bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P5-02-13: A novel detection technique for collagen (and other macromolecules) on H&E slides without special stains for improved cancer prognostics
Authors: Fereidouni Farzad , Borowsky Alexander D. , Levenson Richard M.
Published: March 2020

Background: Stromal density including the characterization of the type, abundance and alignment of collagen and other extracellular matrix (ECM) protein fibers in proximity to breast precancers and cancers has emerged as an important and evolving tool for understanding tumor progression and stratifying/classifying mortality risk. Standard methods for this evaluation including second harmonic generation (SHG) microscopy requires access to fresh or FFPE tissue samples of limited availability. In contrast, standard diagnostic H&E slides are more readily available for large retrospective and prospective studies. Methods: We developed a method for dual emission and transmission (DUET) microscopy that employs combined brightfield and fluorescence modalities, plus quantitative image analysis. The prototype instrument has whole-slide scanning capabilities for collagen detection and pixel-accurate alignment with conventional H&E-stained images. We have analyzed a retrospective cohort of 700 breast cancers with available outcome follow-up of greater than 5 years using this DUET method Results: DUET microscopy provides clear discrimination of collagen and ECM directly from standard H&E specimens, requiring only a few minutes to scan whole slides. Using the method, contrast enhancement similar to special staining techniques (e.g. trichrome, periodic acid Schiff’s, and picrosirius red stains). Image analysis from DUET directly corresponds to SHG data. DUET imaging discriminates between stroma surrounding invasive cancer and benign epithelium. DUET imaging of 700 breast cancers shows outcome correlation. Ongoing multivariate analysis comparing standard measures (grade, tumor infiltrating lymphocytes, tumor phenotype, etc.) to the DUET stromal score will be reported. Conclusions: DUET provides a straightforward, rapid and inexpensive approach for highlighting collagen distribution patterns on existing histology slides. This method should enable current research using improved quantitative tools, including AI-based, for correlation with patient outcomes, by enabling the use of standard and available H&E slides.

Citation Format: Farzad Fereidouni, Alexander D. Borowsky, Richard M. Levenson. A novel detection technique for collagen (and other macromolecules) on H&E slides without special stains for improved cancer prognostics [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 P5-02-13.
Abstract P5-02-14: The MAPK pathway is variably active across breast cancer subtypes, and increased activity may be associated with hormonal therapy resistance
Authors: Stolpe Anja van de , Holtzer Laurent , Wesseling-Rozendaal Yvonne , Verhaegh Wim
Published: March 2020

Background: Based on preclinical research, the MAPK growth factor pathway is thought to be an oncogenic pathway driving breast cancer, potentially in association with the ER pathway. In patients it is unclear how functional activity of the MAPK pathway activity relates to activity of the ER pathway to drive cancer growth. We have reported before on the development of assays, e.g. for the ER pathway, that enable quantitative measurement of activity of signal transduction pathways based on Bayesian computational model inference of pathway activity from measurements of mRNA levels of target genes of the ER transcription factor (Cancer Res., 2014, vol. 74, no. 11, pp. 2936-2945). We now present (1) development of the MAPK-AP1 pathway model, (2) MAPK-AP1 pathway activity and its relation to ER pathway activity in breast cancer; (3) emergence of MAPK pathway activity associated with hormonal therapy resistance. Methods: The MAPK-AP1 pathway model was developed and biologically validated on Affymetrix mRNA data from samples (different cell types) with a known MAPK pathway activity. MAPK-AP1 and ER pathway activity scores were measured on Affymetrix expression data of primary untreated breast cancer samples (GSE45827, n=141) and of fulvestrant sensitive and resistant MCF7 cell line clones (GSE74391). Results: In clinical breast cancer samples, average MAPK pathway activity was increased in all subtypes compared to normal breast tissue, with a large dynamic range indicating that in each subtype there are samples with high and with low pathway activity; ER pathway activity in Luminal A and B subtypes ranged from high to low, and was low in all other subtypes. MAPK-AP1 pathway activity did not correlate with ER pathway activity. Fulvestrant-sensitive MCF7 cells had high ER and low MAPK pathway activity scores, while resistant MCF7 clones exhibited increased MAPK pathway activity and complete loss of ER pathway activity, explaining therapy resistance. Discussion: The MAPK-AP1 pathway is frequently activated in all breast cancer subtypes, independent of ER pathway activity. We hypothesize that in case of resistance to hormonal therapy measurement of both pathway activities may be informative as to the underlying resistance mechanism, i.e. loss of ER pathway activity and/or gain of MAPK pathway activity. Future clinical studies are needed to confirm the role of these signaling pathways in hormonal resistance.

Citation Format: Anja van de Stolpe, Laurent Holtzer, Yvonne Wesseling-Rozendaal, Wim Verhaegh. The MAPK pathway is variably active across breast cancer subtypes, and increased activity may be associated with hormonal therapy resistance [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 P5-02-14.
Abstract P5-02-16: Is surgical excision of intraductal papillomas justified by the rate of upstaging to breast cancer?
Authors: Cotzia Paolo , Ozerdem Ugur , Lee Jiyon , Chun Jennifer , Kaplowitz Elianna , Schnabel Freya , Darvishian Farbod
Published: March 2020

Introduction: The management of intraductal papilloma (IDP) diagnosed on core needle biopsy (CNB) is controversial. Some investigators advocate surgical excision based on an upgrade risk of as high as 24%. Others contend that after adjusting for confounders, including size, clinical presentation, presence of other accompanying high-risk lesions and radiologic correlation, the upgrade risk may be as low as 2.3%. The implications for patient care would be the avoidance of invasive surgical procedures. The purpose of our study was to investigate the upgrade rate of IDP diagnosed on CNB to ductal carcinoma in situ (DCIS) and invasive carcinoma on subsequent surgical excision and the impact of associated high-risk borderline lesions and other clinicopathologic and radiologic variables.

Methods: Our institutional pathology database was queried for all women who had a CNB with a diagnosis of intraductal papilloma between 2005-2018. Two independent pathologists reviewed all the core biopsy slides and excisional biopsy slides. Variables of interest included clinical, imaging and pathologic characteristics. Statistical analyses included Pearson’s chi-square, Wilcoxon rank-sum and logistic regression.

Results: Out of 216 women, 19 (8.8%) upgraded to breast cancer (BC), including 14 (74%) DCIS and 5 (26%) invasive carcinoma. Out of 161 pure IDP without any atypia, 5 (3.1%) upgraded to BC and out of 45 IDP with atypical ductal hyperplasia (ADH), 13 (28.9%) upgraded to BC. Only one patient who upgraded to BC from IDP with ADH had a discordant finding on imaging. When we evaluated the clinicopathologic and radiologic variables associated with upgrading from pure IDP to BC on final pathology, we found that older age (>53 years) at time of biopsy (OR=1.05, 95%CI 1.01-1.09, p=0.027) and concomitant ipsilateral atypical ductal hyperplasia (ADH) (OR=9.69, 95%CI 3.37-27.81, p<0.0001) were associated with a BC upgrade. There was no significant association of upgrading to BC after having a concomitant ipsilateral or contralateral breast cancer.

Conclusions: Our results support surgical excision of IDP on CNB when associated with ADH or diagnosed in women older than 53 years of age. The upgrade rate of 3.1% for IDP without atypia on CNB in younger women does not justify a universal recommendation for routine surgical excision.

Citation Format: Paolo Cotzia, Ugur Ozerdem, Jiyon Lee, Jennifer Chun, Elianna Kaplowitz, Freya Schnabel, Farbod Darvishian. Is surgical excision of intraductal papillomas justified by the rate of upstaging to 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 P5-02-16.
Abstract P5-03-09: Multigene panel analysis in breast and ovarian cancer
Authors: Trapp Elisabeth Katharina , Speicher Michael , Geigl Jochen B , Kolovetsiou-Kreiner Vassiliki , Reisinger Julia , Haas Josef , Petru Edgar , Tamussino Karl , Pristauz Gunda
Published: March 2020

Background: Genetic testing is of prognostic and predictive importance in patients with ovarian cancer and breast cancer. The best explored mutations are those of the BRCA 1 and BRCA2 genes, and the result of BRCA testing impacts treatment and prophylactic options. Data on other breast-cancer-associated genes are accumulating. Methods: All patients who underwent genetic counseling and testing for BRCA 1 and BRCA 2 between 2007 and 2019 at the Medical University of Graz were reviewed. If BRCA testing was negative patients were offered panel testing for other breast and ovarian cancer associated genes including ATM, PETEN, RAD50, RAD51D, RAD51C, TP53, STK11, ATM, NBN, CDH, MSH6, MSH2, MLH1, CHEK2, PALB2, BRIP1, SMO, PETEN, SMO. Results: In total 1905 patients were counseled for genetic testing between 2007 to 2019. In 292 patients (mean age 53yrs) panel gene testing was performed. 114 (39%) of these 292 BRCA-negative patients (55 with breast cancer, 24 with ovarian cancer) had a pathogenic variant (n=32) or a mutation of unknown significance (n=82). The most common pathogenic variant occurred in the CHEK2 gene (n=15). Interpretation: In this series approximately one third of high-risk patients who tested negative for a BRCA mutation had a mutation of unknown significance and/or pathogenic mutation in gene panel testing. This indicates that genetic panel testing should be considered more frequently.

Citation Format: Elisabeth Katharina Trapp, Michael Speicher, Jochen B Geigl, Vassiliki Kolovetsiou-Kreiner, Julia Reisinger, Josef Haas, Edgar Petru, Karl Tamussino, Gunda Pristauz. Multigene panel analysis in breast and ovarian 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 P5-03-09.
Abstract P5-03-11: Germline and somatic variants in patients with inflammatory breast cancer (IBC) detected using cell-free DNA
Authors: Winn Jennifer S. , Hasse Zachary , Pei Jianming , Slifker Michael , Arisi-Fernandez Sebastian M. , Talarchek Jacqueline N. , Obeid Elias , Devarajan Karthik , Wu Hong , Gong Yulan , Cristofanilli Massimo , Alpaugh R.Katherine , Fernandez Sandra Viviana
Published: March 2020

In order to better understand the etiology of inflammatory breast cancer (IBC), we performed a retrospective study to evaluate genomic alterations in 32 IBC patients using circulating DNA from blood. In 20 patients, mutation analyses were also conducted on tumor tissue or tumor cells from pleural effusions; in 15 of these patients, blood and tissue or pleural effusions were collected at the same time. Next generation sequencing (NGS) and a panel of 93 breast cancer related genes (Qiagen) were used for these studies. We found that of the 32 total patients, 11 (34.4%) carried at least one putative pathogenic germline variant, and another 8 patients (25%) carried at least one likely pathogenic germline variant. Ten patients (31.3%) carried only germline variants of uncertain significance and in 3 patients (9.4%) germline variants were not detected. Putative germline pathogenic variants were observed in the BRCA2 (2/32), TP53 (2/32), BRCA1 (1/32), PALB2 (1/32), CHEK2 (1/32), ATM (1/32), PMS1 (1/32), MUTYH (1/32), and MSH2 (1/32) genes. In addition, putative germline likely pathogenic variants were observed in the BARD1 (10/32), RB1 (2/32), APC (1/32), FANCC (1/32), AR (1/32), RAD51C (1/32), RAD51D (1/32) and CASP8 (1/32) genes. Most of the patients in our study had a family history of cancer and seventeen of the patients (53.1%) had family history of breast cancer in particular. Of those patients, 7 had a family history of breast cancer at a young age (<45 years old). Other cancer in their families included prostate (28.1%), colon (28.1%) and skin cancer (12.5%). Somatic variants, pathogenic or likely pathogenic, were detected in: TP53, PTEN, MRE11, PMS2, RB1, AR, KMT2C, PIK3CA and BRCA1. These results suggest a high incidence of germline variants in patients with IBC that could be associated with an increased risk of developing the disease. This data, if validated in a larger cohort, would demonstrate the power that genomic analysis has to identify women at high-risk of developing IBC and who would benefit from early screening.

Citation Format: Jennifer S. Winn, Zachary Hasse, Jianming Pei, Michael Slifker, Sebastian M. Arisi-Fernandez, Jacqueline N. Talarchek, Elias Obeid, Karthik Devarajan, Hong Wu, Yulan Gong, Massimo Cristofanilli, R.Katherine Alpaugh, Sandra Viviana Fernandez. Germline and somatic variants in patients with inflammatory breast cancer (IBC) detected using cell-free DNA [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 P5-03-11.
Abstract P5-04-21: Analysis of serum immune biomarkers for response to therapeutic personalized peptide vaccination in patients with metastatic breast cancer
Authors: Toh Uhi , Saku Shuko , Takao Yuko , Sakurai Sayaka , Takenaka Miki , Shichijo Shigeki , Itoh Kyogo , Akagi Yoshito
Published: March 2020

Purpose: Our results from the previous clinical trials using personalized peptide vaccines (PPV) combined conventional chemo-hormonal therapies have confirmed the potential for clinical benefit in patients who had higher IgG antibody and/or CTL response to the immunized PPV (SABCS 2018 U Toh etc.). The aim of this study is to evaluate the association between the serum immunologic factors including cytokines, haptoglobin (HP), B-cell activating factor (BAFF) etc. and the clinical outcome of patients(pt) with metastatic breast cancer (mBC) who treated by personalized peptide vaccines (PPV). Methods: Peripheral blood samples from 57 pts and 52 pts obtained before and after the vaccination of PPV, respectively. Serum HP and IL-6 were analyzed by ELISA(R&D Systems, Life Technologies)and bead-based multiplex assays(Luminex 200 system)were performed for GM-CSF,IFN-γ,TNF-α, BAFF, TGF-β, IFNγ-induced protein 10(IP-10), IL-1β, IL-2,-4,-5,-8, -10. The association between each factor and clinical outcome was statistically evaluated. Results: Pt’s group (n=28) with low BAFF and high HP level (>544 pg/ml), high IFN-γ and high HP level or low IL-8 and high HP level before PPV treatment showed a significantly shorter median survival time (MST; p=0.015;0.068;0.002, respectively). There was no difference in high BAFF, low IFN-γ or high IL-8 level group(n=29). In contrast, pt’s group with low serum level of IL-10, GM-CSF, IL-5, IL-4 and low HP level (<544 pg/ml MV) after PPV treatment associated with significantly shorter MST (p=0.002; 0.001; 0.001; <0.001, respectively). Conclusions: The combination of serum levels of HP and BAFF, IFN-γ or cytokines of IL-8, -10, - 5, -4 might be useful prognostic biomarkers for mBC pts receiving PPV therapy.

Citation Format: Uhi Toh, Shuko Saku, Yuko Takao, Sayaka Sakurai, Miki Takenaka, Shigeki Shichijo, Kyogo Itoh, Yoshito Akagi. Analysis of serum immune biomarkers for response to therapeutic personalized peptide vaccination in patients with metastatic 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 P5-04-21.
Abstract P5-05-09: Chemo-sensitization of triple negative breast cancer by targeting RNA-binding protein HuR
Authors: Wu Xiaoqing , Wei Lanjing , Gardashova Gulhumay , Zhong Cuncong , Lan Lan , Zhang Qi , Dixon Dan A , Welch Danny R , Aubé Jeffrey , Xu Liang
Published: March 2020

Triple negative breast cancer (TNBC) has a lower 5-year survival rate and higher recurrence rate compared to other types of breast cancer, which is partially due to the acquired resistance to current treatment regimens. The RNA-binding protein Hu antigen R (HuR) is overexpressed in breast cancer. Cytoplasmic HuR accumulation correlates with high-grade malignancy, poor distant disease-free survival and serves as a prognostic factor for poor clinical outcome in breast cancer. HuR promotes tumorigenesis by promoting mRNA stability and translation of proteins implicated in proliferation, survival, angiogenesis, invasion, and metastasis. HuR also modulates sensitivity of breast cancer cells to chemotherapy. HuR knockout in TNBC cells with high HuR sensitizes them to chemotherapy while HuR overexpression induces chemo-resistance. Meanwhile, chemotherapy promotes cytoplasmic HuR accumulation and increases expression of HuR target encoding proteins in TNBC cells. Therefore, there is a positive feedback loop between HuR and chemo-resistance. These findings suggest that HuR plays a critical role in promoting a drug-resistance mechanism and HuR is a potential target for developing a novel therapy to overcome chemo-resistance in TNBC. RNA-binding proteins such as HuR had previously been considered to be “undruggable” due to the lack of a well-defined binding pocket for target RNAs. Nevertheless, using high throughput screening followed by structure-based rational design and lead optimization, we have identified small molecules that potently inhibit HuR-mRNA interaction with nM to sub-µM potency. Our top HuR inhibitor, KH-3, inhibits TNBC cell growth in vitro and in vivo. KH-3 also sensitizes TNBC cells to docetaxel and doxorubicin treatment in vitro. Furthermore, acquired docetaxel-resistant MDA-MB-231 cells and doxorubicin-resistant MDA-MB-231 cells display similar sensitivity to KH-3 to their parental cells. In the study of mechanism of action, several HuR direct targets are found to be involved in acquired docetaxel and doxorubicin resistance. KH-3 can disrupt the interaction of HuR with those target mRNAs. In animal efficacy studies, the combination of KH-3 and chemotherapy shows synergistic effect in both parental and acquired resistant cell xenograft models. Our data provide a proof-of-principle that HuR inhibition by KH-3 may be developed as a promising molecular therapy to overcome chemo-resistance of TNBC with high HuR.

Citation Format: Xiaoqing Wu, Lanjing Wei, Gulhumay Gardashova, Cuncong Zhong, Lan Lan, Qi Zhang, Dan A Dixon, Danny R Welch, Jeffrey Aubé, Liang Xu. Chemo-sensitization of triple negative breast cancer by targeting RNA-binding protein HuR [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 P5-05-09.
Abstract P5-05-11: Novel small molecule STAT3 inhibitors induce apoptosis and suppress cell migration and tumor growth in triple-negative breast cancer cells
Authors: Pan Li , Chen Xiang , Fu Shengling , Li Chenglong , Lo Hui-Wen , Lin Jiayuh
Published: March 2020

Persistent STAT3 signaling is frequently detected in many cancer types and thus could potentially serve as a viable therapeutic target. In this study, we tested two novel small STAT3 inhibitors, LLY17 and LLL12B in triple-negative breast cancer cells, which frequently express persistent STAT3 phosphorylation. LLY17 and LLL12B selectively inhibited IL-6-mediated induction of STAT3 phosphorylation but no effect on IFN-γ mediated induction of STAT1 phosphorylation. LLY17 and LLL12B induced apoptosis in triple-negative breast cancer cells but exhibited minimal toxicity toward normal mammary epithelial cells. RNAi attenuation experiments confirmed the requirement of STAT3 for LLY17 and LLL12B-mediated inhibition of cell viability in triple-negative breast cancer cells. LLY17 and LLL12B inhibited STAT3 phosphorylation in human and murine triple-negative breast cancer cells. In addition, LLY17 and LLL12B inhibited cell migration of human and murine triple-negative breast cancer cells. Furthermore, LLY17 and LLL12B suppressed tumor growth and STAT3 phosphorylation of triple-negative breast cancer cells in vivo in a mammary fat pad murine syngeneic mouse model. Together, our findings suggest that targeting persistent STAT3 signaling pathway by novel oral bioavailable small molecules LLY17 and LLL12B may be a potential approach for the therapy of triple-negative breast cancer.

Citation Format: Li Pan, Xiang Chen, Shengling Fu, Chenglong Li, Hui-Wen Lo, Jiayuh Lin. Novel small molecule STAT3 inhibitors induce apoptosis and suppress cell migration and tumor growth in triple-negative 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 P5-05-11.
Abstract P5-05-13: Inhibition of NOTCH signaing with g-secretase inhibitor AL101 contributes to overcome resistance against HER2-targeted therapy in HER2 amplified breast cancer cells
Authors: Nakad Bothaina , Broner Esther Channah , Sidransky David , Izumchenko Evgeny
Published: March 2020

Notch signaling affects multiple cellular processes including stem cell maintenance, differentiation, proliferation, motility and survival. Activated NOTCH signaling and up-regulation of tumor-promoting NOTCH target genes are well documented in human breast cancer. Growing evidence suggest the novel role of NOTCH pathway as a survival resistance mechanism against HER2-targeted therapy in the HER2 amplified breast cancer subgroup, accounting for 20% of breast cancers. It was reported that tumor cells that develop intrinsic or acquired resistance to HER2 targeted therapy (at either relapse of the dormant resistant cells or at the progression of HER2 disease), express higher levels of NOTCH pathway genes. The small molecule AL101 is an γ-secretase inhibitor that potently inhibits the activation of all 4 NOTCH receptors (NOTCH1-4). We hypothesize that treatment with AL101, could potentially block activation of this intrinsic resistance mechanism and/or inhibit the acquisition of the acquired resistance. The goal of this study is: (a) to test the efficacy of first line treatment of anti-HER2 drugs combined with AL101, and (b) to test the efficacy of the AL101 as a second line therapy for anti-HER2 resistance breast cancer cells lines. Our study demonstrates the potential utility of HER2-targeted therapy in combination with AL101 as a novel strategy for overcoming the NOTCH signaling induced survival resistance mechanism in HER2 amplified breast cancer cells, and suggests NOTCH inhibitors as potential second-line therapy for recurrent or resistant HER2 amplified breast cancer tumors.

Citation Format: Bothaina Nakad, Esther Channah Broner, David Sidransky, Evgeny Izumchenko. Inhibition of NOTCH signaing with g-secretase inhibitor AL101 contributes to overcome resistance against HER2-targeted therapy in HER2 amplified 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 P5-05-13.
Abstract P5-05-16: Quantitative regression of estrogen receptor alpha positive breast cancer
Authors: Boudreau Matthew W , Hergenrother Paul J , Duraki Darjan , Wang Lawrence , Mao Chengjian , Park Ben H , Fan Tim M , Nelson Eric R , Shapiro David J , Moreno Ramon , Bruckheimer Elizabeth , Kiefer Jeffrey , Tarasow Theodore M
Published: March 2020

Treatment of advanced ERα-positive breast cancer remains a major clinical challenge, as the standard therapeutics are mostly cytostatic agents, ultimately leading to drug resistance. Resistant ERα-positive tumors typically retain ERα expression, suggesting an opportunity to develop new therapeutics that move beyond inhibition of this nuclear receptor. Through a medicinal chemistry campaign, we have discovered an estrogen receptor selective activator, the compound ErSO, that – in stark contrast to current ERα modulators – potently kills ERα-positive breast cancer cells. ErSO is effective even against breast cancer cell lines with known mutations in ERα that confer drug resistance. ErSO hyperactivates the anticipatory unfolded protein response, leading to quantitative cell death. ErSO is well-tolerated in mice, orally bioavailable, blood-brain-barrier penetrant. Using sensitive tumor imaging, ErSO often leads to quantitative tumor eradication (without recurrence) in multiple mouse models of ERα-positive breast cancer, including those utilizing breast cancer cell lines harboring mutant ERα. This potent activity against advanced primary and metastatic ERα-positive breast cancers represents a paradigm shift in leveraging of ERα for anticancer efficacy.

Citation Format: Matthew W Boudreau, Paul J Hergenrother, Darjan Duraki, Lawrence Wang, Chengjian Mao, Ben H Park, Tim M Fan, Eric R Nelson, David J Shapiro, Ramon Moreno, Elizabeth Bruckheimer, Jeffrey Kiefer, Theodore M Tarasow. Quantitative regression of estrogen receptor alpha positive 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 P5-05-16.
Abstract P5-08-08: Risk reducing mastectomy in average and high risk patients with locally advanced triple negative breast cancer
Authors: Stjepanovic Neda , Giffoni Danilo , Gandhi Sonal , Jerzak Katarzyna , Lemon Sharon , Ott Karen , Pezo Rossanna , Pritchard Kathleen , Tabbarah Samuel , Trudeau Maureen , Warner Ellen , Tran William , Eisen Andrea
Published: March 2020

Background: Women with locally advanced triple negative breast cancer (LA-TNBC) have a high risk of disease recurrence and are monitored clinically and with annual mammograms. High risk women, such as BRCA1/2 carriers, are additionally monitored for second primary breast cancers (BC) with annual MRIs and may opt for risk reducing mastectomy (RRM) as a prophylactic measure. Our aim was to explore the clinical outcomes of patients (pts) with average BC risk and high BC risk (known BRCA1/2 carriers) who undergo RRM at the time of LA-TNBC diagnosis.

Methods: We included 78 consecutive LA-TNBC pts, stages IIB and III, with resectable unilateral disease, treated at the Sunnybrook Health Sciences Centre from 2009 to 2018. Pts who did not undergo systemic chemotherapy and surgical treatment were excluded, as well as pts with a history of prior BC. Medical records were reviewed for clinical outcomes, pathology and germline BRCA1/2 testing results. Log rank test was used to determine the time to recurrence (TTR) and overall survival (OS) differences among women who underwent RRM and those who did not.

Results: Median age at diagnosis of LA-TNBC was 49 years (range 27-82) and 14 (18%) pts were BRCA1/2 carriers. All pts underwent neoadjuvant chemotherapy with 27 (35%) presenting complete pathological response. Fifteen pts underwent RRM, out of which seven were BRCA1/2 carriers. Mean follow up time was 34 (2-86) months, during which 25 pts (32%) were diagnosed with distant disease recurrence and none with second primary BC. Median TTR was 10 months (range 1-48) and median OS was 18 months (range 2-86). RRM was not associated with TTR (p=0.45) and OS (p=0.98). Presence of germline BRCA1/2 also did not correlate with TTR (p=0.16) and OS (p=0.21).

Conclusions: In our cohort of pts with LA-TNBC, the prognosis was driven by the risk of recurrence rather than the risk of second primary BCs. RRM was not associated with improved clinical outcomes, regardless the BRCA1/2 status and larger studies are required to support this procedure at the time of diagnosis of LA-TNBC.

Citation Format: Neda Stjepanovic, Danilo Giffoni, Sonal Gandhi, Katarzyna Jerzak, Sharon Lemon, Karen Ott, Rossanna Pezo, Kathleen Pritchard, Samuel Tabbarah, Maureen Trudeau, Ellen Warner, William Tran, Andrea Eisen. Risk reducing mastectomy in average and high risk patients with 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 P5-08-08.
Abstract P5-08-22: Associations between MYC alterations and clinical pathological characteristics in Chinese patients and TCGA cohort
Authors: Cao Li , Zhang Guochun , Wang Yulei , Chen Bo , Ren Chongyang , Wen Lingzhu , Guo Liping , Li Kai , Jia Minghan , Liao Ning
Published: March 2020

Background MYC is frequently amplified and its amplification is associated with poor prognosis in breast cancer patients. This study aimed to determine the prevalence of MYC alterations from Chinese patients, the correlations between MYC amplification and clinicopathological characteristics, as well as its impacts on patient outcomes in breast cancer patients.

Methods We analyzed 412 cases of breast cancer specimens in Guangdong Provincial People's Hospital (GDPH) for MYC alterations from June 1, 2017 to September 27, 2018, using next generation sequencing. The associations between MYC amplification and clinicopathological characteristics were determined using chi square. We further compared the our results with those from The Cancer Genome Atlas (TCGA) cohort (n=1079). Kaplan-Meier curves were drawn to determine the impacts of MYC amplification on patient outcomes.

Results MYC was amplified in 12.44% (51/410) in GDPH cohort and the mean copy number of our cohort was 4.42 (2.84-11.27), while the frequency of MYC amplification in TCGA cohort was much higher (21.22%, 229/1079). Except that, we also found two fusions. Among these, one was RTFDC1-MYC fusion (AF=1.62%) and the other was PVT1-MYC fusion (AF=3.33%). The case with PVT1-MYC fusion was also found to have PVT1-MYC co-amplification concurrently. In TCGA cohort, we found MYC amplification to be associated with age (P=0.047), tumor type (P=0.000), ER status (P=0.000), PR status (P=0.000), HER2 status (P=0.008) and molecular subtype (P=0.000). Whereas, except for molecular subtype (P=0.028), we only found MYC amplification to be associated with tumor size (P=0.023) and Ki-67 (P=0.031) in GDPH cohort. According to the survival information from TCGA, patients with MYC amplification had significantly inferior overall survival (OS) in both triple negative breast cancer (TNBC) (P=0.02) and HR+/HER2+ breast cancer patients (P=0.03).

Conclusions This study evaluated the differences of MYC mutations in Chinese and and TCGA cohort breast cancer patients. Except for MYC amplification, we found two rare fusions. Results showed MYC amplified less frequently in Chinese patients and was associated with inferior OS in both TNBC and HR+/HER2+ breast cancer patients. We suggest further research with expand the sample size is necessary to draw the ethnical differences of MYC mutations.

Citation Format: Li Cao, Guochun Zhang, Yulei Wang, Bo Chen, Chongyang Ren, Lingzhu Wen, Liping Guo, Kai Li, Minghan Jia, Ning Liao. Associations between MYC alterations and clinical pathological characteristics in Chinese patients and TCGA cohort [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 P5-08-22.
Abstract P5-08-24: Impaired glucose tolerance decreases mammographic breast density in Japanese women
Authors: Uchida Ken , Kitano Naruki , Yamaguchi Daisuke , Nogi Hiroko , Kamio Makiko , Takeyama Hiroshi
Published: March 2020

Background; Many studies have demonstrated an association between diabetes and breast cancer risk. Purpose; We examined whether fasting glucose and hemoglobin A1c (HbA1c) are associated with mammographic breast density in Japanese women. Methods; Study consisted of 6,203 women who attend breast cancer screening with the medical health check-up (2014-2019). We used mammographic breast density assessed at the first breast screening. Fasting serum glucose and HbA1c were examined at the same day on the breast cancer screening. The association between breast density and fasting serum glucose and HbA1c were analyzed by logistic regression adjusted for potential confounding factors. Serum glucose and HbA1c levels were calculated with continuous variables. BI-RADS c and d were defined as dense breast tissue. Results; Of 6,203 women with mean age of 51 years, dense breast tissue was present in 60.0 % of participants. 960 (15.1%) had hyper-glycemia (≥100) and 2,830 (45.62%) had hyper-HbA1c (>5.5%). As table 1 illustrates, hyper-glycemia and hyper-HbA1c were significantly inversely associated with dense breast tissue, (serum glucose: odds ratio; 0.987 confidence interval: 0.982-0.992, p<0.01, HbA1c: odds ratio; 0.699, confidence interval:0.614-0.796, p<0.01). There was no effect modification of these associations by menopausal status, body mass index (BMI) and other confounding factors. Conclusions; Hyper-glycemia and hyper-HbA1c are associated with a decrease in mammographic breast density in Japanese women.

Table 1 The relations of glucose intolerance and mammographic breast density.odds ratioconfidence intervalp valueFasting serum glucose0.9870.982-0.992<0.01HbA1c0.6990.614-0.796<0.01

Citation Format: Ken Uchida, Naruki Kitano, Daisuke Yamaguchi, Hiroko Nogi, Makiko Kamio, Hiroshi Takeyama. Impaired glucose tolerance decreases mammographic breast density in Japanese women [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 P5-08-24.
Abstract P5-12-12: Prospective evaluation of adherence to adjuvant aromatase inhibitor (AI) therapy among Hispanic/Latino women with breast cancer (BC) living in the border city of El Paso, Texas
Authors: Philipovskiy Alexander , Campbell Aleli , Castillo Brenda , Heydarian Rosalinda , Gaur Sumit , Dwivedi Alok , Nahleh Zeina
Published: March 2020

Background: Adjuvant therapy with AI improve survival and is recommended to all postmenopausal women with hormone receptor-positive BC. A typical duration of the therapy is from 5 to 10 years. Despite clinically proven efficacy early discontinuation rate approaching 10% per year. The purpose of this study was to determine the adherence level through the Morisky Medication Adherence Scale (MMAS-8) among women with breast cancer treated at Texas Tech University Health Sciences Center El Paso (TTUHSC EP). Methods: Institutional review board approval was obtained prior to initiating this prospective study. 133 postmenopausal women were consented and participated in this study. Patients seen at the TTUHSC EP who was diagnosed with stage I-III breast cancer and who were on adjuvant AIs, were given the MMAS-8 questionnaire, and a demographics questionnaire. In order to identify reasons for non-adherence to AIs, all patients were also asked to identify the reason why they did not take their medication if applicable.Results: One hundred thirty-three patients were enrolled, median age 64 (range 41 - 89), 110 (90.2%) identified themselves as Hispanic/Latino. 58.2% have an income of 15K or less. 39% completed eighth grade or less, 34.5% completed high school, and 12% obtained a technical degree. Mean duration of AI therapy was 6.5 years. The majority of patients have high or intermediate levels of adherence 88%. Only 12 % had a low level of adherence. 7 (5.6%) patients scored two or below in the intentional adherence scale, and 18 (13.5%) scored two or below in the unintentional adherence scale (maximum scale is four). Conclusions: Our results indicate that the majority of patients treated at TTUHSC EP have a high or intermediate level of adherence to AI therapy. The main reason listed for non-adherence were mostly unintentional: forgetfulness and missing getting refills on time.

Citation Format: Alexander Philipovskiy, Aleli Campbell, Brenda Castillo, Rosalinda Heydarian, Sumit Gaur, Alok Dwivedi, Zeina Nahleh. Prospective evaluation of adherence to adjuvant aromatase inhibitor (AI) therapy among Hispanic/Latino women with breast cancer (BC) living in the border city of El Paso, Texas [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 P5-12-12.
Abstract P5-14-17: Musculoskeletal side effects over time and association with adherence in women taking neoadjuvant letrozole for estrogen receptor positive DCIS: CALGB 40903 (Alliance)
Authors: Kimmick Gretchen , Dueck Amylou C , Shelby Rebecca , Naughton Michelle , Caudle Abigail , Fruth Briant , Hwang E. Shelley
Published: March 2020

Background: Side effects of and adherence to aromatase inhibitors in women with ductal carcinoma in situ are not well described. Methods: Postmenopausal women in a prospective phase II study of neoadjuvant letrozole for estrogen receptor positive DCIS completed questionnaires on side effects [Menopause Specific Quality of Life Questionnaire (MENQOL), Brief Pain Inventory-short form (BPI-SF), Arthritis Impact Measurement Scales (AIMS2)], well-being (FACT-G), and adherence [Medication-Taking questionnaire] at baseline, 1, 3 and 6 months (mo), and study completion. We used descriptive statistics and paired t-tests to compare 1, 3 and 6 mo results to baseline. Hierarchical linear mixed modeling, controlling for baseline symptom or well-being level, was used to examine effect of symptoms and well-being on intentional and nonintentional nonadherence, based on the Medication-Taking Questionnaire. Results: Included were 84 women, mean age 63 (39-83) years. In univariate analyses, compared to baseline, menopausal symptoms increased [physical (p=0.001 at 3, p<0.001 at 6 mo); vasomotor (p<0.001 at 1, 3, 6 mo), psychosocial (p=0.006 at 6 mo) and sexual (p=0.01 at 6 mo)]. Joint pain and stiffness increased [BPI-SF pain subscale (p=0.048 at 3, p=0.01 at 6 mo); AIMS2 joint pain subscale (p=0.03 at 1, p<0.001 at 3 and 6 mo); AIMS2 stiffness subscale (p=0.004 at 3, p=0.01 at 6 mo)]. Intentional and nonintentional adherence did not significantly change over time (p>0.05). Lower emotional (p=0.049) and functional (p=0.002) well-being by FACT-G and higher joint pain (p=0.03) by AIMS2 were associated with higher nonintentional nonadherence; higher physical side effects of menopause (p=0.001) by MENQOL were associated with lower intentional nonadherence. Conclusions: Among women taking letrozole for DCIS, menopausal symptoms and joint pain/stiffness increased over time with most differences noted at 3 and 6 mo. Lower well-being and higher symptom levels were associated with higher nonintentional nonadherence. NCT01439711.U10CA180821, U10CA180882, UG1CA189823, Breast Cancer Research Foundation, https://acknowledgments.alliancefound.org.

Citation Format: Gretchen Kimmick, Amylou C Dueck, Rebecca Shelby, Michelle Naughton, Abigail Caudle, Briant Fruth, E. Shelley Hwang. Musculoskeletal side effects over time and association with adherence in women taking neoadjuvant letrozole for estrogen receptor positive DCIS: CALGB 40903 (Alliance) [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 P5-14-17.
Abstract P6-03-14: Conditional reprogrammed cells enable us to examine the drug resistance for recurrent metastatic hormone receptor-positive, human epidermal receptor 2-negative breast cancer
Authors: Mimoto Rei , Yogosawa Satomi , Fushimi Atsushi , Nogi Hiroko , Asakura Tadashi , Yoshida Kiyotsugu , Takeyama Hiroshi
Published: March 2020

Objectives: Various new drugs have been developed for treating recurrent hormone receptor-positive/human epidermal receptor 2-negative breast cancer. However, directly identifying effective drugs remains difficult. In this study, we elucidated the clinical relevance of cultured cells derived from patients with recurrent hormone receptor-positive/human epidermal receptor 2-negative metastatic breast cancer. Methods: We generated conditional reprogrammed cells from primary and metastatic breast cancer. CR cells were co-cultured with irradiated mouse fibroblast feeder cells in the presence of the Rho kinase inhibitor Y-27632. We performed microarray analysis using a SurePrint G3 Human GE microarray kit Ver. 2.0, and DNA target sequence using QIAseq Targeted DNA Panels to analyze the genetic variants of the 93 most commonly mutated genes in human breast cancer samples. We examined the pathological features by xenograft model. For drug screening assay, we used Cambridge Cancer Compound Library. Results: The results of microarray analysis, DNA target sequencing and xenograft experiments indicated that the mutation status and pathological features were preserved in CR cells, whereas RNA expression was different from that in the primary tumor cells, especially with respect to cell adhesion-associated pathways. The results of drug sensitivity assays involving the use of primary breast cancer CR cells were consistent with the result of Oncotype Dx. We performed drug screening assays using liver metastases, which were sensitive to 66 drugs. The result reflected the actual clinical course of this patient, resistant to taxanes and sensitive to fulvestrant plus palbociclib. Conclusion: These results supported the use of CR cells obtained from the metastatic lesions of patients with HR+/HER2− breast cancer for predicting the clinical drug efficacy.

Citation Format: Rei Mimoto, Satomi Yogosawa, Atsushi Fushimi, Hiroko Nogi, Tadashi Asakura, Kiyotsugu Yoshida, Hiroshi Takeyama. Conditional reprogrammed cells enable us to examine the drug resistance for recurrent metastatic hormone receptor-positive, human epidermal receptor 2-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 P6-03-14.
Abstract P6-03-19: Oridonalogs reverse chemoresistance in breast cancer cells by targeting STAT3
Authors: Liu Xi , Wen Yefei , Kim Hyejin , Wang Pingyuan , Chen Haiying , Hu Mingdao , Ding Ye , Zhou Jia , Shen Qiang
Published: March 2020

Chemotherapy remains the mainstream treatment option for invasive and metastatic breast cancer. Adriamycin (ADR) is one of the most frequently used and an effective chemotherapeutic agent for treating patients with breast cancer. However, the resistance towards ADR becomes a major obstacle to achieve efficacy and favorable outcomes in breast cancer patients with chemotherapy. We recently developed a serial oridonalogs that may possess the ability to overcome chemoresistance in cancer cells, whereas whether these novel anti-cancer agents reverse ADR resistance in resistant breast cancer cells are not adequately explored and further the mechanism of action has not been studied. In this study, oridonalogs, YD0514, CYD0618, and CYD0686, were used to determine their effects on the proliferation of the ADR-resistant breast cancer cells. We found significant inhibition of proliferation of wild-type breast cancer cell line MCF-7 and ADR-resistant MCF-7/ADR cells, time- and dose-dependently. Among the tested compounds, CYD0618 and CYD0686 were more effective in inducing apoptosis in wild-type and resistant breast cancer cells than YD0514, in comparison to the natural product and lead compound oridonin. In addition, total STAT3 level was found higher in ADR-resistant breast cancer cells, while phospho-STAT3 was higher in resistant cells. CYD0618 inhibited STAT3 activation in ADR-resistant cells. Our findings suggest that STAT3 activation may be critically involved in the development of acquired resistance to ADR, while oridonalogs such as CYD0618 may open the avenue to reverse and overcome ADR resistance in breast cancer by targeting STAT3. Further mechanistic explorations are currently underway.

Citation Format: Xi Liu, Yefei Wen, Hyejin Kim, Pingyuan Wang, Haiying Chen, Mingdao Hu, Ye Ding, Jia Zhou, Qiang Shen. Oridonalogs reverse chemoresistance in breast cancer cells by targeting STAT3 [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 P6-03-19.
Abstract P6-03-24: ORIC-101 robustly inhibits the glucocorticoid pathway and overcomes chemoresistance in triple-negative breast cancer
Authors: Zhou Haiying , Ye Qiuping , Pankov Aleksandr , Kong Wayne , Barkund Shravani , Friedman Lori S. , Sun Jessica D. , Kabbarah Omar
Published: March 2020

ORIC-101 is a novel and selective glucocorticoid receptor (GR) antagonist currently in Ph1 clinical evaluation in solid tumors. In preclinical models, ORIC-101 potently sensitized triple-negative breast cancer (TNBC) cells to chemotherapy by inhibiting GR-mediated resistance through the epithelial-to-mesenchymal transition and anti-apoptosis pathways, both in vitro and in vivo. To inform the clinical development of ORIC-101, we identified pharmacodynamic (PD) biomarkers and established a relationship between those biomarkers, pharmacokinetics (PK), and efficacy in preclinical models. Using genome-wide profiling, we developed a GR activation signature that includes the direct GR transcriptional targets FKBP5 and GILZ, and subsequently validated both genes as ORIC-101 PD biomarkers in a panel of cell lines. We demonstrated that FKBP5 and GILZ are transcriptionally induced by glucocorticoids in a dose-dependent manner, and that the degree of their transcriptional activation is correlated with basal levels of GR in these models. We showed that ORIC-101 robustly inhibits the transcriptional induction of FKBP5 and GILZ and fully reverses GR-mediated chemoresistance in vitro and in vivo. Furthermore, FKBP5 and GILZ are reliable PD biomarkers for ORIC-101 in human-derived peripheral blood mononuclear cells (PBMCs). Importantly, by integrating PK, PD, and efficacy results from numerous preclinical studies, we captured the relationship between ORIC-101 PK, PD biomarker modulation, and chemopotentiation. Altogether, FKBP5 and GILZ mRNA levels are robust PD biomarkers to measure GR pathway engagement and modulation which corresponds with efficacy in response to GR antagonist treatment in preclinical models. These findings will guide the clinical development of ORIC-101 in TNBC.

Citation Format: Haiying Zhou, Qiuping Ye, Aleksandr Pankov, Wayne Kong, Shravani Barkund, Lori S. Friedman, Jessica D. Sun, Omar Kabbarah. ORIC-101 robustly inhibits the glucocorticoid pathway and overcomes chemoresistance 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 P6-03-24.