bluuebunny/crossref_metadata_2025 huggingface dataset:
P3-07-39: Where To Look for Sentinel Lymph Node in Breast Cancer.
Authors: Düran A
Published: June 2012

Hypothesis: The sentinel Lymph node (SLN) is not only the first extra mammary point of metastatic spread, it also undergoes reactive changes. Sonographically this is evident through an increased width of the hypo-echoic cortex of the lymph node. We examined, if it is possible to localize SLN on sono-morphological features, if it is sonographic detection comparable with the radio nuclide tracer method and if false negative rate (FNR) of SLNB can be reduced by ultrsound.

Method: From 1/2001 to 5/2003, 117 patients with breast cancer where prospectively examined for SLN localization using sonography in addition to radio nuclide -Tc99m- and/or patent blue-methods. The lymph node identified as the SLN in ultrasound was marked using a hook-wire. The sonographic parameters used to identify the SLN were: The node with the widest hypo echoic cortex, located in the caudal axilla and the closest to the glandular tissue and with the greatest diameter.

Results: In all 117 patients, in the region of the caudal axilla, an enlarged, reactive, either tumor free or metastatic SLN could be verified. The location of the SLN was in all cases on the lateral-caudal thoracic wall and consistent with the lymph node group at the lateral border of the pectoralis major. The sonographic detection rate of the SLN was 86%. 70.6% of the sentinel lymph nodes where affected by metastatic spread. In those patients with a pT1a-c-tumor the rate of SLN metastatic spread was 20%. The false negative rate (FNR) for SLN localization with Tc99m/Blau was 10.6 %. Experience has shown that the FNR increases with increasing degree of metastatic spread to the SLN. With the addition of sonography of the axilla the FNR could be decreased to 3.5%.

Sonographic SLN detection rate: 86% ( n=101/117)

False-negative-rate (Blue/Tc) 10.7% (n=6sln- /56N+)

False-negative-rate (Blue/Tc + Sonography) 3.5% (n=2sln-/56N+)

Conclusions: The false-negative-rate of detection of suspected lymph nodes can be reduced using sonographic localization of the SLN. Sonography of the axilla should therefore be an integral part of and standard in the sentinel node-biopsy of breast cancer patients.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-07-39.
P3-07-42: Lymphovascular Invasion Best Correlates with Presence of Nodal Metastasis in Sentinel Lymph Node Biopsy.
Authors: Absar MS , Adelekan MO , Patel E , Cotterill S
Published: June 2012

Background. Sentinel lymph node biopsy (SLNB) biopsy is routinely practised for axillary staging with 25–30% having positive SLN. Tumour size is the most important parameter taken into consideration in decision making in node negative patients with a size cut off for 4–5cm dependant on different units. Lymphovascular invasion (LVI) and Ki-67 a cell-cycle antigen are known important prognostic markers along with the tumour grade, oestrogen receptor and herceptin receptor status.

Aim. To examine whether lymphovascular invasion, Ki-67 or any other factors can be used as a predictor for axillary lymph node involvement and hence prognosis.

METHODS. A prospective study of 264 patients with invasive breast cancer undergoing SLN biopsy between January 2009 and December 2010.

Histopathology reports were reviewed regarding LVI, Ki-67, grade, oestrogen, Progesterone and Herceptin receptor and SLN status. Stats direct was used to analyse data. Logistic regression was used and p-value calculated.

RESULTS. LVI (p value=0.0001) and size(p value=0.0273) were the two most significant factors associated with node positivity. Grade of tumour had a p-value of 0.0825 and Ki67 had a p-value of 0.5217 which were not significant.

DISCUSSION. LVI is the factor which best corelates with presence of metastasis in sentinel lymph node. If this information is available at the time of decision making, it should be strongly considered and pathologists should be encouraged to provide the information. In the absence of LVI, size still remains the best predictor of sentinel lymph node metastasis pre-operatively although consideration of other factors, such as the grade is definitely relevant.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-07-42.
P3-07-44: Feasibility of Axillary Reverse Mapping during Sentinel Lymph Node Biopsy in Breast Cancer.
Authors: Noguchi M , Ohno Y , Nakano Y , Noguchi M , Kosaka T
Published: June 2012

Background: The axillary reverse mapping (ARM) procedure is based on the hypothesis that the lymphatic drainage from the upper arm is different from that of the breast. However, the oncologic safety of the procedure has not yet been determined.

Methods: The ARM nodes were identified using a fluorescence imaging system. Sentinel lymph node (SLN) biopsy was performed in patients with clinically uninvolved nodes. If the SLN was positive, ALND was performed with removal of ARM nodes. Otherwise, the identified ARM nodes were preserved unless they were the same as the SLN.

Results: The ARM node was identified in 30 of 91 patients who underwent SLN biopsy, and it was the same as the SLN in 23 patients. However, in 13 patients with a positive SLN who subsequently underwent ALND, ARM nodes were tumor-free when they were not the same as the positive SLN.

Conclusions: There are limits to the principle of non-overlap between breast and arm nodes. However, it may be feasible to spare ARM nodes during ALND in patients with clinically negative nodes.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-07-44.
P3-09-01: Change in Carbohydrate Intake and Breast Cancer Prognosis.
Authors: Emond JA , Patterson RE , Pierce JP
Published: June 2012

Breast tumors over express insulin-like-growth-factor receptors (IGF-IR), and levels of expression may be inversely related to tumor grade. Dietary factors, particularly carbohydrate intake, may stimulate activation of IGF-1R and affect prognosis.

METHODS: Data are from N=2,651 women in the Women's Healthy Eating and Living (WHEL) Dietary Intervention trial, a plant based intervention trial that did not have a carbohydrate goal. All women were diagnosed with breast cancer within the previous 4 years. Carbohydrate dietary intake data were extracted from multiple 24-hour dietary recalls at study entry and one year, and were compared by recurrence status. Time to recurrence was modeled on year-one change in carbohydrate intake adjusted for baseline intake, menopausal status, and disease, treatment, and study characteristics.

RESULTS: Baseline carbohydrate intake was 233 g/day. Women who recurred had a mean increase in carbohydrate intake over the first year, compared to those who did not recur (2.3 vs. −2.7 g/day; p=0.188). Change in starch intakes accounted for 48% of the change in carbohydrate intake (R-squared: 48%; p<0.001). Baseline starch intake did not differ by recurrence status (95.8 g/day; p=0.219). Mean year-one change in starch intake was −4.1 g/day among women who recurred vs. −8.7 g/day among women who did not recur (p=0.015). Year-one change in starch intake was independent of the study intervention (p=0.326). In the adjusted model, a 5-g/day increase in starch related to a 3% increased risk of recurrence (HR=1.03; 95% CI 1.01 - 1.06; p=0.017). The increased risk was limited to women diagnosed with low grade tumors (Table 1).

DISCUSSION: Dietary modifications targeting starch intake warrant further investigation as a preventive measure against breast cancer recurrence.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-09-01.
P3-10-03: Bardoxolone (5MeCDDO) Inhibits Cancer Initiation but Promotes Progression in Rodent Models of Breast Cancer. What Does It Mean for the Antioxidant Response Element (ARE) as a Primary Prevention Target?
Authors: Lubet RA , Townsend R , Vedell P , Steele VE , Grubbs CJ
Published: June 2012

The preventive efficacies of the triterprenoid 5MeCDDO were examined in three preclinical models of breast cancer. We initially evaluated 5MeCDDO in an ER+ mammary model in which female Sprague-Dawley rats were administered MNU, i.v., at 50 days of age. 5MeCDDO (27 ppm) was administered in the diet beginning 5 days after MNU, and continuing for the duration of the study. Doses >50 ppm were toxic. 5MeCDDO failed to decrease tumor latency or multiplicity and, in fact, increased the size of the cancers which did develop. This concentration of 5MeCDDO greatly increased liver to body weight ratios. We also examined the preventive efficacy of 5MeCDDO (54 and 27 mg/kg diet) in a bitransgenic model (MMTV-Neu/p53KO) of ER− mammary cancer. In this model, animals develop cancers which overexpress Neu and fail to have a mutation in the transmembrane domain of Neu. Similarly to results in the MNU model, 5 MeCDDO did not alter either tumor latency or multiplicity. The effect of 5MeCDDO was further evaluated in a third model in which ER+ tumors were induced by the procarcinogen dimethylbenzanthracene (DMBA). DMBA was administered by gavage to female Sprague-Dawley rats at 50 days of age. In this model (which examines the ability of an agent to alter the activation of the carcinogen) the preventive agent was administered beginning 7 days prior to DMBA and was continued until 7 days post DMBA. 5,6 Benzoflavone (500 ppm), a positive control, decreased tumor multiplicity >90%, while 5MeCDDO (27 or 2.7 ppm) decreased multiplicity 65 and 35%, respectively. The efficacy observed in this model is in agreement with the ability of the agent to stimulate the ARE, and to induce a variety of ARE related genes (e.g., GST PI, quinone reductase, etc). Thus, as expected, high induction of the ARE was associated with a decrease in DMBA-induced cancer initiation, but not a decrease in the progression stage of mammary cancer development in three cancer models. This latter finding brings into question whether merely measuring induction of the ARE (e.g., quinone reductase) is sufficient to imply the general preventive efficacy of a given agent or mixture. Supported by NCI contract number HHSN261200433001C.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-10-03.
P3-11-07: Mammary Gland Biopsy To Examine Surrogate Endpoint Biomarkers of Preventive Agent Efficacy.
Authors: Heckman-Stoddard B , Lubet RA , Bode AM , Grubbs CJ
Published: June 2012

Phase II breast cancer prevention trials examine agent activity by sampling and imaging the breast through core needle biopsy, fine needle aspiration, or imaging (e.g., mammography). The biomarker endpoints in normal or at risk breast tissue employed with biopsies or fine needle aspirates (e.g., Ki67 or apoptosis) have often not been formally validated relative to a tumor endpoint. In this study, we have attempted to examine these endpoints in a preclinical model for which we have final tumor data. In the methylnitrosourea (MNU)-induced rat mammary cancer model, estrogen receptor positive cancers develop that are histologically similar to a large majority of human tumors. Here we present a protocol for correlating surrogate endpoint biomarkers and agent efficacy in the same animal. Biopsy samples are taken of the normal mammary gland after MNU treatment, and a week later the animals are started on the preventive agent. After 2 weeks, a second biopsy is taken and the animals are followed for tumor development. To test the protocol, we examined surrogate endpoints of tamoxifen efficacy at human equivalent dosages (5mg/d and 20mg/d). Both doses of tamoxifen prevented the development of tumors in the MNU-treated rats. The pre/post biopsy analysis revealed a statistically significant reduction in Ki-67 consistent with the clinical trial data. Additional biomarkers of apoptosis and the chromosome condensation pathway will be presented.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-11-07.
P3-14-16: Molecular Phenotype and the Use of HER-2 Targeted Agents Influence the Accuracy of Breast MRI after Neoadjuvant Chemotherapy.
Authors: Moon H-G , Han W , Noh D-Y , Ahn S , Kim J , Shin H , Min J
Published: June 2012

Background: Improved understanding of factors affecting the accuracy of breast magnetic resonance imaging (MRI) after neoadjuvant systemic therapy (NST) can lead to more tailored use of MRI in deciding surgical extent after NST.

Materials and Methods: We analyzed the imaging and clinicopathologic data of 463 patients who underwent NST. We aimed to investigate whether the molecular subtypes, as well as the use of targeted therapies, were associated with changes in the accuracy of MRI predicting residual tumor extent.

Results: The accuracy of MRI predicting the residual tumor extent was most accurate in triple negative breast cancer and was least accurate in Luminal A subtype (Pearson's correlation coefficient of 0.754 and 0.531, respectively). Multivariate analysis suggested estrogen receptor status as an independent factor influencing the MRI accuracy. In HER2−amplified tumors, the use of HER2−targeted agents was associated with less accurate MRI prediction. Dual HER2−blockade by using trastuzumab and pertuzumab resulted in lowest MRI accuracy among the patients treated with HER2−targeted agents.

Conclusion: The accuracy of MRI in predicting residual tumor extent was lowest in ER positive tumors treated with NST. In HER2 positive tumors, the use of HER2−targeted agents resulted in less accurate MRI after NST.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-16.
P3-17-05: Beyond HER2 and Hormonal Agents: The Heat Shock Protein 90 Inhibitor Ganetespib as a Potential New Breast Cancer Therapy.
Authors: Friedland JC , Sang J , Modi S , Bradley R , El-Hariry I , Wada Y , Proia DA
Published: June 2012

Background: Ganetespib is a fully synthetic and selective inhibitor of heat shock protein 90 (HSP90), a molecular chaperone recognized as a key facilitator of breast cancer initiation, progression and metastasis.

Methods: Preclinical activity of ganetespib across the four major breast cancer subtypes and inflammatory breast cancer was assessed in vitro and in vivo. Modulation of cell proliferation and viability was determined both in monolayer and three-dimensional cultures. HSP90 client protein expression and activity was monitored by Western blot and protein array. To recapitulate clinical dosing, kinetics of client protein destabilization were measured following short exposures to drug in vitro. Anticancer activity of ganetespib was further investigated in vivo using breast cancer xenografts.

Results: Ganetespib displayed potent, low nanomolar activity in luminal (A and B), basal (A and B) and inflammatory breast cancer cell lines grown as monolayers in vitro. BT-474 (HER2 amplified) luminal cells grown as mammospheres in 3D were equally as sensitive to ganetespib as those grown in monolayer. In luminal cells, ganetespib simultaneously disrupted multiple signaling components including the estrogen and progesterone receptor, several receptor and non-receptor tyrosine kinases, as well as the MAPK pathway. Further, ganetespib effectively inhibited AKT, PDK1 and SGK3 activity in PIK3CA mutant cells suggesting that HSP90 is essential for both AKT-dependent and AKT-independent signaling. Clinically relevant exposure times to ganetespib in vitro resulted in potent, long term destabilization of HER2. In the basal-like breast cancer cell line MDA-MB-231, enriched in CD44+CD24- stem like cells that commonly display chemotherapeutic resistance and activated JAK2/STAT3 signaling, ganetespib (50 nM) induced significant degradation of JAK2 concordant with loss of both tyrosine and serine phosphorylation of STAT3, followed by cell death. The potent anticancer activity in vitro translated in vivo, where ganetespib was effective in modulating breast cancer xenograft growth as a single agent in both luminal and basal-like breast cancer models. Finally, ganetespib has demonstrated encouraging signs of clinical activity in breast cancer patients, including confirmed partial responses in both a triple negative breast cancer patient and a HER2 positive breast cancer patient.

Conclusions: Ganetespib is a highly potent HSP90 inhibitor that displays preclinical activity in breast cancer due to its ability to simultaneously perturb multiple oncogenic signaling pathways.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-17-05.
P3-17-10: EpCAM as a Target for Chemical Antibodies in Metastatic Breast Cancer.
Authors: Shigdar SL , Duan W
Published: June 2012

EpCAM is a 40kDa glycoprotein that functions as an adhesion molecule in benign epithelium. However, it is over-expressed in nearly all carcinomas, including breast carcinomas, and has been implicated in the pathogenesis and progression of cancer. In primary breast carcinoma, its over-expression correlates with a diminished overall survival in patients with node-positive disease. Indeed, recent evidence has shown that EpCAM is expressed at a higher level in metastases than in matched primary breast carcinoma. This has led to the suggestion that EpCAM over-expression is associated with aggressive behaviour, and that it could be considered a promising therapeutic target for breast cancer. Several immunotherapy trials are ongoing, though there are limitations to their delivery and distribution, suggesting a smaller and more effective EpCAM targeting molecule is required.

Aptamers, also known as chemical antibodies, are short-stranded DNA or RNA molecules and are selected via the systematic evolution of ligands by exponential enrichment (SELEX). They are 10 to 20 times smaller than antibodies and exhibit superb tissue penetration, thereby indicating their suitability in cancer targeting. In addition, aptamers are more stable, non-immunogenic and non-toxic. Following 12 rounds of SELEX using EpCAM protein as a target, we generated several EpCAM specific RNA aptamers. These were investigated using flow cytometry and confocal microscopy for their ability to bind to three breast cancer cell lines, MCF-7, T47D and MDA-MB-231. Our 19-nt aptamer showed specific binding to all three cell lines. In addition, it also showed superior penetration of breast cancer 3-D spheroid tumor models, as compared to a control aptamer and negative cell lines. This aptamer has also shown efficient internalisation via receptor-mediated endocytosis, suggesting it to be a suitable targeting moiety for drug delivery to both primary and metastatic tumors. The usefulness of this aptamer in clinical applications is being actively investigated.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-17-10.
P3-18-07: Multiplex RTK Inhibitor Screening Utilizing a Plate-Based Immunoassay with Near-Infrared Detection.
Authors: Finkel DJ , James AE , Felix RA , Wegner GJ
Published: June 2012

Receptor-tyrosine kinases (RTKs) are transmembrane proteins that have been implicated in various cancers and are considered therapeutic targets. The phosphorylation of RTKs on tyrosine residues leads to their activation. We have previously used the Proteome Profiler™ 96 Human Phospho-RTK Antibody Array, a plate-based multiplex immunoassay, to determine the phospho-tyrosine profile of RTKs in MDA-MB-453 breast cancer cells. Most notably, the ErbB family of RTKs were shown to be hyperactivated in this cell line. In this study, we use the same multiplex assay to screen a small molecule kinase inhibitor library (TOCRIS, Catalog # 3514) to identify inhibitors with selectivity towards the ErbB receptors. MDA-MB-453 cells were treated with the kinase inhibitor library prior to treatment with ligands to stimulate ErbB receptor tyrosine phosphorylation and subsequently lysed. The lysates were analyzed with the Proteome Profiler 96 Human Phospho-RTK Antibody Array using near-infrared fluorescent detection. Ligand-dependent tyrosine phosphorylation of all four ErbB receptors was monitored simultaneously and the effects of different kinase inhibitors were determined. While several known ErbB inhibitors blocked ErbB phosphorylation, our screen also identified several inhibitors reported to be selective for other kinases that effectively inhibited ErbB activation. The activation of ErbB2 was selectively inhibited by NH 125, GF 109203X, SB 202190, SB 216763, and ZM 306416 hydrochloride. The results obtained with this multiplex assay were confirmed by singleplex ELISA for ErbB receptors. Hence, the data collected with our multiplex assay provides a rapid method for the analysis of inhibitor effects on a defined signaling pathway. This may facilitate a faster identification of selective kinase inhibitors that have therapeutic potential for treating ErbB-overexpressing cancers.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-18-07.
P4-02-02: The Natural Fetal Estrogen Estetrol (E4), Causes Anti-Estrogenic Effects in Women with Endocrine-Responsive Positive Early Breast Cancer.
Authors: Singer CF , Natter C , Steurer S , Rudas M , Moinfar F , Appels NRCA , Visser M , Kubista E , Bennink C
Published: June 2012

Background: Estetrol (E4) is a natural fetal estrogen which exerts estrogenic effects on reproductive organs and on the bone, and effectively reduces menopausal smyptoms. In contrast to other estrogens, however, E4 has estrogen-antagonistic effects on breast cancer cell lines in vitro and in the rat DMBA model, which would make it a suitable Hormone Replacement Therapy (HRT) in breast cancer patients, particularly in women who are being treated with aromatase inhibitors.

Patients and Methods: We have investigated the effect of 14 days preoperative treatment with 20 mg E4 per day on tumor proliferation, apoptosis, ER-receptors, PgR receptor and several endocrine parameters in a prospective, randomised, double-blind, placebo-controlled, neo-adjuvant study in 15 pre- and 14 postmenopausal women with estrogen-receptor positive early breast cancer. Results: Estetrol induced a significant increase of SHBG, a significant decrease of FSH in postmenopausal women and no increase of gonadotrophins in premenopausal women. Estetrol had no effect on Ki67 expression and on apoptosis-related Bax and Bcl-2, but the apoptosis index in tumor tissue increased significantly. Systemic IGF-1 levels decreased significantly. Surprisingly the intratumoral epithelial ER-alpha expression decreased significantly, whereas the ER-beta expression showed a trend to increase.

Conclusion: Our data suggest that E4 may be suitable and safe for HRT in women with spontaneous or induced menopausal symptoms, since apoptosis increases, IGF-1 decreases and no unfavourable effects are observed on Ki67, Bax and Bcl-2. The decrease of ER-alpha and the increase of ER-beta suggest a mechanism of action, explaining why the natural fetal estrogen E4 has estrogen-antagonistic effects on breast cancer tissue.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-02-02.
P4-07-12: Identification of p53 Mutation in Whole Genome DNA from Single Circulating Tumor Cells (CTCs) and Primary Breast Cancers (BC) from Patients (pts) with Metastatic Breast Cancer (MBC).
Authors: Yang L , Wang Y , Chu P , Liu Q , Hsieh B , Liu X , Yen Y , Bruce R , Somlo G
Published: June 2012

Background: CTCs represent the source of distant metastases, and are also implied in the growth/re-growth of primary BC. Molecular/gene-level characterization of similarities and discordances between CTCs and BCs in pts with MBC may provide useful information for individualized treatment. Since somatic p53 mutations are frequently observed in primary BCs, we set out to assess the feasibility of identifying such mutations in CTCs from pts with MBCs, and compare the findings with those of the primary BCs from the same pts. Material and Method: Fiber-optic Array Scanning Technology (FAST) was used for identification and location of CTCs on large glass substrates. CTCs were identified after blood samples (10 ml) from MBC pts were stained to detect CTCs via automated digital microscopy by morphology, based on immunofuorescence staining for cytokeratin and nucleus, and the absence of CD45. Single CTCs from 10 pts with MBC were identified and removed from the glass substrates. DNA was extracted, and the whole genome of isolated CTCs was amplified by using whole genome amplification method (Sigma). P53 mutations in exon 5, exon 6, exon 7 and exon 8 were assessed. As comparison, genomic DNA from formalin-fixed and paraffin-embedded (FFPE) from primary BCs of the same pts, was amplified using the same method.

Results: p53 mutations were found in 8 out of 10 CTCs, and in 4 out of 10 in primary BC samples. Of 8 mutations detected in CTCs, one silent mutation and 7 missense mutations were seen. One particular point mutation, R181L, previously assessed as functional mutation, was observed in 4 out of 8 CTCs. None of the 4 mutations (a silent mutation, one missense mutation and two different deletions) detected in tumor samples were found in CTCs. We validated that the mutations detected in CTCs were not artifacts occurring during genome amplification, by comparing p53 mutations between unamplified tumor genomic DNA vs. amplified samples.

Conclusion: Whole genome amplification based on extracting DNA from single CTCs using FAST, and identification of mutations such as those in p53, is feasible. The quantitative and qualitative discordance in detecting p53 mutations between CTCs and primary BCs may be due to CTCs acquiring new -possibly epithelial-mesenchymal transition-like-characteristics with metastatic potential as they evolve from the primary tumors or metastatic sites, or, technical issues (analyzing FFPE-preserved vs. CTCs, tumor heterogeneity) may contribute to our findings. Further assessment of the functionality of high frequent functional mutations such as R181L is warranted.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-07-12.
P4-09-08: Secretory Leukocyte Protease Inhibitor as a Differential Diagnostic Biomarker of Tumor Emboli in Inflammatory Breast Cancer.
Authors: Robertson FM , Ye Z , Chu K , Luo AZ , Wright MC , Jin J , Barsky SH , Cristofanilli M , Krishnamurthy S
Published: June 2012

Background: Inflammatory breast cancer (IBC) is the most aggressive and lethal variant of locally advanced breast cancer. Pathologically, IBC is characterized by the presence of nests of cells, defined as tumor emboli, that undergo lymphovascular invasion into the skin and chest wall and represent the metastatic lesion of IBC. Due to the distinct presentation of IBC, it is often misdiagnosed due to a lack of defined biomarkers that are specific for tumor emboli in biopsy samples of IBC patients. To date, the only validated marker that has shown to consistently identify IBC tumor emboli is the surface glycoprotein E-cadherin.

Materials and Methods: With the goal of identifying genes specifically expressed by IBC tumor emboli, the present studies performed whole transcriptome analysis of tumor emboli from skin punch biopsy samples from IBC patients and tumor emboli from the Mary-X pre-clinical model of IBC which were isolated using laser capture microdissection.

Results: Secretory leukocyte peptidase inhibitor (SLPI) was a gene identified as being highly expressed by tumor emboli. This gene was previously identified as a metastasis related gene, has been reported to be associated with poor prognosis in serous ovarian carcinoma and is implicated in mediating resistance to paclitaxel. Immunofluorescence staining and confocal microscopy revealed that SLPI is a robust marker of tumor emboli in skin punch biopsies from IBC patient and in Mary-X tumor emboli. SLPI differentially delineates between IBC tumor emboli and hair follicles present in the skin, which also stain with E-cadherin. An additional marker, Cytokeratin 15 (CK15), can be used in combination with SLPI to differentially identify the components of the skin that are CK15 positive, and IBC tumor emboli that reside within the skin, which are CK15 negative. Use of podoplanin antibodies, which stain lymphovascular endothelium, demonstrate that IBC tumor emboli that express SLPI protein, are completely encircled within the dermal lymphovasculature.

Conclusions: These studies are among the first to identify SLPI as a potential biomarker of tumor emboli in skin punch biopsy samples from IBC patients and in pre-clinical models of IBC. Studies are ongoing to establish the molecular function and role of SLPI in mediating the survival and invasion of IBC tumor emboli. Collectively, these studies are the first to identify SLPI as a potential biomarker of IBC tumor emboli in skin punch biopsy samples. In addition to serving as a potential biomarker of tumor emboli, SLPI may also serve as a therapeutic target for development of approaches to eradicate IBC tumor emboli.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-09-08.
P4-09-20: Expression Profile of Interleukin 17B and the Receptor IL-17BR in Clinical Breast Cancer.
Authors: Sanders AJ , Mansel RE , Mason MD , Jiang WG
Published: June 2012

Introduction:

Interleukin 17B (IL-17B) is a member of the interleukin 17 cytokine family. Members of this family have been implicated in conditions such as autoimmune diseases and the inflammatory response. A number of studies have examined the role of IL17A in cancer progression and angiogenesis and shown a variety of functions, both pro- and anti- tumorigenic. Currently there is little data on IL-17B and the receptor IL-17BR and their involvement in cancer progression. The current study looks at the expression profile of IL-17B and IL-17BR in a clinical breast cancer cohort.

Methods:

The expression profile of IL-17B and IL-17BR was examined in a cohort of human normal breast and breast cancer specimens (normal, n = 34; tumour, n = 109). IL-17B and IL-17BR transcript expression in the samples was analysed using Q-PCR and compared to clinical and pathological data.

Results:

Both IL-17B and IL-17BR expression seemed to correlate with NPI staging. IL-17B levels were low in patients with NPI-1 or -2 cancers (median values 3.1 and 1.1 respectively), with highest levels of IL-17B being observed in the poorer prognosis NPI-3 group (median value 206.9; p = 0.07 NPI-1 vs NPI-3 and p = 0.01 NPI-3 vs NPI-2). Similar to this IL17B levels in TNM stage 1 cancers were significantly lower than those in higher TNM stages (TNM1 median value = 0.3 vs grouped TNM234 median value 10.3, p = 0.03). IL-17BR expression also tended to increase with NPI staging (IL-17BR median expression, NPI-1 = 0.0, NPI-2 = 0.04 and NPI-3 = 1.59; NPI-1 vs NPI-3 p = 0.07). Additionally, levels of IL-17BR were found to be significantly lower in background tissue compared to cancer tissue (median values 0.00 vs 0.01 respectively, p = 0.014).

Conclusion:

IL-17BR expression seems to be higher in tumour tissue compared to normal background tissue. Additionally, expression of IL-17B and IL-17BR both appear to be associated with higher NPI stage, particularly in the poor prognostic NPI-3 group. Expression of IL-17B seems to be elevated collectively in TNM stage 2, 3 and 4 compared to the better prognostic TNM1 stage. Together the data suggests that IL-17B and IL-17BR expression may be useful molecules to identify poorer prognostic breast cancers in patients.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-09-20.
P4-09-35: Co-Expression of Ki-67 Is Critical for Outcome of Cyclooxygenase-2 Positive Breast Cancer.
Authors: Park S , Koo JS , Lee JS , Hwang H , Ko S , Kim SI , Park B-W
Published: June 2012

Background

The purpose was to investigate the implications of cyclooxygenase-2 (COX-2) and Ki-67 expression on the progression and prognosis of breast cancer.

Methods: COX-2 and Ki-67 levels were immunohistochemically determined using tissue microarrays of 1,028 breast tumors treated between November 1999 and August 2005. COX-2 and Ki-67 levels were compared by tumor progression and clinicopathological parameters were investigated in association with both markers status which was divided into 3 subgroups: COX-2(+)/Ki-67(+), COX-2(+)/Ki-67(−), COX-2(−)/Ki-67(any).

Results: COX-2 expression was significantly higher in intraductal carcinoma and progressively decreased in small T1 lesions and then in T2-T4 tumors, but Ki-67 was significantly expressed at high levels in T2-T4 lesions than in intraductal or T1 carcinomas. COX-2 expression was positively associated with favorable parameters such as older age at diagnosis, smaller size, well-differentiation, hormone receptor-positivity, and was inversely associated with Ki-67 expression. Among 816 invasive tumors, COX-2 expression alone was not related to outcomes. In combination with Ki-67 expression, however, COX-2(+)/Ki-67(−) tumors were significantly associated with favorable characteristics including HER2−negativity and demonstrated favorable outcomes. COX-2(+)/Ki-67(+) tumors showed unfavorable factors and the worst outcomes. COX-2(−)/Ki-67(any) subgroup presented intermediate prognosis. Statistical significance of COX-2 combined with Ki-67 was maintained in Cox's models adjusting for clinicopathological parameters among not only whole population but also ER-positive subgroup.

Conclusions: Our study suggests that COX-2 is expressed in early phase of breast cancer development and is associated with favorable prognostic markers. But co-expression of high Ki-67 proliferative index could indicate an aggressive phenotypic change in COX-2 positive breast cancer. The mechanisms should be further investigated.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-09-35.
P4-11-10: Perceptions, Knowledge and Satisfaction with Contralateral Prophylactic Mastectomy among Young Women with Breast Cancer.
Authors: Tracy MS , Meyer ME , Sepucha K , Gelber S , Hirshfield-Bartek J , Troyan S , Morrow M , Schapira L , Come S , Winer E , Partridge AH
Published: June 2012

Background: There has been an increasing prevalence of contralateral prophylactic mastectomy (CPM), particularly among younger women with breast cancer. There has been limited research evaluating patient preference, knowledge and decision-making regarding this issue.

Methods: We surveyed women who had bilateral mastectomy who were enrolled in a multicenter, longitudinal cohort study of women diagnosed with breast cancer at age 40 and younger. The CPM survey included 23 items on decision making, knowledge, and satisfaction with CPM.

Results: Of the 550 patients enrolled as of November 2010, 157 (28.5%) had bilateral mastectomy, of whom 124 completed the CPM survey (response rate 79%). Women with bilateral breast cancer (3) or bilateral prophylactic (1) indications for surgery were excluded. Median age at diagnosis was 37 years (range 26–40); 26 women (21%) reported having a genetic mutation (21 BRCA1 and 5 BRCA2). Excluding mutation carriers, women estimated that a median of 10 of 100 women (range 0–90) would develop contralateral breast cancer in the 5 years after unilateral breast cancer treatment and that 5 of 100 women (range 0 — 98) treated with CPM would develop contralateral breast cancer. Eighteen percent of all respondents believed that women who undergo bilateral mastectomy live longer. Women were asked the importance of potential reasons for undergoing CPM (see Table 1). Eighty-two percent of women were “extremely confident” in their decision to undergo CPM and 92% would “definitely” still choose CPM.

Conclusion: Young women with breast cancer have high rates of CPM. Many young women who have undergone CPM overestimate the risk of contralateral disease and the benefits of CPM, including believing that CPM will prevent metastasis and extend life. Interventions to counsel young women with early breast cancer to help them make optimal surgical treatment decisions are needed.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-11-10.
P4-12-10: A Prospective Study of Physical Activity Patterns and Changes in Breast Cancer Patients during Active Breast Cancer Treatment.
Authors: Kim I-R , Choi E-K , Nam S-J , Lee J , Lee S-K , Yang J , Noh DY , Han W , Cho J
Published: June 2012

Purpose Physical activity (PA) has been shown to benefit cancer patients’ physical functioning, emotional well-being, and symptom management. Moderate PA may reduce the side effects of breast cancer treatment and improve quality of life, but most of the studies have been conducted after active treatment was completed and there is little data on patterns of PA during active treatment. This study aims to evaluate patterns and changes in physical activity among breast cancer patients during active treatment.

Patients and Methods We recruited 411 women with non-metastatic breast cancer between July 2010 and Dec 2010 from two major cancer hospitals in Seoul, Korea. Trained researchers interviewed participants at enrollment (before surgery), and at 2 weeks, 3 months, and 6 months post surgery. Intensity and duration of PA were assessed using the Minnesota Leisure Time Physical Activity Questionnaire, and energy expenditure (the average calories spent per day) was calculated as metabolic equivalents (METs). Quality of life (EORTC), fatigue (BFI), socio-demographic and clinical characteristics were also assessed. After excluding 15 patients with recurrence during follow-up and 65 patients were lost to follow-up, the final sample size was 331 patients (80.5%).

Results The mean (SD) age and BMI of study participants were 46.4 years and 23.3kg/m2 (SD 3.35). 83.7% of women had lumpectomy, and 70.6% and 85.9% had adjuvant chemotherapy and radiotherapy respectively. Breast cancer patients were most likely to spend their energy in lifestyle (walking and driving) and leisure (shopping, reading, and watching TV) activities but spent little energy in sport activities (Table).

Conclusion PA declined after the surgery and gradually recovered at 3 and 6 months post surgery but it did not return to the baseline level. Breast cancer patients may need encouragement and support to perform more intensive physical activities during active treatment.

*Acknowledgement: The research was accomplished by the support from AMOREPACIFIC and Korea Breast Cancer Foundation.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-12-10.
P4-14-03: Support Groups in Breast Cancer: An Evidence Based Assessment of 1606 Patients with Concerning Topics for Support Group Discussion and Presentation.
Authors: Gralla RJ , Morse KD , Rittenberg CN , Petersen JA , Rosen LM , Lesser M
Published: June 2012

Background

Cancer support groups are conducted at most cancer centers. Although there is increasing demand among patients and families for support groups, little data exist outlining which topics patients and caregivers consider as most important for support group discussion and presentation. We conducted a large web-based anonymous survey to determine preferences of patients and caregivers for cancer support groups, including 1606 individuals with breast cancer and 3723 with other malignancies.

Methods: The established patient base of NexCura®, a web-based information resource, was used to survey registered patients and caregivers in this on-line assessment. Participants ranked 26 topics on a 5-point Likert scale which evaluated the importance of each item. Demographic characteristics, clinical factors, and support group content preferences were assessed.

Results: There were 4402 respondents to the invitation to participate, and 3723 patients and caregivers elected to participate (85%). Characteristics included for all 3723 patients: 70% women, mean age 58 (range 20–89). For the 1606 patients with breast cancer, 99.8% were women, the mean age was 56 (range 27–88); 53% were free of cancer. For the whole group, the four most common cancers were breast 45%, prostate 15%, lung 6%, and colorectal 5%. 90% of participants were patients and 10% were caregivers. 80% of participants rated all 26 topics. The table below shows rankings by the top 2 categories (the percent ranking each topic as “Very Important” or “Important”) of the 10 highest rated topics (and the rank order for each item) for patients with breast cancer and for all patients.

Conclusions: 1) This is the largest survey of patients and caregivers concerning support groups for patients with breast cancer and for a general cancer population. 2) Patients with breast cancer ranked most topics similarly to the general cancer population; however, topics dealing with fatigue and stress management were somewhat more highly ranked by those with breast cancer. 3) Physical, psychological, and communication issues were the most highly ranked issues by breast cancer patients and families. 4) These results should guide the content of support groups to meet the needs of patients and caregivers.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-14-03.
P4-17-02: Whole-Brain Radiation Therapy Plus Concomitant Temozolomide for the Treatment of Brain Metastases from Breast Cancer: A Randomized Prospective Multicenter Phase II Study.
Authors: Kirova YM , Hajage D , Gerber S , Le Scodan R , Pierga J-Y , Bourgier C , Campana F , Asselain B , Fourquet A , Levy C
Published: June 2012

BACKGROUND: A previously published study of temozolomide (TMZ) concurrent with whole-brain radiation therapy (WBRT) reported significant improvement in response rates and a nonsignificant trend toward improved overall survival compared with WBRT alone in patients with brain metastases in different type of tumors. A prospective randomized phase II trial of concurrent WBRT and TMZ versus WBRT alone was conducted to assess whether the concurrent use of WBRT-TMZ resulted in measurable radiological response differences at 6 weeks after the treatment in homogeneous population of breast cancer (BC) patients.

PATIENTS AND METHODS: In this intent-to-treat study, patients with metastatic breast cancer to the brain and not suitable for surgery or radio-surgery were enrolled in a randomized prospective multicenter phase II study between February 2008 and December 2010. Patients received temozolomide 75 mg/m(2)/day (days 1–15) concurrently with WBRT 30 Gy/10 fractions. Patients were stratified by type and metastatic sites. The (MRI) response at 6 weeks was the main criteria; response was defined as complete (CR) or partial response (PR). Initial and follow-up MRI were realized on a 1.5T unit (Siemens) by axial SE-T1 WIs and FLAIR WIs with GdDTA injection, EG-3DT1 WIs after GdDTPA. Five target lesions (over 10 mm greatest diameter) were measured in their 3 dimensions. Non measurable lesions were noticed."The treatment tolerance and clinical responses were also evaluated. The study was designed according to a modified Fleming two-stage plan based on response hypotheses of 30% (H0) versus 50% (H1). Twenty or more responses among 50 subjects were needed to declare the treatment effective, with risk errors alpha 9% and beta 7%.

RESULTS: One hundred metastatic breast cancer patients were enrolled in the study, as following: 49 in WBRT-TMZ and 51 in WBRT groups. The median age was 55 years [range, 29–79]. The median follow-up was 12 weeks [range, 1–94]. There were 15/49 (31%) partial responses (PR) in WBRT-TMZ and 18/5 1(35%) PR in WBRT group. No complete responses were observed. The symptoms relief was obtained in 27/49 and 31/51 pts, respectively. The treatment tolerance was acceptable in both groups.

CONCLUSION: The benefit of adding TMZ to WBRT was not confirmed at 6 weeks. The tolerance was good in both groups. Longer follow-up is needed to evaluate the combination of TMZ with WBRT in terms of progression free survival.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-17-02.
P4-17-06: Prognostic Role of Triple Negative Subtype in Breast Cancer Patients with Brain Metastases.
Authors: Mathew A , Mathew IE , Rosenzweig MQ , Brufsky AM
Published: June 2012

Background

Metastatic breast cancer (MBC) patients with brain metastases (BM) have a poorer prognosis compared to patients with metastases to sites such as bone or other visceral organs. The role of breast cancer subtypes such as triple negative (TN) status and its relationship with other known prognostic factors have not been well delineated in the context of metastatic disease to the brain. We conducted a retrospective single institution cohort study of MBC patients with BM to evaluate the association between TN subtype and overall survival from the diagnosis of BM.

Methods: Baseline demographic and tumor specific data including ER, PR and HER2 status were collected on newly diagnosed MBC patients between January 1998 and December 2009. Overall survival was determined from the date of diagnosis of BM. Survival analyses were performed using the Kaplan-Meier method and Cox proportional-hazards model.

Results: Data were available on 186 MBC patients with BM, of whom 156 died during a median follow-up of 10.2 months from the diagnosis of BM; median age was 47.9 years. 91% of patients were Caucasian; 25.3% had triple negative disease. Median survival from the period of diagnosis of BM in patients with triple negative disease was 7 months (Interquartile range, IQR: 3–13) as compared to 11 months (IQR: 5–22) in patients who were HER2−positive or ER/PR-positive. Multivariate analysis found a higher risk of death after BM for TN disease subtype, with a hazard ratio for death of 2.89 (95% confidence interval: 1.89−4.44; p<0.001), when adjusted for variables such as age and stage at initial diagnosis of breast cancer, race, the number of metastatic sites, and the use of metastatic chemotherapy. The administration of metastatic chemotherapy had a significant survival benefit in the analyses, with a hazard ratio for death of 0.52 (95% CI: 0.27−0.99; p=0.048).

Conclusion: This retrospective cohort study in MBC patients with BM provides evidence for a greater risk of death in those with TN disease as compared to HER2−positive or ER/PR-positive subtypes even after adjusting for other prognostic factors.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-17-06.
P4-17-07: The Shifting Landscape of Metastatic Breast Cancer to the CNS.
Authors: Quigley MR , Fukui O , Chew B , Bhatia S , Karlovits S
Published: June 2012

Introduction: Improved survival following the diagnosis of breast cancer, in conjunction with new therapies and diagnostics has potentially altered the characteristics and course of patients presenting with CNS involvement.

Methods: Review of clinical and radiographic records of women presenting to a tertiary medical center with the new diagnosis of CNS metastatic disease from breast cancer. This was a retrospective review from patients identities obtained from two prospective databases Results: There were 88 women analyzed who were treated over the period 1/2003-2/2010, average age 56.9. At the time of initial presentation of CNS disease, 68% of patients had multiple brain metastases, 17% had a solitary metastasis and 15% had only leptomeningeal disease (LMD). The median survival for all patients from the time of diagnosis of breast disease was 50.0 months, and 9.7 months from diagnosis of CNS involvement. The only factor related to overall survival was estrogen receptor positive (ER+) pathology (57.6 v. 38.2 months, p=.02 log-rank); those related to survival post CNS diagnosis were presentation with LMD (p=.004, HR= 3.1, Cox regression) and triple negative hormonal/HER2 status (p=.02, HR= 2.3, Cox regression). Patients with either had a median survival of 3.1 months (no patients in common). Of the 75 patients who initially presented with metastatic brain lesions, 20 (26%) subsequently developed LMD in the course of their disease (median 10.4 months), following which survival was grim (1.8 months median). Of note was that HER2+ status was protective in regard to late development of LMD (14.7 vs. 42.3%, p=.03, Chi-square). Symptoms of LMD were most commonly lower extremity weakness (14/33), followed by cranial nerve deficits (11/33).

Conclusion: Treatment of patients with metastatic brain disease from breast cancer should be tailored to the patient's hormonal status (as it markedly effects survival) and practitioners must be vigilant for the development of LMD, especially as it often presents with non-descript complaints such as back pain.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-17-07.