bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P1-07-26: Global analysis of the transcriptome in matched primary and metastatic tumours defines ER specific gene alterations
Authors: Vareslija Damir , Fagan Ailis , McBryan Jean , Buckley Patrick , Farrell Michael , Hill Arnold DK , Young Leonie
Published: May 2015

The incidence of brain metastasis (BM) among women with metastatic breast cancer (MBC) is currently on the rise, and it is estimated that between 10-30% of patients diagnosed with breast cancer may also develop BM (Weil 2005). BM is considered a late complication in the clinical setting and is an infrequent occurrence even in mice studies that readily metastasise to other organs (Valiente 2014). While pre-menopausal status and negative estrogen receptor (ER) status are seen as main risk factors (Gil-Gil 2013), it is now recognised that BM is emerging as an increasing clinical problem across the various MBC subtypes.

BM patients have very poor overall survival and as a result it is crucial to identify the factors that promote the survival and adaptation of breast cancer cells to allow them to colonise distant sites such as the brain. The ability to predict the BM potential could be of great clinical importance and in this study we decided to investigate the mechanisms underlying BM across the various MBC subtypes.

To our surprise, in a cohort of breast cancer patients we found a comparable number of ER positive and ER negative BM. We established that ER positive patients (n=10) had a substantially longer disease latency period (median disease free survival (DFS) 36 months, range 8-85 months) in comparison to ER negative patients (n=8, HER2 positive, n=2, triple negative, n=6), (median DFS 24 months, range 9-60 months). To understand and elucidate the gene alterations required for successful colonisation of the brain we undertook RNAseq of sequential primary and brain metastatic tumours from ER positive (n=4) and ER negative (n=3) breast cancer patients. Significant elevations in gene expression were observed in the brain metastatic tumours in comparison to the matched primary. Though a large degree of patient heterogeneity was observed, common ER-specific metastatic pathways were identified.

This study highlights the requirement of unique gene sets for the colonisation to the brain and that functional characterisation of the differentially expressed genes will enable the identification of novel molecular targets for prevention and treatment of breast cancer BM.

Citation Format: Damir Vareslija, Ailis Fagan, Jean McBryan, Patrick Buckley, Michael Farrell, Arnold DK Hill, Leonie Young. Global analysis of the transcriptome in matched primary and metastatic tumours defines ER specific gene alterations [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 P1-07-26.
Abstract P1-09-26: Surgery for breast cancer in the elderly is associated with better outcomes
Authors: Jauhari Yasmin A , Chaichanavichkij Pam , Sainsbury Richard J
Published: May 2015

Background

Breast cancer often presents differently in the elderly with more neglected disease. There is patchy evidence to support surgery as a preferred management tool with a positive survival outcome. The objective of this study was to 1. Understand disease presentation and management of patients diagnosed with breast cancer over the age of 80, and 2. To review survival outcome between conservative and surgically managed elderly breast cancer patients.

Method

A retrospective single centre case series was conducted from 2008 to 2014 on patients aged 80 and over at breast cancer diagnosis. Survival outcome between conservative and surgical treatment groups were reported by Kaplan Meier analysis, with comparison by log-rank test.

Results

There were 156 patients, with a median age of 86.6 years (range 80 – 107). 67.9% had invasive ductal carcinoma.

At presentation, 9.6% had T4 fungating lesions and 11.9% had distant metastatic disease. The median tumour size was 25mm (range 4 – 85mm) and 81.5% were oestrogen receptor positive.

Conservative treatment (44.9%, n = 70) was accounted for in 80% of cases by patient choice and/or pre-morbid status precluding surgery. 55.1% of patients underwent surgical resections, the majority of which were performed with curative intent (96.4%). 11 patients had surgery under local anaesthetic with no complications. Median duration of hospital stay was 1 day.

Conservative vs. surgical cohorts were comparable in co-morbidities aside from age (89.6 +/- 5.1 vs. 85.2 +/- 4.2 years, p = 0.005)) and dementia (18 vs. 9 (p = 0.015). The overall survival for those treated conservatively was 29 +/- 4.1 months compared to 40 +/- 6.1 months (p = 0.004) for those having surgery.

Conclusion

The elderly are more likely to present with advanced or neglected breast cancer. Those undergoing surgery had a significant survival advantage and this modality should be offered unless co-morbidities are severe.

Citation Format: Yasmin A Jauhari, Pam Chaichanavichkij, Richard J Sainsbury. Surgery for breast cancer in the elderly is associated with better outcomes [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 P1-09-26.
Abstract P1-10-03: NSABP B-43 is unlikely to produce a cost-effective treatment strategy for HER2+ DCIS
Authors: Alvarado Michael D , Hayes Mitchell T , Sethi Rajni , Ozanne Elissa
Published: May 2015

Background. National Surgical Adjuvant Breast and Bowel Project (NSABP) B-43 is an ongoing randomized clinical trial that compares breast conserving surgery, radiation therapy, and two infusions of trastuzumab to breast-conserving surgery and radiation only for HER2+ ductal carcinoma in situ (DCIS). We sought to identify, from a societal perspective, the level of risk reduction observed in this trial that would be required to make treating HER2+ DCIS patients with trastuzumab cost-effective.

Methods. We developed a Markov decision-analytic model to evaluate these treatment strategies in terms of life expectancy, quality-adjusted life years (QALYs), costs, and the incremental cost-effectiveness ratio (ICER) over 15 years. The results of NSABP B-43 are pending. We therefore assumed the hazard reduction to be 36%, based on the statistical considerations of the trial protocol and explored this in sensitivity analyses. A series of one and two-way sensitivity tests were conducted.

Results. The baseline ICER for switching from a breast-conserving surgery and radiation strategy without trastuzumab treatment to a breast-conserving surgery and radiation strategy with trastuzumab treatment is $1.57 million per life-year gained and $299,616.73 per QALY gained. Compared to a societal willingness-to-pay threshold of $100,000 per QALY gained, adding Herceptin treatment is not cost-effective in the treatment of DCIS under these baseline conditions. In a one-way sensitivity test, we found that the Herceptin strategy only became cost-effective at an 88.3% risk reduction for local recurrence. The model was not sensitive to any costs or probabilities within 20% of baseline values. The model was sensitive to the utilities of having had breast-conserving surgery and radiation with and without trastuzumab treatment. It was not sensitive to other utilities within 0.05 of baseline values.

Conclusions. High risk DCIS treated with breast-conserving surgery and radiation has a low risk of local recurrence as demonstrated in multiple randomized trials. The addition of a costly drug in order to reduce this small risk further is very unlikely to be cost-effective and could be considered overtreatment of a non-fatal disease that is sufficiently managed with local treatment. Prospective cost-effectiveness analyses have the potential to guide allocation of valuable resources for breast cancer research, and should be regularly integrated into the protocol design of large clinical trials.

Citation Format: Michael D Alvarado, Mitchell T Hayes, Rajni Sethi, Elissa Ozanne. NSABP B-43 is unlikely to produce a cost-effective treatment strategy for HER2+ DCIS [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 P1-10-03.
Abstract P1-12-09: Possibility of GnRH agonist plus tamoxifen as an alternative treatment to AC (adriamycin plus cyclophosphamide) chemotherapy plus tamoxifen treatment in premenopausal hormone responsive HER2 negative breast cancer patients
Authors: Park Heeseung , Sohn Guiyun , Son Byung Ho , Lee Jong Won , Ahn SeiHyun
Published: May 2015

Background: The purpose of this study is to compare the treatment outcomes using GnRH agonist plus tamoxifen, and adriamycin and cyclophopsphamide(AC) containing chemotherapy plus tamoxifen in hormone responsive premenopausal node negative breast cancer patients.

Methods: Total 1027 premenopausal women with node negative, hormone receptor positive, Her-2 negative breast cancer were included in this retrospective cohort study. 595 patients (57.9%) were treated with GnRH agonist together with tamoxifen, and 432 patients (42.1%) were treated with adriamycin and cyclophsophamide containing chemotherapy with tamoxifen.

Results: A median follow up period was81 months. In pT1 disease, 7 year DFS (disease free survival)was 98.9% for GnRH agonist plus tamoxifen group and 97.4% for chemotherapy plus tamoxifen group, and in pT2 disease, 7 year DSS was 99.1% for GnRH agonist plus tamoxifen group, and 96.9% for chemotherapy plus tamoxifen groupwith nostatisticalsignificance (p=0.252 & 0.230).In pT1 disease, 7 year RFS was 95.4% for GnRH agonist plus tamoxifen group and 92.9% for chemotherapy plus tamoxifen group, and in pT2 disease, 7 year RFS was 91.6% for GnRH agonist plus tamoxifen group, and 91.7% for chemotherapy plus tamoxifen group with no statistical difference between two treatment groups (p=0.353 & 0.836). In subgroup analysis, ER+/PR+ patients and patientsyounger than 40 years old showed slightly better survival inGnRHagnonist plus tamoxifen group when compared to chemotherapy plus tamoxifen group with p-value of 0.046 & 0.018.

Conclusion: Adding GnRH agonist to tamoxifen is reasonable alternative to adding AC chemotherapy to tamoxifen in premenopausal luminal type node negative breast cancer patients.

Citation Format: Heeseung Park, Guiyun Sohn, Byung Ho Son, Jong Won Lee, SeiHyun Ahn. Possibility of GnRH agonist plus tamoxifen as an alternative treatment to AC (adriamycin plus cyclophosphamide) chemotherapy plus tamoxifen treatment in premenopausal hormone responsive HER2 negative 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 P1-12-09.
Abstract P2-01-16: Role of 18 FDG PET/CT in axillary staging in early breast cancer
Authors: Noblia Cristina , Azar Eugenia , Mansilla Dolores , Osorio Amilcar , Armanasco Eduardo , Montoya Diana , Ipiña Martin , Berman Gaston , Gonzalez Eduardo , Gonzalez Christian , Bruno Gabriel , Parma Patricia , Pulero Carla , Alvarez Ana
Published: May 2015

OBJETIVE To evaluate the 18F-FDG PET/CT capacity for the detection of axillary metastases and compare results with sentinel lymph node biopsy (SLNB).MATERIAL AND METHODS: 99 female patients with clinical T1T2N0 breast cancer were included. Patients with recent breast or axillary surgery, T3T4 disease, ductal carcinoma in situ, inflammatory carcinoma, uncontrolled diabetes mellitus and pregnant or lactation patients were excluded. Pre-operative FDG PET-CT was performed 15 days before surgery, SLNB took place with the combined method (radioisotopes and patent blue). Pearson and Spearman correlation test were used to evaluate association of main variables with a significance level (p) of 0.05.RESULTS: Breast PET-CT results: 80 positive PET/CT. Negative PET/ CT in 19 patients (4invasive lobular carcinoma, 7 tumors <7mm) Sensitivity 81%, specificity 100%.97 patients were operated (2 were stage IV with no surgery criteria). We found significant correlation of the FDG tumor uptake (SUV) with tumor size (p< 0.0001), histological grade (p< 0.009), nuclear grade (p<0.001), mitotic grade (p< 0.007) and Ki 67 (p< 0.0001).In all cases the correlation was positive.There was no correlation with hormonal receptors rate.Axillary PET CT results: positive PET/CT in 16 patients (16%). Of this 6 SNLB were negative (FPR= 9%). Specificity 91%, PET /CT were negative in 81 patients (84%), 17 had axillary metastases(5 micrometastases, 2 isolated tumor cells and 2 lobular carcinoma).Sensitivity:37%.FNR=63%. Correlation of histopatological axillary metastases was positive with breast tumor SUV (P<0.0002) and tumor size (p<0.01), but was not significant with histological, nuclear and mitotic grade, Ki 67,hormonal receptor rate and molecular subtype CONCLUSION: 1- PET / CT does not provide benefits for axillary staging in initial stages due to its low spatial resolution (6-8 mm) 2 –A negative axillary by PET/CT does not replace the sentinel node technique. 3 – We can suspect the presence of axillary metastases when there is an intense FDG uptake in the breast tumor.

Citation Format: Cristina Noblia, Eugenia Azar, Dolores Mansilla, Amilcar Osorio, Eduardo Armanasco, Diana Montoya, Martin Ipiña, Gaston Berman, Eduardo Gonzalez, Christian Gonzalez, Gabriel Bruno, Patricia Parma, Carla Pulero, Ana Alvarez. Role of 18 FDG PET/CT in axillary staging in early 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 P2-01-16.
Abstract P2-01-20: The ratio and size of positive sentinel lymph nodes predicts the involvement of non-sentinel lymph nodes following completion axillary lymph node dissection
Authors: Dave Rajiv V , Chauhan Muhhamed N , Ghaus Maria , Ahmed Sana , Shapra Shiv , Marriott Joshua , Sayers Craig , Kryjak Zbigniew , Ali Deedar
Published: May 2015

Background: The role of Completion Axillary Lymph Node Dissection (CALND) following positive Sentinel Lymph Node Biopsy (SLNB) is being actively debated. The involvement of our unit in the POSNOC trial (which has a no-treatment arm), has prompted a review of our unit’s CALND results, in order to examine predictors of involvement of non-sentinel lymph nodes (n-SLN), to better inform our patients during recruitment.

Methods: We retrospectively analysed our experience of SNLB between July 2008 to 2013. A total of 1152 breast cancer patients underwent SLNB based on lymphoscintigraphy, intraoperative gamma probe detection, and blue dye mapping using 99mTc-nanocolloid and Patent Blue V injected peri-areola.

Results: Out of 1152 SLN biopsies performed, 224 were positive for metastatic disease. 203 patients were anaesthetically capable of progressing to CALND. On univariate analysis, involved n-SLN on CALND could not be predicted by age (<50 years; 16/77 vs ≥50 years; 93/125, p=0.272), size of tumour (<50mm; 44/193 and ≥50mm; 4/10, p=0.188), procedure (mastectomy; 24/93, WLE; 24/106, p=0.444), lymphovascular invasion (22/97 vs 26/106, p=0.812), number of positive SLN (≤2; 45/196, >2; 3/7, p=0.213), receptor status; ER (negative; 3/13, positive 45/187, p=0.619), PR (negative; 6/28, positive 41/169, p=0.478), Her2 (negative; 43/175, positive 5/25, p=0.414), triple negative (2/8 vs 46/192, p=0.612). There was a trend toward higher incidence of positive n-SLN with increasing grade (G0-2; 28/139 vs G3; 20/64, p=0.062) and extracapsular spread (14/41 vs 32/149, p=0.073), but these did not reach statistical significance. Positive n-SLN on CALND was however predicted by macrometastases in SLN (macrometastases; 39/141 vs micrometastases; 9/62, p=0.029) and ratio of positive nodes (<0.5; 18/109 vs ≥0.5; 30/94, p=0.008). There were 4/224 recurrences (3 distant metastases and 1 loco-regional), which were not predicted by any of the clinicopathological variables investigated. 3 patients who recurred only had one positive node on SLNB.

Conclusion

In our series of more than 200 SLNB, a ratio of >0.5 positive SLN yield and presence of macrometastases in positive SLN, were associated with positive n-SLN on CALND.

Citation Format: Rajiv V Dave, Muhhamed N Chauhan, Maria Ghaus, Sana Ahmed, Shiv Shapra, Joshua Marriott, Craig Sayers, Zbigniew Kryjak, Deedar Ali. The ratio and size of positive sentinel lymph nodes predicts the involvement of non-sentinel lymph nodes following completion axillary lymph node dissection [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 P2-01-20.
Abstract P2-03-18: Discovery of novel amplified genes in primary breast cancer with copy number and gene expression analysis of whole exome and transcriptome sequencing data
Authors: Lee Eunshin , Lim Woosung , Lee Kyung-Min , Yoo Tae-kyung , Kim Jongjin , Lee Han-Byoel , Kim Yun-Gyoung , Kang YoungJoon , Kim Min Kyoon , Moon Hyeong-Gon , Noh Dong-Young , Han Wonshik Han
Published: May 2015

Introduction: Copy number alteration of genome is common in breast cancer and tend to have more driver role than single point mutations. Traditionally, genome-wide analysis of DNA copy number changes were done by array CGH or SNP array method. Here, we did DNA whole exome sequencing (WES) and RNA-seq using Next Generation Sequencing (NGS) technology to find common genes or chromosomal regions of which DNA copy was highly amplified and at the same time RNA expression was also upregulated.

Materials and Method: RNA and DNA were extracted fromfresh frozen tissues of 93 breast cancer patients. WES and RNA-seq were done using NGS technology (Illumina HiSeq 2000). As a control, normal DNA from all matched patients were also sequenced. GATK was used to gain mean depth and coverage data for targeted regions.CNVs were calculated with ExomeCNV, a statistical method to detect somatic CNVs using depth-of-coverage information from mapped short sequence reads.To estimate expression levels, the relative transcript abundances were measured in FPKM using Cufflinks.

Results and Discussion: DNA of 1,737 genes were highly amplified (log R>1.0) in two or more samples. The two most commonly amplified chromosomes were chromosome 8 and 17. We applied a cut-off for higher gene expression as relative FPKM >1.5. ERBB2 amplifications and high expression were most common (21.5%) of all genes and it was in agreement withHER-2 IHC and FISH result. Among previously reported amplified genes, FGFR1 (5.4%) and PVT1 (8.6%) in chromosome 8, CCND1, PAK1 (3.2%) and EMSY (4.3%) in chromosome 11, CCNE1 (4.3%) in chromosome 19 were also identified in this study. IGF1R high amplification and expression was found in two samples, and ESR1, MDM2, KIT was found in only one sample each. We found uncommon but novel and recurrent highly amplified and expressed genes: CLK4 in 5q (3.2%), AHI/MYB in 6q (3.2%), MMP7(2.2%) andMALAT1 in 11q (1.1%), and NEK8 in 17q (4.3%) We designed FISH probe for this 5 new genes and confirmed the high amplifications in each sample with FISH. Functional study of these genes will be followed for the driver role of these genes in carcinogenesis and progression of breast cancer cells.

Citation Format: Eunshin Lee, Woosung Lim, Kyung-Min Lee, Tae-kyung Yoo, Jongjin Kim, Han-Byoel Lee, Yun-Gyoung Kim, YoungJoon Kang, Min Kyoon Kim, Hyeong-Gon Moon, Dong-Young Noh, Wonshik Han Han. Discovery of novel amplified genes in primary breast cancer with copy number and gene expression analysis of whole exome and transcriptome sequencing data [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 P2-03-18.
Abstract P2-06-02: Breast cancer stem-like cell activity correlates with tumour progression to metastasis but not with clinical or tumour characteristics
Authors: Howell Sacha J , Alferez Denis , Spence Katherine , Eyre Rachel , Shaw Fran , Simoes Bruno , Santiago-Gomez Angelica , Bramley Maria , Absar Mohamed , Saad Zahida , Chatterjee Sumohan , Kirwan Cliona , Gandhi Ashu , Armstrong Anne C , Wardley Andrew M , Farnie Gillian , Clarke Robert B
Published: May 2015

Introduction: Breast cancers exhibit cellular heterogeneity, containing both stem-like and more differentiated cells. The activity of cancer stem cells (CSC) is likely to be dependent on the microenvironment or niche. Using 158 patient tumour samples, correlations between niche-independent breast CSC activity and clinical and tumour characteristics were tested.

Methods: 104 early breast cancer surgical samples and 54 unrelated metastatic samples from pleural or ascitic fluid were harvested. To test CSC activity, isolated cells were grown in both primary (formation) and secondary (self-renewal) mammosphere (MS) culture. Tumour initiating activity was also tested by transplanting breast cancer fragments or cells into the sub-cutaneous flanks of NSG mice (n=84 early and n=10 metastatic).

Results: No correlation was found between MS growth, MS formation (%), MS self-renewal (%) or in vivo tumour initiation and breast cancer sub-type, grade, node status or Nottingham prognostic index. 33% of the samples that formed MS in vitro initiated tumours in vivo while only 9% that failed to form MS initiated tumour growth. Metastatic compared to early BC samples grew MS more frequently (53/54 compared to 81/104), and had a higher primary MS formation efficiency (1% vs 0.6%; P<0.001) although rates of MS self-renewal were similar. Tumour initiation in vivo was also more frequent in metastatic than early breast cancer samples (7/10 versus 25/84; P<0.02).

Conclusions: In summary, niche-independent breast CSC activity measured in vitro by MS assay and in vivo by xenograft growth is not directly correlated with standard clinical parameters. However, both in vitro and in vivo CSC activity are increased in metastatic samples. These results suggest that breast CSC activity is independent of other prognostic indicators but may predict for poor outcome tumours. Relapse free survival data are maturing and will be presented with analysis of primary tumour ALDH1 expression.

Citation Format: Sacha J Howell, Denis Alferez, Katherine Spence, Rachel Eyre, Fran Shaw, Bruno Simoes, Angelica Santiago-Gomez, Maria Bramley, Mohamed Absar, Zahida Saad, Sumohan Chatterjee, Cliona Kirwan, Ashu Gandhi, Anne C Armstrong, Andrew M Wardley, Gillian Farnie, Robert B Clarke. Breast cancer stem-like cell activity correlates with tumour progression to metastasis but not with clinical or tumour characteristics [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 P2-06-02.
Abstract P2-06-08: SIRT1 inhibitors significantly reduce cancer stem cells and block epithelial mesenchymal transformation in breast cancer cells
Authors: Zhang Songlin , Li Min , Guan Baoxiang , Brown Robert
Published: May 2015

Breast cancer stem cells are contribute to distance metastasis, breast cancer recurrence and drug resistance. SIRT1, a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase, play significant role in DNA repair, cell survival, stem cells and epigenetic modification. SIRT1 has been related to cancer stem cells in chronic myelogenous leukemia. In this study, we investigate the role of SIRT1 in breast cancer stem cells.

SIRT1 inhibitors cambinol and Ex527 are used for treatment in several breast cancer cell lines, including T47D, TB549, MDA-MB-231 and MDA-MB-468. Stem cell markers, SOX-2 and Nanog, are significantly decreased in SIRT1 inhibitor treated cancer cells by qRT-PCR and western blot in T47D cell line. The ALDH positive cells in MDA-MB-231 cell line are significant reduced from 29% to 3.2% with Adeflour assay, and the CD44 expression is significantly reduced in CD44/CD24 flow cytometry analysis. Using qRT-PCR, SIRT1 inhibitors significantly down regulate vimentin (-3.7 folds), N-cadherin and smooth muscle actin (-2.7 folds) and up regulate the gene of E-cadherin, indicating SIRT1 inhibitors can block the epithelial mesenchymal transformation (EMT) of breast cancer. SIRT1 inhibitors can significantly (40-50%) block the cancer cell invasion and migration in several triple negative breast cancer cell lines. SIRT1 inhibitors can inhibit cell proliferation on all tested breast cancer cell lines, and can induce significant cell apoptosis in T47D cells. In xenograft tumor study, SIRT1 inhibitor cambinol can significantly reduce tumor growth and inhibit tumor metastasis.

The molecular mechanism of SIRT1 inhibitors in blocking EMT and reducing cancer stem cells is likely associated with blocking the Wnt pathway. Several down stream target genes of Wnt pathway, such as cyclin D1, c-Myc and c-Jun, are significantly down regulated after using SIRT1 inhibitor cambinol, and the changes are more significant in TGF-beta stimulated cancer cells. Beta-catenin is significantly reduced including the active beta-catenin, and the decreasing beta-catenin protein may be related to the decreased Dvl proteins.

In summary, our study demonstrated that SIRT1 inhibitors can reduce breast cancer stem cell population in several cancer cell lines, block epithelial mesenchymal transformation, and inhibit breast cancer cell invasion and metastasis. SIRT1 inhibitors appear to inhibit Wnt pathway in cancer cells to block EMT and affect cancer stem cells.

Citation Format: Songlin Zhang, Min Li, Baoxiang Guan, Robert Brown. SIRT1 inhibitors significantly reduce cancer stem cells and block epithelial mesenchymal transformation in breast cancer cells [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 P2-06-08.
Abstract P2-06-14: Clinical relevance and biological properties of oligometastatic breast cancer in lung; prognostic impact of CD44+/CD24−/low cells
Authors: Mimoto Rei , Kobayashi Tadashi , Imawari Yoshimi , Kamio Makiko , Kato Kumiko , Nogi Hiroko , Toriumi Yasuo , Uchida Ken , Takeyama Hiroshi
Published: May 2015

Background: Metastatic breast cancer is a systemic disease. Our aim was to evaluate the clinical outcomes of pulmonary metastasectomy of recurrent breast tumors and to identify possible prognostic factors.

Methods: We reviewed data from a registry of patients with lung metastases from breast tumors who received pulmonary metastasectomy in Jikei University Hospital between 2004 and 2011. We analyzed prognostic factors for overall survival (OS) and progression free survival (PFS) after metastasectomy. We also investigated lung metastases for the prevalence of CD44+/CD24−/low tumor cells and evaluated their prognostic significance.

Results: Among 17 patients with lung metastasis of breast tumors, 5-year OS and PFS were 72% and 36%, respectively. Better OS was observed among patients with oligometastatic breast cancer (OMBC). Patients with OMBC, estrogen receptor (ER) positive cells, and disease free intervals (DFI) of >8 years had better PFS. The average prevalence of CD44+/CD24−/low tumor cells in lung metastases of breast cancer was 21%, ranging from 0 to 90%. The presence of CD44+/CD24−/low tumor cells influenced the progression after lung metastasectomy, with median PFS times of only 6 months in patients with high-prevalence of cancer-initiating cells. CD44+/CD24−/low cells with cancer-initiating properties were present in only 9% ± 12 of patients with OMBC but were found in 73% ± 21 of patients with non-OMBC.

Conclusion: Pulmonary metastasectomy may be a treatment option for OMBC patients with lung metastases. Better prognosis of OMBC may be related to low levels of cancer-initiating cells.

Citation Format: Rei Mimoto, Tadashi Kobayashi, Yoshimi Imawari, Makiko Kamio, Kumiko Kato, Hiroko Nogi, Yasuo Toriumi, Ken Uchida, Hiroshi Takeyama. Clinical relevance and biological properties of oligometastatic breast cancer in lung; prognostic impact of CD44+/CD24−/low cells [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 P2-06-14.
Abstract P2-07-03: Pax-5 regulates EMT and MET in breast cancer through FAK1 regulation
Authors: Benzina Sami , O'Brien Pierre , Beauregard Annie-Pier , Guérrette Roxann , Jean Stéphanie , Robichaud Gilles
Published: May 2015

Metastasis accounts for 90% of deaths in breast cancers patients. Therefore, the study of genetic factors regulating cancer malignancy is a top priority to mitigate the morbidity and mortality associated to this disease. One of these factors, Pax-5, normally regulates key biological functions such as cell viability, growth, and differentiation. However, an aberrant expression of this factor results in the development and progression of cancer.

In this study, we developed breast cancer cell models with conditioned expression of the Pax-5 to evaluate signaling pathways relevant to breast metastasis and cancer progression. We found that Pax-5 extinguishes several aspects of cancer aggressivety such as: proliferation, spheroid formation, migration and invasion. At the molecular level, we found that Pax-5 modulates cancer malignancy through the regulation of various components of the epithelial to mesenchymal transitioning (EMT) process in addition to key signaling targets such as: NFκB and the Focal Adhesion Kinase 1 (FAK1). We also demonstrate that Pax-5 decreases FAK1 level trough up-regulation of miR-135b, a direct repressor of FAK1 expression. Altogether, our findings suggest that the presence of the Pax-5 lead to less aggressive breast cancers by promoting mesenchymal to Epithelial transitioning (MET). These findings bring light to molecular mechanisms driving breast cancer malignancy and benefit our quest in the development of diagnostic and therapeutic strategies against breast cancer progression.

Citation Format: Sami Benzina, Pierre O'Brien, Annie-Pier Beauregard, Roxann Guérrette, Stéphanie Jean, Gilles Robichaud. Pax-5 regulates EMT and MET in breast cancer through FAK1 regulation [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 P2-07-03.
Abstract P2-11-01: Treatment of metastatic breast cancer patients by community health practitioners: Practice pattern and competence assessments
Authors: Fagerlie Sara R , Heintz Alison , Haas Maureen
Published: May 2015

Background: The complexity of current treatment and management for patients with metastatic breast cancer continues to rise. The volume and pace of scientific advances make it challenging for the community practitioner to stay abreast of optimal patient care. Education is key in disseminating critical information to practitioners and allows professional reflection of appropriate therapeutic decision making and peer discussion. Understanding the base knowledge, competence, and current practice patterns of the community practitioner is critical to identification community needs and implementation of education that impacts patient care.

Methods: During 2013 and 2014, educational outcomes assessments were gathered during 2 education programs consisting of 47 live independent continuing medical education (CME) activities held within community practices across the USA. Participants were asked a series of case-based questions via an audience response system to assess baseline knowledge, competence, and identify practice patterns Assessments were repeated following the 1-hour CME certified activity. Long-term assessment was conducted electronically 6-weeks following the educational initiative.

Results: The programs educated 958 practitioners, including 515 physicians. Practice patterns for frontline treatment varied at baseline. Education resulted in treatment more highly aligned with practice guidelines and recent advances. At baseline 75% of practitioners and 30% of the physician target audience were unable to identify appropriate next steps in a borderline HER2+ patient. The education reduced the gap by 25%. 6-weeks following the activity 100% of the assessed physician target audience agreed or strongly agreed that the education influenced their interpretation of HER2 testing. Practice gaps in practitioners ability to identify, recall, and interpret practice changing clinical trials were also identified. Newness of treatment data, lack of reimbursement, and treatment side effects were the most common barriers identified in applying the education into clinical practice.

Conclusions: The results highlight the diversity of current clinical practice in the community practice setting for patients with metastatic breast cancer and the positive impact of focused education. Knowledge and competence practice gaps were identified to pinpoint specific areas of benefit for the community practice setting in the treatment of patients with metastatic breast cancer.

Citation Format: Sara R Fagerlie, Alison Heintz, Maureen Haas. Treatment of metastatic breast cancer patients by community health practitioners: Practice pattern and competence assessments [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 P2-11-01.
Abstract P2-12-09: Psycho-oncological intervention in breast cancer patients - A quantitative analysis of tumor associated fatigue treatment
Authors: Eichler Christian , Multhaupt Pia , Multhaupt Sibylle , Wolff Friedrich , Warm Mathias
Published: May 2015

Abstract

Background: Although tumor associated fatigue (TAF) or cancer related fatigue (CRF) is not a new concept, no real headway has been made in the quantitative analysis of its successful treatment. Since 20 to 30% of all breast cancer patients suffer from anxiety and/or depression within the first year of their diagnosis, this issue needs to be addressed and a standard treatment protocol has to be developed. Multimodal approaches are currently being used including increased physical activity, pharmaceutical therapy, and psycho-oncological intervention. This study focused on developing a simple, reproducible protocol for the psycho-oncological support of tumor associated fatigue patients.

Methods: Between the year 2011 and 2012, 23 breast cancer patients fulfilled the diagnosis TAF requirements and were introduced into this study. All patients had received surgery and were currently being monitored in an adjuvant setting. Our method focused on a psycho-oncological support group using a predetermined, highly structured and reproducible treatment manual. Eight weekly, 90 minute sessions were conducted and patients were evaluated before and after this eight session block. Tumor fatigue specific questionnaires such as the multidimensional fatigue inventory (MFI) as well as the hospital anxiety and depression scale (HADS) were used in order to quantitatively evaluate patient TAF.

Results: Of the 23 patients enrolled in the study, only 7 patients fulfilled the TAF diagnostic criteria after the psycho-oncological group treatment. This represents a 70% reduction in diagnosable tumor associated fatigue. The HADS analysis showed a 33% reduction in patient anxiety as well as a 57% reduction in patient depression levels. The MFI scores showed a significant reduction in 4 of the 5 evaluate categories. With the exception of the "mental fatigue" MFI category all results were statistically significant.

Conclusion: This study showed that a highly structured, psycho-oncological group intervention will produce significant improvements in breast cancer patient tumor associated fatigue levels after only 8 sessions. This type of group therapy should be recommended as a standard of care for all TAF breast cancer patients.

Citation Format: Christian Eichler, Pia Multhaupt, Sibylle Multhaupt, Friedrich Wolff, Mathias Warm. Psycho-oncological intervention in breast cancer patients - A quantitative analysis of tumor associated fatigue treatment [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 P2-12-09.
Abstract P2-12-14: The effect of low intensity exercise for mental status and quality of life of Japanese early breast cancer patients
Authors: Kamio Makiko , Kawase Kazumi , Nogi Hiroko , Uchida Ken , Takeyama Hiroshi
Published: May 2015

Objective: Breast cancer is one of the most common cancers, and it accounts for 20% of malignant tumors of women. Psychological damage of the breast cancer patient is serious. In our institution, approximately 30% of the early breast cancer patients diagnosed as depressed mental status before operation. Breast cancer patients have to receive hormone therapy, chemotherapy, and radiation therapy for a long term after operation. Depressed mental status affects execution of the treatment, and the interruption of the treatment brings the risk of cancer recurrence. As a treatment for depressed mental status of cancer patients, medication and psychotherapy are common, but some previous reports showed exercise is effective. Exercises provided in these reports were various kinds and strength, and the standard prescription is not established. We investigate the effect of walking program as a mild aerobic exercise, whether it improves the depressed mental status and quality of life (QOL) of breast cancer patients.

Methods: 25 early breast cancer patients were recruited. Depressed mental status and QOL were assessed by Center for Epidemiologic Studies Depression Scale (CES-D) and Medical Outcomes Study 36-item Short Form Health Survey (SF-36). Physical activity was measured by accelerometer (Lifecorder PLUS, Suzuken), and estimated using metabolic equivalent foe task (MET). Participants mounted accelerometer after discharge, and baseline physical activity was recorded till 1 month after operation. After recording baseline physical activity, we instructed to perform walking or mild aerobic exercise. Scores of CES-D and SF-36, and physical activity data were measured again after two months.

Results: Physical activity after intervention was significantly increased as compared to baseline (8.5±5.5 vs 12.3±6.9 MET.h/week, p=0.02 ). At pre-operation phase, nine patients (36%) regarded as depressed mental status by CES-D, and depressed patients decreased to five at the time of 3 months after operation. A subscale of SF-36 ( mental health ) reduced significantly compared with pre-operation and 3 months after operation ( p<0.01 ). Physical activity after intervention was correlated with the scores of CES-D and all subscales of SF-36.

Conclusion: This study demonstrated the possibility that walking program as a mild exercise improves mental status and QOL of perioperative breast cancer patients. It is necessary to examine in more detail for clinical application.

Citation Format: Makiko Kamio, Kazumi Kawase, Hiroko Nogi, Ken Uchida, Hiroshi Takeyama. The effect of low intensity exercise for mental status and quality of life of Japanese early 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 P2-12-14.
Abstract P2-13-07: Prophylactic mastectomy in young women with breast cancer
Authors: Metran Nascente Cristiane , Wright Frances , Helwig Christel , Li Nim , Mandel Rodica , Kiss Alex , Warner Ellen
Published: May 2015

Background: In recent years women with unilateral breast cancer (BC) have been increasingly requesting contralateral or bilateral prophylactic mastectomy (PM) despite only requiring unilateral mastectomy (M) or lumpectomy (L) respectively. This trend has been observed even in women at low risk for contralateral BC, particularly among younger women.

Objective: Determine the rates of ‘unexplained’ PM (UPM) and factors associated with this choice, among a prospective cohort of newly diagnosed young women with BC at our centre.

Methods: We reviewed the records of all patients diagnosed with BC at age ≤ 40 years from Feb ‘08 to Sept ’13 at Sunnybrook who consented to have their clinical data entered in a prospective research database. Psychosocial data - HADS [Hospital Anxiety and Depression Scale] and IES [Impact of Event Scale] - were prospectively collected from all consenting women at baseline and at completion of active treatment. Among the 149 patients treated with curative intent, 43 received unilateral M, 59 L and 47 contralateral or bilateral PM. These groups were compared with respect to demographics, risk factors, use of pre-operative MRI, pathology, treatment and surgeon gender. Differences in variables between the groups were analyzed using analysis of variance for continuous variables and chi-square test for categorical variables.

Results: The mean age of all patients was 35 years old (21-40 range). Among the 47 patients who had PM, the first surgery was L for 15 (32%), unilateral M for 27 (57%) and bilateral M for 5 (11%). Twenty-four (51%) fulfilled high risk criteria (19 BRCA mutation, 4 strong family history, 1 chest radiation) and 2 (4%) had suspicious findings in the contralateral breast. The other twenty-one patients (45%) underwent UPM for "peace of mind" alone. Thirty-three (33%) of UPM patients had T3-4 tumors. There were no statistically significant differences between the UPM group and the combined M plus L groups, except for more multicentric/ multifocal disease in the UPM groups (43% vs 9% p≤0.0001).

Discussion: Fourteen percent of young women at our centre, a 1/3 with a relatively poor prognosis had UPM. Data correlating surgical choice with baseline and follow-up psychological variables will be presented. There appears to be a need for an educational/psychological intervention at the time of BC diagnosis for non-high-risk women contemplating preventive breast surgery to ensure that such a choice is truly informed.

Citation Format: Cristiane Metran Nascente, Frances Wright, Christel Helwig, Nim Li, Rodica Mandel, Alex Kiss, Ellen Warner. Prophylactic mastectomy in young women with 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 P2-13-07.
Abstract P2-14-04: Is the combination of fat grafts and platelet rich plasma effective and safe? An experimental study in rats
Authors: Freitas-Junior Ruffo , Blumenschein Alexandre R , Moreira Marise AR , Cysneiros Maria-Auxiliadora PC , Pereira Roseana N
Published: May 2015

Autologous fat grafts and lipofilling can be used for breast reconstruction after breast conserving therapy. Fat is considered an ideal filler because of its low cost, ease of harvest, abundance in the human body and low immunogenic and allergic reaction due to its autologous nature. Platelet rich plasma (PRP) is a plasma fraction, with platelet count above baseline, generally obtained via centrifugation of blood. PRP theoretically promotes tissue regeneration due to fact that it concentrates a greater amount of growth factors essential in the process of tissue regeneration and neovascularization. This paper aims to examine if the association of fat grafts and PRP improves graft viability in female rats, through an experimental, randomized and blinded study, which involved 47 animals. These animals underwent fat graft harvest from their inguinal fat deposits and fat grafting subcutaneously to their cranial region. In 22 animals the fat graft was mixed with PRP and in 25 the fat was grafted by itself. After a 100 day period, the animals were sacrificed and the fat grafts were analyzed using scores from 0 (absent) to 4 (abundant), in optical microscopy by two independent and blinded pathologists, by means of the following variables: fat graft cell viability, fat necrosis, tissue inflammation and fibrosis. Regarding fat graft cell viability, the PRP group scored moderate/abundant in 63% of the cases and the fat graft only group scored absent/slight in 72% of the cases (p<0.05). The PRP group presented lower fat necrosis scores and lower tissue inflammation scores when compared to the fat graft only group (p<0.05). The presence of tissue fibrosis was rarely observed in both groups. Tumors (dermoid cysts) within the fat grafts were observed in 3 animals in which the grafts were mixed with PRP. It is concluded that PRP improves the viability and integration of fat grafts in rats, but more studies are needed to fully understand the exact mechanisms that lead to this improvement and assess the safety of the method for use in humans.

Citation Format: Ruffo Freitas-Junior, Alexandre R Blumenschein, Marise AR Moreira, Maria-Auxiliadora PC Cysneiros, Roseana N Pereira. Is the combination of fat grafts and platelet rich plasma effective and safe? An experimental study in rats [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 P2-14-04.
Abstract P3-04-12: Pathological and molecular effects of lack of PR expression in ER positive breast tumors
Authors: Ellsworth Rachel E , Valente Allyson L , Hueman Matthew T , Shriver Craig D
Published: May 2015

Background: Evaluation of hormone receptor status is standard in breast cancer diagnosis; however, prognosis and treatment decisions are frequently based on the status of the estrogen receptor (ER) but not the progesterone receptor (PR). To determine how PR status affects etiology and outcome of ER positive tumors, pathological and molecular characteristics of ER+PR+ and ER+PR- tumors were assessed.

Methods: ER and PR positivity were defined as >10% staining and all patients with ER+PR+ and ER+PR- were identified. Differences in pathological characteristics were evaluated using Chi-square tests with P<0.05 defining significance. RNA was isolated from primary tumor cells after laser-microdissection and hybridized to U133A 2.0 arrays. Gene expression data was analyzed by ANOVA using a false-detection rate <0.5 and >2.0-fold difference to define significance.

Results: Of the 1,139 ER+ tumors, 21% were PR-. Age at diagnosis, ethnicity, tumor size, lymph node and Ki67 status did not differ between groups; however, patients with PR- tumors were significantly more likely to be diagnosed at an advanced stage, with high-grade, HER2 positive tumors, and more likely to die of disease. Thirty genes were differentially expressed including significantly higher expression levels of APOBEC3B and significantly lower expression of GREB1, MAPT and SCUBE2.

Discussion: Expression of PR significantly alters tumor biology and clinical outcomes of ER positive tumors. Genes with altered expression in PR negative tumors are associated with more aggressive characteristics, such as increased invasion, kataegis, regulation of ER and response to tamoxifen. Thus, PR status is critical in the diagnosis and treatment of patients with ER positive breast tumors.

Citation Format: Rachel E Ellsworth, Allyson L Valente, Matthew T Hueman, Craig D Shriver. Pathological and molecular effects of lack of PR expression in ER positive breast tumors [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 P3-04-12.