bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B78: Targeting the translational apparatus in MYCN-driven medulloblastoma
Authors: Meyerowitz Justin G. , Gustafson W. Clay , Nekritz Erin , Swartling Fredrik , Shokat Kevan M. , Ruggero Davide , Weiss William A.
Published: May 2015

Amplification of MYCN is associated with high-risk SHH-driven and group 4 medulloblastoma, while mis-expression and amplification of MYC is associated with aggressive group 3 tumors. The biology of these tumors, particularly the group 3/4 tumors, is poorly understood, with no effective targeted therapies. We have recently developed a model of group 4 medulloblastoma in which high levels of mutationally-stabilized MYCN protein drive oncogenesis. We have shown in other tumor types that modulation of the translational apparatus downstream of the mammalian target of rapamycin (mTOR) is required for MYC-driven oncogenesis and that there is a synergistic relationship between MYC and the mTOR axis to promote tumor formation. mTOR signals through two primary outputs, rpS6 kinase (S6K) and the translation initiation factor eIF4E. A new class of clinical mTOR active site inhibitors disrupts signaling through both effectors, whereas the allosteric binder rapamycin disrupts only S6K. We describe genetic and therapeutic studies aimed at distinguishing the effects of S6K and eIF4E in both tumor formation and in therapy. These mechanistically distinct activities have enormous therapeutic implications, as in our medulloblastoma model, active site inhibitors of mTOR, but not rapamycin, demonstrate efficacy. Taken together, this supports the idea that signaling through S6K is dispensable, whereas eIF4E is required for MYC-driven oncogenesis.

Citation Format: Justin G. Meyerowitz, W. Clay Gustafson, Erin Nekritz, Fredrik Swartling, Kevan M. Shokat, Davide Ruggero, William A. Weiss. Targeting the translational apparatus in MYCN-driven medulloblastoma. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B78.
Abstract PR04: Novel somatic and germline mutations in intracranial germ cell tumors
Authors: Wang Linghua , Yamaguchi Shigeru , Terashima Keita , Burstein Mathew D. , Nakamura Hideo , Susuki Tomonari , Nishikawa Ryo , Natsume Atsushi , Terasaka Shunsuke , Ng Ho Keung , Adesina Adekunle , Gibbs Richard , Wheeler David , Lau Ching
Published: May 2015

Intracranial germ cell tumors (IGCTs) are rare and biologically diversified tumors affecting mainly male adolescents with the highest incidence in Japan and other Asian countries2. They are divided into two main groups, pure germinoma and nongerminomatous GCTs (NGGCTs). About 10% of germinomas and most NGGCTs remain refractory to multimodality therapy. Little is currently known about IGCTs except for KIT mutation/overexpression, which is observed in ∼25% of pure germinomas and is rarely seen in NGGCTs. As yet, there are no clues for the puzzle of onset during puberty, geographic and gender discrepancy in incidence of IGCTs. Here we report the analysis of 62 cases by whole-exome sequencing, deep-targeted sequencing and SNP array. The KIT/RAS pathway was frequently mutated in pure germinomas and mixed GCTs with germinoma components. In contrast, NGGCTs appear to have a paucity of clinically actionable mutations. We identified novel recurrent somatic mutations in KIT and 8 additional genes in KIT/RAS pathway that have not been previously associated with IGCTs: downstream mediators of KIT including KRAS, NRAS, MTOR, AKT1 and its negative regulator CBL (11%). We showed frequent focal amplification at AKT1 locus (19%), leading to AKT1 overexpression. Moreover, we identified loss-of-function mutations in BCORL1 (10%), a transcriptional corepressor and tumor suppressor. Furthermore, we report for the first time, significant enrichment of novel and rare germline variants in JMJD1C, a histone demethylase and coactivator of the androgen receptor, among Japanese IGCT patients. Our data suggested a strong association of JMJD1C variants and the risk of developing of IGCTs (odds ratio=3.57). This study establishes a molecular foundation for understanding the biology of IGCTs and suggests potential promising targets for development of novel therapeutics.

This abstract is also presented as Poster A14.

Citation Format: Linghua Wang, Shigeru Yamaguchi, Keita Terashima, Mathew D. Burstein, Hideo Nakamura, Tomonari Susuki, Ryo Nishikawa, Atsushi Natsume, Shunsuke Terasaka, Ho Keung Ng, Adekunle Adesina, Richard Gibbs, David Wheeler, Ching Lau. Novel somatic and germline mutations in intracranial germ cell tumors. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr PR04.
Abstract BS2-1: Collective invasion in breast cancer is led by specialized cancer cells with basal gene expression
Authors: Ewald Andrew J
Published: May 2015

Metastasis is the major driver of mortality and morbidity from breast cancer. Unfortunately, there are very few therapies that are effective in the metastatic setting. The overall hypothesis guiding our work is that a deeper biological understanding of the cellular and molecular mechanisms driving metastatic progression would facilitate the development of novel therapeutic concepts. A major barrier to achieving this goal is that the essential cellular steps occur deep within the body over a period of months to years.

To overcome this barrier, we developed a novel organoid invasion assay that enables us to prospectively identify the most invasive cells within primary breast tumors. We initially explanted organoids from advanced tumors derived from the MMTV-PyMT transgenic mouse model of luminal B breast cancer. Surprisingly, we discovered that the cells that lead invasion into the extracellular matrix express basal epithelial genes, such as keratin-14, p63, and P-cadherin, both in 3D culture and in vivo. We next demonstrated that the cells leading invasion in mouse models of Her2 overexpressing (MMTV-Neu) and basal breast cancer (C3(1)-Tag) also expressed basal epithelial markers. We then adapted our organoid invasion assay to study primary human breast tumors in real-time and found that keratin-14+ cells lead collective invasion across diverse molecular subtypes of breast cancer, both in 3D culture and in vivo. With these correlations firmly established, we returned to the MMTV-PyMT mouse model to dissect the mechanisms underlying collective invasion. Using a keratin-14 reporter line we revealed that the basal invasion program can be induced in luminal phenotype cancer cells and that these newly keratin-14+ cells can lead collective invasion. We then identified shRNA constructs to knockdown keratin-14 and demonstrated that it is required for collective invasion in 3D culture and in vivo.

Our current work focuses on using next generation sequencing to identify targetable genes required for the invasive process and using in vivo lineage analysis to study the relationship between collective invasion and distant metastasis.

Citation Format: Andrew J Ewald. Collective invasion in breast cancer is led by specialized cancer cells with basal gene expression [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr BS2-1.
Abstract ES2-3: Management of metastatic HER2 positive disease: optimizing current therapies and an overview of new agents in development
Authors: Krop Ian
Published: May 2015

Amplification of the HER2/neu gene occurs in approximately 20% of invasive breast cancers and is associated with aggressive clinical behavior. The development of HER2-targeted therapies, including trastuzumab, lapatinib, pertuzumab and trastuzumab emtansine (T-DM1) has revolutionized the treatment of this disease, leading to dramatic improvements in clinical outcomes. Given these improvements, the goals in treating patients with advanced HER2-positive breast cancer are to both extend survival as well as to minimize toxicities of therapy. In patients with newly diagnosed metastatic breast cancer, pertuzumab, in combination with trastuzumab and docetaxel, markedly improves survival and only mildly increases toxicity compared to trastuzumab and docetaxel. Pertuzumab, trastuzumab, and a taxane should thus be considered the standard of care for most patients in the first line setting. In the second line setting, the antibody-drug conjugate T-DM1is the standard of care as it is associated with longer survival and less toxicity than capecitabine and lapatinib. In 3rd and later lines of therapy, continuation of HER2-directed therapy is important, but there are no definitive data that a particular regimen (e.g. trastuzumab + chemotherapy, lapatinib + chemotherapy, trastuzumab + lapatinib) is superior in this setting. Thus decisions regarding choice of therapy should be guided by patients' preferences regarding toxicity profiles and route of administration.

Although HER2-directed therapy has improved outcomes, resistance to these agents eventually develops in almost all patients. CNS metastases represent one increasingly common manifestation of treatment resistance in HER2-positive cancers. Understanding mechanisms of resistance and development of novel agents to overcome this resistance is critical. A multitude of agents designed to overcome resistance are currently being evaluated in the clinic including PI3-kinase inhibitors, more potent tyrosine kinase inhibitors, new antibody-drug conjugates, and novel immunotherapies. In addition, studies evaluating the genomic alterations present in metastatic HER2-positive cancer tissue are beginning to provide clues as to the mechanisms of resistance present in treatment refractory disease. It is possible that with continued improvements in therapies and a better understanding of molecular resistance mechanisms, mortality associated with metastatic HER2-positive breast cancer can be largely eliminated.

Citation Format: Ian Krop. Management of metastatic HER2 positive disease: optimizing current therapies and an overview of new agents in development [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr ES2-3.
Abstract OT3-1-06: A phase 2 single-arm study to evaluate the clinical activity, safety and tolerability of enzalutamide (ENZA) with trastuzumab in patients with advanced human growth factor receptor 2 (HER2)-positive breast cancer
Authors: Trudeau Maureen E , Winer Eric , Steinberg Joyce L , Liosatos Maggie , Poondru Srinivasu , Dydo Michael , Zhou Yun , Westphal Michael , Peterson Amy C , Gradishar William
Published: May 2015

Background

Androgen receptor (AR) expression is observed in ∼60% of patients (pts) with HER2+ breast cancer1. In vitro, ENZA inhibits proliferation of AR+/HER2+ cell lines and enhances the activity of trastuzumab. ENZA also inhibits proliferation of trastuzumab resistant HER2 positive cells2.

Methods

Any amount of AR expression (local or central) is allowed, submission of tissue is mandatory. Patients must have measurable disease per RECIST 1.1, and have received 1 to 4 prior lines of anti-HER2 therapy in the advanced / metastatic setting. Brain imaging is required to exclude patients with CNS metastases. Pts with a seizure history are excluded.

Women with metastatic or locally advanced HER2+, AR+, and ER-/PgR- breast cancer will receive daily ENZA (160 mg) continuously and trastuzumab (6 mg/kg) administered every 21 days, until disease progression (NCT02091960). The primary endpoint (EP) is clinical benefit rate (CBR) where benefit is defined as complete or partial response (CR or PR) or stable disease (SD) ≥24 weeks according to RECIST 1.1 criteria. Additional EPs include safety and tolerability, and the relationship between AR expression and ENZA activity. If the CBR is ≥3 in 21 evaluable pts, the sample size will increase to 66 pts.

The primary EP will be analyzed in pts with centrally confirmed AR expression (≥10% nuclear staining by IHC), who have received at least one dose of ENZA, and have ≥1 post-baseline tumor assessment. The null hypothesis (H0), that the true CBR is 10%, will be tested against a 1-sided alternative. This Simon’s two-stage design yields 90% power when the true response rate is 25% with a 1-sided type 1 error rate of 5%. Enrollment is expected to continue through 2016.

References:

1. Collins LC, Cole KS, Marotti JD, Hu R, Schnitt SJ, Tamimi RM. Androgen receptor expression in breast cancer in relation to molecular phenotype: results from the Nurses' Health Study. Mod Pathol. 2011;24(7):924-31.

2. J. Richer, AACR Advances in Breast Cancer, San Diego, CA, October 2013.

Citation Format: Maureen E Trudeau, Eric Winer, Joyce L Steinberg, Maggie Liosatos, Srinivasu Poondru, Michael Dydo, Yun Zhou, Michael Westphal, Amy C Peterson, William Gradishar. A phase 2 single-arm study to evaluate the clinical activity, safety and tolerability of enzalutamide (ENZA) with trastuzumab in patients with advanced human growth factor receptor 2 (HER2)-positive breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT3-1-06.
Abstract P1-02-11: Role of FDG-PET/CT in prediction of underestimation of invasive breast cancer in cases of ductal carcinoma in situ diagnosed at needle biopsy
Authors: Shigematsu Hideo , Kadoya Takayuki , Yoshimura Noriko , Kajitani Keiko , Emi Akiko , Masumoto Noriko , Haruta Rumi , Kataoka Tsuyoshi , Okada Morihito
Published: May 2015

Background: The aim of this study was to evaluate the significance of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for predicting the underestimation of invasive breast cancer in cases of ductal carcinoma in situ (DCIS) at needle biopsy.

Patients and Methods: Of 83 consecutive cases with diagnoses of DCIS at primary needle biopsy who underwent curative surgery between 2010 and 2013, the association between the maximum standardized uptake value (SUVmax) on FDG-PET/CT before excision and the underestimation of invasive breast cancer was examined.

Results: There were 29 (34.9%) cases diagnosed to have invasive breast cancer at excision. Receiver operating characteristics (ROC) curve analysis showed the cutoff value of SUVmax to predict underestimation of invasive breast cancer was 1.6. The rates of underestimation were 61.5% for patients with a tumor of SUVmax > 1.6 and 11.4% for patients with a tumor SUV max ≤ 1.6 (p <0.001). High value of SUVmax was significantly associated with symptomatic presentation (p < 0.001), palpability (p < 0.001), mass formation (p = 0.013), high Breast Imaging Reporting and Data System category (p = 0.011) and core needle biopsy (p = 0.007). In multivariate analysis, high SUVmax was only significant predictive factor of underestimation of invasive breast cancer (HR 11.7, 95% CI 3.70-37.0, p < 0.001).

Association between each preoperative variable and underestimation of invasive component in multivariate analysis in cases of DCIS diagnosed at needle biopsyVariables HR (95% CI)P valuePresentationsymptomatic vs. screening detected1.64 (0.43-6.22)0.47Palpableyes vs. no1.54 (0.36-6.69)0.58Lesion size< 2cm vs. ≥ 2cm1.23 (0.34-4.40)0.76Mass formationyes vs. no1.28 (0.36-4.44)0.7BI RADS category5 vs. 3, 42.92 (0.80-10.7)0.11Biopsy devicemammotome biopsy vs. CNB2.16 (0..64-7.30)0.21Nuclear gradehigh vs. not highhigh vs. not high 2.24 (0.51-9.78)0.29SUVmaxhigher vs. lower11.7 (3.70-37.0)< 0.001BI RADS, Breast Imaging Reporting and Data System; DCIS, ductal carcinoma in situ; IBC, invasive breast cancer; SUVmax, maximum standardized uptake value

Conclusion: SUVmax on FDG-PET/CT is useful for predicting the underestimation of invasive breast cancer in cases of DCIS at needle biopsy.

Citation Format: Hideo Shigematsu, Takayuki Kadoya, Noriko Yoshimura, Keiko Kajitani, Akiko Emi, Noriko Masumoto, Rumi Haruta, Tsuyoshi Kataoka, Morihito Okada. Role of FDG-PET/CT in prediction of underestimation of invasive breast cancer in cases of ductal carcinoma in situ diagnosed at needle biopsy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-02-11.
Abstract P1-03-03: Experience in the community oncology practice with a 25-gene hereditary cancer panel
Authors: Diab Sami , Rodriguez Patricia , Leininger Anna , Clark Lisa , Janicek Mike F , Smith Ellen B , Sandbach John , Saam Jennifer , Langer Lucy
Published: May 2015

Introduction:

The identification of patients with an inherited cancer syndrome is becoming increasingly relevant in the treatment and prevention of cancer. Testing with a panel of genes provides the opportunity to rapidly identify or rule out deleterious mutations in several genes simultaneously and, thus, has the potential to streamline the testing process and more efficiently and accurately provide results. We report on the experience of panel-based testing in the community oncology setting.

Objectives:

To evaluate the performance of a 25-gene hereditary cancer test in the community oncology setting and describe the patient characteristics and test findings.

Methods:

We retrospectively evaluated the 25-gene panel testing data obtained between September 2013 and February 2014 in 6 large community oncology practices. The gene panel was based on next generation sequencing and rearrangement analysis of 25 genes with cancer risk data: BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2, EPCAM, APC, MUTYH, CDKN2A, CDK4, PALB2, CHEK2, SMAD4, BMPR1A, STK11, TP53, CDH1, PTEN, ATM, NBN, BARD1, BRIP1, RAD51C, and RAD51D. Personal and family history was obtained by health care provider report on test requisition forms.

Results:

The panel test was performed on 359 individuals during the time period. 69.9% of these patients had a phx of at least one of the eight panel cancers: breast, ovarian, colorectal, endometrium, pancreas, melanoma, prostate, and/or stomach. cancer diagnosis. 97.8% of the patients tested met the 2013 NCCN guideline criteria for HBOC, 2012 NCCN guideline criteria for Lynch Syndrome, or both. 37 pathogenic mutations were found in 34 distinct patients. The variant rate in this population was 35.4%. Mutations were identified in 16 different genes, and only 20 of the 37 mutations (54.1%) were found to be in the 6 genes included in HBOC and Lynch Syndrome testing (BRCA1, BRCA2, MSH6, MLH1, MSH2, PMS2).

Conclusion:

The 25-gene hereditary cancer panel increased the identification of deleterious mutations which would otherwise not have been detected. The variant rate in this setting is similar to the rate reported previously in both community and academic centers where panel testing is used. Use of a hereditary cancer panel in the community oncology practice may improve detection rates and provide an opportunity for enhanced cancer management.

Citation Format: Sami Diab, Patricia Rodriguez, Anna Leininger, Lisa Clark, Mike F Janicek, Ellen B Smith, John Sandbach, Jennifer Saam, Lucy Langer. Experience in the community oncology practice with a 25-gene hereditary cancer panel [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-03-03.
Abstract P1-03-04: The impact of Angelina Jolie (AJ)'s story on genetic referral and testing at an academic cancer centre
Authors: Raphael Jacques , Verma Sunil , Hewitt Paul , Eisen Andrea
Published: May 2015

Introduction/background

In May 2013, AJ revealed to the media that she had undergone preventive double mastectomy. The actress had a family history of breast and ovarian cancer and tested positive for the BRCA1 gene mutation. Media coverage has been extensive, but it’s not clear what messages the public and professional medical staff took from this personal story that sometimes could be misleading.

Methods

We conducted a retrospective review in our centre using data from the clinical database of the Familial Cancer Program in a tertiary care cancer centre. The impact of AJ’s story on genetic counseling referrals was assessed by comparing the number of referrals made 6 months before and after the story. In addition, the quality of referrals was reported by comparing the number of patients who qualified for genetic testing as defined by the Ontario Ministry of Health and Long Term Care and the ones who carried a BRCA1/2 mutation before and after the media release.

Results

The number of women referred for genetic counseling increased by 85% after the release of AJ’s story (479 before versus 887 after). This translated to an increase of 99% in the number of women who qualified for a genetic testing (211 before versus 419 after). Among them, 120 and 254 women had a history of breast and ovarian cancer in their family, 16 and 37 women had a history of male breast cancer in their family and 28 and 15 women were diagnosed with breast cancer at the age of 35 or less before and after AJ’s story respectively. Furthermore, the number of BRCA1/2 carriers identified increased by 107% (29 (14 BRCA1, 15 BRCA2) before and 60 (32 BRCA1, 28 BRCA2) after).

Conclusion

This study clearly shows that the number of genetic referrals doubled after AJ’s story. Nevertheless, the quality of referral remained the same with nearly the same percentage of patients who qualified for genetic testing and who were identified as BRCA1/2 carriers. The challenge is to meet the increased demand for cancer genetic services including screening, counseling, testing, and preventive surgery. After AJ’s story the current model of genetic counseling may need to be revisited.

Key words: Angelina Jolie; BRCA1/2; genetic referral; genetic counseling; genetic testing.

Citation Format: Jacques Raphael, Sunil Verma, Paul Hewitt, Andrea Eisen. The impact of Angelina Jolie (AJ)'s story on genetic referral and testing at an academic cancer centre [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-03-04.
Abstract P1-06-06: Meta-analysis reveal novel mechanism of bisphenol A effect on mammary gland
Authors: Gu Xiang , Gao Hui , Wang Danhan , Bandyopadhyay Abhik , Dong Qiaoxiang , Sun LuZhe
Published: May 2015

Pubertal exposure to bisphenol A (BPA) has been shown to cause abnormal mammary gland development and neoplastic transformation in adults. However, the mechanism of this BPA effect still remains largely unknown. We exposed 21-day-old Balb/c mice to BPA by gavage (25 µg/kg/day) during puberty for 3 weeks. Primary mammary cells were isolated at 6 weeks, and 2 and 4 months of age and subsequently sorted into Lin-CD49f-CD24-stromal cells, Lin-CD49fhighCD24med MaSCs-enriched basal cells and Lin-CD49flowCD24high luminal progenitor-enriched cells with FACS for gene expression analysis. The Gene Ontology (GO) Enrichment Analysis shows that upon BPA treatment, the biological processes (BPs) significantly enriched in luminal compartment were related to response to organic substance and hormone stimuli at early stage (2 month old) whereas to cell cycle regulation at late stage (4 month old), consistent with published study in mammary gland morphology where BPA promoted the expansion of luminal population. However, the BPs enriched in spheres derived from basal cells (highly enriched with MaSCs) collected at late stage (4 month old) were mainly related to cell adhesion, epithelial differentiation and in stromal cells were related with vascular development for tissues collected either immediately after BPA treatment or 6 weeks later at 4-month of age. More interestingly, the Downstream Function Effects Analysis performed by Ingenuity Pathway Analysis reveal the changes in any compartments will all lead to significant activation of cancer-related downstream effects including hyperplasia, neoplasm of mammary tumor, proliferation of tumor cells and invasion of breast cancer, although there are few overlapping common genes in these compartments and conditions upon BPA treatment, indicating the different mechanism in response to BPA treatment and tumorigenesis. Network analysis revealed that the potential upstream regulators for these enriched BPs are TGFβ1, VEGF, PPARG, Estrogen/ Estrogen Receptor, glucocorticoid, ERK and NOTCH signaling. Together with our recently published data, this study reveals the difference in immediate and delayed response to pubertal BPA treatment and indicates that cross-talk between several growth factor and hormonal receptor signaling pathways may contribute to the altered cellular processes by BPA, consistent with the role of BPA as an endocrine disruptor.

Citation Format: Xiang Gu, Hui Gao, Danhan Wang, Abhik Bandyopadhyay, Qiaoxiang Dong, LuZhe Sun. Meta-analysis reveal novel mechanism of bisphenol A effect on mammary gland [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-06-06.
Abstract P1-07-17: Transcription factor Fra-1 modulates the adhesive properties of breast cancer cells contributing to a metastatic phenotype
Authors: Oliveira-Ferrer Leticia , Kürschner Melanie , Labitzky Vera , Wicklein Daniel , Müller Volkmar , Schumacher Udo , Milde-Langosch Karin , Schröder Christine
Published: May 2015

Fra-1, a component of the transcription factor AP-1 family, has been found to be overexpressed in carcinomas with high metastatic potential such as in triple-negative breast cancer. The effect of Fra-1 on the morphology, motility and invasive potential of breast cancer cells has been previously described. Since tumor cell adhesion plays an essential role in the metastatic process, especially for extravasation from blood vessels, we investigated the influence of Fra-1 on breast cancer cell interactions with the endothelium.

Using the human breast cancer cell lines MCF7 (weakly invasive, estrogen receptor (ER)-positive) and MDA MB 231 (strongly invasive, ER-negative) with stable Fra-1 overexpression, we performed dynamic cell-flow adhesion assays on surfaces coated with E-selectin or with human pulmonary microvascular endothelial cells (HPMEC). Our analyses revealed increased adhesion of Fra-1 overexpressing MCF7 cells to E-selectin but also to activated endothelial cells, whereas the per se highly invasive and Fra-1-positive MDA MB 231 cell line showed enhanced cell rolling and tethering on E-selectin and endothelium-coated surfaces, but no increased firm adhesion after Fra-1 overexpression. These different behaviors correspond to an up-regulation of various adhesion-related proteins such as CD44, Integrin α5 and CEACAM6 in Fra-1 overexpressing MCF7 cells measured by microarray analysis and flow cytometry in comparison to weaker differences in the expression of adhesion molecules found in the Fra-1 overexpressing MDA MB 231 cell line. In line with these results and based on cDNA microarray data of breast cancer patients (n=175) high Fra-1 expression significantly correlates with shorter overall survival and higher rate of lung metastasis in ER-positive breast cancer patients (n=130), but has no impact on the prognosis of patients with ER-negative tumors.

Thus, in addition to its pro-invasive and pro-migratory effect, Fra-1 might influence the metastatic potential of breast cancer cells by changing the expression of adhesion molecules resulting in increased adherence to endothelial cells under flow conditions.

Citation Format: Leticia Oliveira-Ferrer, Melanie Kürschner, Vera Labitzky, Daniel Wicklein, Volkmar Müller, Udo Schumacher, Karin Milde-Langosch, Christine Schröder. Transcription factor Fra-1 modulates the adhesive properties of breast cancer cells contributing to a metastatic phenotype [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-07-17.
Abstract P1-07-35: Fatty acid binding protein 5 promotes metastatic potential of triple negative breast cancer
Authors: Powell Catherine A , Nasser Mohd W , Wochna Jacob C , Shilo Konstantin , Zhang Xiaoli , Ganju Ramesh K
Published: May 2015

Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer that has a poor prognosis for patients, not only due to its aggressive nature, but also due to the lack of effective therapeutic strategies. High mortality is associated with metastasis of the primary TNBC. We analyzed the role of fatty acid binding protein 5 (FABP5), an intracellular fatty acid transport protein, in aggressive breast cancers, especially TNBC. FABP5 expression was analyzed in a tumor microarray (TMA) containing 423 breast cancer patient samples and found that FABP5 expression is associated with tumor grade, triple negative status, and disease-free survival. Next, a mechanistic approach was taken and found that FABP5 knockdown TNBC cell lines express lesser EGFR protein compared to control, and upon EGFR activation express less phospho-FAK and phospho-Pyk2. We found that EGFR was not down regulated at the transcriptional level in FABP5 knockout cells. Further analysis indicated the role for Cbl, an E3 ubiquitin-protein ligase, as a potential mechanistic target for the down-regulation of EGFR protein in FABP5 knockdown cell lines. EGFR is over-expressed in aggressive breast cancers, especially TNBC. Though EGFR is highly expressed in aggressive subtypes of breast cancer, targeted therapeutic strategies have not been successful in clinic. EGFR has been shown to be involved in distant metastasis in aggressive breast cancers. We found a correlation between FABP5 and EGFR expression and metastasis-free survival using publically available datasets from The Cancer Genome Atlas. We next studied the functional consequence of FABP5 knockdown in TNBC cell lines. We showed that EGF-induced FABP5 knockdown cells migrated less compared to control. Additionally, FABP5 knockdown cells were significantly less able to migrate into a wound in response to EGF stimulation. EGF-induced cell attachment of FABP5 knockdown cells is significantly decreased compared to control. Our findings suggest FABP5 modulates metastatic potential of TNBC through alterations in EGFR expression and downstream migratory signaling molecules.

Citation Format: Catherine A Powell, Mohd W Nasser, Jacob C Wochna, Konstantin Shilo, Xiaoli Zhang, Ramesh K Ganju. Fatty acid binding protein 5 promotes metastatic potential of triple negative breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-07-35.
Abstract P1-12-16: Efficacy of adjuvant tamoxifen in hormone receptor-positive premenopausal breast cancer patients according to the body mass index
Authors: Altundag Kadri , Sendur Mehmet AN , Aksoy Sercan , Babacan Taner , Ozisik Yavuz
Published: May 2015

Introduction: Obesity is an independent risk factor for the development of breast cancer and has been associated with poor breast cancer outcomes. But, this association usually depend on hormone-receptor positivity and ovarian activity. Obesity was confirmed as an adverse prognostic factor in patients treated with aromatase inhibitors, but the adverse effects in patients treated with tamoxifen was not known exactly. Thus, we aimed to examine the efficacy of adjuvant tamoxifen in hormone receptor-positive premenopausal breast cancer patients according to the body mass index (BMI).

Material-Methods: Newly diagnosed hormone receptor-positive breast cancer patients who were premenopausal and non-metastatic were enrolled to the study. Patients with BMI ranging between 18.5 and 24.9 kg/m2 as normal weight patients (Arm A, n = 408), and patients with a BMI ranging ≥ 25 kg/m2 were overweight and obese patients (Arm B, n = 418).

Results: The median follow-up time for this analysis was 36 (6-327) months. The median age was 39.5 (22-57) and 43 (20-56) in Arm A and Arm B, respectively (P<0.0001). The mean BMI was 22.1 ± 1.8 kg/m2 and 29.2 ± 3.3 kg/m2 of Arm A and Arm B, respectively ( P = <0.001). In both normal weight and overweight patients, the other baseline clinico-pathologic properties and the treatment history with radiotherapy and chemotherapy were similar and not statistically significant. In overweight and obese patients the history of diabetes mellitus and hypertension was significantly higher compared to normal weight patients. In patients with normal weight patients DFS rate was 88.5% and 78.2% whereas in overweight and obese patients DFS rate was 87.2% and 70.9% in the third and fifth years respectively (Figure 1) ( P = 0.43). In patients with normal weight patients OS rate was 98.5% and 93.2% whereas in overweight and obese patients OS rate was 94.6% and 87.4% in the third and fifth years respectively (Figure 2) ( P = 0.02).

Conclusion: Our study showed that BMI have no worse effect on recurrence risk in patients treated with tamoxifen in hormone-receptor positive premenopausal breast cancer. Poor survival outcome was observed in overweight and obese patients can be due to dose limitations of chemotherapeutic agents and higher rate of comorbid diseases.

Citation Format: Kadri Altundag, Mehmet AN Sendur, Sercan Aksoy, Taner Babacan, Yavuz Ozisik. Efficacy of adjuvant tamoxifen in hormone receptor-positive premenopausal breast cancer patients according to the body mass index [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-12-16.
Abstract P1-15-13: Short term toxicity of intra-operative radiotherapy for patients with breast cancer treated at a single center
Authors: Shai Ayelet , Zur Maoz , Leviov Michelle , Bitterman Arie , Eitan Shiloni , Steiner Mariana
Published: May 2015

Introduction:

Intra-operative radiotherapy (IORT) is increasingly being used for the treatment of low risk breast cancer. In the randomized TARGIT trial, late toxicity was not different between patients treated with IORT and external beam radiotherapy. Early toxicity of IORT has not been fully characterized.

Methods:

IORT with one dose of 20 Gy using the Intrabeam© device has been offered as an alternative to standard treatment as part of a single center prospective single arm trial. Patients over 60 years with clinically node negative, < 2 cm invasive duct carcinomas were eligible. Patients aged 50-60 years, patients with tumors 2-3.5 cm and patients with invasive lobular carcinomas were treated with IORT if they were not candidates for standard treatment.

For the present study information regarding complications occurring within the first year after surgery was analyzed. Patients treated between 2006 and 2012 were included in this analysis.

Results:

393 patients were treated from 2006 – 2012. 4 were lost to follow up. Median age was 70 years (55-90) and median clinical tumor size was 1.2 cm (5-30).

102 patients (26.2%) had a complication. Infections were most frequent. Misdiagnosis of radiation dermatitis as infection in some cases cannot be excluded. Clinically meaningful seromas occurred in 10.2% of patient and 8.2% had a wound dehiscence, possibly related to rupture of pre-existing seromas.

Table 1Complication typeN (%)N with grade 3 (%)N with grade 4 (%)median time to recovery (range)Infection42 (11)3 (3.3) 0.62 (0.1 - 3.8)Seroma40 (10.2)  13.2 (0.3-50)Wound dehiscence33 (8.5)2 (0.5) 5.8 (0.36-15.3)Bleeding11 (2.8)3 (0.8)  Skin necrosis2 (0.5) 2 (0.5)3.88 (3.45-4)frequency, severity and time to recovery of acute complications of IORT.

18 patients (4.6%) had a grade 3 complication. 2 patients (0.5%) had grade 4 radiation induced skin necrosis of small size and both resolved within 4 months. All other complications resolved completely (table 1). Risk factors for complications in this cohort will also be presented.

Conclusions:

Intra-operative radiotherapy was associated with a relatively high rate of clinically meaningful seromas and wound dehiscence and rare small size skin necrosis. Most complications were mild – moderate. 5% of patients experienced grade 3 or 4 complications, and all resolved completely. Further study of the factors predisposing to severe complications is warranted.

Citation Format: Ayelet Shai, Maoz Zur, Michelle Leviov, Arie Bitterman, Shiloni Eitan, Mariana Steiner. Short term toxicity of intra-operative radiotherapy for patients with breast cancer treated at a single center [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-15-13.
Abstract P2-01-09: Application of the Z0011 criteria on Dutch breast cancer patients
Authors: Verheuvel Nicole C , Tjan-Heijnen Vivianne CG , Voogd Adri C , Roumen Rudi MH
Published: May 2015

Background

The American College of Surgeons Oncology Group reported a randomized controlled trial (Z0011-trial) among women with T1-2N0M0 breast cancer treated with breast conserving therapy. It showed that axillary lymph node dissection may be redundant in selected sentinel node positive patients. Though, it raises questions as to the general applicability of these results. Therefore, this study aims to examine the practice changing effect and the clinical relevance of the criteria described in the Z0011 trial, when applied to a Dutch population of patients diagnosed with invasive breast cancer.

Methods

This is a multicenter study including patients with T1-2N0-1M0 invasive breast cancer treated in either of the 10 different hospitals affiliated with the Dutch National Cancer Registry region South in the period between January 2007 and December 2012. All patients underwent a clinical examination, a mammography and sonographic examination of the breast and the ipsilateral axilla. Chi-square analyses or a Fisher’s exact test were used to assess differences in patient and tumor characteristics the Z0011 population and the Dutch cohort. A p-value of ≤0.05 was considered statistically significant.

Results

A total of 11,031 patients had invasive breast cancer, of whom 5368 patients were treated with breast conserving therapy. In 6.8% axillary status was determined by the ultrasound guided lymph node biopsy and in 93.1% axillary metastases were found trough the sentinel node procedure after a negative or inconclusive ultrasound. When applying the Z0011 criteria to our study population of node positive patients, 5.7% of all breast cancer patients, equalling 11.8% of patients receiving breast conserving therapy, met the Z0011 criteria.

Conclusion

These results suggest that when applying the Z0011 criteria to all node positive patients, including patients with a positive sentinel node and patients with a positive ultrasound guided lymph node biopsy, only in 5.7% of all invasive breast cancer patients could be spared an ALND and its morbidity. This is a small practice changing effect. Nevertheless, it is worthwhile to consider implementing the findings of Z0011 trial in daily clinical practice.

Citation Format: Nicole C Verheuvel, Vivianne CG Tjan-Heijnen, Adri C Voogd, Rudi MH Roumen. Application of the Z0011 criteria on Dutch breast cancer patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-01-09.
Abstract P2-01-14: Pre-operative axillary staging results in over-treatment in some breast cancer patients
Authors: Pieri Andrew , Cain Henry , Aspinall Sebastian
Published: May 2015

Introduction

Following a diagnosis of breast cancer, pre-operative ultrasound staging of the axilla is recommended. Patients found to have metastatic disease on biopsy or FNA can proceed directly to axillary clearance (ALNC) at the time of their breast tumour excision. However, although ultrasound staging is a sensitive test to detect axillary disease, it does not differentiate between low and high volume nodal metastasis. Recent evidence suggests that, in selected patients with low volume axillary disease following SLNB, completion ALNC may be safely omitted. This has been reflected in the recently updated ASCO guidelines. In light of this current trend towards axillary conservation, some patients undergoing ALNC after positive axillary staging may be over-treated.

The aims of this study is to establish the nodal burden of patients undergoing ALNC following positive axillary staging and to compare the nodal burden of those patients with those undergoing completion ALNC after a positive SLNB.

Methods

Data was collected prospectively over 12 months from nine hospitals within the North of England Cancer Network. Age, tumour characteristics, breast operation, axillary staging results, axillary operation(s) and nodal results were recorded.

Results

A total of 1010 patients with breast cancer underwent pre-operative axillary staging. 215 patients (21%) had an ALNC. Of these, 115 (53%) cases underwent a primary ALNC after positive staging. The remaining 100 (47%) patients had a completion ALNC following a positive SLNB. The nodal burden for patients undergoing ALNC is shown in the table below:

Total number of positive nodesALNC after positive stagingALNC after positive SLNB n patients% patientsn patients% patients087001322847472131124243121011114111044≥539341414Totals115 100 

Analysis of the data revealed that tumour size was a significant predictor of low volume axillary disease (i.e. <3 nodes positive) [p=0.02, Mann-Whitney test].

Conclusion

In this study, 46% of patients undergoing ALNC after positive staging had low volume disease (2 or less positive nodes). In the context of recent evidence if these patients had undergone a SLNB following the positive pre-operative staging they may have avoided a completion ALNC.

This study demonstrates tumour size to be a significant predictor of low volume axillary disease and thus may be an important factor to consider alongside pre-operative staging when selecting patients who may be better managed by a SLNB rather than proceeding directly to ALNC.

Citation Format: Andrew Pieri, Henry Cain, Sebastian Aspinall. Pre-operative axillary staging results in over-treatment in some breast cancer patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-01-14.
Abstract P2-03-19: Discovery of the genes that underpin the transition to malignant phenotype of breast tumors in highly consanguineous region
Authors: Gupta Ishita , Ouhtit Allal , Shanmuganathan Somya , Al-Riyami Hamad
Published: May 2015

Breast cancer (BC), a multifactorial and heterogeneous disease is a predominant women form of cancer worldwide affecting 22.9%. The rationale of this study is based on the following observations: 1) in Oman, a significantly increasing number of younger females (25-40 years) present to the clinic with advanced stage of BC; 2) in Oman, the rate of consanguinity is significantly high (52%); and 3) the transition from normal/begnin to malignant phenotype of breast tumor requires the involvement of a subset of specific genes. The long-term objective of this study is to identify and validate the subset of genes that are responsible for this malignant transformation using functional genomic studies, focus on this young age group of patients attending BC clinic (sporadic and familial). RNA samples were isolated from 40 Breast Tumors and 40 Normal tissues and analyzed by Microarray Gene Expression Profiling. Among a number of genes that were up and down regulated, BRIP1, HOXB3 and MAGED1 were identified as potential genes that might underpin the transition to the malignant phenotype; these genes were validated by RT-PCR using the same RNA samples that were examined by microarray. Pathway analysis was carried out to identify the major functional pathways connecting these genes. Ongoing sequencing of these genes using DNA extracted from the same samples will ultimately identify any genetic alteration that can affect the normal function of these genes. Functional validation assays aim to validate further the physiological relevance of these genes in tumor malignancy, and perhaps other novel genes specific to BC in the Omani population. Identification and validation of these genes will potentially pave the way towards the design of anti-cancer therapeutic strategies.

Citation Format: Ishita Gupta, Allal Ouhtit, Somya Shanmuganathan, Hamad Al-Riyami. Discovery of the genes that underpin the transition to malignant phenotype of breast tumors in highly consanguineous region [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-03-19.
Abstract P2-05-13: Transcriptomic profiling of patient sequential tumours provides cutting edge view of global metastatic expression changes following endocrine therapy
Authors: McBryan Jean , Fagan Ailis , McCartan Damian , Bolger Jarlath C , Bane Fiona T , Byrne Christopher , McIlroy Marie , Hill Arnold D , Young Leonie S
Published: May 2015

Disease recurrence is a common problem in breast cancer and yet the mechanisms enabling tumour cells to evade therapy and colonise distant organs remain unclear. Here, for the first time, RNAsequencing has been performed on matched primary, nodal and liver metastatic tumours from three tamoxifen-treated patients following metastatic disease progression. Despite all primary tumours being of a luminal subtype and all cancers metastasising to the liver, the extent of patient heterogeneity at the gene level was striking. Less than 3% of the genes differentially expressed between sequential tumours were common to all patients. Larger divergence was observed between primary and liver tumours than between primary and nodal tumours, reflecting both the latency time to disease progression and the genetic impact of endocrine therapy. Furthermore, a xenograft model demonstrated the ability of tamoxifen to drive disease progression and establish distant metastatic disease in the endocrine resistant setting. Common functional pathways altered during metastatic, endocrine-resistant progression included ECM receptor interactions and focal adhesions. This novel global analysis highlights the influence of primary tumour biology in determining the transcriptomic profile of metastatic tumours, as well as the need for adaptations in cell-cell communications in order for tumour cells to successfully colonise distant host organs.

Citation Format: Jean McBryan, Ailis Fagan, Damian McCartan, Jarlath C Bolger, Fiona T Bane, Christopher Byrne, Marie McIlroy, Arnold D Hill, Leonie S Young. Transcriptomic profiling of patient sequential tumours provides cutting edge view of global metastatic expression changes following endocrine therapy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-05-13.