bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P3-08-19: Biomarkers associated with dcis related breast cancer death
Authors: Wadsten Charlotta , Hartman Johan , Fredriksson Irma , Garmo Hans , Wärnberg Fredrik , Sund Malin 
Published: March 2020

Abstract
Introduction In primary ductal carcinoma in situ of the breast (DCIS) tumour biological features associated with risk of invasive recurrence and metastasis may already be present at the pre-invasive stage. The aim of this study was to investigate the correlation of biological markers in DCIS and the risk of subsequent breast cancer death. Patients and methods A nested case-control study was conducted in a population based cohort of women diagnosed with primary DCIS between 1992 and 2012. Women who later died from breast cancer were identified. Four controls per case were selected randomly by incidence density sampling from the same cohort. Tumour blocks were retrieved for histopathological reevaluation and immunohistochemical analysis (IHC) of Oestrogen Receptor (ER), Progesterone Receptor (PR), Human Epidermal Growth Receptor 2 (HER2) and Ki67 expression. Odds ratios (OR) for risk of breast cancer death with 95% CI was calculated using conditional logistic regression. Results From a cohort of 6964 women with primary DCIS, tumour specimens were available for 66 patients who died from breast cancer and these were compared to samples from 195 controls. DCIS with intense lymphocytic infiltration was associated with an increased risk of breast cancer related death in univariate analysis (OR 2.25; 95%CI 1.02-4.99). None of the biomarkers were individually related to increased risk. In multivariable analysis and stepwise adjusting for age, tumour size and treatment; PR negativity in combination with lymphocytic infiltration (OR 4.40; 95%CI 1.20-16.14), PR negativity, lymphocytic infiltration and presence of comedonecrosis (OR 5.48; 95%CI 1.71-17.57) and the combination of PR negativity, lymphocytic infiltration, comedonecrosis and HER2 positivity (OR 7.54; 95%CI 2.00-28.43) were all independently associated with increased risk of breast cancer related death. Conclusion In the present study, the combination of PR negativity and periductal lymphocytic infiltration was associated with risk of breast cancer related death after primary DCIS. Combining biomarker expressions in DCIS with features in the peritumoural stroma may be useful tools for prognostication.
Citation Format: Charlotta Wadsten, Johan Hartman, Irma Fredriksson, Hans Garmo, Fredrik Wärnberg, Malin Sund. Biomarkers associated with dcis related breast cancer death [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-19.
Abstract P3-08-37: Dynamic and subtype-specific interactions between tumor burden and prognosis in breast cancer
Authors: Kim Hong-Kyu , Lee Sae Byul , Choi Yunhee , Ju Young Wook , Lee Han-Byoel , Han Wonshik , Noh Dong-Young , Lee Jong Won , Moon Hyeong-Gon , Choi Jihye 
Published: March 2020

Abstract
Purpose Recent updates of the AJCC staging system in breast cancer incorporated biologic characteristics along with the traditional anatomic tumor burden for outcome prediction. However, potential interactions between the prognostic effect of anatomic factors and the biologic characteristics are not reflected in the new system. In this study, we evaluated the interactions between the prognostic relevance of anatomic tumor burden and the molecular subtypes.
Methods From the Korean Breast Cancer Registry Database, we investigated the relationship between the prognostic importance of anatomic tumor burden and molecular subtypes in patients with invasive breast carcinoma who were treated between 1980 and 2014. Tumors were classified into four different molecular subtypes based on the hormonal receptor status and HER2 expression status. (1) HR+/HER2- subtypes; (2) HR+/HER2+ subtypes; (3) HR-/HER2+ subtypes; (4) HR-/HER2- subtypes.
Results Breast cancers with different molecular subtypes had unique outcome patterns in relation to anatomic tumor burden. In HR+/HER2+ and HR-/HER2- tumors, the increase in T stages exhibited profound rise in the hazard of death, while the presence of metastatic node was more important in HR+/HER2+ and HR-/HER2+ tumors in 131,178 Stage I to III breast cancer patients. The patterns for increasing risk of deaths along with tumor growth (per centimeter) and metastatic nodes (per one node) were examined in 67,038 patients with tumors 7cm or smaller and less than 8 metastatic nodes. HR+/HER2- and HR-/HER2- tumors showed persistent increase in risk of deaths as tumors grow while the effect was modest in HER2+ tumors. In contrast, the increased number of metastatic nodes was accompanied with persistent rise of risk in HR-/HER2+ tumors while the effect was minimal after 3 or 4 nodes in HR-/HER2- tumors. The interactions between the prognostic significance of anatomic tumor burden and molecular subtypes were statistically significant.
Conclusion Our data demonstrates that the prognostic implication of tumor growth and spread, measured by the increase in tumor size and number of metastatic nodes, shows significant association with the molecular subtypes of the breast cancer. Additionally, our data suggest that the association between the prognostic impact and the anatomic tumor burden is rather dynamic that linear within a specific molecular subtype.
Citation Format: Hong-Kyu Kim, Sae Byul Lee, Yunhee Choi, Young Wook Ju, Han-Byoel Lee, Wonshik Han, Dong-Young Noh, Jong Won Lee, Hyeong-Gon Moon, Jihye Choi. Dynamic and subtype-specific interactions between tumor burden and prognosis in breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-37.
Abstract P3-08-42: Disease-free survival prognostic signature in triple-negative breast cancer based on high-throughput proteomics data
Authors: Auñon Pilar Zamora , Adrián Silvia García , Trilla-Fuertes Lucia , Gámez-Pozo Angelo , Prado-Vázquez Guillermo , Zapater-Moros Andrea , Almirón Mariana Díaz- , Vacas Rocío López , Chiva Cristina , Chiva Cristina , Sabidó Eduard , Arranz Enrique Espinosa , Vara Juan Ángel Fresno 
Published: March 2020

Abstract
Introduction Triple negative breast cancer (TNBC) accounts for 15-20% of the breast cancer and is characterized by an aggressive phenotype and worst prognosis. TNBC does not benefit from any targeted therapy, so further characterization would be needed to define subgroups with potential therapeutic value. Material and methods 125 TNBC paraffin samples were analyzed using high-throughput proteomics based on SWATH-MS. Survival analyses and a prognostic predictor were done using BRB Array Tools. Proteins related with disease-free survival were established and, then, a prognostic signature was built based on their p-values. Results and discussion Using SWATH-MS, 1,206 proteins were identified in a cohort of 125 TNBC tumors. Of these 1,206 proteins, 29 proteins were related with disease-free survival. In addition, a prognostic signature based on the expression of two proteins, RMB3 and NIPSNAP1, was defined. The predictor split our population into a low-risk and a high-risk group (p=0.0002, HR= 6.519). Multivariate analysis showed that the prognostic signature based on the expression of these two proteins supplied significant information to the clinical parameters. Conclusion SWATH-MS proteomics demonstrates its utility in the analysis of TNBC paraffin samples. Moreover, this proteomics data allows us to build a prognostic signature based on the expression of two proteins (RBM3 and NIPSNAP1). This prognostic signature could be used in the future to identify a population with a high-risk of relapse that may be directed to a clinical trial.
Citation Format: Pilar Zamora Auñon, Silvia García Adrián, Lucia Trilla-Fuertes, Angelo Gámez-Pozo, Guillermo Prado-Vázquez, Andrea Zapater-Moros, Mariana Díaz- Almirón, Rocío López Vacas, Cristina Chiva, Cristina Chiva, Eduard Sabidó, Enrique Espinosa Arranz, Juan Ángel Fresno Vara. Disease-free survival prognostic signature in triple-negative breast cancer based on high-throughput proteomics data [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-42.
Abstract P3-08-66: Metaplastic breast cancer in patients older than 65 years
Authors: Chahine Johnny , Thapa Bicky , Jia Xuefei , Haddad Abdo 
Published: March 2020

Abstract
Background: Metaplastic breast cancer (MBC) is a rare histologic subtype of breast cancer. It comprises less than 1% of all breast cancers. We evaluated the clinical characteristics and outcomes of MBC in geriatric patients older than age 65.
Methods: We reviewed the chart of the pathologically proven MBC cases from 2000-2017. Only patients with age more than 65 years were included in the study for analysis.
Results: A total of 48 MBC patients were included in the study. Thirty-six (76%) were white and 11 (23%) black. The number of patients in stages I, II, III, and IV were 12, 26, 6, and 4, respectively; 39 (81%) had nuclear grade III. Three (6%) had progesterone receptor positive, 3 (6%) were Her2 positive, and 4 (10%) were estrogen receptor positive. The most common distant metastases were lung (20%), followed by bone (12%). Fifty percent had a lumpectomy, 11% had hormonal therapy, and 60% had radiation therapy. Only 50% of patients received chemotherapy, out of which 46% received anthracycline. On univariable analysis, stage of the MBC and metastasis to the lung, bone, and brain were associated with worse overall survival (OS). There was no statistical significance in OS when stage II was compared with stage I MBC. Stage III had median OS of 18 months with HR of 3.25 (95% CI 0.85, 12.44) (p=0.086) and stage IV had 10 months median OS with HR of 11.17, (95% CI 2.37, 52.62) (p=0.002). Hormonal therapy, radiation therapy, and type of chemotherapy (anthracycline vs. non-anthracycline) did not show any statistical significance in regards to OS and progression-free survival.
Conclusion: In our study, MBC demonstrated overall poor survival and progression-free survival. Only stage of the MBC and metastasis to brain bone and lung proved to predict worse survival.
Citation Format: Johnny Chahine, Bicky Thapa, Xuefei Jia, Abdo Haddad. Metaplastic breast cancer in patients older than 65 years [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 P3-08-66.
Abstract P3-08-71: Medication use to reduce mammographic breast density in premenopausal women: A systematic review
Authors: Salazar Ana S. , Rakhmankulova Malika , Simmon Laura E. , Toriola Adetunji 
Published: March 2020

Abstract
Background: Mammographic breast density (MBD) is a strong modifiable risk factor for breast cancer, especially in premenopausal women. It is estimated that up to 39% of breast cancer cases in premenopausal women could potentially be prevented by reducing dense breasts to non-dense breasts. Therefore, reducing breast density through targeted interventions is an excellent opportunity to substantially reduce breast cancer incidence in premenopausal women. We performed a critical evaluation of the literature to determine the associations of chemoprevention agents use with MBD. This will guide the management of premenopausal women at risk for breast cancer. Methods: Eleven databases were searched on July 2019. We included interventional, cross-sectional, longitudinal or observational studies in Englishreporting the associations of medication with mammographic breast density in premenopausal womenwith no history of breast cancer. Two researchers extracted the data and assessed the quality of the studies. Supplements not otherwise specified were excluded. Results: After de-duplication process, 1,464 citations were screened for eligibility. Seven studies met our inclusion criteria: two observational, four randomized controlled, and one non-randomized controlled trials (RCT). There were two categories of medications: dietary supplements (i.e. vitamin D, calcium, isoflavone) and drugs (non-steroidal anti-inflammatory drugs [NSAIDs], selective estrogen receptor modulators (SERMs) goserelin, and GnRHA deslorelin acetate). In observational studies, calcium use was associated with a significant reduction in MBD, while vitamin D and NSAIDs showed no reduction6. Likewise, Isoflavone and vitamin D in doses of 1000, 2000 or 3,000IU/day were not associated with a reduction in MBD in two different RCT. Groselin, GnRHA, deslorein acetate, statins were not associated with MBD reduction in an RCT’s. SERMs (tamoxifene and raloxifene) were the only drugs associated with reductions in MBD in RCTs. Conclusions: Only a very limited number of medications (SERMs) are associated with reductions in MBD. In view of their low uptake and adherence, identifying other medications that can reduce MBD is crucial, as these could have utility in breast cancer prevention.
Citation Format: Ana S. Salazar, Malika Rakhmankulova, Laura E. Simmon, Adetunji Toriola. Medication use to reduce mammographic breast density in premenopausal women: A systematic review [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 P3-08-71.
Abstract P3-09-18: Immunization of breast cancer patients in combination with standard-of-care chemotherapy: Results of a phase Ib clinical trial
Authors: Makhoul Issam , Jousheghany Fariba , Mohammed Saddam , Siegel Eric , Pennisi Angela , Beck J Thaddeus , Hutchins Laura , Kieber-Emmons Thomas , Monzavi-Karbassi Behjatolah 
Published: March 2020

Abstract
We have developed a peptide mimotope-based cancer vaccine, P10s-PADRE, targeting tumor associated carbohydrate antigens (TACAs). We have previously shown safety, feasibility and induction of immune response in a phase I clinical trial in stage IV breast cancer patients. In the current clinical trial, immunization with P10s-PADRE vaccine is combined with the standard-of-care chemotherapy in neo-adjuvant setting in subjects diagnosed with early stage ER-positive breast cancer. Various schedules (timing of vaccination doses relative to chemo) for combination therapy were tested. Immunological endpoint variable include antibody response and activation of natural killer (NK) cells as tested in peripheral blood mononuclear cells. Tumor size before treatment and after surgery was measured for each subject. The secondary endpoint was pathologic complete response (pCR). We observed induction of antibody response and activation of NK cells independent of each other. Vaccination affected the expression of several NK markers including CD94 and NKp46 as we observed a significant upregulation of NKp46 (median = 1.79, P&lt;0.0001), and CD94 (median = 1.50, P&lt;0.0001) in response to immunization. The data indicate a significant increase in serum IFN-γ (Median=1.74, P=0.0016) upon vaccination. Increase in IFN-γ was positively correlated with increase in both CD69 (r = 0.46, P=0.0321) and NKp46 (r = 0.39, P=0.0763) on CD56-dim NK cells. Tumor shrinkage was associated with an increase in NK cells, upregulation of NKp46 and CD94 molecules, and increase in frequency of NKp46-positive and CD94-positive CD56-dim NK cells. Among 25 subjects enrolled in 5 different immunization schedules, 5 experienced complete eradication of their primary tumors that was associated with vaccine induced increase in the frequency of CD94-positive CD56-dim NK cells (p= 0.0473). The results are intriguing and warrant expansion of the immunologically effective combination schedule to further establish the clinical efficacy along with potential biomarkers of response.
Citation Format: Issam Makhoul, Fariba Jousheghany, Saddam Mohammed, Eric Siegel, Angela Pennisi, J Thaddeus Beck, Laura Hutchins, Thomas Kieber-Emmons, Behjatolah Monzavi-Karbassi. Immunization of breast cancer patients in combination with standard-of-care chemotherapy: Results of a phase Ib clinical trial [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 P3-09-18.
Abstract P3-10-09: Gene deletion of IRS1 inhibited IGF-I, insulin and estradiol stimulated MCF-7L breast cancer cell growth
Authors: Zhang Xihong , Yee Douglas 
Published: March 2020

Abstract
Targeting of the type I insulin-like growth factor receptor (IGF-IR) has not been successful in breast cancer. Data suggest the highly homologous insulin receptor (IR) may be an alternate growth stimulatory pathway used by cancer cells. Since both receptors phosphorylate the insulin receptor substrate-1 (IRS-1) protein as an immediate consequence of ligand binding, disruption of both receptors could be accomplished by suppression of IRS-1. To test this hypothesis, we created a doxycycline-inducible IRS-1 shRNA lentiviral construct to infect hormone dependent MCF-7 breast cancer cells. IRS-1 shRNA downregulation resulted in decreased responses to IGF-I, insulin, and estradiol in monolayer and anchorage independent growth assays. Decreased IRS-1 levels also suppressed estradiol stimulated gene expression and estrogen receptor binding to DNA. Xenograft growth was also inhibited by induction of IRS-1 shRNA. These data show IRS-1 is a critical regulator of endocrine responsive breast cancer. To further study the critical effects of IRS1 in ER positive breast cancer biology, CRISPR technology was used to delete IRS1 from MCF-7L cells. We analyzed 5 CRISPR IRS1 gene edited clones. Two different commercial available IRS1 antibodies were used to examine IRS1 protein expression. Clones #16, #20 did not show any IRS1 expression, while clones #22, #33 and #38 showed truncated IRS1 expression. IGFIRβ and Insulin R levels were comparable to the parent MCF-7L cells in all the clones, while IRS2 and ERα levels were significantly lower in clone #16. IRS phosphorylation, detected by PY20 antibody, was significantly lower in clone #16. The downstream signaling measured by pAKT and pErk1,2 did not change in all clones compared to those in MCF-7L. In all the clones, ERα ser118 phosphorylation by estradiol stimulation (10 nM) and ERα downregulation by fulvestrant treatment (100 nM) were not affected by IRS1 knockout. IGF-I (5 nM), insulin (10 nM) and estradiol (10 nM) stimulated monolayer cell growth in clone #16 was completely inhibited, while other clones were partially inhibited. In contrast, growth in clone #22 was not inhibited due to extremely high IRS2 expression and compensation. In conclusion, when the IRS1 gene was deleted, multiple growth stimulatory ligands (IGF-I, insulin and estradiol) were inhibited in breast cancer cells. However, IRS-2 compensated for IRS-1 gene deletion in one of the clones we studied. Thus, targeting the IRS proteins may inhibit multiple ligands that cause growth stimulation in ER positive breast cancer therapy.
Citation Format: Xihong Zhang, Douglas Yee. Gene deletion of IRS1 inhibited IGF-I, insulin and estradiol stimulated MCF-7L breast cancer cell 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 P3-10-09.
Abstract P3-10-17: CREBBP alterations lead to CDK4/6 inhibitor sensitivity in triple negative breast cancer
Authors: Natrajan Rachael 
Published: March 2020

Abstract
Fundamental to the effective clinical use of new therapeutic agents for cancer is the identification of genetic biomarkers of sensitivity as well as the identification of additional patient populations who would benefit from treatment. Here, through an unbiased functional genomics approach in a model of aggressive disease using cancer cell line spheroid cultures, we have uncovered a role for the histone acetyltransferase CREBBP as a tumour suppressor in aggressive hard to treat triple-negative breast cancers (TNBCs). We find that CREBBP protein expression is altered in a substantial proportion of TNBCs, as well as other solid tumours, including lung and lymphoma where CREBBP inactivating mutations are common. We found CREBBP alterations are associated with higher genomic heterogeneity and poorer patient survival in TNBCs and resulted in upregulation of the FOXM1 transcriptional network. Strikingly, treatment with clinical CDK4/6 inhibitors (CDK4/6i), that indirectly target FOXM1 activity, selectively impaired growth in spheroids, cell line xenografts and patient derived models from multiple tumour types with CREBBP alterations. Here we provide the pre-clinical and mechanistic rationale for assessing CREBBP alterations as a biomarker of single-agent CDK4/6 inhibitor response in a new patient population. This represents a novel synthetic lethal approach to targeting triple negative breast cancers with limited therapeutic options.
Citation Format: Rachael Natrajan. CREBBP alterations lead to CDK4/6 inhibitor sensitivity in triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-10-17.
Abstract P3-10-20: Targeting the tyrosine phosphatase SHP2 is efficacious against HER2-positive breast cancer
Authors: Agazie Yehenew , Hartman Zachary 
Published: March 2020

Abstract
Accumulating evidence suggests that the Src homology phosphotyrosyl phosphatase 2 (SHP2) is a bona fide oncogene. These conclusions are primarily based on the positive role of SHP2 in receptor tyrosine kinase (RTK) signaling in multiple systems. Because overexpression of the human epidermal growth factor receptor 2 (HER2) is one of the primary causes of BC, we investigated the potential of SHP2 targeting in this subtype of BC. We have used our recently patented SHP2 inhibitor called WGMDY (US 9,932,288) for targeting SHP2 under cell culture and in vivo conditions. We have also used the recently reported allosteric SHP2 inhibitor called SHP099 particularly in the cell culture studies. We found that HER2-positive BC cells are highly sensitive to SHP2 inhibition with WGMDY as determined by loss of viability in 2D, transformation in soft agar, and cancer stem cell properties in suspension cultures. Similar results were obtained with SHP099 albeit at a reduced rate. Analysis of protein and RNA extracts showed inhibition of the Ras-ERK and the PI3K-Akt signaling pathways by WGMDY, but SHP099 tend to activate Akt signaling. In addition, WGMDY blocked overexpression of the HER2 protein in HER2-positive BC cells. As such, we focused on WGMDY for the in vivo efficacy studies. The results showed that WGMDY induces regression of preformed tumors in a concentration dependent manner. Histopathology analyses of tumors showed induction of necrosis in treated samples. Hence, WGMDY has a promising anti-cancer effects in HER2-positive BC.
Citation Format: Yehenew Agazie, Zachary Hartman. Targeting the tyrosine phosphatase SHP2 is efficacious against HER2-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 P3-10-20.