bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract OT2-01-18: RIBECCA - A phase IIIb, multi-center, open label study for women with estrogen receptor positive locally advanced or metastatic breast cancer treated with ribociclib (LEE011) in combination with letrozole
Authors: Fasching PA , Decker T , Fehm T , Janni W , Kuemmel S , Lueftner D , Schneeweiss A , Schuler M , Guderian G , Schmidt-Wetzel S , Reiners R , Schubert J , Brucker S
Published: March 2017

Introduction:

The double blind, placebo-controlled MONALEESA-2 trial met its primary endpoint of clinically meaningful improvement in PFS at the pre-planned interim analysis for the combinatorial treatment of the cyclin-dependent kinase (CDK) 4/6-Inhibitor ribociclib and letrozole vs. letrozole monotherapy for postmenopausal, estrogen receptor positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) women who were naïve to treatment for advanced disease.

Here we present the national, multi-center, open-label, single-arm phase IIIb trial RIBECCA assessing the efficacy and safety of the combination of ribociclib and letrozole in an additional population, accompanied by a set of exploratory objectives.

Methods:

Main inclusion criteria allow enrollment of women with metastatic or locally advanced breast cancer not amenable to curative treatment by surgery or radiotherapy, and histological or cytological confirmation of ER+, HER2- breast cancer, irrespective of their menopausal status.

The primary objective is to assess the Clinical Benefit Rate (CBR) after 6 months, the secondary objectives include progression free survival (PFS), overall survival (OS), safety and change in quality of life.

The exploratory objectives include the assessment of biomarkers (e.g. ctDNA, CTCs, miRNA) predictive for response and the occurrence of adverse events of special interest. The influence of CDK4/6-inhibition on the immune system will be another exploratory endpoint of this study.

Conclusion:

With a planned recruitment of 500 patients in about 100 trial sites the RIBECCA trial will contribute to a better understanding of the safety, efficacy and possibly mechanisms related to CDK4/6-inhibition through ribociclib.

Citation Format: Fasching PA, Decker T, Fehm T, Janni W, Kuemmel S, Lueftner D, Schneeweiss A, Schuler M, Guderian G, Schmidt-Wetzel S, Reiners R, Schubert J, Brucker S. RIBECCA - A phase IIIb, multi-center, open label study for women with estrogen receptor positive locally advanced or metastatic breast cancer treated with ribociclib (LEE011) in combination with letrozole [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-01-18.
Abstract OT3-04-04: 21-gene recurrence score® in patients with primary metastatic ER+ HER2- breast cancer
Authors: Barinoff J , Anastasiadou L , Brandi C , Junker-Stein A , Silbermann J , Langenfeld M , Fortmann C , Thill M
Published: March 2017

Background and Purpose

Results from the 21-gene Recurrence Score (RS) are prognostic and predictive for recurrence in early breast cancer independent of clinical-pathological parameters. Prognostic information and distribution of RS in primary metastatic breast cancer (PMBC) was reported in a previous study by King et al but remains ultimately unclear in ER+ HER2- patients. We hypothesize that there is a prognostic correlation between RS and TTP/OS in PMBCindependent of clinical-pathological parameters, and the objective of the study is to evaluate the test for that cohort.

Patients and Trial Design

Between 2004 and 2014, 150 patients with first diagnosis of ER+/HER2- PMBC were enrolled in a multicenter, prospectively collected database. Pretreatment breast tumor samples will be analyzed by using 21-gene RS. Minimum follow-up will be 24 months.

Methods and Statistical Analysis

Patient characteristics, time to first progression (TTP), overall survival (OS) and treatment modalities will be described. The association between RS risk groups and both TTP and OS will be assessed by Kaplan-Meier estimates and compared with the log-rank test. Multivariate Cox regression models will be utilized to adjust for covariates. Additionally, assessing correlation of RS results using RS cut offs of 18 and 30 and additionally of 11 and 25 as well as analysis of quantitative ER from Oncotype DX assay for patients treated first-line with endocrine therapy are planned.

First results are expected to be presented in 2017.

Contact information for people with a specific interest in the trial:

Dr. Jana Barinoff

barinoff.jana@googlemail.com.

Citation Format: Barinoff J, Anastasiadou L, Brandi C, Junker-Stein A, Silbermann J, Langenfeld M, Fortmann C, Thill M. 21-gene recurrence score® in patients with primary metastatic ER+ HER2- breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT3-04-04.
Abstract OT3-04-05: Measuring the impact of MammaPrint on treatment in breast cancer patients: A prospective registry (IMPACt)
Authors: Soliman H , Untch S , Blumencranz L
Published: March 2017

This abstract was not presented at the symposium.

Citation Format: Soliman H, Untch S, Blumencranz L. Measuring the impact of MammaPrint on treatment in breast cancer patients: A prospective registry (IMPACt) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT3-04-05.
Abstract P1-02-05: Prognostic role of PIK3CA mutational status in circulating tumor DNA (ctDNA) from HER2-positive metastatic breast cancer patients
Authors: Lim J , Lee K-H , Min A , Kim S-G , Kim J-E , Kim T-Y , Han S-W , Oh D-Y , Kim T-Y , Lim S-A
Published: March 2017

Phosphatidylinositol-4, 5-biphosphate 3-kinase, catalytic subunit alpha (PIK3CA) is one of the most commonly mutated genes in breast cancer. But the prognostic and predictive role of PIK3CA mutations remains a matter of debate. It has been suggested that PIK3CA mutations are related to resistance to trastuzumab-based therapies, but they were also related to relatively indolent disease with better progression-free survival. Recently, circulating tumor DNA has been proposed to be a sensitive biomarker for detecting the presence of specific genetic aberrations in various cancer types, providing prognostic and predictive information. In this study, we evaluated prognostic and predictive role of PIK3CA mutations in patients with HER2-positive metastatic breast cancer treated with 1st line trastuzumab and taxane combination chemotherapy.

Thirty-four patients with blood samples obtained before 1st line trastuzumab and taxane combination chemotherapy were included in the study. We analyzed two PIK3CA hotspot mutations (E545K, H1047R) in ctDNA by digital droplet PCR (RaindropTM). The samples were collected from April 2005 to December 2011, centrifuged and stored as plasma, and were analyzed in 2015, after 4-10 years of storage period.

Median age was 47 years (range: 31 to 75 years), and histologic type of cancer was ductal carcinoma in all cases. PIK3CA mutations were detected in 21 (61.8%) of 34 patients. Patients with mutated PIK3CA in ctDNA had longer progression-free survival (PIK3CA wild type vs mutant, 11.0 months vs 22.0 months; P = 0.013). In hormone receptor positive group, patients with mutated PIK3CA had longer progression-free survival (PIK3CA wild type vs mutant, 12 months vs 18 months, P=0.17). Patients with PIK3CA mutations had a lower objective response rate than patients with wild-type, but there was no statistical significance (CR+PR; PIK3CA wild type vs mutant, 84.6% vs 66.7%, P=0.43). There was no significant difference in response rate (P = 0.48) or PIK3CA mutational status (P = 0.44) according to hormonal receptor status (estrogen receptor and/or progesterone receptor).

In conclusion, PIK3CA mutations were frequently detected by digital PCR from ctDNA of patients with HER2-positive breast cancer and they were related to significantly better PFS. We plan to analyze the PIK3CA mutation status in matched tumor tissue.

Citation Format: Lim J, Lee K-H, Min A, Kim S-G, Kim J-E, Kim T-Y, Han S-W, Oh D-Y, Kim T-Y, Lim S-A. Prognostic role of PIK3CA mutational status in circulating tumor DNA (ctDNA) from HER2-positive metastatic breast cancer patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-02-05.
Abstract P1-02-08: Provista-002: A prospective, multi-center study to determine the effectiveness of a biomarker assay to distinguish benign from invasive breast cancer in women with BI-RADS 3, 4 and 5 imaging reports
Authors: Wolf J , Lourenco A , Alpers J , Rohatgi N , Constantini C , Hollingsworth A , Grobmyer S , Pederson H , Haythem A , Polen W , Northfelt D , Morris M , Baker K , Ghosh K , Kass F , Arterbery E , Yang R , Tran Q , Letsios E , Mulpuri R , Reese DE
Published: March 2017

This abstract was not presented at the symposium.
Abstract P1-02-10: Reduced serum B-cell maturation antigen levels predict poor outcome in metastatic breast cancer patients in a phase 3 randomized 2nd-line hormone therapy trial
Authors: Ali SM , Leitzel K , Li M , Udd K , Wang J , Sanchez E , Chen H , Berenson J , Lipton A
Published: March 2017

Background: B-cell maturation antigen (BCMA) is a member of the tumor necrosis factor receptor family and has two ligands, B-cell activating factor (BAFF) and a proliferation inducing ligand (APRIL). These ligands activate cell proliferation and inhibit apoptosis of normal and malignant B-cells including in multiple myeloma (MM) cell lines. Berenson et al have recently reported that circulating BCMA levels are elevated in B-cell malignancies and can be used to monitor disease and predict PFS and OS for patients with MM, Waldenstroms's macroglobulinemia and chronic lymphocytic leukemia (CLL). On the other hand, recent studies have shown that serum BCMA levels are very low among patients with MM in complete remission with low antibody levels and those with primary immune deficiencies specifically those with combined variable immune deficiency and X-linked agammaglobulinemia. Studies of the potential role of serum BCMA for patients with solid tumors has not been evaluated to date.

Methods: The pretreatment serum from 139 patients with hormone receptor-positive metastatic breast cancer who were enrolled in a phase 3 randomized clinical trial of second-line hormone therapy was evaluated using an ELISA for BCMA. The BCMA ELISA was from R&D Systems (Minneapolis, MN). Serum BCMA was correlated with TTP using categorical serum BCMA cutpoints.

Results: Pretreatment serum BCMA levels had a median of 55.61 ng/ml, an interquartile range of 34.20 and 78.79 ng/ml, and full range from 3.99 to 1193.26 ng/ml. In univariate analysis for TTP, reduced serum BCMA correlated with shorter TTP at the following dichotomous cutpoints: 15 ng/ml [HR=2.60, p=0.064, n=6 (4.3%) of patients below cutpoint]; 20 ng/ml [HR=2.88, p=0.005, n=10 (7.2%) of patients below cutpoint]; 25 ng/ml [HR=2.16, p=0.023, n=13 (9.4%) of patients below cutpoint]; and 30 ng/ml [HR=1.77, p=0.016, n=27 (19.4%) of patients below the cutpoint].

Conclusions: In a phase 3 randomized clinical trial of second-line hormone therapy among patients with hormone receptor-positive metastatic breast cancer, reduced pretreatment serum BCMA was associated with shorter TTP. This may be due to the association of reduced serum BCMA with immune deficiency; and, thus, lead to shorter TTP among patients with metastatic breast cancer. Evaluation of serum BCMA as a new biomarker to predict outcomes for breast cancer and other solid tumor patients deserves further study.

Citation Format: Ali SM, Leitzel K, Li M, Udd K, Wang J, Sanchez E, Chen H, Berenson J, Lipton A. Reduced serum B-cell maturation antigen levels predict poor outcome in metastatic breast cancer patients in a phase 3 randomized 2nd-line hormone therapy trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-02-10.
Abstract P1-03-02: Intratumoral heterogeneity of Ki67 expression in early breast cancers exceeds variability between individual tumours
Authors: Focke CM , Decker T , van Diest PJ
Published: March 2017

Background

Regional differences in proliferative activity are commonly seen within breast cancers, but little is known on the degree of intratumoral heterogeneity of Ki67 expression. Our aim was to study intratumoral heterogeneity of Ki67 expression in early breast cancers and its association with clinicopathological features like estrogen receptor (ER) status, grade and histological type.

Methods

The Ki67-labelling index (Ki67-LI) was assessed in hot, cold and intermediate spots of 233 invasive breast cancers by counting a total of 1020 cells, according to a protocol of the International Ki67 in Breast Cancer Working Group. Differences between the spots per tumor were further analyzed for clinicopathological subgroups defined by ER status, grade and histological type.

Results

All clinicopathological subgroups showed significant differences in Ki67-LI between hot, intermediate and cold spots (p <0.001). The coefficient of variance (CV) between the spots was higher in ER positive than in ER negative cancers (72.6% vs 49.2%, p <0.001), and was highest in grade 3 (96.12%), grade 1 (87.27%) and invasive lobular tumors (83.59%), and lowest in medullary (26.48%) cancers. Nested analysis of variance indicated that in both ER positive and ER negative cancers, variance in Ki67-LI within tumours contributed more to the total variance (56% for ER positive, 60% for ER negative cancers) than the variance between tumors.

Conclusion

Intratumoral heterogeneity in Ki67-LI is an ubiquitous phenomenon across various pathological subgroups of breast cancer that may impact assessment of Ki67 levels for clinical decision making, and sheds new light on recommended cut-offs.

Citation Format: Focke CM, Decker T, van Diest PJ. Intratumoral heterogeneity of Ki67 expression in early breast cancers exceeds variability between individual tumours [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-03-02.
Abstract P1-03-05: A comprehensive molecular analysis of medullary breast carcinoma: A model of immunomodulatory triple negative breast cancer subtype
Authors: Romero P , Deniziaut G , Benhamo V , Fuhrmann L , Berger F , Bhalshankar J , Gruel N , MacGrogan G , Popova T , Manié E , Stern M-H , Stoppa-Lyonnet D , Rouzier R , Delattre O , Bieche I , Vincent-Salomon A
Published: March 2017

Medullary breast carcinoma (MBC) is a rare subtype of triple negative breast cancer (TNBC)with specific genomic features within the spectrum of basal-like carcinoma. The frequent association between BRCA constitutive mutation and MBC phenotype has been reported previously. In this study including 19 MBC and 36 non-MMB basal-like carcinoma (BLC), we refine the genomic and transcriptomic knowledge about this entity. Using pan genomic Affymetrix genome-wide human SNP6.0 array, we show that i/ MBC harbour more copy number alterations and losses of heterozygocity than BLC and that ii/ the high frequency of BRCAness genomic trait among MBC. Unsupervised and supervised analysis of GeneChip Uman Genome U133 Plus 2.0 Array transcriptomic generated data confirmed that MBC clearly differ from BLC in terms of gene expression level, with 92 genes overexpressed and 154 genes underexpressed in MBC over BLC. Immune response and inflammatory response are the most differentially represented pathways in MBC over BLC. Pro apoptotic gene BCLG is by far the more overexpressed gene in MBC. A validation study conducted with RT-QPCR among 526 breast tumors form all molecular subtype confirmed the specificity of BCLG overexpression in MBC, which was confirmed at protein level using immunohistochemisytry. Moreover, we show that a vast majority of MBC belong o the immunomodulatory TNBC subtype according to Lehman et al. Finally, we confirm the better prognosis of MBC toward BLC. Our observations epitomize the importance of developing DNA repair targeting drugs and immunotherapy based trials in order to improve the outcome of such a specific entity.

Citation Format: Romero P, Deniziaut G, Benhamo V, Fuhrmann L, Berger F, Bhalshankar J, Gruel N, MacGrogan G, Popova T, Manié E, Stern M-H, Stoppa-Lyonnet D, Rouzier R, Delattre O, Bieche I, Vincent-Salomon A. A comprehensive molecular analysis of medullary breast carcinoma: A model of immunomodulatory triple negative breast cancer subtype [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-03-05.
Abstract P1-03-12: A simulation study depicting the inconsistency of adjuvant online compared to genomic testing when determining the benefit of chemotherapy
Authors: Khawaja S , Thomas D , Udayasankar S , Munir A , Huws A , Sharaiha Y , Holt S
Published: March 2017

Background: Prognostic factors have been used for years to determine the benefit of adjuvant chemotherapy in breast cancer. However, reporting of the size and grade of the tumor are affected by interobserver variability in reporting. This can result in a change in the results of adjuvant online and an impact on decision making of chemotherapy. On the contrary, genomic testing such as oncotype Dx is reproducible. The purpose of our study was to assess the effect of pathological discordance on the adjuvant online results on a cohort of patients who also underwent oncotype Dx testing.

Materials and Methods: A total of 143 patients' histologies were included in this study. The results of the Phase III WSG-Plan B trial concerning central vs. local grade discrepancy rates were utilized to randomly change the grade of the tumors. 61 percent of grade 1 cancers were upgraded to grade 2 and 2% upgraded to grade 3. 4 percent of grade 2 cancers were downgraded to grade 1 and 26% were upgraded to grade 3. 1 percent of grade 3 cancers were downgraded to grade 1 and 25% were downgraded to grade 2. Likewise, change was made in the size of the tumor in 20 percent of patients. 8 to 10mm, 18-20, 28-30, and 48-50mm changed to 11, 21, 31 and 51mm respectively. 11-13mm, 21-23, 31-33, and 51-53mm was changed to 10, 20, 30, and 50mm. Ten percent of patients had the ER and Her 2 status changed.

Results: The simulation results showed that when the grade was only altered, the spearman correlation of the predicted 10 year mortality on adjuvant online with the original data was significantly changed from 1 to a result of 0.788. When the changed size was additionally added, the coefficient was 0.836. With the altered ER status, the result was 0.749 and with the Her 2 change, the spearman correlation was minimally changed to 0.742. The scattergrams showed a large number of outliers when the alteration in size was added to the altered grade.

Conclusion: Our simulation study confirms that with minimal changes in the clinical parameters because of the lack of perfect correlation between pathologist's results, there is a significant difference in the 10 year predicted mortality on adjuvant online. This is one step further in understanding the lack of correlation between adjuvant online and oncotype Dx, and the inconsistency of chemotherapy decision making with the sole use of adjuvant online.

Citation Format: Khawaja S, Thomas D, Udayasankar S, Munir A, Huws A, Sharaiha Y, Holt S. A simulation study depicting the inconsistency of adjuvant online compared to genomic testing when determining the benefit of chemotherapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-03-12.
Abstract P1-04-03: Cross-talk between RNA methyltransferase and demethylase regulates breast cancer growth and progression
Authors: Subbarayalu P , Eedunuri VK , Timilsina S , Rajamanickam S , Viswanadhapalli S , Abdelfattah N , Onyeagucha BC , Cui X , Mohammad TA , Huang TH-M , Huang Y , Chen Y , Rao MK
Published: March 2017

The importance of RNA methylation in biological processes has just begun to emerge. However, our understanding of the role and mechanism by which RNA methylation may play a role in tumorigenesis is unclear. Here, we report that RNA N6-adenosine methyltransferase protein METTL14 supports breast cancer growth and progression. We show that METTL14 mediates its pro-tumorigenic function by activating the expression of RNA binding protein HuR and consequently inducing the transcriptional stability of key cell cycle-associated genes, TGFβ and its signaling partners as well as HMGA2, VEGF and PDGF that are known to play critical roles in cancer growth and metastasis. Importantly, m6 A RNA methylation levels of METTL14 target genes were significantly lower in breast cancer patients compared to normal matched controls. The decreased RNA methylation level resulting in increased activity of these target genes in breast cancer patients is regulated by a feedback loop between RNA demethylase ALKBH5 and METTL14. Our results reveal that ALKBH5 regulates the expression of METTL14 and HuR, which in turn transcriptionally stabilizes ALKBH5. Furthermore, we demonstrate that like METTL14, ALKBH5 also supports breast cancer growth and progression. Taken together, these findings suggest that a collaboration between RNA methylation and demethylation machinery may set up a threshold of RNA methylation that ensures the stability of genes that play a vital role in normal cell proliferation; and any perturbation of that threshold may lead to uncontrolled expression/activity of those genes resulting in tumor growth and progression.

Citation Format: Subbarayalu P, Eedunuri VK, Timilsina S, Rajamanickam S, Viswanadhapalli S, Abdelfattah N, Onyeagucha BC, Cui X, Mohammad TA, Huang TH-M, Huang Y, Chen Y, Rao MK. Cross-talk between RNA methyltransferase and demethylase regulates breast cancer growth and progression [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-04-03.
Abstract P1-04-07: Environmental influence on epigenetic markers in the development of breast cancer
Authors: He C , Wu W , Gao H , Nephew K , Li L , Schneider B , Han J , Liu Y
Published: March 2017

Aberrant DNA methylation plays an important role in breast cancer initiation and progression. We hypothesize that environmental risk factors contribute to causal alterations in DNA methylation and that such causal changes have already occurred prospectively in normal breast tissue before tumor occurrence. In order to test this hypothesis, normal breast tissue from healthy women must be used. We therefore conducted an integrative molecular epidemiological study that combined the environmental regulation of DNA methylation in normal breast tissue and the differential DNA methylation profiling in tumor and normal breast tissue. We examined for the first time the environmental impact on DNA methylation in normal breast tissue from healthy women and determine the association of these epigenetic changes with breast cancer development. Potentially causal DNA methylation markers identified from our study has the potential to make a major scientific and clinical impact in understanding breast cancer etiology as well as developing novel, more effective prevention and treatment strategies.

Citation Format: He C, Wu W, Gao H, Nephew K, Li L, Schneider B, Han J, Liu Y. Environmental influence on epigenetic markers in the development of breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-04-07.
Abstract P1-04-11: The epigenetic landscape of oestrogen receptor-alpha positive breast cancer
Authors: Patten DK , Corleone G , Kate G , Dimitri HJ , Palmieri C , Raoul CC , Luca M
Published: March 2017

This abstract was withdrawn by the authors.
Abstract P1-05-14: Copy number aberration-induced gene breakage analysis identifies recurrent FOXP1 fusions in breast cancer
Authors: Mohd Noor A , Maguire S , Watkins J , Quist J , Mirza H , Tutt A , Gillett C , Natrajan R , Grigoriadis A
Published: March 2017

Background: Genomic instability is a critical feature of breast cancers, which manifests in genome-wide copy number aberrations (CNA), often causing “gene breakage” and the generation of fusion genes. We aimed to identify aborted transcripts with underlying CNAs and to investigate the molecular landscape of breast cancers harbouring such events.

Methods: A walking student's t-test algorithm was applied to Affymetrix Exon 1.0ST array data of 123 breast cancers to identify regions of aborted transcription and overlaid with DNA breakpoints derived from matched Affymetrix SNP6 ASCAT-segmented copy number. Aborted transcripts were investigated as potential fusion gene partners through RNA-seq analysis of 151 breast cancer samples (TCGA) and 51 breast cancer cell lines (BCCL) using ChimeraScan. Clinical correlates were established for clinicopathological features, genomic instability measures, and gene expression-based molecular classifiers including PAM50, TNBCtype, IntClust subtypes and immune signatures.

Results: One hundred and six genes with recurrent CNA-induced aborted transcription were identified. Aborted transcription showed hormone receptor subtype-specificity for 7 genes (nTNBC=1, nNon-TNBC=6) and was less prevalent in samples of IntClust 2 and IntClust 4 subtypes (p: 0.0043, 0.0011). Aborted transcripts were more frequently observed in samples with greater copy-neutral loss of heterozygosity (p=0.012), while aborted transcription of 54/106 genes significantly affected enrichment of 27 tumor-infiltrating lymphocyte subpopulations.14 aborted transcripts were found as a fusion gene with one partner in RNA-seq of TCGA and BCCL, while 19 were involved in multiple fusion events (range=1-6, median=2). Nine of 106 genes displayed gene breakage and fusion events exclusively in samples with an enriched tandem duplication phenotype. Notably, FOXP1, localised to a tumour suppressor locus at 3p14.1, reported the highest number of fusion configurations (n=6) with concurrent aborted transcription across all RNA-seq datasets (nPRADA=9, nTCGA=38, nBCCL=6).

Conclusion: CNA-induced gene breakage affects the molecular landscape of breast cancers and is linked with many genomic configurations of interest including copy-neutral loss of heterozygosity and tandem duplications. In particular, the role of recurrent gene fusions of the tumour suppressor, FOXP1, in tumourigenesis warrants further investigation.

Citation Format: Mohd Noor A, Maguire S, Watkins J, Quist J, Mirza H, Tutt A, Gillett C, Natrajan R, Grigoriadis A. Copy number aberration-induced gene breakage analysis identifies recurrent FOXP1 fusions in breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-05-14.
Abstract P1-05-17: Interrogating the impact of pregnancy on breast cancer biology using DNA copy number profiling
Authors: Nguyen B , Brown DN , Rothé F , Desmedt C , Majjaj S , Pruneri G , Peccatori F , Azim HA , Sotiriou C
Published: March 2017

Background

Epidemiological evidence indicates a clear relationship between pregnancy and breast cancer (BC) risk. However, little is known regarding the impact of pregnancy on BC biology. DNA copy number aberrations (CNAs) play an important role in breast carcinogenesis. BC during pregnancy is a rare disease but yet could serve as a good model to study the impact of pregnancy on BC biology.

Methods

We retrospectively included 54 pregnant and 113 non-pregnant BC patients matched for age and stage with complete clinico-pathological, gene expression and 5-year follow-up data. CNAs were assessed using Affymetrix OncoScan FFPE arrays. We identified the CNAs associated with pregnancy using a multivariate logistic regression adjusted for classical clinico-pathological features. We further evaluated their impact on gene expression.

Results

After quality control, CNA profiles were obtained for 38 pregnant and 87 non-pregnant BC patients. We identified 13 regions with copy number gains, 11 of which were more frequently gained in pregnant compared to non-pregnant controls and 5 regions with copy number loss, 3 of which were more frequently lost in pregnant patients (p≤0.05). Of interest, we identified 4 genes previously identified as driver event associated with CNAs in breast cancer (S. Nik-Zainal et al, Nature 2016). AKT1 and CDKN2A/B were more frequently gained in the pregnant compared to the non-pregnant (23.7% vs. 8.0%, p=0.068 and 18.4% vs. 4.6% p=0.036) and ARID1B was less frequently gained in the pregnant cohort (2.6% vs. 13.8%, p=0.02). Interestingly, PAPPA which had been previously identified as a pregnancy-dependent oncogene (Takabatake Y. et al, EMBO Mol Med. 2016) was also more frequently gained in the pregnant compared to the non-pregnant patients (21.1% vs 5.8%, p=0.03). We next evaluated the effect of these CNAs on their own gene expression levels and found that AKT1 and CDKN2A/B CNAs were affected by gene-dosage effect.

Conclusions

In this study, we were able to identify several genomic alterations associated with pregnancy that could further elucidate the impact of pregnancy on BC risk. Moreover, by combining CNAs with gene expression, we were able to identify genes whose expression were associated with CNAs and therefore could be considered potential drivers of this rare disease.

Citation Format: Nguyen B, Brown DN, Rothé F, Desmedt C, Majjaj S, Pruneri G, Peccatori F, Azim Jr HA, Sotiriou C. Interrogating the impact of pregnancy on breast cancer biology using DNA copy number profiling [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-05-17.
Abstract P1-05-31: Studying the interactome of breast cancer: The cancer cell map initiative
Authors: Kim M , Kim K , Soucheray M , Swaney D , Krogan N
Published: March 2017

This abstract was not presented at the symposium.
Abstract P1-08-02: Mutant GATA3 actively promotes the growth of normal and malignant mammary cells
Authors: Kenny PA , Chandiramani N , Lofgren KA
Published: March 2017

GATA3 is a transcription factor expressed in luminal breast epithelial cells and is required for mammary gland development. Analysis of TCGA data reveals that somatic heterozygous mutations in GATA3 occur in up to 15% of estrogen receptor positive breast tumors, and that these tumors are diagnosed a median of eight years earlier than other estrogen receptor positive tumors, suggesting a more aggressive phenotype. These mutants have been proposed to be null alleles resulting in haploinsufficiency, however the mutation spectrum of GATA3 in breast cancer is in sharp contrast to that found in HDR syndrome, a true GATA3 haploinsufficiency disease. Based on this disparity, we propose that there is a selective pressure to mutate and retain a portion of the GATA3 in breast cancer. Here we focus on the GATA3 mutants which lack the second zinc finger which is responsible for GATA motif binding. Expression of these mutants accelerated xenograft tumor growth by ZR751 cells, and transgenic expression in mouse mammary glands promoted precocious lobuloalveolar development. We have used integrated gene expression and ChIP-Seq profiling to demonstrate that these zinc-finger deleted proteins retain the ability to associate with the genome by tethering to complexes associated with FOXA1 and AP-2gamma recognition motifs, where they modulate the expression of adjacent genes. These data support a model in which the GATA3 mutations recently observed in breast cancer encode for active transcription factors which elicit proliferative phenotypes in normal mammary epithelium and promote the growth of estrogen receptor positive breast cancer cell lines.

Citation Format: Kenny PA, Chandiramani N, Lofgren KA. Mutant GATA3 actively promotes the growth of normal and malignant mammary cells [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-08-02.
Abstract P1-09-12: Dose dense adjuvant chemotherapy in patients with early breast cancer: Differential treatment effects according to composite index of benefit
Authors: Puglisi F , Ceppi M , Cognetti F , De Placido S , Bruzzi P , De Laurentiis M , Bisagni G , Cavazzini G , Durando A , Turletti A , Valle E , Montemurro F , Barni S , Ardizzoni A , Gamucci T , Colantuoni G , Del Mastro L
Published: March 2017

Background In patients with node-positive early breast cancer (EBC), dose-dense adjuvant chemotherapy improves disease-free survival (DFS) compared with standard interval chemotherapy. The GIM2 trial supports the value of dose-dense chemotherapy and suggests that the benefit is present in patients with hormone receptor-negative or hormone receptor-positive tumours (Del Mastro et al. Lancet 2015). In order to individualize decision making, there is a need to examine the absolute treatment effects of dose dense chemotherapy according to patient and tumor characteristics.

Patients and Methods The randomized phase III GIM2 trial enrolled 2091 patients. The primary endpoint was DFS. A continuous, composite measure of treatment benefit for each patient was determined from a Cox model incorporating potential predictive factors (age: 25-40/41-55/56-71; histological grade: 1+2/3; hormonal receptor status: positive/negative). Subpopulation treatment effect pattern plot methodology was used to reveal differential treatment effects on DFS according to composite index. The study focused on patients with HER2–negative disease (N=1287).

Results On average, the magnitude of benefit with dose dense chemotherapy versus standard chemotherapy ranged widely across different subpopulations, as quantified by the composite measure of relevant variables. The highest benefit was observed in patients with high grade, hormone receptor-negative disease (hazard ratio for DFS 0.44, 95% CI 0.23-0.83). Of note, a relevant benefit was observed also in patients with high grade, hormone receptor-positive disease (hazard ratio for DFS 0.74, 95% CI 0.50-1.09).

Conclusion The absolute improvement in DFS with dose dense adjuvant chemotherapy is substantial in some patients with node-positive HER2-negative breast cancer, particularly those regarded as having high index risk (hormone receptor-negative, high grade disease). Interestingly, a significant effect of dose dense chemotherapy was observed also in patients with hormone receptor-positive, high grade disease.

Citation Format: Puglisi F, Ceppi M, Cognetti F, De Placido S, Bruzzi P, De Laurentiis M, Bisagni G, Cavazzini G, Durando A, Turletti A, Valle E, Montemurro F, Barni S, Ardizzoni A, Gamucci T, Colantuoni G, Del Mastro L. Dose dense adjuvant chemotherapy in patients with early breast cancer: Differential treatment effects according to composite index of benefit [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-09-12.
Abstract P1-10-14: Early results of toxicity for high-risk patients treated with hypofractionated regional nodal irradiation
Authors: Barry PN , Ahmad M , Wilson MR , Brown CM , Dragun AE
Published: March 2017

This abstract was withdrawn by the authors.
Abstract P1-11-05: Influence of race and age on mastectomy rates in women with stage I, hormone-sensitive breast cancers: A SEER-based study
Authors: Bazan JG , Bittoni MA , Fisher JL , White JR
Published: March 2017

Background: Breast conserving therapy (lumpectomy [L] and breast radiotherapy [RT]) results in equivalent cancer control outcomes in comparison to mastectomy (M) for early stage breast cancer (BC) based on randomized controlled trials (RCT). Since 2004, RCT support that L alone without RT yields equivalent survival and acceptable local regional outcomes in women ≥70 years old with stage I (T1N0) hormone-sensitive (HS) BC on endocrine therapy. Based on this, we hypothesized that M rates should decrease substantially in this low risk elderly population and sought to examine the influence of race on M rates in this group and how these trends compare to younger aged Stage I HS patients.

Methods: We used the Surveillance Epidemiology and End Results (SEER) registry data to conduct this study. We included women with T1N0 HS BC classified as either ER-positive or PR-positive from 2000-2012 divided into 2 age groups [elderly (≥70 years old) and non-elderly (20-69 years old)] and 3 race groups [white, black, and Asian-Pacific-Islander/American Indian/Alaskan Native (API)]. We compared M rates in women diagnosed before 2004 compared to those diagnosed from 2005-2012. Statistical analyses were performed using differences in proportions (p<0.05 considered statistically significant).

Results: 261,079 women met the study criteria (N=87,009 elderly; N=174,070 non-elderly). In elderly Stage I HS BC, a 5.2% reduction in the M rate is seen: 32.6% before 2004 to 27.4% after 2004 (p<0.0001). M rates remained higher (with less reduction) in elderly Black (30.8 %) and API (33.6 %) vs. White (26.8%) [p<0.0001 for White vs. Black and for White vs. API]. In non-elderly Stage I HS BC, after 2004 M rates increased from 29.2% to 31.8% (p<0.0001). Non-elderly white women had the largest absolute increase in M rates (31.2% vs. 28.5%, p<0.0001) followed by API women (35.1% vs. 37.1%, p=0.0222). M rates did not change after 2004 in non-elderly black women (31.7% vs. 31.7%, p=0.9953).

Conclusions: In patients with favorable stage I HS BC, M rates have decreased only modestly in elderly women since 2004 when L alone w/o RT was established as appropriate treatment. In comparison, M has increased since 2004 in non-elderly women. These trends are driven mostly by white women in both the elderly and non-elderly. Further research is needed to identify why M, which is associated with higher cost and morbidity than L alone, has not changed substantially in elderly very favorable BC, particularly for non-whites.

Citation Format: Bazan JG, Bittoni MA, Fisher JL, White JR. Influence of race and age on mastectomy rates in women with stage I, hormone-sensitive breast cancers: A SEER-based study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-11-05.
Abstract P2-01-13: Can axillary lymph node clearance be avoided in women with node positive breast cancer receiving primary chemotherapy?
Authors: Chowdhury MHR , Thillai K , Lucey A , Michalarea V , Mera A , Karapanagiotou E , Sandri I , Mansi J
Published: March 2017

Background

For patients who receive primary chemotherapy for their early breast cancer the current practice for lymph node positive (LN) disease at presentation is in transition, with a drive towards sentinel LN biopsy (SLNB) rather than axillary node clearance (ANC) for patients who achieve a good response to primary chemotherapy. Boileau et al initially reported that approximately 30% of patients could potentially avoid clearance, but with a recommendation for further evaluation before including SLNB in guidelines for biopsy proven node-positive disease prior to primary chemotherapy for early breast cancer.

Methods

This was a retrospective single centre study. Examining the records of all patients who had received primary chemotherapy between January 2010 and October 2014.

Patients were identified through the Guy's Breast Cancer Database and chemotherapy prescribing system. To fully assess the LN status, all patients were cross-referenced with the electronic notes on our electronic noting system (MOSAIQ), radiology on Patient Archiving and Communication System (PACS) and histology on our Electronic Patient Record (EPR).

Results:

1526 patients were identified, of whom 156 underwent primary chemotherapy. 111 patients had suspicious nodes on imaging (ultrasound and/or MRI) and underwent LN biopsy. 69 patients had positive nodes pre-chemotherapy. 28 of these 69 patients (40.6%) had negative nodes at ANC, of these 14 (50%) had complete pathological complete response (pCR) in their primary tumour(s) of whom 12 (86%) had radiological CR prior to surgery. Of the 41 who remained positive only three achieved pCR of their primary tumour after chemotherapy.

22 patients were LN positive post primary chemotherapy, despite having been identified as initially LN negative. Of these 9 had a negative pre chemotherapy biopsy, and only 1 of these 22 patients had a pCR.

Discussion:

We have confirmed that ANC may be avoided in selected patients with LN involvement at presentation. In our series over 40% could have had SLNB instead. Factors supporting this approach include those patients who have an excellent radiological response to primary chemotherapy. Conversely, 22 of 87 (25%) had positive LN after chemotherapy having been initially thought to be LN negative at presentation, highlighting the possible need for multiple nodal sampling prior to chemotherapy as well as further nodal assessment after chemotherapy for complete staging.

Citation Format: Chowdhury MHR, Thillai K, Lucey A, Michalarea V, Mera A, Karapanagiotou E, Sandri I, Mansi J. Can axillary lymph node clearance be avoided in women with node positive breast cancer receiving primary chemotherapy? [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-01-13.
Abstract P2-01-15: Clinical application of multimodal fluorescent-radioactive system in advanced breast cancer patients with neoadjuvant therapy; interim analysis for 65 patients
Authors: Lee S , Jung S-Y , Kim S-K , Lee ES , Lee MH , Park SJ , Kang H-S , Lee KS , Park IH , Sim SH , Kim Y , Kwon Y , Joo J , Kang SH
Published: March 2017

Purpose

This study aimed to evaluated the identification rate and operation time of sentinel lymph node biopsy (SLNB) by a multimodal fluorescent-radioactive system (MFS) using a mixture of indocyanine green (ICG), radioisotope (RI) compared with the RI alone in advanced breast cancer patients with neoadjuvant therapy.

Methods

In this phase II randomized study, we enrolled 65 patients with advanced breast cancer with neoadjuvant therapy. Then, they received SLNB with either MFS or RI. We compared the identification rate, operation time of SLNB and number of sentinel lymph nodes. We also evaluated the safety. We analyzed the data of 65 patients for interim analysis.

Results

The mean age of the MFS group and RI group was 51.7 and 45.9 years (p=0.024), respectively. There were no differences in histopathological characteristics, including tumor size, node positivity, and hormone receptor status between two groups. The radiologic study showed the clinically complete response in axillary lymph nodes after neoadjuvant therapy. In MFS group, sentinel lymph nodes (SLNs) were identified in 30 patients and we could not identify the SLNs in one patient. In RI group, we identified the SLNs in 33 patients and also could not identify them in one patient. (p=0.947). The average numbers of SLNs in the MFS and RI group were similar. (2.32±1.10 vs. 2.18 ± 1.57, respectively; p=0.668) The operation time of SLNB was similar in the each group (11.65 ± 6.49 vs. 9.47 ± 6.26, respectively, p= 0.174) There were no complication, including allergic reactions, skin staining or necrosis.

Conclusions

This study is the randomized trial that compared MFS using ICG and RI and the conventional RI method for SLNB in the advanced breast cancer with neoadjuvant therapy. The multimodal fluorescent-radioactive system is a feasible and safe method for SLNB for the breast cancer patients with neoadjuvant therapy. We will evaluate the 130 patients for final analysis.

Citation Format: Lee S, Jung S-Y, Kim S-K, Lee ES, Lee MH, Park SJ, Kang H-S, Lee KS, Park IH, Sim SH, Kim Y, Kwon Y, Joo J, Kang SH. Clinical application of multimodal fluorescent-radioactive system in advanced breast cancer patients with neoadjuvant therapy; interim analysis for 65 patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-01-15.
Abstract P2-01-24: Evaluating lymph node ratio (LNR) as a prognostic indicator in node-positive breast cancer
Authors: Kelliher A , Boyce M , Donnellan E , O Connor D , Murphy C , Bird B
Published: March 2017

Purpose: To determine whether LNR can provide additional prognostic information to pN staging in node-positive breast cancer patients.

Methods: We previously reported on the utility of LNR as a prognostic indicator in lymph node-positive early breast cancer. We present an updated analysis with a prolonged median follow-up of 85 months. A retrospective review of original histopathology reports was undertaken in a sample group of 214 patients diagnosed with node-positive breast cancer between January 2000 and January 2011. The LNR was defined as the number of positive lymph nodes divided by the total number of lymph nodes (LNs) removed. LNR cut off points were divided into low (≤0.14), intermediate (0.15-0.39) and high (≥0.40) by trichotomy. Patients were also divided into three groups based on nodal status in accordance with the AJCC staging system. Those with 1-3 positive nodes were classified as pN1, those with 4-9 positive nodes were pN2 and those with 10 or more positive nodes were classified as pN3. Overall survival (OS) and invasive Disease Free Survival (iDFS) were calculated using the Kaplan Meier Method.

Results: The mean age at diagnosis was 58 (SD=12) years. The median follow-up time was 85 months. The 5-year OS and iDFS for node-positive patients were 80% and 70%, respectively. The mean number of lymph nodes examined was 15.2 (SD=6.6) and the mean number of positive nodes was 5.3 (SD=6.1).

When patients were stratified according to LNR groupings OS was 80% in the low LNR group, decreasing to 67% in the intermediate LNR group and 47% in the high LNR group (p<0.0001). Similarly, iDFS in the low LNR group was 71% decreasing to 57% in the intermediate LNR group and 42% in the high LNR group (p<0.0009).

Conclusions: These updated results from a cohort of patients with lymph node-positive early breast cancer at a median follow-up of over 7 years confirms the utility of LNR as a prognostic indicator. Univariate and multivariate analyses to assess the ability of LNR to discriminate risk in addition to AJCC nodal grouping will be presented.

Citation Format: Kelliher A, Boyce M, Donnellan E, O Connor D, Murphy C, Bird B. Evaluating lymph node ratio (LNR) as a prognostic indicator in node-positive breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-01-24.
Abstract P2-01-25: Upfront immunohistochemistry to evaluate sentinel lymph nodes in breast cancer: Reasonable or not?
Authors: Liu Y-J , Zander D , Karamchandani D
Published: March 2017

This abstract was withdrawn by the authors.