bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P3-03-43: Incorporation of MSKCC nomogram to guide the application of intra-operative sentinel lymph node frozen section evaluation in patients with early breast cancer
Authors: Yang H , Wang S , Shen D , Cao Y , Tong F , Chen D , Liu P , Peng Y 
Published: May 2019

Abstract
Background and Objectives:
Although de-escalation of axillary surgery becomes more popular, axillary lymph node dissection (ALND) is still the standard care for sentinel lymph node(SLN) positive patients not meeting the criteria of ACOSOG Z0011 in many hospitals, and frozen section (FS) of SLN is one of the valuble intra-operative assesments to avoid axilla re-operation although it was controversial due to accuracy and efficiency concerns. This study was to assess the performance of selective use of frozen section evaluation guided by MSKCC lymph node metastasis risk prediction nomogram to optimize the proceudure to be more accurate and cost effective.
Methods:
Surgical pathology records of consecutive 2582 biopsies in 2552 patients breast cancer patients from 2011 to 2017 were reviewed, intra-operative frozen section diagnosis were compared to post-operative paraffin reports. We calculated the sensitivity, specificity, accuracy and FNR for different MSKCC risk, the axilla re-operation rate with or without FS and the number needed to treat (NNT) to avoid second ALND was also analyzed.
Results:
The sensitivity, specificity, and FNR of FS were 84.7%, 99.9%, and 15.3% respectively. The axilla re-operation rates were significantly decreased if FS was done(4.7%±0.4% with FS versus 35.8%±5.8% without FS, P&lt;0.001). The estimated axilla re-operation rate without FS was positively correlated with MSKCC risk(r=0.99, P&lt;0.001), while NNT to avoid second ALND by FS were negatively correlated with MSKCC risk(r=-0.98, P&lt;0.001). When patients were divided into four groups according to quartile MSKCC risk, the axilla re-excisional rates were 18.4%, 25.1%, 38.7%, 58.7% without FS, while 4.8%, 3.2%, 5.6%, 3.2% with FS, and NNT correspondingly decreased from 7.3, 4.5, 3.0 to 1.8. An decision-making algorithm for application of FS was proposed.
Conclusion:
Stratified decision-making algorithm based on MSKCC prediction model improved the efficiency of FS to avoid axilla re-operatioin in patients undergoing sentinel lymph node biopsy. We recommend FS be restricted to patients with MSKCC risk higher than 0.5 who do not meet ACOSOG Z0011 criteria.
Citation Format: Yang H, Wang S, Shen D, Cao Y, Tong F, Chen D, Liu P, Peng Y. Incorporation of MSKCC nomogram to guide the application of intra-operative sentinel lymph node frozen section evaluation in patients with early breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-03-43.
Abstract P3-06-12: Genetic heterogeneity of DCIS is a predictor of invasive cancer
Authors: Fortunato A , Mallo D , King L , Hardman T , Hall A , Marks JR , Hwang S , Maley CC 
Published: May 2019

Abstract
Background: Heterogeneity is a hallmark of human cancers that is apparent both between and within individual tumors. Intra-tumor heterogeneity provides the genetic fuel for natural selection in clonal evolution and cancer progression. Tumors with high levels of genetic heterogeneity are hypothesized to be more likely to progress to invasion and metastasis
Methods: We measured the mutational loads from separate areas of pure DCIS and compared this to genetic heterogeneity in DCIS lesions that co-exist with invasive cancer, as a surrogate for progression. Cases of pure DCIS and DCIS diagnosed concurrent with invasive cancer were identified. Two areas of DCIS from each case a minimum of 0.8 cm apart and control tissues were macro-dissected and the DNA extracted from FFPE samples. To analyze the data, we developed new bioinformatics methods that allowed analysis of small amounts of degraded DNA extracted from FFPE samples across multiple regions. Our bioinformatics pipeline was optimized on a series of 28 independent technical replicates of the same DNA sample sequenced twice, as training tools to find the best filtering parameters.
Results: Whole exome sequencing was performed on two geospatially separated blocks for each case (41 pure DCIS and 30 DCIS adjacent to invasive disease). Minimum coverage for inclusion in this study was 40X over at least 50% of the exome. We used the ratio of private mutations (only in 1 area) to public (found in both areas) mutations as a measure of intra-tumor heterogeneity. Overall mutational load of DCIS was not a significant predictor to progression; however notably, DCIS adjacent to invasive disease patients had a higher ratio of private/public mutations (heterogeneity) in coding domains (Mann-Whitney p=0.016. Functional analysis of mutated coding genes (DAVID 6.8) shows a statistically significant enrichment in signal transduction, olfactory receptors (G-protein-coupled receptors) and cell-matrix interactions in both tumor types, after FDR correction. DCIS adjacent to invasive disease had an enrichment of mutated genes involved in additional cellular functions such as microtubule activity (fold enrichment =7.6, FDR=0.002), protein-protein interactions (fold enrichment =3.65, FDR=5.11E-04) and extracellular matrix remodeling (fold enrichment =8.3, FDR=0.02).
Conclusion: We present an approach to measure clonal heterogeneity using a bulk sequencing strategy applied to geospatially distinct foci of DCIS. Our findings suggest that functional heterogeneity may play an important evolutionary role as a driver for invasive progression.
Citation Format: Fortunato A, Mallo D, King L, Hardman T, Hall A, Marks JR, Hwang S, Maley CC. Genetic heterogeneity of DCIS is a predictor of invasive cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-06-12.
Abstract P3-07-03: Withdrawn
Authors: Rinkenbaugh AL , Sinha VC , Zhang X , Shao J , Piwnica-Worms H 
Published: May 2019

Abstract
This abstract was withdrawn by the authors.
Citation Format: Rinkenbaugh AL, Sinha VC, Zhang X, Shao J, Piwnica-Worms H. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-07-03.
Abstract P3-07-07: Withdrawn
Authors: Jiang Y-Z , Ma D , Suo C , Shi J , Xue M , Stover DG , Verschraegen C , Kaklamani V , Wang P , Shi L , Huang W , Shao Z-M 
Published: May 2019

Abstract
This abstract was withdrawn by the authors.
Citation Format: Jiang Y-Z, Ma D, Suo C, Shi J, Xue M, Stover DG, Verschraegen C, Kaklamani V, Wang P, Shi L, Huang W, Shao Z-M. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-07-07.
Abstract P3-08-12: PIK3CA mutations in breast cancer: Mutational landscape and clinical implications in ER+/HER2- subtype
Authors: Ahn HK , Park S , Hyun SH , Park K , Lee E , Kim J-Y , Nam SJ , Kim SW , Lee JE , Lee SK , Yu JH , Ahn JS , Im Y-H , Park YH 
Published: May 2019

Abstract
Introduction: PIK3CA mutation is one of the most frequent genomic alterations in breast cancer. We evaluated PIK3CA mutational status including spatial and temporal heterogeneity, clinical characteristics and prognostic impact focused on ER+/HER2- subtype.
Methods: We performed targeted ultra-deep sequencing (CancerSCAN™) of breast cancer tissue in a prospective cohort. Burden of disease was assessed by metabolic tumor volume(MTV) in 18F-FDG-PET scan. Association with clinical characteristics or survival were tested in ER+/HER2- subtype, using Chi square test or Kaplan-Meier method.
Results: PIK3CA analyses were performed in 1274 breast cancer specimens from 1091 patients. 957 patients had early breast cancer. PIK3CA alterations were found in 397 patients(36.3%), and frequency of PIK3CA mutation was significantly lower in triple negative breast cancer(19.0%), compared with 40.4% in ER+/HER2-, 40.9% in ER+/HER2+, and 45.2% in ER-/HER2+ subtype(p&lt;0.0001). 158 patients had more than two biopsies. Among 92 patients with second biopsy within one month, 11%(10/92) had spatial heterogeneity of PIK3CA mutation. After neoadjuvant chemotherapy, 10%(3/30) of patients had change of PIK3CA mutational status. Serial biopsy at time of recurrence revealed loss or gain of PIK3CA mutation in 10 out of 59 patients (17%). In ER+/HER2- subtype, PIK3CA had a trend toward longer distant disease free survival without statistical significance. In patients with stage IV ER+/HER2- disease, PIK3CA hotspot mutations were associated with significant longer overall survival(OS) (71.0 vs. 37.8 months, p=0.048) and better progression free survival(PFS) at 1st line palliative treatment (37.7 vs. 9.4 months, p = 0.0004). Frequency of symptomatic recurrence, recurrence as oligometastases, and specific metastatic sites were not associated with PIK3CA mutational status, except that bone metastases at first distant metastases was less prevalent in patients with PIK3CA hotspot mutations(35.6% vs. 53.8% in PIK3CA wt, p=0.048). Metabolic tumor volume(MTV) at time of first distant metastases was not associated with presence of PIK3CA mutation.
Conclusion: We observed variations in PIK3CA mutational status in more than 10% of patients with &gt;1 repeated biopsy. In stage IV ER+/HER2- disease, PIK3CA hotspot mutation seemed to be associated with longer PFS and OS, however metabolic tumor burden was not associated with PIK3CA alterations.
Citation Format: Ahn HK, Park S, Hyun SH, Park K, Lee E, Kim J-Y, Nam SJ, Kim SW, Lee JE, Lee SK, Yu JH, Ahn JS, Im Y-H, Park YH. PIK3CA mutations in breast cancer: Mutational landscape and clinical implications in ER+/HER2- subtype [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-08-12.
Abstract P3-08-24: Mutational characterization of HER2-positive breast cancer
Authors: Velasco Sánchez A , Gasol Cudos A , Morales S , Veas Rodriguez J , Serrate López A , Mele Olivé J , Canosa Morales C 
Published: May 2019

Abstract
Background: Studies of mutational analysis have been widely reported in various global series of breast cancer. However, in the era of different phenotypes of breast cancer, these analyses should be more specific in order to find differences in each phenotype that could predict response to treatment. Particularly HER2 positive is a special subtype with different connotations that make the analysis of its genotype very interesting.
Methods: Cohorts of 47 consecutive samples of HER2 positive breast cancer, treated in our institution were analyzed. It was conducted a mutational study with NGS technique of the most common genes involved in breast cancer.
Results: 10 patients were metastatic at diagnostic, 17 with negative estrogen receptor expression, the median value of Ki67 was 45 (20-95) and the median initial tumor size was 33.5 mm (18-111). Inmunohistochemical expression of HER2 was +3 in 31 tumors and +2 in 15 with a median ratio by FISH of 3,2 (1,18-8,3). We also analyzed the expression of HER by PCR of mRNA in 35 samples with a median expression of 2,49 (0,26-33,15). 38 patients underwent surgical excision of the tumor with a pathologic complete response observed in 19.
We found a total of 38 significant mutations and the genes with more frequent mutations were MCPH1 (100%), HNF1 (98%), p53 (96%), somatic BRCA1 (62%), TSC1 (30%), PIK3CA (23%), ATM (21%), ALK (15%) and somatic BRCA2 (13%). Although the aim of the study was to find the most frequent mutations in this subtype, we have also analyzed possible correlations of those with pathological response or with more common variables, finding no significance in any of them.
Conclusions: In our series, we found a high percentage of mutations in MCPH1, HNF1 and p53 genes with almost 100% of mutations in p53 that are also limited in a very specific area. Also interesting is the 62% of mutations found in BRCA1 and 13% in BRCA2 that could allow more specific treatments in this subgroup. Although the study did not have the power to assess the predictive factor of these mutations, it is very suggestive that in the 7 patients with BRCA mutations, 6 achieved a complete pathological response.
Citation Format: Velasco Sánchez A, Gasol Cudos A, Morales S, Veas Rodriguez J, Serrate López A, Mele Olivé J, Canosa Morales C. Mutational characterization of HER2-positive breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-08-24.
Abstract P3-09-03: RelB facilitates cell migration and invasion in breast cancer via MMP1 upregulation
Authors: Wang M , Tang J 
Published: May 2019

Abstract
Background: RelB is a subunit of the nuclear factor-κB (NF-κB) signaling famliy and appears aberrant expression in breast cancer. The aim of the present study was to further investigate the role of RelB in breast cancer and whether RelB might be a therapeutic target.
Methods: 120 cases of breast cancer patients were collected from the Jiangsu Province Hospital during 2015-2017. Immunohistochemistry (IHC) was performed to detect RelB expression in breast cancer tissues and para-cancer tissues. The relationship between RelB expression and clinical pathologic parameters were investigated. Detection the expression of RelB in 4 kinds of human breast cancer cell lines (MCF-7, T47D, MDA-MB-231, BT-549) by Western blot and RT-qPCR.Knockout of RelB in TNBC cell lines (BT-549 and MDA-MB-231) was using the CRISPR/Cas9 genome editing system. CCK-8 and flow cytometry were performed to observe the proliferation, cycle and apoptosis of MDA-MB-231 and BT-549 after knockout of RelB. Transwell and wound healing experiments were performed to observe cell invasion and migration ability. RT-PCR and Western blotting were performed to detect the expression of mRNA and protein of EMT marker and MMP1 respectively. The luciferase reporter gene was performed to detect whether RelB binding with MMP1 promoter region. In vivo efficacy was tested using the xenograft model and lung metastasis model.
Results: RelB was highly expressed in triple-negative breast cancer (TNBC) tissues compared with that in adjacent tissues. RelB levels were remarkably associated with the pTNM stage (p=0.01981) and ER expression (p=0.4689). RelB expressions in TNBC cell lines were higher than that of hormone receptor positive MCF-7 cells. In vitro studies showed that RelB deletion promoted apoptosis and suppressed breast cancer cell survival, migration and invasion by decreasing snail, vimentin and MMP1. RelB deletion inhibited cell cycle progression and G1/S transition by upregulating p21 and p27 expression. In vivo studies showed that 231-RelB-KO cells completely impaired tumor formation in xenograft models and lung metastasis model in nude mice.
Conclusion: RelB is aberrant constitutive expressed in clinical specimens and cell lines of breast cancer, especially in TNBC. RelB regulates malignant phenotypes of breast cancer, including cell survival, migration and invasion, as well as apoptosis and the cell cycle. Moreover, RelB can induce MMP1, which facilitates the invasion of tumor. Collectively, our findings highlight that RelB might serve as a therapeutic target for triple negative breast cancer.
Citation Format: Wang M, Tang J. RelB facilitates cell migration and invasion in breast cancer via MMP1 upregulation [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-09-03.
Abstract P3-09-06: CXCL1 chemokine stimulates migration and invasion in ER-negative breast cancer through activation of the ERK/MMP-2/9 signaling axis
Authors: Liu S , Yang C , Guo S , Chen R 
Published: May 2019

Abstract
Chemokine (C-X-C motif) ligand 1 (CXCL1), a member of the CXC chemokine family, has been reported to be a critical factor in inflammatory diseases and tumor progression. However, its functions and molecular mechanism in estrogen receptor α (ER) negative breast cancer (BC) has little been known. In this study, we discovered that CXCL1 is overexpression in ER-negative breast cancer tissues and cell lines compared with ER-positive patient tissues and cell lines. Treatment with recombinant human CXCL1 protein promotes ER-negative BC cell migration and invasion in dose-dependent manner and stimulates the activation of p-ERK1/2, but not p-STAT3 or p-AKT. Whereas, knockdown of CXCL1 in BC cells attenuates these effects. Moreover, CXCL1 induces the expression of MMP2/9 via ERK1/2 pathway. The blockage of ERK by its antagonists (U0126) can abolish the effect of CXCL1 on MMP2/9 expression. Furthermore, immunohistochemical (IHC) analysis revealsa strong positive correlation between CXCL1 and p-ERK1/2 expressions in BC tissues. In conclusion, our study illustrates that CXCL1 is highly expressed in ER-negative BC and stimulates cell migration and invasion through ERK/MMP2/9 pathway, which may serve as a potential therapeutictarget in ER-negative breast cancer.
Citation Format: Liu S, Yang C, Guo S, Chen R. CXCL1 chemokine stimulates migration and invasion in ER-negative breast cancer through activation of the ERK/MMP-2/9 signaling axis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-09-06.
Abstract P3-10-17: mRNA expression of HER2 by PCR as a strong predictor of pathologic response to neoadjuvant antiHER2 therapy
Authors: Gasol Cudós A , Morales Murillo S , Veas Rodriguez J , Velasco Sánchez A , Serrate López A , Melé Olivé J , Canosa Morales C 
Published: May 2019

Abstract
Background: Pathologic response to neoadjuvant therapy is the most important prognostic factor so new agents should aim to improve it. HER2 expression in breast cancer provides prognostic and predictive information of response to antiHER2 therapy. The quantification of HER2 expression by mRNA is one of the most potent markers of cellular dependence to HER2 pathway.
Methods: From a series of 160 patients with early or locally advanced HER2 positive breast cancer who received neoadjuvant treatment with chemotherapy and antiHER2 drugs, mRNA expression of HER2 was analyzed in 69 specimens and it was correlated to pathologic complete response (pCR).
Results: Median age was of 52.5 years (29-86), tumor size of 33mm (10-111), 39 (53%) patients had nodal involvement. Median ki67 expression was of 45% (17-80), 28 (38%) tumors were estrogen receptor (ER) positive and 46 (62%) negative. We also analyze the expression of tumor-infiltrating-lymphocytes (TILs) by immunohistochemistry in 43 samples because their expression is also a strong predictive of pathologic response. A total of 31/69 patients (45%) achieved a pCR with a median of mRNA expression of 7,55 (3,8 – 11) in comparison with 2.03 (1,2 -2,8) in patients without pCR (p: 0,002). In the univariable analysis, variables correlated to pCR were estrogen receptor=0 (OR 0,186 IC 95% 0,063-0,549, p: 0,002), mRNA (OR 5,689 IC 95% 1,854-17,452, p: 0,002) and TILs (OR 15,167 IC 95% 3,223-71,38, p: 0,001) and in the multivariable analysis, TILs and mRNA expression were found to be independent predictive factors for pCR. The quantification of HER2 by mRNA obtained an impressive response specially in ER negative patients with a rate of pCR of 100% in samples of mRNA expression upper of 3,6 and ER negative. However, patients with mRNA expression lower than 3,6 with a pCR rate of 32%, could reach to an 80% rate if they had high TILs expression.
Conclusions: Quantification of HER2 expression by mRNA is a strong predictive factor of pCR (OR 5,689); achieving a 100% pCR in ER negative tumors. TILs are also a predictive factor for pCR (OR 15,167) and its combination with mRNA expression could improve pCR rates; thus, patients with mRNA expression lower than 3,6, if they had a higher TILs expression could reach to an 80% pCR.
Citation Format: Gasol Cudós A, Morales Murillo S, Veas Rodriguez J, Velasco Sánchez A, Serrate López A, Melé Olivé J, Canosa Morales C. mRNA expression of HER2 by PCR as a strong predictor of pathologic response to neoadjuvant antiHER2 therapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-10-17.
Abstract P3-10-22: BluePrint molecular subtyping versus HER2 assessment by immunohistochemistry and FISH in the real-world diagnostic setting
Authors: Treece T , Audeh W , Navarro F , Wei J 
Published: May 2019

Abstract
Background: Both the Aphinity and ExteNET trials for anti-HER2 targeted agents were challenged in showing significant benefit of added HER2-targeted treatment. The findings suggested biological heterogeneity in HER2+ cancers, not entirely identified by IHC/FISH, requiring more nuanced biomarkers to clearly identify patient subsets who may derive benefit from new HER2-targeted agents. We have previously shown that BluePrint (80-gene) molecular subtyping reclassifies nearly half of HER2+/ER+ patients to Luminal-type with differential neoadjuvant treatment response (Whitworth, Ann Surg Oncol 2014; Whitworth, ASCO 2018). Here, we evaluated the reclassification rate in the real-world diagnostic setting. Methods: Physicians regularly provide pathology reports to Agendia, Inc for samples which are processed for MammaPrint (70-gene signature) and BluePrint molecular assays as part of routine diagnostic care. For this analysis, 4986 sequentially available pathology reports (submitted between October 2016 to October 2017) were reviewed; HER2 and ER IHC results were captured. The molecular subtype was compared to IHC/FISH status. Results: HER2 IHC/FISH results were available for 1568 samples. Of those, 85% (1330/1568) were HER2-nonamplified, 10% (153/1568) were HER2-equivocal, and 5% (85/1568) were HER2-amplified by IHC/FISH. Of the HER2-nonamplified tumors, BluePrint reclassified 0.1% (2/1330) as HER2-type. Of the HER2-equivocal tumors, none were HER2-type by BluePrint; 91% (139/153) were Luminal-type and 9% (14/153) were Basal-type. Of the HER2-amplified tumors, 15% (13/85) were dominant HER2-type, 79% (67/85) were dominant Luminal-type, and 6% (5/85) were Basal-type. Conclusions: In this set of tumors identified as HER2-amplified by IHC/FISH, BluePrint reclassified 85% of tumors to non-HER2 molecular subtypes, mostly Luminal-type for ER-positive tumors and Basal-type for ER-negative tumors. Moreover, BluePrint gave clarity where IHC/FISH could not, classifying all HER2-equivocal tumors to non-HER2 subtypes. Additional therapeutic options should be explored for HER2+/ER+ BluePrint Luminal-type patients who have observed much lower pCR rates versus BluePrint HER2-type patients (12% vs. 51%, respectively; Lee, AACR 2018).
HER2 IHC/FISH vs BluePrint SubtypeHER2 IHC/FISH StatusHER2-type Luminal-type Basal-type Total IHC ER-IHC ER+IHC ER-IHC ER+IHC ER-IHC ER+ Nonamplified (ER-Unknown, n=28)118120353361330Equivocal (ER-Unknown, n=6) 2131104153Amplified (ER-Unknown, n=2)112 664 85Total21310140067401568
Citation Format: Treece T, Audeh W, Navarro F, Wei J. BluePrint molecular subtyping versus HER2 assessment by immunohistochemistry and FISH in the real-world diagnostic setting [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-10-22.