bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P3-08-11: The application of machine learning techniques to standardize breast cancer grading and develop multivariate risk outcome models
Authors: Prastawa Marcel , Madduri Abishek Sainath , Veremis Brandon , Shtabsky Alexander , Marami Bahram , Zeineh Jack , Donovan Michael Joseph , Fernandez Gerardo
Published: March 2020

Background: The 2019 NCCN guidelines and the College of American Pathology (CAP) endorse consistent, unambiguous comprehensive pathology reporting for invasive breast cancer. Challenges surrounding inter-pathologist variability and the lack of quantitative, standardized approaches to histologic grade are significant and critical to patient management. We developed an automated multi-network machine learning platform for histologic grading and examined performance with clinical outcome. Methods: Using the Cancer Genome Atlas (TCGA) breast cancer (BCA) image dataset and clinical data as a training cohort, we evaluated 420 conventional H&E images (one slide per patient). An artificial intelligent (AI) / deep-learning based workflow is used to normalize staining differences, identify regions of tumor vs. normal and characterize individual cellular attributes of breast cancer grading systems including overall gland structure, nuclear morphology, and mitotic figures. Individual features were correlated with overall survival using the concordance index (c-index). Support vector models and Kaplan-Meier incidence curves were used to further understand feature importance. Results: Using the AI platform, 88 image features representing BCA gland morphology and cellular-nuclear attributes were generated from 420 patients with 36 events including metastasis and or death with a median overall survival (OS) of 5-years. Three clinical variables were available including AJCC stage, grade and age at diagnosis. Image features were prioritized on C-index <0.5 or >0.5 which reflects increased or reduced risk of poor outcome, respectively. A training model consisting of image features + clinical data produced a C-index of 0.85, Hazards ratio 11, p<0.001. Only 1 clinical feature (stage) and 9 imaging features (all with individual c-indices <0.5) representing nuclear shape, size, number and mitotic figure activity were selected.

Conclusions: Our innovative lab-based AI / deep-learning platform produced accurate BCA risk models to predict metastasis and OS through automated H&E BCA grading. Future analyses include a multi-site validation study to confirm these initial training results.

Citation Format: Marcel Prastawa, Abishek Sainath Madduri, Brandon Veremis, Alexander Shtabsky, Bahram Marami, Jack Zeineh, Michael Joseph Donovan, Gerardo Fernandez. The application of machine learning techniques to standardize breast cancer grading and develop multivariate risk outcome models [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 P3-08-11.
Abstract P3-10-16: Identification of molecules that enhance the efficacy of eribulin in TNBC and IBC cell lines
Authors: Lee Jangsoon , Fuson Jon A , Liu Huey , Pearson Troy , Tripathy Debu , Lim Bora , Ueno Naoto T
Published: March 2020

BACKGROUND: Eribulin mesylate, a non-taxane microtubule-dynamics inhibitor, is an effective chemotherapy drug for patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens. We are seeking to enhance the anti-tumor activity of eribulin in metastatic breast cancer cell lines. The purpose of this study was to identify kinase targets that markedly enhance the efficacy of eribulin using high-throughput nonbiased synthetic lethal RNA interference (RNAi) screening and to validate these targets in combination with eribulin using triple-negative breast cancer (TNBC) and inflammatory breast cancer (IBC) cell lines which are heterogeneous diseases and characterized by their high metastatic potential and poor prognosis.

METHODS: High-throughput RNAi screening (709-human-kinome library) was performed to identify target kinases. The Bliss scoring method was used to identify potential targets from the screening (using a Bliss score cut-off of 0.15), and protein-protein interactome analysis (STRING V.11) and Ingenuity Pathway Analysis (IPA) were used to identify therapeutic target pathways. To validate the in vitro efficacy of selected targets, we performed CellTiter-Blue or sulforhodamine B cell proliferation and anchorage-independent colony-formation assays in 18 TNBC and 6 IBC cell lines treated with eribulin with or without inhibitors of the discovered targets.

RESULTS: In vitro proliferation data demonstrated that single-agent eribulin had a nanomolar range of half-maximal inhibitory concentrations (0.2 - 4.0 nM) in most of the tested cell lines. RNAi screening identified 130 relevant kinase targets. IPA and STRING analysis revealed PI3K/AKT/mTOR, MAPK, JNK, and PAK1 as major canonical pathways that could be targeted to enhance the cytotoxic effect of eribulin. In in vitro cell line validation, PAK1 inhibitor NVS-PAK1-1 and mTOR inhibitor everolimus showed strong combinational anti-tumor effect (combination index values = 0.1 - 0.9), and JNK inhibitor JNK-In-8 showed moderate combinational anti-tumor effect (combination index values = 0.5 - 0.9) in combination with eribulin. Inhibitors of PI3K (copanlisib) and MEK (trametinib) showed combinational anti-tumor effect in some cell lines.

CONCLUSION: We identified that PAK1, mTOR, and JNK inhibitors enhanced the anti-proliferation effects of eribulin in TNBC and IBC cell lines. Our data inform new treatment strategies with eribulin for TNBC and IBC that could lead to clinical trials of innovative combination therapy based on eribulin.

Citation Format: Jangsoon Lee, Jon A Fuson, Huey Liu, Troy Pearson, Debu Tripathy, Bora Lim, Naoto T Ueno. Identification of molecules that enhance the efficacy of eribulin in TNBC and IBC cell lines [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 P3-10-16.
Abstract P3-11-26: Investigating the synergistic anti-cancer effects on mitochondrial function in breast cancer cells using arctigenin, cinnamaldehyde, and chlorogenic acid individually and in combination
Authors: Schuster Caroline , Gollahon Lauren S
Published: March 2020

One of the major obstacles in current breast cancer treatment efficacy is the ability of breast cancer cells to develop resistance to chemotherapeutic drugs. In addition, a second major obstacle is the off-target cytotoxicity of these drugs on normal cells, leading to debilitating side effects. Many of these current chemotherapeutics target DNA (repair, replication, division). As a result, the bystander effect to normal cells and tissues is significant. However, one major difference between cancer and normal cells is their metabolism. The Warburg Effect suggests that cancer cells prefer a glycolytic, hypoxic environment. Emerging studies have begun to delineate differences in mitochondrial function between cancer and normal cells. In this study, we sought to exploit this metabolic difference by investigating alternative breast cancer treatment options based on application of natural product components. Previous studies from our lab demonstrated the efficacy of a mixture of plant extracts in killing cancer cells. Proteomics studies showed significant mitochondrial disruption in the cancer cells compared to normal cells. Here, we investigate three of the main components, identified by Mass Spectometry, to determine their anticancer properties compared to the whole extracts’ mixture. Arctigenin, chlorogenic acid, and cinnamaldehyde all demonstrate anti-cancer activity. We hypothesize that each component of the whole extract causes breast cancer cell death by disruption of mitochondrial activity and metabolic shifts, and lead to an increase in oxidative stress that is further amplified by combination treatment. These small molecules were administered to MDA-MB-231 and MCF-7 breast cancer or normal MCF-10A and MCF-12F breast cells, either alone or in combination. To evaluate differences in cell response, mitochondrial integrity and metabolic shifts were evaluated by flow cytometry, fluorescence microscopy and the Agilent Seahorse XF Cell Mito Stress Test. The ladder measures the mitochondria’s oxygen consumption rate, basal respiration, ATP production, proton leak, maximal respiration, spare respiratory capacity, and non-mitochondrial respiration. This study provides evidence that targeting the mitochondria may be a more effective anticancer treatment and that either components of natural products or combinations thereof offer new approaches in treating breast cancer that significantly reduce off-target effects to normal cells.

Citation Format: Caroline Schuster, Lauren S Gollahon. Investigating the synergistic anti-cancer effects on mitochondrial function in breast cancer cells using arctigenin, cinnamaldehyde, and chlorogenic acid individually and in combination [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 P3-11-26.
Abstract P4-05-23: Validation of proteome based molecular stratification of breast cancer using 1,229 patient samples from four independent datasets
Authors: Gyorffy Balazs
Published: March 2020

Introduction. In routine diagnostics, four genes are used to determine the molecular subtype and the optimal systemic therapy for breast cancer patients, ESR1, PGR, HER2, and in some cases MKI67. While these can be measured by different molecular genetic methods, immunohistochemistry is still the most widely used technique. The aim of present study was to determine how effective recent proteomic technologies are in measuring the expression of these genes.

Methods. A literature search was performed to identify available proteome-level datasets. Differential expression was compared using Mann-Whitney test. Receiver operating characteristics (ROC) was computed to validate discriminative power and to determine the optimal cutoff values. Each dataset was processed separately.

Results. All together four datasets with a total of 1,229 specimens with proteome level-data were identified. One dataset was generated using RPPA (reverse phase protein lysate microarray, n=874) and three using LC-MS (liquid chromatography-mass spectrometry, n=355). In all four datasets combined, a total of 7,419 proteins were measured. It was not possible to analyze all combinations because of limited data availability - HER2 data was available in the RPPA study only, and ESR1/PGR in the LC-MS studies only. The determination of HER2 status by IHC and HER2 protein expression by RPPA show very high correlation (p=2.9E-18). ESR1 protein expression determined by LC-MS show a significant correlation to IHC results (p=0.04). The ROC analysis for HER2 delivered an area under the ROC curve (AUC) of 0.74 (p=1.9e-20). For ESR1, the AUC was 0.61 (p=0.03). ESR1 and PGR show a moderate correlation in LC-MS data (correlation coefficient=0.17, p=0.04). Finally, when comparing MKI-67 expression between normal (n=53) and tumor samples (n=65) within one dataset, tumor samples had significantly higher expression (fold change=2.22, p=3.9E-05).

Conclusions. The RPPA method achieved high correlation with IHC results. Our results suggest that proteomic technologies will be capable to deliver molecular stratification enabling the discrimination of breast cancer subtypes in the future.

Citation Format: Balazs Gyorffy. Validation of proteome based molecular stratification of breast cancer using 1,229 patient samples from four independent datasets [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 P4-05-23.
Abstract P4-05-24: A stroma-adjusted ZEB1 expression signature is associated with decreased immune cell infiltration and poor overall survival in breast cancer
Authors: Block C James , Wu Guojun
Published: March 2020

The epithelial-to-mesenchymal transition (EMT) is a critical physiologic process which can be activated by cancer cells to enhance metastatic and chemoresistant properties in experimental models. Recent studies have identified positive associations between the expression of EMT-associated gene signatures with both the immune response and survival in multiple cancer types. Although these studies relied upon whole-tumor RNA sequencing data, which can be confounded by infiltrating immune and stromal cells, they failed to investigate this potential confounding effect. In this study, we comprehensively dissected the associations between the expression of multiple EMT transcription factors with stromal and immune cell tumor infiltration in breast cancer. We demonstrated that previously-reported associations between the expression of EMT marker genes and immune activity were confounded by stromal cell infiltration. Adjusting for this confounding effect eliminated these reported associations. Interestingly, we discovered that stroma-adjusted ZEB1 expression has a unique, inverse association with immune cell activity in multiple cancer types, most significantly in breast cancer. Further analysis revealed that ZEB1 is significantly correlated with reduced tumor infiltration of multiple immune cell types. By deriving a high-confidence stroma-adjusted ZEB1-activated gene signature, we confirmed that ZEB1 transcriptional activity has similar associations with both tumor immune activity and stromal content as ZEB1, thus identifying potential mechanisms underlying decreased immune cell infiltration. Finally, multivariate survival analysis reveals that the ZEB1 gene signature has significant associations with reduced overall survival in breast cancer patients. In conclusion, this study identifies a novel association between stroma-adjusted ZEB1 expression and tumor immune activity and addresses the critical issue of confounding between EMT-associated genes and tumor stromal content.

Citation Format: C James Block, Guojun Wu. A stroma-adjusted ZEB1 expression signature is associated with decreased immune cell infiltration and poor overall survival 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 P4-05-24.
Abstract P4-09-09: Characteristics of stage 1 to 3 breast cancer patients with amplification of centromere of chromosome 17
Authors: Voutsadakis Ioannis , Davies Vanessa
Published: March 2020

Background: Amplification of the centromeric region of chromosome 17 (CEP17) as measured by In Situ Hybridization (ISH) of the CEP17 probe is used clinically as part of the ISH assay for HER2 status determination in breast cancer. The value of amplification of CEP17 beyond its use in the HER2 ISH test and characteristics of cases bearing CEP17 amplification, have not been fully explored.

Methods: A retrospective review of charts of patients with stage 1 to 3 breast cancer that had a dual probe HER2/ CEP17 FISH test in our cancer center during an eight-year period was performed. Data on demographic, and cancer-specific characteristics of the included patients were extracted. The group of patients with an amplified CEP17 defined as mean copy number ≥3 per nucleus was compared with the group without amplification.

Results: Two hundred and two patients were included in the analysis. Amplification of CEP17 was observed in 36 patients (17.8%). All patients in the amplified group had a concomitant amplification of HER2 (mean copy number ≥3 per nucleus). In the CEP17 non-amplified group 78 of 166 patients (47%) had an amplified HER2 status. More patients in the amplified group had a clinical HER2+ status according to the 3-protein classifier (33.3% versus 11.5% in the non-amplified group) and less patients in the amplified group had a clinical ER+/ HER2- status (63.9% versus 81.8% in the non-amplified group, x2 p=0.0003). Other significant differences between the amplified and CEP17 non-amplified groups were observed in their lymph node (LN) status (55.6% of patients in the amplified group versus 36.8% in the non-amplified group were lymph node positive, p= 0.04) and in the nuclear heterogeneity component of grade (90.9% of patients in the amplified group were nuclear grade 3 versus 66.9% in the non-amplified group, p= 0.02). There were no statistically significant differences between the groups in overall stage, grade, menopause status or histology.

Conclusion: Patients with amplification of CEP17 had a co-amplified HER2 and were more commonly HER2+, LN positive and grade 3 in the nuclear component of grade.

Citation Format: Ioannis Voutsadakis, Vanessa Davies. Characteristics of stage 1 to 3 breast cancer patients with amplification of centromere of chromosome 17 [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 P4-09-09.
Abstract P4-09-11: PIK3CA somatic alterations in 412 chinese invasive breast cancers: Higher frequency of mutant H1047R detected by next generation sequencing compared to breast cancer in caucasians
Authors: Jia Minghan , Liao Ning , Chen Bo , Zhang Guochun , Wang Yulei , Chen Xiaoqing , Guo Liping , Cao Li , Mok Hsiaopei , Ren Chongyang , Li Kai , Li Cheukfai , Wen Lingzhu , Lin Jiali , Wei Guangnan , Zhang Zhou , Balch Charles M
Published: March 2020

Purpose: Somatic alterations of PIK3CA gene is an important therapeutic target in breast cancer (BC). The PI3Kα-specific inhibitor alpelisib was remarkably active against PIK3CA-mutated, HR-positive/HER2-negative BC in the SOLAR-1 trial. We hypothesized that PIK3CA alterations in Chinese BC patients across different molecular subtypes might differ from other ethnic groups and this information would be useful for selecting anti-PI3K therapy. Methods: The molecular profile of the PIK3CA gene was analyzed in 412 Chinese untreated invasive BC patients with ER/HER2 molecular subtypes, using a 540 gene next-generation sequencing panel. The results were compared to the molecular profile of Caucasian breast cancer patients in The Cancer Genome Atlas(TCGA-white). Results: Compared to wild type, PIK3CA alterations were more frequent in the ER+ subtype (49.3%, p=0.024), and tumors with low ki67 proliferation (58.3%, p=0.007) and low histological grade (grade I/II/III 80%, 53.4%, 35.9%, p<0.001). Compared to TCGA Caucasian race (TCGA-white), Chinese BC patients had a higher alteration frequency (45.6% vs. 34.7%, p<0.001). The p.H1047R mutation predominantly occurred among three hot spots (p.E545K, p.E542K and p.H1047R) for Chinese BC compared to that of the TCGA-white cohort (66.1% vs 43.7%, p=0.01). Nine novel mutation sites of PIK3CA were observed in the Chinese cohort that was absent among Caucasian BC patients. Among the four ER/HER2 molecular subtypes, ER+/HER2+ tumors harbored the most PIK3CA alterations (51.6%), while ER-/HER2- harbored the least (30.0%). However the latter presented the highest frequency of copy number amplification (19.05%). Conclusion: PIK3CA alterations prevail in nearly half of Chinese BC patients and has some different molecular features compared to that of Caucasian BC patients. The PIK3CA distribution patterns differed among four ER/HER2 subtypes. The results provide more insights for evaluating the results of PIK3CA inhibitors.

Citation Format: Minghan Jia, Ning Liao, Bo Chen, Guochun Zhang, Yulei Wang, Xiaoqing Chen, Liping Guo, Li Cao, Hsiaopei Mok, Chongyang Ren, Kai Li, Cheukfai Li, Lingzhu Wen, Jiali Lin, Guangnan Wei, Zhou Zhang, Charles M Balch. PIK3CA somatic alterations in 412 chinese invasive breast cancers: Higher frequency of mutant H1047R detected by next generation sequencing compared to breast cancer in caucasians [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 P4-09-11.
Abstract P4-12-16: A seven year single institution experience with IntrabeamTM intraoperative radiation therapy:recurrence rates and predictors of recurrence
Authors: Munford Christina , Burak William E , Miller Krista , Davis Jennifer , Neal Nicole , Price Caleb , Bertke Matthew , Hasselle Michael , Pederson Aaron
Published: March 2020

Objectives: Patients undergoing single fraction intraoperative radiation therapy (IORT) for early stage breast cancer were analyzed to determine rates of local recurrence and to identify predictors of local recurrence.

Materials and Methods: Patients who underwent intraoperative radiotherapy (IORT 20 Gray at 50kV using the INTRABEAMTM IORT system) have been analyzed over a 7 year period. The procedures were performed at a single institution by a single surgical and radiation oncology group. Post-operative whole breast radiotherapy (WBRT) was generally recommended in high risk patients with positive sentinel lymph nodes (SLN), lymphovascular invasion (LVI), extensive intraductal component (EIC), or positive margins requiring re-excision. Local recurrence was defined as any same breast recurrence during the follow-up period.

Results: A total of 438 patients were included in the analysis. Median follow-up was 35 months. Median age was 68 years, mean tumor size on preoperative ultrasound was 1.2 cm. Patient characteristics are listed below:

Patient/Tumor CharacteristicnGrade 1-232474.5%Grade 311125.5%Presence of LVI429.9%Presence of EIC4811.6%ER Negative429.7%PR Negative7918.4%DCIS only6514.4%Invasive Lobular only102.2%Positive SLN276.9%Re-excision performed6013.7%

A total of 16 patients (3.7%) had a local or simultaneous local/regional recurrence. Median time to recurrence was 24.5 months. When analyzing associations between predictor variables and local recurrence using logistic regression, it was found that high tumor grade, EIC, LVI, DCIS or DCIS component, and need for re-excision were significant (p<0.05) predictors of local recurrence. Furthermore, there was a strong association with local recurrence and time to local recurrence when adjuvant endocrine therapy was recommended but the patient was either non-compliant or discontinued use due to side-effects (odds ratio 0.064, p<0.0005).

Conclusions: INTRABEAMTM IORT can be used in select breast cancer patients with low local recurrence rates. Unfavorable tumor features and non-compliance with adjuvant endocrine therapy result in the highest risk of local recurrence. Better patient selection and pre-treatment education should minimize this risk.

Citation Format: Christina Munford, William E Burak Jr, Krista Miller, Jennifer Davis, Nicole Neal, Caleb Price, Matthew Bertke, Michael Hasselle, Aaron Pederson. A seven year single institution experience with IntrabeamTM intraoperative radiation therapy:recurrence rates and predictors of recurrence [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 P4-12-16.
Abstract P4-17-06: Treatment strategies in male breast cancer: Results of a prospective multicenter study
Authors: Eggemann Holm , Brucker Cosima , Schirrmeister Susen , Ringsdorf Uta , Augustin Doris , Schrauder Michael , Thill Marc , Flock Felix , Kraudelt Susanne , Gad Gabriele , Kleine-Tebbe Anke , Reinisch Mattea , Dan Costa Serban- , Ignatov Atanas
Published: March 2020

Background. In this prospective analysis, we aimed to characterize the treatment opinions on male breast cancer (MBC). Patients and methods. In this prospective cohort study we included patients treated between May2009 and June 2018 for MBC. Results. The median follow-up was 30 months (range 2-84 months) and the median age at diagnosis was 69 years (range 27-96 years). Radical mastectomy was performed in 354 (96.2%) cases. Most (n=194, 52.9%) patients underwent sentinel-node biopsy (SNB). However, the vast majority of patients with clinical and sonographic suspicious axillary lymph nodes (n=72, 81.8%) underwent ALND. Adjuvant radiation of chest wall post mastectomy or of the breast post breast conserving surgery was performed in 193 (51.9%) patients. Systemic therapy was administered to 155 (41.0%) patients, and was administered predominantly in the adjuvant setting. Most common was anthracycline-taxane-based therapy. Of patients with HER2 (n=43) overexpressing tumors, 29 (67.4%) received trastuzumab. Adjuvant endocrine therapy was administered to 92.3% of patients, predominantly tamoxifen. Important decision criteria for adjuvant radiation and chemotherapy were advanced stage of disease, lymph node metastases, undifferentiated tumors, lymph- and blood vessel invasion. During the follow up period 609 cycles of chemotherapy were administered (median 6 cycles per person). Haematological and non-haematological toxic effects were observed in 68 (16.4%) and 57 (53.3%) patients, respectively. Grade 3 and 4 haematological events were rare. The most common was neutropenia in 17 (15.8%) and febrile neutropenia in 10 (9.3%) cases. Nausea and vomiting were the most commonly observed grade 3 and 4 non-haematological adverse events observed in 7 (4.6%) cases. Endocrine therapy was discontinued in 53 (16.2%) patients and chemotherapy in 25 (16.1%) cases. Conclusions. In this large prospective study, we found that MBC is treated according to current guidelines and treatment seems to be not inferior in comparison with that treatment of FBC.

Citation Format: Holm Eggemann, Cosima Brucker, Susen Schirrmeister, Uta Ringsdorf, Doris Augustin, Michael Schrauder, Marc Thill, Felix Flock, Susanne Kraudelt, Gabriele Gad, Anke Kleine-Tebbe, Mattea Reinisch, Serban- Dan Costa, Atanas Ignatov. Treatment strategies in male breast cancer: Results of a prospective multicenter study [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 P4-17-06.
Abstract P5-01-02: Identification and validation of a serum microRNA panel for detection of early-stage breast cancer
Authors: Zhou Lihan , Zou Ruiyang , Loke Sau Yeen , Hartman Mikael , Goo Patrick C.K , Lee-Lim Ann S.G. , Too Heng-Phon
Published: March 2020

Background: Survival outcomes of breast cancer patients can be significantly improved by early detection and treatment. Implementation of mammogram-based screening has significantly improved early detection of breast cancer in the west. However, the use of screening mammography is less prevalent in Asia partly due to social and cultural reasons. The aim of this study was to determine if a serum microRNA (miRNA) panel could be used as blood-based biomarkers to assist in the early detection of breast cancer.

Methods: We carried out a multi-center, multi-ethnic study to identify and validate miRNA biomarkers for the early detection of breast cancer. A total of 1042 subjects including 540 breast cancer cases (predominantly stage 1 and 2 cases) and 502 matched controls from 6 independent sources were included in this study. Among these, there were 750 American and European subjects recruited by biobanks and 292 Singaporean Asian Subjects recruited at the National Cancer Centre Singapore and the National University Hospital. The study was conducted in 3 phases in which sera of 289 European Caucasian serum samples (Discovery Cohort) were first interrogated to identify differentially expressed miRNAs between early-stage breast cancer cases and matched controls among 520 circulating miRNA candidates by quantitative RT-PCR using MiRXES assays. The remaining 753 subjects from 5 independent sources were assigned into two groups for biomarker optimization/algorithm development (Optimization Cohort, n=374) and validation (Validation Cohort, n=379).

Results: Among the 520 circulating miRNAs measured, 241 were quantified in absolute copy numbers for 289 subjects in the Discovery Cohort. Thirty-three candidate miRNAs were identified. These miRNAs consistently showed differential expression between cancer and control subjects in the Optimization Cohort. A multi-variant panel of 8 miRNAs and an algorithm was developed using the Discovery and Optimization Cohort, with an AUC of 0.981 and 0.918 respectively. When validated in the independent Validation Cohort, the panel demonstrated an AUC of 0.915.

Conclusion: We developed and validated a serum miRNA panel that is both sensitive (72.2 - 77.4%) and specific (90.2 - 91.5%) in detecting early stage of breast cancer in both Caucasian and Asian populations.

Citation Format: Lihan Zhou, Ruiyang Zou, Sau Yeen Loke, Mikael Hartman, Patrick C.K Goo, Ann S.G. Lee-Lim, Heng-Phon Too. Identification and validation of a serum microRNA panel for detection of early-stage 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 P5-01-02.
Abstract P5-03-10: The spectrum of BRCA1 and BRCA2 mutations and clinicopathologic characteristics of young-onset breast cancer in BRCA-carriers and non-carriers
Authors: Chen Lili , Fu Fangmeng , Lv Jinxing , Wang Chuan
Published: March 2020

Background: For now, Seldom studies have reported that relationship between BRCA1/2 mutation and their clinical characteristics in young-onset breast cancers. This study is the first article which characterizes the risk factor profiles in Chinese patients selected by the age of onset (<40 years old).Patient and method:A total of 1371 consecutive unselected Chinese young-onset breast cancer patients were collected form Fujian Union hospital, China, screened for germline BRCA1/2 mutation. The full-exome sequencing in the next generation sequencing technology was performed in all patients to examine the BRCA1/2 mutation.Result: In our study, 25 (1.8%) and 61 (4.4%) patients were identified with BRCA1 and BRCA2 mutation among the unselected early-onset breast cancer patients, respectively. BRCA1 mutations were associated with pregnancies (p=0.026), BRCA1-carriers had a higher likelihood of HR positive(p<0.001), or HER-2 negative(p<0.001), or high grade(p=0.002) than non-carriers. Among BRCA2 mutations, the age of onset was younger than non-carriers(P=0.017), BRCA2-carriers were more likely to have lymph node metastasis(P=0.004). with HR positive or HER-2 negative were likely to detected positive for BRCA2(p<0.001).

Citation Format: Lili Chen, Fangmeng Fu, Jinxing Lv, Chuan Wang. The spectrum of BRCA1 and BRCA2 mutations and clinicopathologic characteristics of young-onset breast cancer in BRCA-carriers and non-carriers [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 P5-03-10.
Abstract P5-05-12: Small molecule targeting regulated cell death pathways in treating triple negative breast cancer
Authors: Yenugonda Venkata Mahidhar , Waters Ariana , Yadavalli Sivaramakrishna , Marzese Diego , Senugupta Surojeet , Nurmammadov Elmar , Quan Yueqin , Nomura Natsuko , Allnutt Annamarie , Kesari Santosh
Published: March 2020

The absence of hormone and Her2 receptor expression in triple negative breast cancer (TNBC) precludes the use of targeted therapy available for other breast cancer subtypes, and cytotoxic chemotherapy such as paclitaxel and doxorubicin remains the mainstay of treatment for TNBC. However, patients with TNBC have higher relapse rates, with residual disease after chemotherapy and shorter overall survival, leaving space for further improvement beyond these cytotoxic chemotherapies. We have identified a new chemical entity, VMY- BC-1, that potently blocks growth in TNBC cell lines compared to other breast cancer subgroups or normal-like breast epithelial cells. Our molecule reduces invasion and induces apoptosis in TNBC cell lines. VMY-BC-1 is orally bioavailable and has promising pharmacological properties, and has demonstrated TNBC growth inhibition in vivo. Quantitative proteomics with tandem mass tag (TMT) and Ingenuity Pathway Analysis (IPA) identified significantly altered pathways upon treatment with VMY-BC-1 in the human TNBC cell line, MDA-MB-231. These include activation of the apoptosis, autophagy, and DNA damage pathways, and inhibition of the mTOR1, PI3K, and AKT pathways (Z score = 0.156, p value =1.97E-10). Thermal proteome profiling (TPP) analysis identified proteins interacting with VMY-BC-1 that relate to activated autophagy and DNA damage pathways, such as UNC-51 like kinase 1 (ULK1) and ataxia-telangiectasia mutated (ATM). Importantly, in line with our in vitro observations, in addition to a significantly lower expression of ULK1 on TNBC (T-test; p value = 2.127E-10), we observed that patients with tumors with high ULK1 expression have a larger relapse-free survival (n=3,951; HR=0.77 [0.69-0.86]; log rank; p=5.1E-06). Moreover, our small molecules activated autophagy mediated signaling pathways through ULK1 phosphorylation. These data suggest that autophagy and DNA damage pathways could be therapeutically targeted in TNBC.

Citation Format: Venkata Mahidhar Yenugonda, Ariana Waters, Sivaramakrishna Yadavalli, Diego Marzese, Surojeet Senugupta, Elmar Nurmammadov, Yueqin Quan, Natsuko Nomura, Annamarie Allnutt, Santosh Kesari. Small molecule targeting regulated cell death pathways in treating 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 P5-05-12.
Abstract P5-06-07: Desloratadine and loratadine increase breast cancer survival
Authors: Olsson Håkan Lars , Fritz Ildiko , Wagner Philippe
Published: March 2020

Background: As tumors maintain an inflammatory microenvironment, anti-inflammatory medication can be used in cancer therapy. While H2-antihistamines have already shown effects as adjuvant anti-cancer drugs, H1-antihistamines have not been widely studied in this role, though they are among the most ubiquitously used medications globally, and have become increasingly sophisticated, affordable, and safe. Here, we aim to determine the effects of H1-antihistamines on breast cancer mortality.

Methods: We investigated the effects of six H1-antihistamines (cetirizine, clemastine, desloratadine, ebastine, fexofenadine and loratadine) on breast cancer-specific and overall mortality in a nation-wide register-based study of all 61,627 Swedish women with newly diagnosed breast cancer July 1st 2005 - December 31st 2013. 14,711 women used H1-antihistamines. Both peri- and post-diagnostic antihistamine use was analyzed, using Cox regression models, and use in patient subgroups based on age or estrogen receptor status.

Results: We found a consistently beneficial effect of desloratadine use (HR = 0·67; 95% CI 0·55-0·81, P < 0·001) on survival, as well as of loratadine use (HR = 0·80; 95% CI 0·67-0·95, P = 0·012), regardless of age or estrogen receptor status, or whether breast cancer-specific or overall survival was analyzed, and a consistently negative effect on survival of clemastine use (HR = 1·45; 95% CI 1·27-1·67, P <0·001).

Conclusions: We suggest immediate trials of desloratadine and loratadine as adjuvant treatment of breast cancer. Especially promising is the results for ER-breast cancer. Further studies on the effects of ebastine and possibly fexofenadine may be merited, as well as further studies of H1-antihistamines, particularly desloratadine, as treatment options for other malignancies.

Breast cancer survival adjusted for prognostic factorsTypeHRLow CIHighCIUp-valueCetirizin1.160.981.350.07clemasine1.341.131.590.0006desloratadine0.680.550.860.001ebastin0.490.270.860.01fexofenadin1.060.571.970.85loratadine0.780.620.960.02

Citation Format: Håkan Lars Olsson, Ildiko Fritz, Philippe Wagner. Desloratadine and loratadine increase breast cancer 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 P5-06-07.
Abstract P5-07-12: Prediction and clinical utility of a contralateral breast cancer risk model
Authors: Giardiello Daniele , Steyerberg Ewout W , Hauptmann Michael , Adank Muriel A , Jager Agnes , Oldenburg Hester OA , Hooning Maartje J , Schmidt Marjanka K ,   Breast Cancer Association Consortium
Published: March 2020

Background: Breast cancer survivors are at risk for contralateral breast cancer (CBC), with the consequent burden of further treatment and potentially less favorable prognosis. We aimed to develop and validate a CBC risk prediction model, and evaluate its applicability for clinical decision-making.

Methods: We included data of 132,756 invasive non-metastatic breast cancer patients from 20 studies with 4,682 CBC events and a median follow-up of 8.8 years. We developed a multivariable Fine and Gray prediction model (PredictCBC-1A) including patient, primary tumor, and treatment characteristics, and BRCA1/2 germline mutation status, accounting for the competing risks of death and distant metastasis. We also developed a model without BRCA1/2 mutation status (PredictCBC-1B). Prediction performance was evaluated using calibration and discrimination, calculated by a time-dependent Area-Under-the-Curve (AUC) at 5 and 10 years after diagnosis of primary breast cancer, and an internal-external cross-validation procedure. Decision curve analysis was performed to evaluate the net benefit of the model to quantify clinical utility.

Results: In the multivariable model, BRCA1/2 germline mutation status, family history and systemic adjuvant treatment showed the strongest associations with CBC risk. The AUC of PredictCBC-1A was 0.63 (95% prediction interval (PI) at 5 years: 0.52–0.74; at 10 years: 0.53–0.72). Calibration in-the-large was -0.13 (95%PI: -1.62–1.37) and the calibration slope was 0.90 (95%PI: 0.73–1.08). The AUC of Predict-1B at 10 years was 0.59 (95% PI: 0.52–0.66); calibration was slightly lower. Decision curve analysis for preventive contralateral mastectomy showed potential clinical utility of PredictCBC-1A between thresholds of 4-10% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers.

Conclusions: We developed a reasonably calibrated model to predict the risk of CBC in women of European-descent, however, prediction accuracy was moderate. Our model shows potential for improved risk counseling, but decision regarding contralateral preventive mastectomy, especially in the general breast cancer population, remains challenging.

Citation Format: Daniele Giardiello, Ewout W Steyerberg, Michael Hauptmann, Muriel A Adank, Agnes Jager, Hester OA Oldenburg, Maartje J Hooning, Marjanka K Schmidt, Breast Cancer Association Consortium. Prediction and clinical utility of a contralateral breast cancer risk model [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 P5-07-12.
Abstract P5-08-23: Personalized, prevention decision aid developed for breast cancer risk-reducing discussions and interventions in the WISDOM study
Authors: Keane Holly , Huilgol Yash , Shibley W. Patrick , Shieh Yiwey , Goodman Deborah , Tice Jeff , Belkora Jeff , Sepucha Karen , Ozzane Elissa , Fiscalini Allison , Esserman Laura
Published: March 2020

Problem statement: Breast cancer risk reduction has been validated by Level I evidence generated in large-scale clinical trials, however uptake of chemoprevention among women at high risk remains very low.

Methods: A patient-facing shared decision-making aid was designed to inform women enrolled in the PCORI-funded WISDOM Study of their individualized breast cancer risk and ways to reduce their risk. It built upon a breast health decision tool used for the prior ten years. The tool displays the key factors that are used to calculate a participant’s risk (Breast Cancer Surveillance Consortium [BCSC] and Polygenic Risk Score). The aid also estimates the anticipated change in a participant’s risk due to particular risk-reduction interventions (medication, lifestyle). After Institutional Review Board approval, we used a mixed-methods analysis to evaluate the decision aid. Expert opinion was sought from decision scientists, low literacy experts, breast health specialists, epidemiologists, and breast cancer specialists, in order to generate a tool with suitable language and adequate communication of content. We piloted the decision-making aid with 15 elevated risk WISDOM Study participants without a common mutation associated with breast cancer.

Results: To date, the pilot has enrolled 10 elevated-risk participants with an average age of 63. Six have completed the quantitative survey. 3 (50%) indicated that they would consider chemoprevention. 6 (100%) indicated that they would consider lifestyle changes, such as exercise or reducing their body mass index (BMI). 3 (50%) indicated the aid has been “extremely helpful” and 6 (100%) indicated that they had a better understanding of their breast cancer risk. Participants also indicated the benefit of visuals and greater engagement with high-risk counselors when using the aid. The full pilot data plus the ongoing experience will be presented.

Conclusion: The WISDOM Study shared decision-making aid represents a novel, participant-centered approach to integrate breast cancer prevention and personal breast cancer risk. This decision aid will be used in the WISDOM Study to evaluate whether risk-based screening will improve uptake of chemoprevention in the WISDOM Study population.

Citation Format: Holly Keane, Yash Huilgol, W. Patrick Shibley, Yiwey Shieh, Deborah Goodman, Jeff Tice, Jeff Belkora, Karen Sepucha, Elissa Ozzane, Allison Fiscalini, Laura Esserman. Personalized, prevention decision aid developed for breast cancer risk-reducing discussions and interventions in the WISDOM study [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 P5-08-23.
Abstract P5-11-20: Efficacy observation of 306 patients with fulvestrant 500mg treatment in hormone-receptor positive HER2 negative metastasis breast cancer, a real world study
Authors: Lei Wen , Li Huiping , Song Guohong , Zhang Ruyan , Ran Ran , Yan Ying
Published: March 2020

Background: Fulvestrant 500mg has been proved better efficacy in breast cancer with hormone receptor positive (HR+),and then become an optional strategy for primary or second line treatment of HR+ positive metastasis breast cancer (MBC).

Methods: In this real world study, we retrospectively analyzed the patients with HR+ HER 2 negative MBC who received fulvestrant 500mg treatment at Beijing cancer hospital during January 2015 to December 2018. Clinical benefit rate (CBR), progression free survival (PFS), overall survival (OS) and adverse events were investigated.

Results: There were 306 patients enrolled, median age was 48.7(range 20-75) years, median line of fulvestrant was 2.11(range 1-6), 68.3%(209/306) patients were involved with visceral metastasis. The CBR was 68.6%, median PFS was 8.41m (95%CI: 7.079m-9.743m, range 0.89m-80.16m). Among the patients received fulvestrant at the first line, the PFS was 10.55m(95%CI:6.46m-14.64m, range 0.92m-34.3m). The median OS hasn’t been obtained. In subgroup analysis, the patients without liver metastasis(12.49m vs. 4.60m, p<0.001), small tumor burden(metastasis number 1-2 vs. 3-4 vs. >4, 12.65m vs. 7.72m vs. 3.98m respectively, p<0.001) and experience no or less line of chemotherapy(none vs. 1-2 lines vs. >2 lines, 14.06m vs. 7.79m vs. 3.52m respectively, p<0.001) for metastatic disease were obtained more benefit from fulvestrant treatment. For patients with visceral metastasis, the patients absence of liver metastasis was corelated with longer PFS 9.27m than 4.60m(p<0.001). There were 20(6.54%) adverse events occurred in 306 patients, 95%(19/20) were grade 1-2. The most common adverse event was oral ulcer, and serious adverse events were observed in 1 patients (0.33%) with pulmonary embolism.

Conclusions: Fulvestrant was an effective and safe regimen in endocrine therapy for hormone receptor positive HER2 negative MBC. The patients who were in first line treatment, absence of liver metastasis and small tumor burden might be more benefit from fulvestrant.

Corresponding authors: Huiping Li, huipingli2012@hotmail.com; Guohong Song, songguohong918@hotmail.com, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital & Institute, 52 Fucheng Rd, Beijing 100142, China

Citation Format: Wen Lei, Huiping Li, Guohong Song, Ruyan Zhang, Ran Ran, Ying Yan. Efficacy observation of 306 patients with fulvestrant 500mg treatment in hormone-receptor positive HER2 negative metastasis breast cancer, a real world study [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 P5-11-20.
Abstract P5-12-10: Tamoxifen versus anastrozole as adjuvant therapy in early stage breast cancer in premenopausal women on ovarian function suppression: A meta-analysis of randomized clinical trials
Authors: Sidahmed Shima , Abdalla Ahmed , Kheiri Babikir , Bachuwa Ghassan
Published: March 2020

Introduction: Different strategies have been studied in adjuvant treatment for hormone positive early stage breast cancer. The addition of ovarian function suppression (OFS) therapy to Tamoxifen in premenopausal women was proven to prolong disease-free survival and overall survival compared with Tamoxifen alone. However, trials that examined the use of anastrozole inhibitor (AI) in the presence of OFS in comparison to Tamoxifen with OFS showed contradicting results. Therefore, we conducted this meta-analysis of randomized clinical trials (RCTs) comparing these two approaches. Methods: A comprehensive search of the electronic database (PubMed) from inception to July 2019 was conducted to identify all RCTs that compared OFS with Tamoxifen versus OFS with AI in premenopausal females with breast cancer. The primary endpoint was event-free survival, defined as females without events (local or distant recurrence, cancer in the contralateral breast, secondary non-breast malignancy, or death) at the longest follow-up duration. The secondary endpoints were death, the incidence of distant metastasis, and the incidence of contralateral breast cancer. We calculated the odds ratios (ORs) and 95% confidence intervals (CIs) for all dichotomous data. Heterogeneity was explored by the Cochran Q statistic and I-squared (I2) statistic. P-values <0.05 were considered statistically significant. Results: We included 4 RCTs with 7,202 total patients (mean age 43.8). At baseline, T1 disease represented 53.5% and nodal positive disease was 44.5%. After a median follow-up period of 78 months, there was a non-significant reduction of event-free survival with the AI group compared with the Tamoxifen group (OR=1.13; 95% CI=0.87-1.47; P=0.37). In addition, there were no significant differences between both groups with regard to deaths (OR=1.11; 95% CI=0.50-2.47; P=0.8). The incidence of distant metastasis did not differ between both groups (OR=1.02; 95% CI=0.82-1.26; P=0.86). Similarly, there were no differences in the incidence of contralateral breast cancer between both groups (OR=1.30; 95% CI=0.86-1.96; P=0.21). Conclusions: Among premenopausal women with early breast cancer, the use of AI plus OFS versus Tamoxifen plus OFS was not associated with significantly reduced event-free survival. Given the limited number of RCTs and low events, further, adequately powered trials are needed to validate this finding.

Citation Format: Shima Sidahmed, Ahmed Abdalla, Babikir Kheiri, Ghassan Bachuwa. Tamoxifen versus anastrozole as adjuvant therapy in early stage breast cancer in premenopausal women on ovarian function suppression: A meta-analysis of randomized clinical trials [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 P5-12-10.