bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P2-08-07: Prognostic significance of immune checkpoint receptors in node-negative breast cancer
Authors: Schmidt M , van de Sandt L , Heimes A-S , Battista M , Lebrecht A , Almstedt K , Hoffmann G , Rahnenführer J , Hengstler JG 
Published: May 2016

Abstract
Background: Immune checkpoint blockade is increasingly discussed in breast cancer. We examined the prognostic significance of the immune checkpoint receptors cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) in node-negative breast cancer.
Methods: Microarray based gene-expression data for CTLA-4 (221331_x_at) and PD-1 (207634_at) were analysed in four previously published cohorts (Mainz, Rotterdam, Transbig, Yu) of node-negative breast cancer patients not treated with adjuvant therapy (n=824). A meta-analysis of previously published cohorts was performed using a random effects model. Prognostic significance of CTLA-4 as well as PD-1 for metastasis-free survival (MFS) was examined in the whole cohort and in different molecular subtypes: luminal (ER+/HER2-), basal-like (ER-/HER2-) and HER2+. Independent prognostic relevance was analysed using multivariate Cox regression.
Results: Higher RNA expression of CTLA-4 was related to better MFS in a meta-analysis of the whole cohort (HR 0.58, 95% CI 0.38-0.88, P=0.0102). Prognostic significance was most pronounced in the HER2+ positive molecular subtype (HR 0.23, 95% CI 0.08-0.65, P=0.0062) as compared to luminal (HR 0.68, 95% CI 0.39-1.18, P=0.1744) and basal-like (HR 0.53, 95% CI 0.25-1.15), P=0.1087) carcinomas of the breast. PD-1 RNA expression, however, was not associated with outcome in the whole cohort of patients (HR 0.88, 95% CI 0.32-2.43, P=0.1853). A trend for improved survival was noticed in basal-like breast cancer (HR 0.40, 95% CI 0.15-1.08, P=0.0701). Neither luminal (HR 0.81, 95% CI 0.28-2.36, P=0.2122) nor HER2+ (HR 0.85, 95% CI 0.27-2.68, P=0.7759) patients showed an association of PD-1 with MFS. CTLA-4 showed independent prognostic significance (HR 0.393, 95% CI 0.224-0.688, P=0.001) in multivariate analysis. In addition to CTLA-4, only histological grade of differentiation (HR 2.335, 95% CI 1.490-3.660, P&lt;0.0001) and tumor size (HR 1.924, 95% CI 1.260-2.937, P=0.002), but neither PD-1 nor age nor HER2 status nor hormone receptor status retained an independent prognostic association with MFS.
Conclusions: The immune checkpoint receptor CTLA-4 has independent prognostic significance in node-negative breast cancer. Higher expression of CTLA-4 is associated with improved outcome. The prognostic impact of CTLA-4 differs between molecular subtypes and is most pronounced in HER2+ breast cancer.
Citation Format: Schmidt M, van de Sandt L, Heimes A-S, Battista M, Lebrecht A, Almstedt K, Hoffmann G, Rahnenführer J, Hengstler JG. Prognostic significance of immune checkpoint receptors in node-negative breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-08-07.
Abstract P2-08-17: Prognostic impact of breast cancer subtypes in elderly patients
Authors: Bergen ES , Tichy C , Berghoff AS , Rudas M , Dubsky P , Bago-Horvath Z , Mader RM , Gnant M , Dieckmann K , Zielinski CC , Steger GG , Preusser M , Bartsch R 
Published: May 2016

Abstract
Background
We aimed to analyze the impact of BC subtypes on the clinical course with special emphasis on the occurrence of brain metastases (BM) and outcome in an elderly breast cancer population.
Patients and Methods
571 patients ≥65 years receiving treatment for BC from 2007-2011 were identified from a BC database. BC subtypes and clinical characteristics including overall survival (OS) were obtained by chart review. Statistical analysis was performed using the Chi Square test, the log rank test and time depended covariate cox regression model as appropriate.
Results
Three-hundred-eighty/571 (63%) were grouped among the young-old (65-74 years), 182/571 (31.9%) among the old-old (75-84 years), and 29/571 (5,1%) among the oldest-old (≥85 years). 392/571 (68.8%) patients presented with luminal BC, 119/571 (20.8%) with HER2 positive and 59/571 (10.3%) with triple negative BC. After a median follow up of 38 months (range 0-204), 115/571 (20.1%) patients presented with metastatic recurrence. Highest recurrence rate was observed in HER2 positive BC patients (43/119 (36.1%)), followed by triple negative (15/59 (25.4%) and luminal BC (57/392 (14.5%); p&lt;0.001; Chi Square test). BM occurred significantly more frequently in HER2 positive BC patients (9/119 (7.6%) compared to triple negative (2/59 (3.4%) and luminal BC patients (6/392 (1.5%); p=0.003; Chi Square test). Occurrence of metastases (HR 7.7; 95% CI 5.2-11.4; p&lt;0.001) as well as development of BM (HR 3.5; 95% CI 1.9-6.4; p&lt;0.001) had a significant impact on OS prognosis as entered in a time depended covariate cox regression model.
Conclusions
In contrast to younger BC patients, HER2 positive BC subtype and not triple negative BC subtype was linked to the most aggressive clinical course including the development of metastatic disease and BM in our elderly cohort.
Citation Format: Bergen ES, Tichy C, Berghoff AS, Rudas M, Dubsky P, Bago-Horvath Z, Mader RM, Gnant M, Dieckmann K, Zielinski CC, Steger GG, Preusser M, Bartsch R. Prognostic impact of breast cancer subtypes in elderly patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-08-17.
Abstract P2-08-21: Stromal co-expression of urokinase-type plasminogen activator (uPA) and plasminogen activator Inhibitor (PAI-1) protein by IHC predicts poor disease outcome in endocrine-treated postmenopausal patients with receptor-positive early breast cancer
Authors: Singer CF , Filipits M , Jahn S , Abete L , Jakesz R , Greil R , Bauernhofer T , Kwasny W , Seifert M , Fitzal F , Schmitt M , Moinfar F , Gnant M 
Published: May 2016

Abstract
Background Elevated levels of intratumoral uPA and PAI-1 in ELISA-based measurements are associated with a high recurrence risk and allow to identify patients who might particularly benefit from adjuvant chemotherapy. The clinical utility of ELISA-based protein analysis is, however, greatly limited by the requirement of fresh tumor tisssue. We have therefore evaluated in a large clinical trial patient cohort with long-follow-up whether immunohistochemical detection of uPA and PAI-1 in FFPE archived tumor samples is also able to identify women with poor prognosis.
Patients and Methods 547 postmenopausal women with hormone receptor–positive, early breast cancer who had received at least 5 years of endocrine therapy in the prospectively designed ABCSG-06 trial, and in whom FFPE tumor tissue was available, were included in this analysis. uPA and PAI-1 protein expression was evaluated by immunohistochemistry, and correlated with distant-disease free (DDFS) and overall survival (OS).
Results Stromal co-expression of uPA and PAI-1 was detected in 166 of 276 (60%) evaluable tumor samples and was weakly associated with tumor size (p=0.012, Chi Square test) but not with age, nodal status, grading, or receptor status. Women with intratumoral uPA/PAI-1 expression were more likely to have a shorter DDFS in multivariate analysis (HR for relapse p=1.870; 95% CI 1.184-2.955; p=0.007 Cox regression analysis) and and OS (adjusted HR for death p=1.291; 95% CI 0.928-1.795; p=0.129) than women without. After a median follow-up of 10 years, women with uPA/PAI-1-positive tumors experienced a significantly shorter DDFS (p&lt;0.0001 log rank test) and OS (p=0.020).
Conclusions Stromal co-expression of uPA and PAI-1 in breast cancer samples predicts poor DDFS and OS in postmenopausal women with hormone-receptor positive early-stage breast cancer who receive endocrine therapy.
Citation Format: Singer CF, Filipits M, Jahn S, Abete L, Jakesz R, Greil R, Bauernhofer T, Kwasny W, Seifert M, Fitzal F, Schmitt M, Moinfar F, Gnant M. Stromal co-expression of urokinase-type plasminogen activator (uPA) and plasminogen activator Inhibitor (PAI-1) protein by IHC predicts poor disease outcome in endocrine-treated postmenopausal patients with receptor-positive early breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-08-21.
Abstract P2-09-02: Panel testing for familial breast cancer: Tension at the boundary of research and clinical care
Authors: Campbell IG , Thompson ER , Rowely SM , Li N , McInerny S , Devereux L , Wong-Brown MW , Trainer AH , Mitchell G , Scott RJ , James PA 
Published: May 2016

Abstract
Gene panel sequencing is revolutionizing germline risk assessment for hereditary breast cancer. Despite scant evidence supporting the role of many of these genes in breast cancer predisposition, results are often reported to families as the definitive explanation for their family history. We assessed the frequency of mutations in 18 genes commonly included in hereditary breast cancer panels among 2,000 index cases from breast cancer families and 1,997 population controls. Cases were predominantly breast cancer-affected women referred to specialized familial cancer centers (BRCA1 and BRCA2 wild-type). Controls were cancer-free women from the LifePool study (www.lifepool.org). Sequencing data were filtered for known pathogenic or novel loss of function mutations.
The frequency of pathogenic mutations in BRCA1 and BRCA2 in the control group was 0.2% (4 mutations) and 0.4% (8 mutations), respectively, which is consistent with previous indirect estimates for Caucasian populations but to our knowledge this the largest direct assessment of their prevalence.
Excluding 18 mutations identified in BRCA1 and BRCA2 among the cases and controls, a total of 69 cases (3.5%) and 26 controls (1.3%) were found to carry an "actionable mutation". PALB2 was most frequently mutated (22 cases, 3 controls), while no mutations were identified in PTEN or STK11. Among the remaining genes, loss of function mutations were rare with similar frequency between cases and controls.
The frequency of mutations in most breast cancer panel genes among individuals selected for possible hereditary breast cancer is low and in many cases similar or even lower than that observed among cancer-free population controls. While multi-gene panels can significantly aid in cancer risk management, they equally have the potential to provide clinical misinformation and harm at the individual level if the data is not interpreted cautiously.
Citation Format: Campbell IG, Thompson ER, Rowely SM, Li N, McInerny S, Devereux L, Wong-Brown MW, Trainer AH, Mitchell G, Scott RJ, James PA. Panel testing for familial breast cancer: Tension at the boundary of research and clinical care. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-09-02.
Abstract P2-09-15: Rapid BRCA analysis: Experience of a single institution
Authors: Mailliez A , Herin H , Revillion F , Adenis C , Peyrat J-P , Bonneterre J 
Published: May 2016

Abstract
The interest of rapid BRCA analysis, even before the initial treatment could modify the surgical indications (ie total mastectomy and immediate reconstruction even in case where tumorectomy would be suitable). The aim of this study was to evaluate the indications and consequences of this rapid determination of BRCA status in our institution.
Patients
Rapid BRCA analysis was conducted in 129 patients (pts) treated for breast cancer and addressed to the genetician at Oscar Lambret Center between 2009 and 2014: in 98 pts to discuss breast and axilla surgical modalities, in 4 cases to discuss oophorectomy, in 3 cases to have access to PARP inhibitors. In the other 24 pts, the reasons were debatable: patient leaving abroad, patient requiring reproductive assisted technology.....
Results
38 deleterious mutations (29,4%) were identified (31 BRCA1, 7 BRCA2) in 38 pts.
Cancer treatment was on going for 107 pts, programmed for 12 pts and finished for 10.
The median time between cancer diagnosis and genetic counseling was 81 days (5-5160), between blood sample collection and BRCAs analysis 37 days (13-132), between availability of the laboratory results and the information to the patient: 39 days (1-234); 7 pts (5.4%) never came to obtain the laboratory results.
Treatment was modified after genetic counselling for 8 pts out of 119 (7%). Six of them had BRCA1 deleterious mutations. Three decided subsequent radical mastectomy and adjuvant radiation was cancelled, another had a radical mastectomy before radiation, another treated for bilateral breast cancer had a bilateral radical mastectomy before radiation and the last treated for unilateral breast cancer had a bilateral radical mastectomy before radiation.
Out of these 8 pts, two did not have a deleterious mutation. One had a bilateral radical mastectomy before laboratory result and one with BRCA variant of unknown significance had a homolateral radical mastectomy.
Conclusion discussion
Our experience shows that rapid BRCA analysis is feasible. In this selected population the mutation rate is very high. However, first, it appears that indications for rapid BRCA analysis were variable and not always relevant. Second, genetic result impacts on treatment only in 7% of pts. Indications could be justified by the use of PARP inhibitors. Up to now, the indications of rapid genetic analysis are rare.
Citation Format: Mailliez A, Herin H, Revillion F, Adenis C, Peyrat J-P, Bonneterre J. Rapid BRCA analysis: Experience of a single institution. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-09-15.
Abstract P2-09-17: Frequency of large rearrangements in BRCA1, BRCA2, ATM, CHEK2, and PALB2 in hereditary cancer testing
Authors: Bissonnette J , Doonanco K , Xu Z , Klein RT , Hruska KS 
Published: May 2016

Abstract
Objectives
Large deletions and duplications are recognized as a cause of many inherited cancer syndromes; however, few studies have examined the frequency. In one study, large rearrangements accounted for 11-14% of pathogenic variants in BRCA1 and 1-3% of pathogenic variants in BRCA2 (Judkins 2012). Additionally, in a study of invasive ovarian cancer patients, large deletions and duplications accounted for 6% of BRCA1 and 3% of BRCA2 pathogenic variants (Zhang 2011). The frequency of large deletions and duplications in moderate penetrance genes, such as ATM, CHEK2, and PALB2, has not been carefully studied. We therefore sought to determine the frequency of pathogenic and likely pathogenic (P/LP) large deletions and duplications in BRCA1, BRCA2, ATM, CHEK2, and PALB2.
Methods
We analyzed a consecutive case series of patients who had BRCA1/2 and cancer panel testing. The data were analyzed to determine the percentage of deletions or duplications of greater than 250 bp identified on array comparative genome hybridization as a percentage of all pathogenic variants (PVs)/likely pathogenic variants (LPVs) in each of BRCA1, BRCA2, ATM, CHEK2, and PALB2.
Results
Large deletions/duplications accounted for 10.1% (55/545) of cases with a BRCA1 PV/LPV and 1.8% (10/556) of cases with a BRCA2 PV/LPV. By ethnicity, BRCA1/2 large deletions/duplications accounted for a higher fraction of PV/LPVs in Asians (11.3%) and Hispanics (8.1%). In Hispanic individuals, all of the large deletions/duplications were identified in BRCA1, accounting for 14.6% of all BRCA1 PV/LPV in this group. In the moderate penetrance genes, large deletions/duplications accounted for 4.6% (9/195), 5.1% (22/436), and 9.9% (13/132) of cases with a PV/LPV in ATM, CHEK2, and PALB2, respectively. There were two recurrent deletions in our cohort: the CHEK2 founder Slavic deletion of exons 9-10 observed in 16 of our cases, and a deletion of exon 11 in PALB2 observed in 6 cases.
Conclusions
Large deletions/duplications account for a substantial proportion of clinically significant variants in hereditary cancer genes. The proportion of large deletions/duplications in BRCA1 and BRCA2 reported here is similar to previous data. However, our cohort suggests that Asian individuals may have a higher proportion of mutations due to large deletions/duplications than previously reported. Among moderate risk cancer genes, PALB2 has the highest proportion of large deletions/duplications.
Citation Format: Bissonnette J, Doonanco K, Xu Z, Klein RT, Hruska KS. Frequency of large rearrangements in BRCA1, BRCA2, ATM, CHEK2, and PALB2 in hereditary cancer testing. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-09-17.
Abstract P2-09-18: Exploration of the diagnostic utility of next generation sequencing with TruSight cancer panel for BRCA negative hereditary breast and ovarian cancer patients
Authors: Dacheva D , Dodova R , Mitkova A , Kamenarova K , Tzveova R , Popov I , Vlahova A , Taushanova – Hadjieva M , Valev S , Dikov T , Timcheva K , Christova S , Mitev V , Kaneva R 
Published: May 2016

Abstract
Background. Breast cancer is the most commonly diagnosed malignancy and the most frequent cause of death in women due to cancer. About 5% to 10% of breast cancers are thought to be hereditary. Pathogenic mutations in BRCA1/2 genes across Hereditary Breast and Ovarian Cancer (HBOC) patients estimates are at around 15-20%. Other less common genes have also been associated with an increased risk of developing breast cancer, such as mutations in the TP53, PTEN, RAD51C, CDH1, ATM, CHEK2 or PALB2 tumor suppression genes. NGS based sequencing panels allow fast and simultaneous screening of large number of high- and low-penetrance susceptibility genes in these patients.
Methods. In the current study we included a group of 31 Bulgarian female breast cancer patients, selected following the strict BCLC and NCCN criteria for hereditary cancer. All of them were prescreened by direct sequencing and MLPA analysis, and tested negative for pathogenic mutations in BRCA1 and BRCA2 genes. Next generation target resequencing using a panel of 94 cancer related genes (Illumina TruSight cancer panel) was performed to explore the hereditary component beyond BRCA1/2 genes in these patients. All detected mutations and variants of unknown clinical significance (VUSs) were confirmed by Sanger sequencing method.
Results. Pathogenic and likely pathogenic mutations were found in 14 out of 31 BRCA1/2 negative patients: 1 new frameshift mutation in ATM gene; 6 new likely pathogenic missense mutations in PTCH1, RAD51C, MET, MUTYH, ATM and CHEK2; 7 previously reported pathogenic missense variants in WRN, ERCC4, PALB2, PRF1, RET, SDHB and AIP genes. In addition 27 VUSs (one new splice donor variant in ALK gene and 26 missense variants) were found.
Conclusions. The use of next generation target resequencing with TruSight Cancer panel lead to identification of clinically relevant pathogenic variants in 45% of the investigated patients. This could be the preferred diagnostic method in HBOC patients, carefully selected according the strict BCLC and NCCN criteria.
Citation Format: Dacheva D, Dodova R, Mitkova A, Kamenarova K, Tzveova R, Popov I, Vlahova A, Taushanova – Hadjieva M, Valev S, Dikov T, Timcheva K, Christova S, Mitev V, Kaneva R. Exploration of the diagnostic utility of next generation sequencing with TruSight cancer panel for BRCA negative hereditary breast and ovarian cancer patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-09-18.
Abstract P2-11-07: Mutually exclusive expression pattern of the immune co-inhibitory molecules B7-H4 and PD-L1 in triple negative breast cancer
Authors: Shaffer DR , Nagashima K , Cortez-Retamozo V , Feldman I , Smith J , Zafari M , Larson R , Mabry R , Novorantseva T , Briskin M , Sathyanaryananan S 
Published: May 2016

Abstract
B7-H4 (VTCN1, B7x, B7S1) is a transmembrane protein belonging to the B7 family of costimulatory proteins and has been shown to inhibit T cell proliferation, cytokine secretion, and cytotoxic lymphocyte (CTL) induction. B7-H4 expressed on tumor cells or macrophages has been associated with poor prognosis and impaired T cell function in renal cell and ovarian cancers. Here we show B7-H4 is abundantly expressed in human breast cancer with triple negative breast cancer (TNBC) having the highest overall B7-H4 mRNA expression. We developed a specific and sensitive immunohistochemistry (IHC) assay for evaluation of B7-H4 protein and quantified B7-H4 expression in 156 breast tumor samples. Approximately 70% of the breast tumor samples had detectable B7-H4 expression whereas none of the normal or benign breast tissues stained positive for B7-H4. Multiplex IHC and flow cytometry studies showed that the majority of B7-H4 expression was restricted to the tumor epithelial cells, the CD45+ immune cells were negative for B7-H4 expression. Interestingly none of the TNBC samples that were positive for B7-H4 showed detectable expression of PD-L1 suggesting that B7-H4 and PD-L1 checkpoint proteins may act in a mutually exclusive manner.
To evaluate the role of B7-H4 on tumor immune evasion, we overexpressed murine or human B7-H4 on the mouse colon-26 (CT26) tumor cell line and injected these cells intravenously into Balb/c mice. By day 14 we observed significantly more tumors as well as larger percent tumor area in the lungs of mice given CT26 cells transduced with human or mouse B7-H4 as compared to vector control transduced cells. These data suggest B7-H4 expression in tumors can accelerate tumor growth in immune competent mice and that targeting B7-H4 may provide therapeutic benefit. Given the mutually exclusive expression patterns of B7-H4 and PD-L1 a B7-H4 targeting agent may provide particular benefit in those patients where current anti-PD-1/PD-L1 therapies are not effective.
Citation Format: Shaffer DR, Nagashima K, Cortez-Retamozo V, Feldman I, Smith J, Zafari M, Larson R, Mabry R, Novorantseva T, Briskin M, Sathyanaryananan S. Mutually exclusive expression pattern of the immune co-inhibitory molecules B7-H4 and PD-L1 in triple negative breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-11-07.