bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P3-05-08: Sortilin-related receptor regulates receptor tyrosine kinase traffic and signaling
Authors: Akhrass Hussein Al , Conway James , Barok Mark , Andersen Olav , Ivaska Johanna
Published: March 2020

Understanding the mechanisms of resistance to targeted therapies is a major challenge in epidermal growth factor receptor 2 (ERBB2)-amplified breast cancer and acquired resistance to ERBB2 inhibition is a common feature of recurrent tumors. In such a setting, the activation of intracellular oncogenic signaling pathways, through alternative growth factor receptors, adds a layer of complexity to therapeutic options. Our aim is to scrutinize the intracellular retrograde transport of ERBB-family receptors and to assess whether the key sorting proteins involved within this pathway represent a potential vulnerability in ERBB2-amplified breast cancer. Sortilin-related receptor (SorLA; SORL1) is a vacuolar protein sorting 10 (VPS10)-domain receptor well characterized for its role in Alzheimer’s and metabolic diseases. In a previous study, we demonstrated a previously unknown role of SorLA in cancer. SorLA increases ERBB2 stability by stimulating its recycling from endosomes back to the plasma membrane thus sustaining ERBB2 oncogenic signaling in vitro. In an orthotopic xenograft model, SorLA silencing inhibits tumor growth adding translational relevance for SorLA targeting in breast cancer. Here we investigate possible crosstalk inputs from other growth factor receptors, and we evaluate the potential of SorLA inhibition as a unique strategy to halt the progression of ERBB2-amplified tumors.

Citation Format: Hussein Al Akhrass, James Conway, Mark Barok, Olav Andersen, Johanna Ivaska. Sortilin-related receptor regulates receptor tyrosine kinase traffic and signaling [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 P3-05-08.
Abstract P3-07-09: The preoperative systemic inflammatory response as a strong prognostic factor in breast cancer patients
Authors: Yamashita Nami , Akiyoshi Sayuri , Sano Eiki , Shigechi Tomoko , Hisamatsu Yuichi , Tokunaga Eriko , Oki Eiji , Mori Masaki
Published: March 2020

Background: Recent reports show that the preoperative systemic inflammatory response status correlate with the survival rate in cancer patients. The Prognostic Nutritional Index (PNI), Controlling Nutritional Status (CONUT), Neutrophil Lymphocyte Ratio (NLR) and Platelet Lymphocyte Ratio (PLR) score are used as screening tools for immunonutritional status and reported to be a predictor of postoperative recurrence in patients with various gastrointestinal cancers. However, the clinical importance of these scoring in breast cancer has not been fully elucidated. The aim of this study is to investigate the clinical impact of preoperative systemic inflammatory response on long-term survival of breast cancer patients. Patients and Methods: We retrospectively analyzed 653 consecutive stage I-III breast cancer patients who were treated from January 2002 to December 2013. The PNI score was calculated as 10 x serum albumin (g/dl) + 0.005 x total lymphocyte count (per mm3). The CONUT score is calculated from three parameters, serum albumin, cholesterol, and total lymphocytes count. The patients were divided into two groups according to each value. The uni- and multivariate Cox regression analyses were performed to evaluate the prognositic value of the systemic inflammatory response in breast cancer. Results: The malnutritional or high SIR status was observed in 170 (26%),131 (20%), 119 (18%) and 226 (35%) patients as low-PNI, high-CONUT, elevated NLR and PLR, respectively. The relapse-free survival (RFS) and overall survival (OS) rates were significantly lower in the low-PNI group (RFS: p<0.0001, OS: p<0.0001) and high-CONUT group (RFS: p=0.0009, OS: p=0.0018). No significant association was found between NLR, PLR and prognosis. In the multivariate analysis, low-PNI was the independent prognostic factors for OS (HR4.71, p=0.0023). In the subset analysis, the low-PNI group showed poor prognosis especially in the postmenopausal, hormone receptor negative patients. The low-PNI also had poorer prognosis in post-recurrence survival. Conclusions: The preoperative systemic inflammatory response, especially PNI, is a strong independent predictor of long-term survival among breast cancer patients.

Citation Format: Nami Yamashita, Sayuri Akiyoshi, Eiki Sano, Tomoko Shigechi, Yuichi Hisamatsu, Eriko Tokunaga, Eiji Oki, Masaki Mori. The preoperative systemic inflammatory response as a strong prognostic factor 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 P3-07-09.
Abstract P3-08-39: Pathological complete response following neoadjuvant chemotherapy in operable breast cancer patients: Is obesity a predictive factor?
Authors: Wang Haiyun , Zhang Shijia , Yee Douglas , Beckwith Heather , Potter David , Blaes Anne
Published: March 2020

Background: Overweight and obesity are associated with greater disease-specific mortality and overall mortality in cancer patients. Neoadjuvant chemotherapy offers a unique setting to assess breast cancer chemosensitivity in vivo, and thus can help us understand why obesity is associated with poor prognosis in breast cancer patients. The effect of increased Body mass index (BMI) in breast cancer patients undergoing neoadjuvant chemotherapy remains controversial.

Purpose: To review and analyze the association between BMI and pathological complete response (pCR) rate for operable breast cancer after neoadjuvant chemotherapy (NACT).

Data sources: Pub Med and Cochrane Database to December 31, 2018

Study selection: We included observational studies and randomized trials that evaluated association of BMI with pCR in operable breast cancer patients that underwent NACT.

Data extraction and analysis: Two authors independently extracted data and rated study quality; discrepancies were resolved through consensus.

Results: We identified 13 studies including a total of 14179 women with operable breast cancer who underwent NACT. Among them, two studies were pooled analysis of prospective clinical trials (10622 patients); the rest were retrospective case control studies (3557 patients). The influence of categorical BMI on pCR after NACT was analyzed. All studies provided data with BMI divided into two subgroups (BMI <25 vs BMI ≥25). Pooled analyses demonstrated overweight/obese women were less likely to achieve pCR after NACT when compared with women in the under-/normal weight group, OR=0.77 (95% CI: 0.71, 0.84). 10 studies provided data with BMI divided into three groups (BMI <25, 25 ≤BMI< 30, BMI ≥30). Pooled analyses showed compared to under-/normal weight group, both overweight (OR= 0.81 95% CI: 0.72, 0.89) and obese (OR = 0.62 95% CI: 0.54, 0.69) groups were less likely to achieve pCR to NACT. We were not able to perform pooled analysis of association between BMI and pCR in subtypes of breast cancer based on hormone receptor and HER-2 status; as only two studies provided these data and breast cancer subtypes were defined differently. There was moderate heterogeneity in between these studies.

Conclusion: Overweight and obese breast cancer patients had lower pCR rates compared to those with under-/normal weight. Further prospective studies may help to confirm this finding and to clarify underlying mechanisms.

Citation Format: Haiyun Wang, Shijia Zhang, Douglas Yee, Heather Beckwith, David Potter, Anne Blaes. Pathological complete response following neoadjuvant chemotherapy in operable breast cancer patients: Is obesity a predictive factor? [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 P3-08-39.
Abstract P3-08-54: Pattern of hepatic metastasis as a prognostic index in breast cancer liver metastasis
Authors: Lee Jieun , Choi Moon Hyung , Lee Ahwon , Lee Sung Hak
Published: March 2020

Background Liver is one of a common site of metastasis in metastatic breast cancer, and associated with visceral crisis in breast cancer. The clinical course and prognosis of breast cancer with liver metastasis (BCLM) is quite different with other solid cancers presenting with liver metastasis. BCLM patients frequently develop hepatic failure due to liver metastasis, but there are no clinicopathologic or radiologic parameters estimating the prognosis of BCLM during their clinical course. In this study, we analyzed the relationship of radiologic, clinicopathologic characteristics and survival outcomes in BCLM patients. Methods Between January 2009 to May 2019, 156 BCLM patients were analyzed. Baseline and final abdomen CT scan or liver MRI during treatment was reviewed by experienced radiologist. The pattern of liver metastasis was classified as oligometasis (3 or less metastatic lesions), non-confluent mass formation, confluent mass formation, infiltrative and pseudocirrhosis pattern. Clinicopathologic characteristics including child-pugh score (CPS) and survival outcomes including liver metastasis associated overall survival (LMOS) was analyzed Results Among 156 patients, 77 patients were initially presented with oligometastasis, 58 patients with non-confluent mass-forming pattern, 14 patients with confluent mass formation, and 7 patients with infiltrative liver metastasis. Patients who showed liver metastasis at initial recurrence or metastasis showed confluent mass-forming (9 patients, 64.3%) or infiltrative liver metastasis (6 patients, 85.7%) as presentation. At patient’s death, initial confluent mass-forming or infiltrative liver metastasis patients showed hepatic dysfunction with CPS 2 or 3. Patients with oligometastasis showed superior LMOS compared to non-confluent mass-forming, confluent mass-forming and infiltrative liver metastasis with worst survival outcome (median LMOS 55.03 months vs. 36.87, 36.93 and 8.8 months, P=0.0021). In luminal B patients, radiologic liver metastasis pattern at patient’s death or last follow-up were associated to cause of patient’s death such as hepatic failure (P=0.044). There were no survival benefit of patients who received local treatment for liver metastasis, compared to patients who only received systemic chemotherapy. Conclusion Initial hepatic metastasis pattern were associated with LMOS, especially infiltrative liver metastasis associated to poor survival outcome. There were no survival benefit of local treatment of liver metastasis during follow-up. Authors are planning on subsequent analysis based on pathologic classification of liver metastasis.

Citation Format: Jieun Lee, Moon Hyung Choi, Ahwon Lee, Sung Hak Lee. Pattern of hepatic metastasis as a prognostic index in breast cancer liver 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 P3-08-54.
Abstract P3-08-61: The association of disease free survival and the impact of tumor subtype on overall survival in advanced breast cancer patients: A real-world study from the China National Cancer Center
Authors: Li Yiqun , Xu Binghe , Ma Fei , Li Qing , Zhang Pin , Yuan Peng , Wang Jiayu , Luo Yang , Cai Ruigang , Li Qiao , Mo Hongnan , Guan Xiuwen , Lin Shaoyan , Chen Yimeng , Wang Zijing
Published: March 2020

Objective: In breast cancer, tumor subtype and disease free survival (DFS) are correlated with prognosis. The aim of this study was to assess whether the effect of tumor subtype on survival was associated with DFS. Methods: The China National Cancer Center database was used to identify 1784 breast cancer women diagnosed between January 1987 to June 2017. Overall survival (OS) was defined as the time from first tumor recurrence or relapse to death due to any cause. Eligibility required metastatic patients with documented ER, PR, and HER2 status. Tumor subtype was classified into four groups: HR+HER2-, HR+HER2+, HR-HER2+ and triple negative breast cancer (TNBC) group. Results: In patients whose DFS < 2 years, we found significant differences between tumor subtype and OS (P=0.007), with HR+HER2- presenting most favorable survival while TNBC showing worst prognosis. A similar pattern was observed in patients whose DFS < 3, 4 and 5 years (all P<0.001). However, when disease recurrence occurred within 1 year, no differences in survival were observed among tumor subtypes (P=0.508). Subsequent first-line treatment analysis in the overall ‘DFS< 1 year’ group and the four subtype groups showed that combined chemotherapy did not significantly improve patient survival compared with single agent chemotherapy (all P> 0.1). Of note, if DFS was longer than five years, the impact of different tumor subtype on survival was not obvious (P=0.438). Conclusion: No survival differences were found among tumor subtypes when DFS was shorter than one year, indicating particularly poor prognosis even in the HR+HER2- subtype, possibly due to primary treatment resistance. Subsequent more intensive first-line treatment with combined chemotherapy might not help in prolonging survival.

Citation Format: Yiqun Li, Binghe Xu, Fei Ma, Qing Li, Pin Zhang, Peng Yuan, Jiayu Wang, Yang Luo, Ruigang Cai, Qiao Li, Hongnan Mo, Xiuwen Guan, Shaoyan Lin, Yimeng Chen, Zijing Wang. The association of disease free survival and the impact of tumor subtype on overall survival in advanced breast cancer patients: A real-world study from the China National Cancer Center [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 P3-08-61.
Abstract P3-11-19: Preclinical model of TNBC: Dasatinib attenuates Src pathway signaling and combined with veliparib and carboplatin potently inhibits tumor growth
Authors: Sun yuliang , Lin Xiaoqian , Aske Jennifer , Williams Casey , Abramovitz Mark , Leyland-Jones Brian
Published: March 2020

Background: The combination of a poly ADP ribose polymerase (PARP) inhibitor with a DNA-damaging agent has shown promise in treating triple-negative breast cancer (TNBC); however, not all patients respond to this combination. The Src protein kinase modulates multiple cancer cell properties and plays a key role in tumorigenic processes. However, Src inhibitors as single agents have shown limited effects in solid tumors. In this study, we examined the antitumor effects of the Src inhibitor dasatinib, the PARP inhibitor veliparib, and the DNA-damaging agent carboplatin in TNBC cells in vitro and tumors in vivo to try to identify the combination with the most clinical potential. Methods: The BRCA-mutated and PTEN null TNBC cell line, SUM149PT, was used in this study. For in vitro studies, proliferation, cellular apoptosis, and 3D on-top clonogenic growth were measured, tube formation assays and western blot analysis were performed. For in vivo studies, a xenograft model was used to examine treatment responses, and immunohistochemical analysis was performed. Results: Surprisingly, treatment with the combination of veliparib plus carboplatin led to an increase in Src phosphorylation. Importantly, addition of dasatinib attenuated Src overexpression induced by veliparib plus carboplatin and further inhibited the downstream signaling of Src, thereby enhancing the antitumor efficacy of veliparib plus carboplatin. In an SUM149PT xenograft model, the triple combination of dasatinib with veliparib plus carboplatin showed greater tumor growth inhibitory effects compared with single agents or double combinations. No systemic toxicity was observed in mice treated with the triple combination. Conclusion: Here, we provide novel evidence that veliparib combined with carboplatin drives Src activation in the preclinical model tested. Moreover, we provide provocative in vitro and in vivo data highlighting the potential for increasing therapeutic efficacy by combining dasatinib with veliparib and carboplatin in BRCA-mutated and PTEN null TNBC.

Citation Format: yuliang Sun, Xiaoqian Lin, Jennifer Aske, Casey Williams, Mark Abramovitz, Brian Leyland-Jones. Preclinical model of TNBC: Dasatinib attenuates Src pathway signaling and combined with veliparib and carboplatin potently inhibits tumor growth [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 P3-11-19.
Abstract P3-11-25: Real-world treatment patterns and clinical outcomes among women with HR+/HER2- advanced or metastatic breast cancer treated in real-world settings in Italy and Germany
Authors: De Laurentiis Michelino , Harbeck Nadia , Law Ernest , Ajmera Mayank , Mitra Debanjali , Davis Keith , Brucker Sara , De Placido Sabino
Published: March 2020

Background: Palbociclib is a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) that, when combined with an aromatase inhibitor (AI) or fulvestrant, has been shown in clinical trials to prolong progression-free survival (PFS) in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) advanced or metastatic breast cancer (ABC/MBC). This study sought to describe real-world treatment patterns and clinical outcomes among patients with HR+/HER2- ABC/MBC treated with palbociclib in clinical practice settings in Italy and Germany. Methods: MARIA is an ongoing non-interventional, prospective multi-center study that includes women in Italy and Germany initiating their first or second therapy in the HR+/HER2- ABC/mBC setting. Data from 67 sites were used to assess patient and treatment characteristics and progression-free survival (PFS) among patients receiving palbociclib in combination with AI or fulvestrant. Landmark PFS estimates at 6-, 12-, and 18-months were reported by line of therapy (first- and second-line). Results: Overall, 72 patients formed the interim analytic cohort. Among these, 63 (47%) and 9 (7%) received palbociclib + AI as first- and second-line therapy, respectively. Twenty-six (20%) and 37 (27%) of patients received palbociclib + fulvestrant as first- and second-line therapy, respectively. Approximately 96%, 78%, and 64% of patients receiving palbociclib + AI as first-line therapy were progression free at 6-, 12-, and 18-months, respectively. Among patients receiving palbociclib + fulvestrant as first-line therapy, 6-, 12-, and 18-month PFS was 91%, 64%, and 39%, respectively. For second-line therapy, 6-, 12-, and 18-month PFS was 75%, 38%, 38% among palbociclib + AI users and 71%, 54%, and 45% for palbociclib + fulvestrant. Conclusions: This interim analysis indicates that PFS among women with ABC/mBC HR+/HER2-negative breast cancer in Italy and Germany receiving palbociclib, in combination with letrozole or fulvestrant is comparable to published randomized clinical trial results and other real-world observational studies. Further follow-up is required for longitudinal analysis and to estimate overall survival. Funding: Pfizer

Citation Format: Michelino De Laurentiis, Nadia Harbeck, Ernest Law, Mayank Ajmera, Debanjali Mitra, Keith Davis, Sara Brucker, Sabino De Placido. Real-world treatment patterns and clinical outcomes among women with HR+/HER2- advanced or metastatic breast cancer treated in real-world settings in Italy and Germany [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 P3-11-25.
Abstract P4-01-06: Elacestrant (RAD1901) inhibits growth of ex vivo cultured circulating tumor cells derived from hormone receptor-positive metastatic breast cancer (mBC) patients including those harboring ESR1 mutations
Authors: Dubash Taronish Dorab , Bardia Aditya , Reeves Brittany A , Chirn Brian , Szabolcs Annamaria , Wittner Ben S , Iafrate John , Ting David , Patel Hitisha K , Bihani Teeru , Toner Mehmet , Haber Daniel A , Maheswaran Shyamala
Published: March 2020

Women with metastatic hormone receptor positive (HR+) breast cancer benefit from therapies targeting the Estrogen Receptor (ER), but the tumors eventually acquire resistance leading to disease progression. Endocrine resistance involves multiple mechanisms, including deregulation of ER signaling due to activating mutations in the ligand-binding domain of the ESR1 gene. In addition, recent reports describe specific contexts of ESR1 mutations in the preclinical setting where tamoxifen and fulvestrant have demonstrated limited activity. These data together with the frequency of ESR1 mutations (~20-60%) observed in mBC patients in the clinic suggest a need for more effective agents. The activity of elacestrant (RAD1901), an oral selective estrogen receptor degrader (SERD) with demonstrated activity against tumors harboring ESR1 mutations, both in preclinical models and in patients with previously treated advanced breast cancer, was assessed in ex vivo cultures of circulating tumor cells (CTCs) derived from women with metastatic HR+ breast cancer who had received multiple prior hormone therapies. Cultured breast CTCs underwent apoptosis following exposure to elacestrant, and CTCs harboring mutant ESR1 were significantly growth inhibited (IC50: 17.65 ± 3.32 nM) by elacestrant compared to the standard-of-care (SOC) agent fulvestrant. Furthermore, elacestrant eliminated the fulvestrant-resistant CTC populations in vitro. Elacestrant treatment led to significant suppression of ER target genes, PGR and GREB1. Elacestrant is currently being investigated versus standard of care endocrine monotherapy in a Phase 3 clinical trial (EMERALD) in patients with ER+/HER2- advanced/metastatic breast cancer. A co-primary endpoint of the EMERALD trial is evaluation of progression-free survival in patients whose tumors harbor ESR1 mutations.

Citation Format: Taronish Dorab Dubash, Aditya Bardia, Brittany A Reeves, Brian Chirn, Annamaria Szabolcs, Ben S Wittner, John Iafrate, David Ting, Hitisha K Patel, Teeru Bihani, Mehmet Toner, Daniel A Haber, Shyamala Maheswaran. Elacestrant (RAD1901) inhibits growth of ex vivo cultured circulating tumor cells derived from hormone receptor-positive metastatic breast cancer (mBC) patients including those harboring ESR1 mutations [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 P4-01-06.
Abstract P4-01-15: CTC with EMT phenotype are associated with PD-L1 expression in tumor associated stroma in primary breast cancer patients
Authors: Mego Michal , Kalavska Katarina , Karaba Marian , Minarik Gabriel , Benca Juraj , Sedlackova Tatiana , Manasova Denisa , Pindak Daniel , Mardiak Jozef , Cierna Zuzana
Published: March 2020

Background: Circulating tumor cells (CTCs) play role in tumor dissemination and are an independent survival predictor in breast cancer (BC) patients. PD-L1 is prognostic factor in BC and PD-L1 inhibitors prolonged survival in metastatic triple-negative breast cancer. The aim of this study was to assess correlation between CTCs and tumor PD-L1 in BC. Methods: This study included 299 primary BC patients treated by surgery from March 2012 to February 2015. Peripheral blood mononuclear cells (PBMC) were depleted of hematopoietic cells using RossetteSepTM negative selection kit. RNA extracted from CD45-depleted PBMC was interrogated for expression of EMT (TWIST1, SNAIL1, SLUG, ZEB1) and epithelial (CK19) gene transcripts by qRT-PCR. Patient samples with higher epithelial and/or mesenchymal gene transcripts than those of healthy donors (n=60) were considered as CTC positive. Expression of PD-L1 in surgical specimens was evaluated by immunohistochemistry and quantified by multiplicative score (proportion of cells with staining x intensity of staining). Results: CTCs were detected in 75 (25.1%) of patients. CTCs exhibiting only epithelial markers were present in 28 (9.4%) of patients, whereas CTCs with only EMT markers were observed in 53 (17.7%) of patients. In 6 patients, CTCs exhibit both epithelial and EMT markers. Patients with EMT_CTCs had significantly higher mean ± SEM score of PD-L1 expression in tumor associated stroma than those of patients without EMT_CTCs (2.66 ± 0.62 vs. 0.88 ± 0.29, p=0.048). There was no association between CTCs and PD-L1 expression in cancer cells including CTCs subtypes. Tumors without PD-L1 expression had significantly better disease-free survival compared to patients with PD-L1 expression (HR = 0.50, 95%CI 0.29 - 0.86, P = 0.001), however, this prognostic value was restricted to CTC positive subpopulation (HR = 0.24, 95%CI 0.10 - 0.56, P = 0.002), while, in CTC negative patients PD-L1 lack prognostic value (HR = 0.77, 95%CI 0.39 - 1.54, P = 0.45) Conclusion: Our data suggest link between PD-L1 expression in tumor associated stroma and CTCs with EMT phenotype and thus further support connection between immunosuppression and EMT. PD-L1 expression is prognostic only in patients with detectable CTC in peripheral blood suggesting different biology of tumors with detectable CTCs.

Citation Format: Michal Mego, Katarina Kalavska, Marian Karaba, Gabriel Minarik, Juraj Benca, Tatiana Sedlackova, Denisa Manasova, Daniel Pindak, Jozef Mardiak, Zuzana Cierna. CTC with EMT phenotype are associated with PD-L1 expression in tumor associated stroma in primary 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 P4-01-15.
Abstract P4-04-02: Epigenomic analysis of cancer stem cells (CSCs) from triple-negative breast cancer (TNBC) reveals p63 and p73 as core metastasis drivers
Authors: Lambert Arthur , Fiore Christopher , Chutake Yogesh , Verhaar Elisha , Chen Mei Wei , Donaher Joana , Reinhardt Ferenc , Engstrom Ian , Yuan Bingbing , Bierie Brian , Farouq Daneyal , Carulli John , Olson Eric , Guenther Matthew , Weinberg Robert
Published: March 2020

Cancer stem cells (CSCs) are key drivers of cancer metastasis, drug resistance, and disease recurrence. While the transcriptional regulatory circuitry that underlies the generation and propagation of the breast CSC state is not completely understood, defining the core regulators of the CSC state has the potential to reveal how these cells arise and point to potential targetable pathways for therapeutic intervention.

We isolated CSCs by selecting for surface expression of integrin β4 (ITGB4). ITGB4-hi cells are highly enriched for CSCs and display cellular and molecular features indicative of their residence in an intermediate EMT state, including the ability to seed metastasis in vivo. Using ITGB4-hi CSCs isolated from the SUM159 breast cancer cell line, we deployed epigenome mapping by H3K27ac ChIP-seq, nucleosome occupancy by ATAC-seq, and transcriptome analysis by RNA-seq. Using comparative analysis of enhancer usage and DNA accessibility, we identified the transcriptional regulatory circuitry of breast cancer CSCs and pinpointed the master transcription factors that control the CSC state.

We find that p63/p73 proteins function as master transcriptional regulators in breast CSCs and establish super-enhancers at critical CSC state genes. Loss of p63 and p73 disrupts the transcriptional circuitry of CSCs and leads to a highly mesenchymal state that is incompatible with metastatic colonization. Re-introduction of p63/p73 expression into non-CSCs leads to reactivation of the CSC transcriptional program and enables metastasis. These findings reveal the unique transcriptional circuitry of CSCs and suggest potential dependencies and pathways for therapeutic targeting of cells in the CSC state.

Citation Format: Arthur Lambert, Christopher Fiore, Yogesh Chutake, Elisha Verhaar, Mei Wei Chen, Joana Donaher, Ferenc Reinhardt, Ian Engstrom, Bingbing Yuan, Brian Bierie, Daneyal Farouq, John Carulli, Eric Olson, Matthew Guenther, Robert Weinberg. Epigenomic analysis of cancer stem cells (CSCs) from triple-negative breast cancer (TNBC) reveals p63 and p73 as core metastasis drivers [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 P4-04-02.
Abstract P4-05-17: ESR1 related chromothripsis enhances concordant gene transcription on chromosome 17q11.1-q24.1 in luminal breast cancer
Authors: Lin Chun-Lin
Published: March 2020

Chromothripsis is an event of genomic instability leading to complex chromosomal alterations in cancer. Although studies have proposed models to explain its initiation, few discussed how transcription factors (TFs) influence chromothripsis for tumor progression. Frequent long-range chromatin interactions between TFs and targets may promote extensive translocations and copy-number alterations in proximal contact regions through inappropriate DNA stitching. Herein we surveyed genomic alterations of chromosome 17 in 1,014 breast tumors in the Cancer Genome Atlas (TCGA) cohort and found five adjoining regions from 17q11.1 to 17q24.1 being hotspots of chromothripsis. Inter-/intra-chromosomal rearrangements of these regions occurred more frequently in ERα-positive tumors than in ERα-negative tumors. In addition, the rearrangement sites were often mapped within or close to dense estrogen receptor 1 (ESR1) sites localized on the regions or other chromosomes. This chromothriptic event was linked to concordant upregulation of 96 loci that predominantly regulate cell-cycle machineries in advanced luminal tumors. Genome-editing analysis confirmed that an ESR1 transcription hub localized on 20q13 coordinately regulates a subset of these loci localized on 17q23 through long-range chromosome interactions. One of these loci, Tousled Like Kinase 2 (TLK2) known to participate in DNA damage checkpoint control, is an actionable target using phenothiazine antipsychotics (PTZs). The antiproliferative effect of PTZs was prominent in high TLK2-expressing cells, compared to low expressing cells. Collectively, we identified a group of luminal breast tumors displaying 17q-related chromothripsis for which antipsychotics can be repurposed as treatment adjuncts.

Citation Format: Chun-Lin Lin. ESR1 related chromothripsis enhances concordant gene transcription on chromosome 17q11.1-q24.1 in luminal 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 P4-05-17.
Abstract P4-13-05: The oncological safety of autologous fat grafting after breast conserving surgery for breast cancer: A systematic review, meta- analysis and meta regression analysis of observational studies
Authors: Tayeh Salim , Carmichael Amtul R , Darr Humaa , Al-Fardan Zuhair , Kasem Abdul , Hamdi Moustapha , Mokbel Kefah
Published: March 2020

Background: Autologous fat grafting (AFG) has been widely adopted to correct deformities resulting from breast conserving surgery (BCS) for breast cancer. However, clinical and animal studies and in vitro experiments have revealed conflicting results regarding the oncological safety of AFG.

Aim: The aim of this study was to systematically evaluate the current literature regarding the oncological safety of AFG in patients who underwent BCS for breast cancer by performing a meta-analysis of observational studies.

Methods: A literature research was performed using the PubMed and Embase search engines from conception until May 2019 to identify all studies of patients who underwent AFG following BCS for breast cancer. Reference lists of retrieved articles and relevant previous reviews were also searched. The primary outcome was the locoregional recurrence rate. For case-control studies a standard meta-analysis was performed to calculate a pooled relative risk (RR). For case series studies, subgroup analysis and meta-regression techniques were used with historical control data to increase reliability.

Results: 26 studies reporting on 1640 BCS patients who had undergone AFG met the inclusion criteria for analysis. There were 11 case-control studies and 15 case series. For the case-controlled studies, meta-analysis using the random effects model revealed no significant difference in the locoregional recurrence rates between the AFG and control groups [RR=0.82(95% CI= 0.41-1.66)]. The mean follow up duration from surgery for the AFG group and the control group was 39 and 49 months, respectively. For the case series and historical controls, the locoregional recurrence rates were 1.85% and 2.53% respectively (p=0.33) according to subgroup and meta regression analysis. There was no strong evidence of publication bias however selection bias could not be excluded.

Conclusions: Our study suggests that AFG does not increase the risk of locoregional recurrence after BCS for breast cancer. However further prospective research is needed to confirm the oncological safety of this technique particularly in patients with high risk disease.

Citation Format: Salim Tayeh, Amtul R Carmichael, Humaa Darr, Zuhair Al-Fardan, Abdul Kasem, Moustapha Hamdi, Kefah Mokbel. The oncological safety of autologous fat grafting after breast conserving surgery for breast cancer: A systematic review, meta- analysis and meta regression analysis of observational studies [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 P4-13-05.
Abstract P5-05-05: Suppression of FOXM1 activities and breast cancer growth in vitro and in vivo by a new class of compounds
Authors: Katzenellenbogen Benita S. , Ziegler Yvonne , Laws Mary J , Guillen Valeria S. , Kim SungHoon , Dey Parama , Smith Brandi P. , Gong Ping , Bindman Noah , Zhao Yuechao , Carlson Kathryn , Yasuda Mayuri A. , Singh Divya , Li Zhong , El-Ashry Dorraya , Madak-Erdogan Zeynep , Katzenellenbogen John A.
Published: March 2020

The transcription factor FOXM1 is up-regulated and overexpressed in aggressive, therapy-resistant forms of hormone receptor-positive and triple negative breast cancers, and is associated with less good patient survival. FOXM1 signaling is also a key driver in many other cancers. Here, we identify a new class of compounds effective in suppressing FOXM1 activity in breast cancers, and displaying good potency for antitumor efficacy. The compounds bind directly to FOXM1 and alter its proteolytic sensitivity, reduce the cellular level of FOXM1 protein by a proteasome-dependent process, and suppress breast cancer cell proliferation and cell cycle progression and increase apoptosis. RNA-seq and gene set enrichment analyses indicate that the compounds decrease expression of FOXM1-regulated genes and suppress gene ontologies under FOXM1 regulation. Several compounds have favorable pharmacokinetic properties and show good tumor suppression in preclinical breast tumor models. These compounds may be suitable for further clinical evaluation in targeting aggressive breast cancers driven by FOXM1.

(Supported by Breast Cancer Research Foundation grant (BCRF-083 to BSK), The Julius and Mary Landfield Cancer Research Fund (to BSK), NIH grant R01 DK015556 (to JAK), NIH T32 GM070421 Fellowship (to VSG), Bankhead-Coley Foundation grant 09BW04 (to DEA), USDA award ILLU-698-909 and National Center for Supercomputing Applications Faculty Fellowship (to ZME), and UIUC Environmental Toxicology Scholarship (to BPS)).

Citation Format: Benita S. Katzenellenbogen, Yvonne Ziegler, Mary J Laws, Valeria S. Guillen, SungHoon Kim, Parama Dey, Brandi P. Smith, Ping Gong, Noah Bindman, Yuechao Zhao, Kathryn Carlson, Mayuri A. Yasuda, Divya Singh, Zhong Li, Dorraya El-Ashry, Zeynep Madak-Erdogan, John A. Katzenellenbogen. Suppression of FOXM1 activities and breast cancer growth in vitro and in vivo by a new class of compounds [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 P5-05-05.
Abstract P5-05-15: Activation of osteocytes connexin43 hemichannels suppresses breast cancer bone metastasis, a potential therapeutic target
Authors: Riquelme Manuel A. , Gu Sumin , Chavez Jeffery B. , An Zhiqiang , Jiang Jean X.
Published: March 2020

Bone is a fertile place for metastasized breast cancer cell (BCC), however, mechanical loading is reported to inhibit BCC growth. Osteocytes, representing over 95% of bone cells, are mechanosensitive; they coordinate bone remodeling and modulate the extracellular environment. Mechanical loading activates osteocityc connexin 43 (Cx43) hemichannels, which mediates communication between the intracellular and extracellular space with message of molecules below 1 kDa. We have shown that ATP released by osteocytic hemichannels through the activation of BCC P2X7 receptor, inhibits BCC growth and migration. Here, we evaluate if activation of Cx43 hemichannels in osteocytes plays a critical role in inhibiting breast cancer bone metastasis. Our lab develops a monoclonal antibody, MHC2, which binds to extracellular domain of Cx43 and increases the activity of osteocytic hemichannels. This antibody was immune-reactive in HeLa cells transfected with Cx43 and osteocytes cell line MLO-Y4. It also labeled mouse osteocytes in situ. MHC2 antibody enhanced the activity of Cx43 hemichannels in cells and in vivo osteocytes and promoted the ATP release from osteocytic MLO-Y4 cells. Moreover, conditioned media collected from MHC2-treated osteocytes reduced BCC migration in vitro. The weekly injection of MHC2 reduced the breast cancer growth in bone in WT mice, but not in specific osteocyte Cx43 knockout mice. MHC2 antibody increase levels of lymphocytes T cytotoxic (CD3+/CD8+) and helper (CD3+/CD4+) in tumor and draining lymph nodes. Moreover, the weekly injection of MHC2, in intracardiac injected tumor cells model, in both immunocompetent and immune-compromised mice increased survival rate and reduced tumor spreading. As is known, osteocytic Cx43 hemichannels are permeable to ATP. We showed that P2X7 specific agonist benzoyl ATP reduced in vitro breast cancer cell migration, increased cytoplasmic free Ca2+ and induced formation of tubulin bundles, an indicator of cytoskeleton reorganization. The effect of benzoyl ATP required activation of CamKII in breast cancer cells. Our results suggest that Cx43 hemichannels are likely a potential therapeutic target in treating breast cancer growth and metastasizing to the bone, probably through the enhancement of the extracellular ATP level and the activation of P2X7/CamKII axis.

Citation Format: Manuel A. Riquelme, Sumin Gu, Jeffery B. Chavez, Zhiqiang An, Jean X. Jiang. Activation of osteocytes connexin43 hemichannels suppresses breast cancer bone metastasis, a potential therapeutic target [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 P5-05-15.
Abstract P5-07-14: Chronic kidney disease in breast cancer treatment and survival
Authors: Hill Deirdre A , Argyropoulos Christos , Roumelioti Maria-Eleni , Unruh Mark
Published: March 2020

Background: Presence of chronic kidney disease (CKD Stages 3-5) prior to breast cancer diagnosis may increase the risk of mortality among women with invasive breast cancer. However, the evidence base is limited, and the magnitude of this mortality risk is unknown. Breast cancer therapy may also be altered by presence of CKD. We sought to understand the role of CKD in breast cancer survival, with particular attention to receipt of recommended treatment.

Methods: All women diagnosed with invasive breast cancer from 1992-2016 in 18 SEER-Medicare sites (age 66 or older; n= 168701) were evaluated for breast cancer-specific mortality (BCSM) using multivariate Cox models, with estimation of hazard ratios (HR) and 95% confidence intervals (CI). All analyses were adjusted for age, race/ethnicity, diagnosis year, tumor characteristics, and socioeconomic factors, and also for diabetes, myocardial infarction, and congestive heart failure prior to diagnosis. Separate analyses were run according to receipt vs non-receipt of standard of care for breast cancer treatment (defined according to National Comprehensive Cancer Network (NCCN) guidelines.

Results: Median follow-up was 63 months (26 months with CKD). Women with CKD were at increased risk of BCSM (CKD Stage 3: HR 1.2; 95% CI 1.0-1.5; CKD Stage 4 HR 1.7; 95% CI 1.3-2.2; CKD Stage 5/End Stage Renal Disease HR 1.5; 95% CI 1.1-2.1), compared to women without CKD. In analyses of any CKD, restricted to women who met NCCN guideline therapy recommendations, women had an elevated risk of BCSM regardless of whether they did (HR 1.6; 95% CI 1.1-2.1) or did not (HR 1.4; 95% CI 1.0-1.8) receive recommended chemotherapy, and whether they did (HR 1.6; 95% CI 1.1-2.3) or did not (HR 1.3; 95% CI 0.9-2.0) receive recommended radiotherapy.

Discussion: Women with CKD have an increased risk of breast cancer mortality regardless of receipt of guideline-based treatment. CKD is underascertained in Medicare claims data, thus the reported results (likely underestimates) will be presented with sensitivity analyses. CKD may influence breast cancer outcomes due to associated systemic inflammation and comorbid conditions, as well as release of soluble mediators such as cytokines, chemokines, growth factors, and factors involved in remodeling of the extracellular matrix and epithelial-mesenchymal transition. As such factors involved in CKD progression also influence cancer, increased understanding may provide clues to ameliorate adverse outcomes in both disease entities.

Citation Format: Deirdre A Hill, Christos Argyropoulos, Maria-Eleni Roumelioti, Mark Unruh. Chronic kidney disease in breast cancer treatment and survival [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 P5-07-14.
Abstract P5-08-19: The risk of breast, ovarian and endometrial cancer in obese women submitted to bariatric surgery: A meta-analysis
Authors: Ishihara Beatriz Pércia , Farah Daniela , Fonseca Marcelo Cunio Machado , Nazário Afonso Celso Pinto
Published: March 2020

Background: Obesity is related to major risk factors for a number of noncommunicable diseases including cancer. There is a high incidence of breast and endometrial cancer in obese women. Thus, we performed a systematic review followed by meta-analysis to evaluate the relationship between bariatric surgery, a method widely used to treat obesity, and the risk of developing breast, ovarian and endometrial cancer in obese women.

Methods: MEDLINE, EMBASE, LILACS and Cochrane databases were searched from inception until January 2019 which retrieve studies to assessed the risk of breast, ovarian and endometrial cancer in obese women submitted to bariatric surgery. There was no language restriction. We extracted and combined data from studies in order to assess the risk ratio (RR) of developing these cancers. A random-effects, meta-analytic model was applied in all calculations. The New Castle Ottawa and GRADE were used to assess quality and bias of the included studies. Trial registered in PROSPERO (CRD42019112927).

Results: We found 188 articles and only seven of those were included in our meta-analysis, which incorporated a total of 150,528 patients in the bariatric surgery arm and 1,461,938 women in the control arm. The total risk of developing breast, ovarian and endometrial cancer was 0.37 (95%CI [0.28 to 0.48]; I2=87%; 7 studies). The risk of breast cancer was reduced by 61% [RR: 0.39 (95%CI [0.24 to 0.64]; I2= 90%; 6 studies). The risk of ovarian cancer was reduced by 53% [RR: 0.47 (95%CI [0.27 to 0.81]; I2= 0%; 3 studies). The risk of endometrial cancer was reduced by 67% [RR: 0.33 (95%CI [0.21 to 0.51]; I2= 88%; 7 studies).

Conclusion: Bariatric surgery may have a protective effect by reducing the risk of developing breast, ovarian and endometrial cancer in obese women. However, high heterogeneity was found and not explained by our subgroup analysis. Although we couldn’t separate the types of surgeries performed, we hypothesized that the high heterogeneity might be due to the types of surgery. Therefore, we suggest more research with appropriate report of the type of the surgery by group.

Citation Format: Beatriz Pércia Ishihara, Daniela Farah, Marcelo Cunio Machado Fonseca, Afonso Celso Pinto Nazário. The risk of breast, ovarian and endometrial cancer in obese women submitted to bariatric surgery: A meta-analysis [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 P5-08-19.
Abstract P6-03-18: The accumulation of IGFBP-1 results in EGFR/MAPK activation and drives the development of tamoxifen resistance in breast cancer cells
Authors: Zheng Yan
Published: March 2020

Insulin-like growth factor (IGF) system plays a significantly role in cellular processes, including proliferation, survival, and mitogenesis. The IGF system consists of two soluble ligands, IGF-1 and IGF-2; two transmembrane receptors, IGF-1R and IGF-2R; and six high affinity IGF binding proteins, IGFBPs 1-6. Evidence shows that the IGF system is involved in breast cancer. For example, at least 50% of breast cancer tumors have elevated IGF-1R signaling; the level of circulating IGF-1 is found positively associated with the incident of estrogen receptor positive breast cancer. Tamoxifen, a selective estrogen receptor modulator and antagonist for estrogen receptor alpha (ERα) in breast tissue, is a commonly prescribed adjuvant treatment for patients presenting with ERα-positive breast cancer. However, tamoxifen resistance also occurs, and its exact mechanism is not well understood. Recently, we discovered that the accumulation of IGFBP-1 was stimulated by tamoxifen treatment, which subsequently prevented the activation of IGF-1R and inhibited the proliferation in MCF-7 cells. As a result, we hypothesized that the accumulation of IGFBP-1 due to the long-term tamoxifen exposure would result in tamoxifen resistance. In order to mimic the accumulation of IGFBP-1 after tamoxifen treatment, we employed MCF-7 and T-47D breast cancer cells to generate stable cell lines with IGFBP-1 overexpression. We found that the expression of IGF-1R was largely reduced in both MCF7-BP1 and T47D-BP1 cells, which was also observed in tamoxifen resistant MCF-7 and T-47D cells. Furthermore, we demonstrated that both MCF7-BP1 and T47D-BP1 were not responsive to tamoxifen, and epidermal growth factor receptor (EGFR) signaling pathway was significantly upregulated, as shown by higher levels of EGFR, phospho-EGFR (pEGFR), and phospho-Erk (pErk). Also, we found that the inhibition of Erk phosphorylation by MEK1 inhibitor PD98059 sensitized the stable cells to tamoxifen, showing that elevated pErk was protective against tamoxifen. Lastly, the transient knockdown of IGFBP-1 in MCF7-BP1 and T47D-BP1 resulted in significantly lower level of pErk and increased sensitivity to tamoxifen, further showing the role of IGFBP1 accumulation in the establishment of tamoxifen resistance and the activation of EGFR/MAPK pathway.

Citation Format: Yan Zheng. The accumulation of IGFBP-1 results in EGFR/MAPK activation and drives the development of tamoxifen resistance in breast cancer cells [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 P6-03-18.