors: Blanter Julia , Zimmerman Brittney , Tharakan Serena , Cascetta Krystal , Ru Meng , Tiersten Amy
Published: March 2020

BACKGROUND: BRCA mutated tumors have been shown to be associated with higher recurrence scores as compared to BRCA negative breast cancer patients. Prior studies have demonstrated 7-19% discordance between oncotype RS and tumor grade (TG) in breast cancer patients. We developed a large oncotype database to determine if BRCA mutation status is associated with discordance.

METHODS: We identified 723 patients (32 (4%) BRCA positive patients and 691 (96%) BRCA negative patients) with early-stage, hormone positive BC treated between 2006-2018, with tumor characteristics available for analysis.

Discordance was defined as one or two-step difference between RS (low, intermediate, high risk) and TG (well (WD), moderately (MD) and poorly (PD) differentiated).

BRCA status was defined as BRCA 1 deleterious mutation, BRCA 2 deleterious mutation, BRCA mutation of unknown type, BRCA variant of undetermined significance (VUS) or other mutation.

N(%) or median were used to describe patients’ characteristics between groups and compared by Mann-Whitney U test at the confidence level of 5%.

RESULTS: Among these patients, there were 32 patients (4% of total) who had any documented mutation or VUS. 16% had documented deleterious mutation in BRCA 1, 22% BRCA 2, 6% BRCA unknown type, 25% BRCA VUS, and 31% other VUS (most commonly CHEK2 and ATM).

Median RS was 23.5 in patients with deleterious BRCA mutations (1, 2 or unknown) vs. 16 in patients in the BRCA negative database which was statistically significant (p<0.01).

One step and two-step discordance was present in 46% and 8% respectively of patients with deleterious BRCA mutations vs. 53% and 11% respectively in the BRCA negative database.

CONCLUSIONS: Patients with deleterious BRCA mutations demonstrated no difference in rates of discordance as compared to BRCA negative patients. We further demonstrated that patients with BRCA positive tumors display higher recurrence scores than patients with BRCA negative tumors.

Citation Format: Julia Blanter, Brittney Zimmerman, Serena Tharakan, Krystal Cascetta, Meng Ru, Amy Tiersten. BRCA mutations and association with discordance in a large oncotype database [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-07-11.
Abstract P3-07-13: Neoadjuvant composite score as a prognostic marker in early and locally advanced triple negative breast cancer
Authors: Dubashi Biswajit , Kayal Smita , Matta Kirankumar , Thumaty Divya bala , Yadav Nisha , Kadambari D , ch Toi Pampa , Gunaseelan K , Ganesan Prasanth
Published: March 2020

Aim Triple negative subtype (TNBC) is an aggressive breast cancer with inferior survival. Pathological CR (pCR) is a good surrogate endpoint for survival among patients receiving neoadjuvant chemotherapy (NACT). We attempted to validate the composite score(CPS) (Jaccqueline et al, J Clin Oncol 26:246-252) combining clinical and pathological variables among TNBC patients receiving NACT at our center. Methodology Data of patients with TNBC who underwent NACT between January 2014 to July 2017 was retrospectively analysed. The composite CPS score included cTN stage and y pTN stage, and ranged from 0 to 4. This was calculated using an online software (http://www3.mdanderson.org/app/medcalc/index.cfm?pagename=bcnt). The scores obtained from the calculator was used to develop a risk grouping into low risk (0,1) and High risk (2,3,4). Overall survival (OS)and disease free survival (DFS) were calculated using the Kaplan-Meier method and differences was examined using the log rank test. Results Seventy-eight patients with TNBC [median age: 45 (24-75)] had received NACT (anthracyclines and taxanes). Early and locally advanced breast cancer constituted 17 (21.8 %) and 61 (78.2%) respectively and 22 (28.2 %) achieved pCR. After a median follow up of 28 months (5-62), 3-yr DFS and OS were 59% and 82% respectively for the entire population. The 3-yr DFS in low (n=18) and high risk (n=60) patients was 85.7% and 51.4% respectively (p=0.032). The 3-yr OS in the low and high risk was 93% and 79% respectively(p=0.28, NS). Conclusion Our study supports the use of the composite clinical pathological score (CPS) as a prognostic marker in patients with non-metastatic triple negative breast cancer. The risk stratification developed may help identify patients who may require additional adjuvant therapy.

Citation Format: Biswajit Dubashi, Smita Kayal, Kirankumar Matta, Divya bala Thumaty, Nisha Yadav, D Kadambari, Pampa ch Toi, K Gunaseelan, Prasanth Ganesan. Neoadjuvant composite score as a prognostic marker in early and locally advanced triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-07-13.
Abstract P3-08-19: Biomarkers associated with dcis related breast cancer death
Authors: Wadsten Charlotta , Hartman Johan , Fredriksson Irma , Garmo Hans , Wärnberg Fredrik , Sund Malin
Published: March 2020

Introduction In primary ductal carcinoma in situ of the breast (DCIS) tumour biological features associated with risk of invasive recurrence and metastasis may already be present at the pre-invasive stage. The aim of this study was to investigate the correlation of biological markers in DCIS and the risk of subsequent breast cancer death. Patients and methods A nested case-control study was conducted in a population based cohort of women diagnosed with primary DCIS between 1992 and 2012. Women who later died from breast cancer were identified. Four controls per case were selected randomly by incidence density sampling from the same cohort. Tumour blocks were retrieved for histopathological reevaluation and immunohistochemical analysis (IHC) of Oestrogen Receptor (ER), Progesterone Receptor (PR), Human Epidermal Growth Receptor 2 (HER2) and Ki67 expression. Odds ratios (OR) for risk of breast cancer death with 95% CI was calculated using conditional logistic regression. Results From a cohort of 6964 women with primary DCIS, tumour specimens were available for 66 patients who died from breast cancer and these were compared to samples from 195 controls. DCIS with intense lymphocytic infiltration was associated with an increased risk of breast cancer related death in univariate analysis (OR 2.25; 95%CI 1.02-4.99). None of the biomarkers were individually related to increased risk. In multivariable analysis and stepwise adjusting for age, tumour size and treatment; PR negativity in combination with lymphocytic infiltration (OR 4.40; 95%CI 1.20-16.14), PR negativity, lymphocytic infiltration and presence of comedonecrosis (OR 5.48; 95%CI 1.71-17.57) and the combination of PR negativity, lymphocytic infiltration, comedonecrosis and HER2 positivity (OR 7.54; 95%CI 2.00-28.43) were all independently associated with increased risk of breast cancer related death. Conclusion In the present study, the combination of PR negativity and periductal lymphocytic infiltration was associated with risk of breast cancer related death after primary DCIS. Combining biomarker expressions in DCIS with features in the peritumoural stroma may be useful tools for prognostication.

Citation Format: Charlotta Wadsten, Johan Hartman, Irma Fredriksson, Hans Garmo, Fredrik Wärnberg, Malin Sund. Biomarkers associated with dcis related breast cancer death [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-19.
Abstract P3-08-37: Dynamic and subtype-specific interactions between tumor burden and prognosis in breast cancer
Authors: Kim Hong-Kyu , Lee Sae Byul , Choi Yunhee , Ju Young Wook , Lee Han-Byoel , Han Wonshik , Noh Dong-Young , Lee Jong Won , Moon Hyeong-Gon , Choi Jihye
Published: March 2020

Purpose Recent updates of the AJCC staging system in breast cancer incorporated biologic characteristics along with the traditional anatomic tumor burden for outcome prediction. However, potential interactions between the prognostic effect of anatomic factors and the biologic characteristics are not reflected in the new system. In this study, we evaluated the interactions between the prognostic relevance of anatomic tumor burden and the molecular subtypes.

Methods From the Korean Breast Cancer Registry Database, we investigated the relationship between the prognostic importance of anatomic tumor burden and molecular subtypes in patients with invasive breast carcinoma who were treated between 1980 and 2014. Tumors were classified into four different molecular subtypes based on the hormonal receptor status and HER2 expression status. (1) HR+/HER2- subtypes; (2) HR+/HER2+ subtypes; (3) HR-/HER2+ subtypes; (4) HR-/HER2- subtypes.

Results Breast cancers with different molecular subtypes had unique outcome patterns in relation to anatomic tumor burden. In HR+/HER2+ and HR-/HER2- tumors, the increase in T stages exhibited profound rise in the hazard of death, while the presence of metastatic node was more important in HR+/HER2+ and HR-/HER2+ tumors in 131,178 Stage I to III breast cancer patients. The patterns for increasing risk of deaths along with tumor growth (per centimeter) and metastatic nodes (per one node) were examined in 67,038 patients with tumors 7cm or smaller and less than 8 metastatic nodes. HR+/HER2- and HR-/HER2- tumors showed persistent increase in risk of deaths as tumors grow while the effect was modest in HER2+ tumors. In contrast, the increased number of metastatic nodes was accompanied with persistent rise of risk in HR-/HER2+ tumors while the effect was minimal after 3 or 4 nodes in HR-/HER2- tumors. The interactions between the prognostic significance of anatomic tumor burden and molecular subtypes were statistically significant.

Conclusion Our data demonstrates that the prognostic implication of tumor growth and spread, measured by the increase in tumor size and number of metastatic nodes, shows significant association with the molecular subtypes of the breast cancer. Additionally, our data suggest that the association between the prognostic impact and the anatomic tumor burden is rather dynamic that linear within a specific molecular subtype.

Citation Format: Hong-Kyu Kim, Sae Byul Lee, Yunhee Choi, Young Wook Ju, Han-Byoel Lee, Wonshik Han, Dong-Young Noh, Jong Won Lee, Hyeong-Gon Moon, Jihye Choi. Dynamic and subtype-specific interactions between tumor burden and prognosis in breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-37.
Abstract P3-08-42: Disease-free survival prognostic signature in triple-negative breast cancer based on high-throughput proteomics data
Authors: Auñon Pilar Zamora , Adrián Silvia García , Trilla-Fuertes Lucia , Gámez-Pozo Angelo , Prado-Vázquez Guillermo , Zapater-Moros Andrea , Almirón Mariana Díaz- , Vacas Rocío López , Chiva Cristina , Chiva Cristina , Sabidó Eduard , Arranz Enrique Espinosa , Vara Juan Ángel Fresno
Published: March 2020

Introduction Triple negative breast cancer (TNBC) accounts for 15-20% of the breast cancer and is characterized by an aggressive phenotype and worst prognosis. TNBC does not benefit from any targeted therapy, so further characterization would be needed to define subgroups with potential therapeutic value. Material and methods 125 TNBC paraffin samples were analyzed using high-throughput proteomics based on SWATH-MS. Survival analyses and a prognostic predictor were done using BRB Array Tools. Proteins related with disease-free survival were established and, then, a prognostic signature was built based on their p-values. Results and discussion Using SWATH-MS, 1,206 proteins were identified in a cohort of 125 TNBC tumors. Of these 1,206 proteins, 29 proteins were related with disease-free survival. In addition, a prognostic signature based on the expression of two proteins, RMB3 and NIPSNAP1, was defined. The predictor split our population into a low-risk and a high-risk group (p=0.0002, HR= 6.519). Multivariate analysis showed that the prognostic signature based on the expression of these two proteins supplied significant information to the clinical parameters. Conclusion SWATH-MS proteomics demonstrates its utility in the analysis of TNBC paraffin samples. Moreover, this proteomics data allows us to build a prognostic signature based on the expression of two proteins (RBM3 and NIPSNAP1). This prognostic signature could be used in the future to identify a population with a high-risk of relapse that may be directed to a clinical trial.

Citation Format: Pilar Zamora Auñon, Silvia García Adrián, Lucia Trilla-Fuertes, Angelo Gámez-Pozo, Guillermo Prado-Vázquez, Andrea Zapater-Moros, Mariana Díaz- Almirón, Rocío López Vacas, Cristina Chiva, Cristina Chiva, Eduard Sabidó, Enrique Espinosa Arranz, Juan Ángel Fresno Vara. Disease-free survival prognostic signature in triple-negative breast cancer based on high-throughput proteomics data [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-42.