bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation of clinical data and expression levels of six tumor supressor genes in breast cancer.
Authors: Celebiler Cavusoglu A , Kilic Y , Saydam S , Canda T , Sevinc AI , Baskan Z , Sakizli M
Published: December 2010

Abstract #1058

As the scientists and physicians began to share more information for improving the personalization in medicine, we aimed to check the expression profiles for major tumor suppressor genes of 70 breast tumor samples obtained from the Dokuz Eylul Breast Tumor Biobank. We tried to figure out the levels of expressions of tumor suppressor genes by the quantity of the RNA which belongs to the examined gene in the tumor tissue samples. The expression level was measured by quantitative RT-PCR using total RNA extracted from the tissues. Fluorescence amplification plots were observed and the Ct values were used for comparing the expression levels. For quantification, we chose to normalize the Ct differences by using Genorm software with averaging four housekeeping genes (PUM1, RPL13A, ACTB, B2M). Correlation analysis is performed between genetic expression levels and the data obtained from the clinical records of the biobank.  Although further statistical analysis is still continuing, we observed direct significant correlations between ki67 level and BRCA1 expression and between intraductal component level and CDH1 expression. Also significant relations between tubuler formation and BRCA1 expression; between intraductal component and P16 expression were observed. Dermal infiltration had significant correlatios with both TIMP3 and P16 expressions. Significant inverse correlation between estrogen receptor level and BRCA1 expression were found as well as the inverse correlation between progesteron receptor level and TIMP3 and BRCA1 expression levels. Staging had only significant correlations with TIMP3 levels.  We also found out that expression status of BRCA1 and BRCA2; BRCA2 and CDH1; BRCA1 and GSTP1, and GSTP1 and TIMP3 shows significant correlations within themselves.  *This study is supported by TÜBITAK, The Scientific and Technological Research Council of Turkiye.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1058.
TWIST1 and PITX2 expression in bone marrow of women with clinical stage II/III breast cancer identifies patients at risk for the development of early metastatic disease.
Authors: Dasgupta N , Watson M , Fleming T , Trinkaus K , Ferguson A , Aft R
Published: December 2010

Abstract #108

Background: The presence of disseminated tumor cells (DTCs) in bone marrow of women with newly diagnosed breast cancer has been associated with increased risk of recurrent disease development. We have previously described a 67-gene signature associated with the presence of DTCs using gene array analysis after immunomagnetic enrichment of these cells and found that the expression of one of the 67-genes in bone marrow of breast cancer patients, TWIST1, correlated with the development of early recurrent disease. We have now tested the remaining genes in the 67-gene signature for correlation with the development of recurrent disease. Our goal is to identify genes associated with DTCs with high metastatic potential for early detection and intervention.  Methods: Expression of each of the 67 genes was analyzed using qRT-PCR in a breast cancer cell lines (MCF7, SKBR3, MDA/MB 231) diluted into normal human bone marrow at varying concentrations. Levels of expression in the breast cancer cells and in human bone marrow were quantitated. Genes with high expression in breast cancer cell lines and no observed expression in normal human bone marrow were further tested by qRT-PCR for expression in a validation set of bone marrows comprised of 50 specimens collected from 30 patients with clinical stage II/III breast cancer prior to any treatment. Thirteen of these patients developed recurrent disease within 16 months.  Results: Within the 67 gene signature, 5 genes were identified that were highly expressed in breast cancer cell lines and had no detectable expression in normal human bone marrow. Expression of the 5 genes as well as keratin 19 were examined in the validation set of bone marrows. PITX2 was expressed in the bone marrow of 5 of the 13 patients who recurred within one year. Only expression of TWIST1 and PITX2 were found to correlate with the time to development of early recurrent disease (p <0.0001 and 0.0002 respectively).  Conclusion: We have found that the expression of TWIST1 and PITX2 in the bone marrow of breast cancer patients prior to any treatment identifies patients at risk of early distant disease recurrence. These genes are not expressed in normal human bone marrow. Both are transcription factors involved in the embryonic development and appear to be expressed by DTCs with high metastatic potential. Expression of TWIST1 and PITX2 may prove to be excellent markers for identifying women at high risk for distant relapse and lead to new targets for chemotherapeutic intervention.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 108.
Focal adhesion kinase overexpression in breast cancer molecular subtypes.
Authors: Melucci E , Buglioni S , Di Benedetto A , Perrone-Donnorso R , Marandino F , Antoniani B , Avetrani P , Nisticò C , Vici P , Cognetti F , Fabi A , Mottolese M
Published: December 2010

Abstract #1091

Focal adhesion kinase (FAK) is a protein tyrosine kinase which regulates multiple cellular processes including growth, differentiation, adhesion, motility and apoptosis and is a critical mediator of signalling events between cells and their extracellular matrix.  FAK is highly expressed in invasive breast cancer (BC) where its upregulation has been implicated in the acquisition of an invasive tumor phenotype. Hierarchical cluster analysis identified subgroups of BC with separate gene expression profiles which detect four main tumor phenotypes, Luminal A (LA), Luminal B (LB), Basal-like (B), and HER2 subtype (HS) characterized by significant differences in prognosis. Up to now, there are no data concerning FAK distribution within the molecular BC subtypes. In this study FAK overexpression was evaluated, by immunohistochemistry (IHC), in a retrospective series of 193 invasive BC surgically treated at our Institution between 2002 and 2005. Associations with conventional pathological factors and with molecular subtypes were analyzed by Multiple Correspondence Analysis (MCA) and chi square test, aimed to determine the impact of FAK high positivity within BC molecular subtypes and to define a biologic profile associated to aggressive bio-pathologic variables such as tumor size (T), nodal status (N), grading (G), p53, Bcl2, Ki-67, p-AKT, p-MAPK . The anti-FAK 4.47 monoclonal antibody was used to detected FAK expression which was scored as high (2 or 3 intensity and ≥ 90% positive cells) or low (0 or 1 intensity and < 90% positive cells).  FAK was overexpressed in 41.7% of LA, 70% of LB, in 48.0% of HER2 subtype and 52.2% of Basal-like BC. The relationships among the bio-pathological factors, analysed by MCA, showed that FAK+ is located in the quadrant containing more aggressive tumor phenotypes such as HER2 and Basal like subtypes together with T3-4, N+, G3 and p53+, high Ki67, Bcl2–, p-MAPK+, p-AKT+. Moreover, in LA tumors, FAK overexpression is significantly related to nodal status (p=0.05), grading (p=0.007), p53 nuclear accumulation (p=0.047) and p-AKT overexpression (p=0.001) and it appears to be a useful tool in identifying BC patients at higher risk of progression.  The presence of FAK upregulation in LA subtype, may represent a useful tool in identifying those LA patients who would benefit from more aggressive adjuvant therapy. In this context, further investigations are necessary to better assess the prognostic role of FAK overexpression in low risk BC.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1091.
Genetic counseling for BRCA1 and BRCA2 mutations in African American women.
Authors: Halbert C , Kessler L , Troxel AB , Stopfer JE , Domchek S
Published: December 2010

Abstract #1099

Background: Efforts are now focused on increasing access to genetic counseling and testing for BRCA1 and BRCA2 (BRCA1/2) mutations to address cancer disparities in African American women; however, limited empirical data are available on the effects of these services. Therefore, we evaluated the effects of genetic counseling among African American women at increased risk for hereditary disease.  Materials and Methods: This study was conducted between February 2003 and November 2006. Participants were African American women (n=139) at increased risk for having a BRCA1 or BRCA2 (BRCA1/2) mutation. The effects of genetic counseling, including culturally tailored (CTGC) versus standard (SGC) counseling, on changes in risk perception and psychological functioning were evaluated.  Results: Women who participated in genetic counseling had a significantly greater likelihood of reporting reductions in perceived risk compared to non-participants (P=0.03). Women who received BRCA1/2 results also had a significantly greater likelihood of reporting decreases in cancer worry (P=0.03). Similar effects were found among women who had a high prior probability of having a BRCA1/2 mutation (P=0.03) and those affected with cancer (P=0.04). There were no differences in CTGC and SGC in study outcomes.  Discussion: African American women may experience some benefit from receiving BRCA1/2 test results. Participation in counseling and receiving test results may be especially beneficial to African American women who have high prior probability of having a BRCA1/2 mutation and those affected with cancer. Continued efforts should be made to increase access to genetic counseling and testing among African American women at increased risk for hereditary disease.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1099.
A gene expression signature predicts chemopreventive response of an EGFR inhibitor in a rat mammary cancer model.
Authors: Lu Y , Liu P , Wang Y , Grubbs C , Lubet R , You M
Published: December 2010

Abstract #1111

Rats treated with the carcinogen methylnitrosourea (MNU) develop multiple, hormonally dependent mammary tumors. The efficacy of the epidermal growth factor receptor (EGFR) inhibitor Gefitinib (Iressa) to prevent MNU-induced mammary cancers in female Sprague-Dawley rats was determined. Rats were given a single dose of MNU (75 mg/kg body weight) at 50 days of age. Rats bearing MNU-induced small palpable cancers showed variable responses to treatment with Iressa; with approximately 50% having a complete regression and the remaining 50% having a partial or no response. We conducted exon array studies of differentially expressed genes and/or alternative splicing exons related to the responses (complete vs partial or no response). Preliminary studies showed that, although there were genes whose expression was similarly modulated in both groups, a gene expression signature can be identified that is highly predictive of which rat mammary tumors are susceptible to treatment with Iressa. Cross validation results indicated that gene expression signatures may be useful in predicting the response of a rat mammary tumor to treatment with Iressa. Currently, we are conducting validation studies in a separate set of rat mammary tumors.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1111.
Prospective evaluation of neurotoxicity in breast cancer patients treated with adjuvant paclitaxel.
Authors: Crew KD , Zauderer MG , Cho C , Weimer LH , Brafman L , Fuentes D , Sierra A , Hershman DL
Published: December 2010

Abstract #1115

Background: Taxanes are increasingly used in the treatment of early stage breast cancer (BC). Up to 30% of patients develop moderate-severe neurotoxicity during treatment. We recently reported that about 60% of BC patients complain of some neuropathy up to 2 years after completing adjuvant paclitaxel (T) treatment. The prevalence, severity, and natural history of this syndrome have not been well described.  Methods: Using a prospective cohort study design, women with stage I-III breast cancer undergoing adjuvant paclitaxel were enrolled. At baseline, 4 weeks, 8 weeks, 3 months, and 6 months, all patients completed the Functional Assessment of Cancer Therapy-Taxane (FACT-Tax) and quantitative sensory testing (touch perception and vibration threshold) was conducted. The FACT-Tax includes a 16-item subscale which measures the severity of neurotoxicity, where lower scores represent worsening symptoms. Blood was obtained at baseline and 2 weeks post-treatment to measure serum nerve growth factor (NGF) levels.  Results: A total of 34 out of a target of 50 patients have been enrolled to date; median age: 48 (32-77); White/Hispanic/Black/Other: 10/17/4/1; median body mass index (kg/m2): 28 (21-44); stage I/II/III: 4/19/8; paclitaxel regimen T q2wks x4/T q2wks x6/T qwk x12: 19/8/5. Compared to baseline, there was a significant decrease in vibration sense at 8 weeks during active treatment. Mean scores on the Neurotoxicity subscale of the FACT-Tax decreased from 37.3 at baseline to 30.7 at week 4 (p=0.009) and 29.7 at week 8 (p=0.006). These scores remained lower than baseline at 3 months and 6 months after completing paclitaxel treatment (33.7 and 33.2, respectively). At 6 months, up to 50% of patients reported persistent numbness or discomfort in the hands and feet. Serum NGF analyses are underway to determine whether this biomarker correlates with neuropathy symptoms.  Discussion: To our knowledge, this is one of the first studies to prospectively evaluate persistent neuropathy in women prior to, during and following adjuvant paclitaxel therapy. Over 50% of patients developed moderate to severe neuropathy during active treatment, which persisted 6 months post-treatment. Taxane-based chemotherapy has been shown to improve survival, however, neurotoxicity is the main long-term side effect. Understanding the natural history of this toxicity and validating appropriate measures to be used in interventions to prevent and treat taxane-induced neuropathy are critical.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1115.
Perception and measurement of strength and range of movement in women following treatment for breast cancer.
Authors: Lee M , Kilbreath SL , Beith J , Ward L , Refshauge K , Simpson JM
Published: December 2010

Abstract #1124

Introduction: About half the women who undergo breast cancer surgery report consequent shoulder problems. However, their perception of symptoms such as loss of movement and strength may not be reflected in physical measurements. The aim of this study was to compare the women's perception of symptoms with objective measurements of muscle strength and range of motion (ROM). Methods: One hundred thirty two women (mean age 53 years, SD 12) with early stage breast cancer participated in this study within 6 weeks of their surgery. Participants rated their perception of shoulder ROM and strength on a 5-point likert scale, with the anchors “no impairment” (0) to extreme (4). Shoulder abduction and forward flexion muscle strength were tested using a hand-held dynamometer and ROM with a digital inclinometer. Muscle weakness was defined as a deficit > 20% compared to the unaffected side in either movement. Limited ROM was categorized as > 20° deficit compared to the unaffected side. Results: Thirty two percent of women reported minor weakness, 17% reported moderated weakness, 4% reported major weakness, and no women reported extreme weakness. In addition, 36% reported a minor limited ROM, 32% reported moderate limited ROM, 11% reported major limited ROM, and no women reported extreme limited ROM. Fifty eight percent of women had > 20% muscle weakness and 15% of women had > 20° limited ROM in either shoulder flexion or abduction. There was a moderate relationship between participants' perception and objective measurements in range of motion (Spearman's rho = 0.55 and 0.57 for abduction and flexion, respectively) and a weak relationship for muscle strength (0.28 and 0.18). Interestingly, 28 women reported having no weakness on their affected side, although, strength measurements showed > 20% weakness compared to the unaffected side. Also, 20 women showed less than 20% strength difference between arms but reported having minor to major loss of muscle strength. Conclusion: The women's perception was weakly related to the objective measurements. Physical and psychological factors may contribute to the perception of symptoms. Acknowledgement: Supported by NSW Cancer Council.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1124.
Excellent outcomes with adjuvant toremifene or tamoxifen in early stage breast cancer.
Authors: Lewis JD , Chagpar AB , Shaughnessy EA , Edwards MJ
Published: December 2010

Abstract #1130

Purpose: Fareston (toremifene) and tamoxifen, both selective estrogen receptor modulators (SERMs), are therapeutically equivalent in treating metastatic breast cancer. We hypothesized that toremifene may have superior therapeutic efficacy as adjuvant therapy for early breast cancer.  Patients and Methods: The North American Fareston versus Tamoxifen Adjuvant (NAFTA) trial, a multicenter investigator-initiated randomized controlled trial, assigned 1813 female peri- or post-menopausal patients with hormone receptor positive invasive breast cancer to adjuvant treatment with either tamoxifen or toremifene. The primary outcomes evaluated were disease-free survival (DFS), defined as the time from registration to local and/or systemic recurrence, and overall survival (OS), defined as the time from registration until death from any cause. Both an intention-to-treat and a per-protocol analysis were performed.  Results: Median follow-up was 59 months. The baseline characteristics of the two treatment groups were generally well balanced, although the tamoxifen group tended to be older (median age: 68 vs. 67 years, p=0.096), with larger tumors (median tumor size: 1.3 cm vs. 1.2 cm, p=0.086), of higher grade (proportion Grade 3: 18.3% vs. 15.7%, p=0.081). Based on intention-to-treat, mean OS was not significantly different between tamoxifen and toremifene ((98.1 mo. vs. 98.6 mo., respectively, p=0.628). Similarly, mean DFS was not significantly different between tamoxifen and toremifene (96.4 mo. vs. 96.7 mo., respectively, p=0.790). Controlling for patient age, tumor size, and tumor grade, a Cox multivariate survival analysis found no difference between patients randomized to toremifene vs. tamoxifen in terms of OS (OR = 0.951; 95% CI: 0.623-1.451, p=0.951) or DFS (OR = 1.037; 95% CI: 0.721-1.491, p=0.846). Of the 1813 patients in the study, 104 (5.7%) had a protocol violation after randomization and did not start a study drug. The proportion of such patients was evenly distributed between the tamoxifen and toremifene groups (5.2% vs. 6.3%, respectively, p=0.394). Excluding these patients, survival times were similar between the tamoxifen and toremifene groups (mean OS: 96.401 vs. 96.776, p=0.766; DFS: 98.170 vs. 98.646, p=0.607). Cox proportional hazards models for OS (p=0.951) and DFS (p=0.843) failed to demonstrate a significant difference between the two treatment arms in the per-protocol analysis.  Conclusions: Women treated with adjuvant hormonal therapy enjoyed excellent DFS and OS. No significant differences were found between treatment with either tamoxifen or toremifene. Treatment of hormone receptor positive patients with either of these SERMs is appropriate.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1130.
The effect of quantitative oestrogen receptor expression on recurrence in postmenopausal women with early stage breast cancer.
Authors: Mansell J , Monypenny IJ , Skene AI , Abram P , Carpenter R , Gattuso JM , Wilson CR , Angerson WJ , Doughty JC
Published: December 2010

Abstract #1131

Introduction: Approximately 15% of postmenopausal women treated with adjuvant tamoxifen will experience disease recurrence within 5 years. This may reflect resistance of the primary tumour to tamoxifen. We aim to determine if quantitative oestrogen receptor (ER) expression has an effect on the incidence and type of recurrence in this patient group.  Methods: All postmenopausal women diagnosed with early stage breast cancer between 1995 and 2001 in 3 hospitals were included. All ER immunohistochemistry was performed on one site by a single pathologist. A percentage of ER expression was assigned to each tumour. Patients were grouped into high ER (≥70% expression) and low ER (<70% expression). Recurrence was defined as distant, locoregional and contralateral. The cumulative risk of recurrence was calculated using the Kaplan-Meier method. Hazard ratios were calculated using Cox regression analysis. Clinical and pathological factors found to be significant on univariate analysis were included in the multivariate analysis.  Results: 1563 patients were included in the analysis with a median follow up of 5 years. 190 (12.2%) were classified as having low ER expression. Median age at diagnosis was 62 in the high ER and 59 in the low ER group (p=0.001). There was no significant difference in tumour size, grade and nodal status between ER groups. Low ER expression was associated with significantly higher cumulative recurrence at 5 yrs compared with high ER (17.5% (95% CI 12.0-23.0) vs 11.0% (95% CI 9.2-12.8), p <0.008, log rank test). This difference was only seen in distant recurrence events (15.3% (95% CI 10.0-20.6) vs 8.6% (95% CI 7.0 – 10.2)) with the number of locoregional and contralateral events very similar between the two groups. Using multivariate Cox regression analysis, low ER was a significant predictor of recurrence within 5yrs after adjustment for tumour size, grade, nodal status and mode of presentation (HR 1.64 (95% CI 1.11-2.44), p = 0.014).  Conclusions: Postmenopausal women with early stage breast cancer who have tumours with low ER expression are at a significantly increased risk of distant recurrence compared with women with tumours showing high ER expression. This should be considered when making decisions regarding adjuvant treatment.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1131.
Managing cancer treatment-induced bone loss: 24-month results from the Study of Anastrozole with the Bisphosphonate RisedronatE (SABRE).
Authors: Van Poznak C , Hannon R , Clack G , Campone M , Mackey JR , Apffelstaedt J , Eastell R ,   on Behalf of the SABRE Investigators
Published: December 2010

Abstract #1137

Aim: To investigate the management of bone health in postmenopausal women with early breast cancer (BCA) scheduled to receive anastrozole.  Methods: Postmenopausal women with hormone receptor-positive early BCA were assigned to 1 of 3 strata depending on their pre-existing risk of fragility fracture. Patients (pts) with a bone mineral density (BMD) T-score <-2.0 for either spine or hip, or those pts deemed by the investigator to be at increased risk of fracture, were designated higher-risk (H) for fracture and received anastrozole 1 mg/day plus risedronate 35 mg/week orally. Moderate-risk (M) pts (T-score <-1.0 for spine or hip but ≥-2.0 at both sites) were randomized in a double-blind manner to receive anastrozole plus risedronate (A+R) or anastrozole plus placebo (A+P). Pts with T-scores ≥-1.0 at both spine and hip were designated lower-risk (L) and received anastrozole alone. All pts received calcium and vitamin D. Lumbar spine and total hip BMD were assessed at baseline, 12, and 24 months.  Results: BMD changes at 24 months are shown in the table. In M, a significant difference in favor of the A+R group compared with the A+P group was seen for both lumbar spine and total hip (both p<0.0001). In H, risedronate therapy was associated with increases in BMD at the lumbar spine (p=0.0006) and total hip (p=0.01). In L, no bisphosphonate therapy was associated with a significant decrease in BMD at the lumbar spine (p=0.01) but not at the total hip. Pts who withdrew did not appear to have an impact on the results. The safety and tolerability profile of anastrozole was similar to that already established and was not significantly altered by the addition of risedronate.  Conclusions: In postmenopausal women at risk for fragility fracture receiving adjuvant anastrozole for BCA, the addition of risedronate at doses established for preventing and treating osteoporosis resulted in favorable affects in BMD over 24 months.   

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1137.
A synthetic PPARγ ligand sensitizes breast cancer cells to tamoxifen-induced apoptosis.
Authors: Lee Y , Kim J , Yun HJ
Published: December 2010

Abstract #1149

Blockade of estrogen receptor (ERa) by tamoxifen has been considered as a promising therapeutic approach to breast cancer. However, since not all the tumor cells are sensitive to tamoxifen, there is a need for the development of strategies to overcome the tamoxifen-resistance. Recently it has been known that ERa binds to peroxisome proliferator-activated receptor (PPAR) response element and negatively interferes with PPARg signaling in breast cancer cells, whose activation inhibits the growth of various cancer cells. Here we firstly wished to determine whether ERa inhibits PPARg-mediated cell death of human breast cancer cells. Troglitazone, a synthetic PPARg ligand, caused cell death and G1 arrest in both ERa-positive MCF-7 and ERa-negative MDA-MB-231 in a dose-dependent manner, but their degree shows differences between two cells. Troglitazone induced less cell death and G1 cell arrest in ERa-positive MCF-7 than ER-negative MDA-MB-231. The differences were abolished by PPARg knockdown using PPARg specific siRNA, indicating that ER inhibits PPARg-dependent anti-tumor action of PPARg agonist on breast cancer cells. Moreover, troglitazone sensitized breast cancer cells to tamoxifen-induced apoptosis, suggesting that the dose of tamoxifen for breast cancer therapy could be lowered by combination with troglitazone. Our results suggest that ERa-mediated inhibition of PPARg signaling pathways contribute to the growth of breast cancer cell and inhibition of ERa with PPARg activation could be a better approach for ERa-dependent breast cancer.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1149.
A randomised study comparing the effects of anastrozole and letrozole on lipid metabolism.
Authors: McCaig FM , Renshaw L , Williams L , Young O , Murray J , Macaskill EJ , McHugh M , Riermersma R , Dixon JM
Published: December 2010

Abstract #1152

Background:  Aromatase inhibitors (AIs) reduce circulating oestrogen which may have a detrimental effect on lipid metabolism. Letrozole (L) decreases circulating oestrogen levels to a greater degree than anastrozole (A). This study compares the effects of adjuvant anastrozole and letrozole on lipid metabolism.  Patients and Methods:  This was an open, randomised pharmacodynamic study. Plasma lipids were measured in a subset of 57 out of 182 postmenopausal women with invasive ER positive breast cancer. As part of their adjuvant hormone therapy, patients were randomized to receive either  · 12 weeks of L followed by 12 weeks of A (L→A) or  · 12 weeks of A followed by 12 weeks of L (A→L).  Fasting blood and urine samples were collected at the same time of day and the same day at entry and after 12 weeks of each drug.  · 29 had no prior tamoxifen and  · 27 had received tamoxifen.  The following lipoproteins were measured:  - Triglyceride - HDL  - Cholesterol - ApoA1  - ApoB  - Cholesterol  - cLDL  HDL and ApoA1 are cardioprotective whereas ↑ levels of the others are associated with an ↑ risk of coronary artery disease.  Results:  (Expressed as absolute changes +/- 95% CI)  Patients who stopped tamoxifen >12 weeks prior to trial entry were considered tamoxifen free. Patients who had stopped tamoxifen <12 weeks prior to trial entry were considered to have tamoxifen in their system at trial entry.  A vs L:   There were no significant differences detected between A and L.  A vs L in tamoxifen vs no tamoxifen groups:  Triglycerides. Both A and L resulted in a significant decrease in triglycerides in patients who had tamoxifen in their systems, A = -0.02 (-0.24, 0.20) and L = 0.08 (-0.13, 0.29) vs those with no prior tamoxifen A = 0.51 (0.35, 0.68) and L = 0.56 (0.39, 0.72). A p = 0.0003 and L p = 0.001 respectively.  ApoB. Both A and L resulted in a significant decrease in ApoB in patients who had tamoxifen in their systems, A = 0.78 (0.64, 0.91) and L = 0.84 (0.71, 0.97) vs those with no prior tamoxifen A = 0.92 (0.82, 1.02) and L = 0.91 (0.80, 1.01). p = 0.03 for both drugs.  HDL. A resulted in a significant increase in HDL in patients who had tamoxifen in their systems 1.68 (1.49, 1.86) vs those with no prior tamoxifen 1.38 (1.24, 1.53) p = 0.02.  There were no significant changes for any other variables measured.  Conclusions:  There were no significant differences between letrozole and anastrozole in their effects on lipids.  Patients who had recently completed tamoxifen and commenced anastrozole or letrozole showed beneficial changes in their lipid profile compared to patients with no tamoxifen in their systems.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1152.
HER-2/neu over-expressing DCIS phenotypes and the transition from in situ to invasive breast cancer: implications for breast cancer prevention.
Authors: Roses RE , Paulson EC , Sharma A , Schueller JE , Nisenbaum H , Weinstein S , Fox KR , Zhang PJ , Czerniecki BJ
Published: December 2010

Abstract #1161

Background: Prognostically significant invasive breast cancer subtypes, distinguishable through immunohistochemistry for ER, PR and HER-2/neu expression, have recently been identified. The implication of similar phenotypic patterns in ductal carcinoma in situ (DCIS) lesions remains uncertain. The objective of this study was to determine whether DCIS phenotypes are associated with different rates of progression to invasive cancer.  Methods: Immunohistochemical staining for ER, PR and HER-2/neu was performed on biopsy and resection specimens from consecutive patients evaluated with DCIS between March 2003 and May 2008. DCIS lesions were characterized as luminal A (ER+ or PR+, HER-2/neu-), luminal B (ER+ or PR+, HER-2/neu+), HER-2/neu positive (ER- and PR-, HER-2/neu+) or basal-like (ER-, PR- and HER-2/neu-). All patients underwent breast MRI and those patients with evidence of invasive disease greater than 1cm in largest dimension were excluded from the analysis. Rates of invasive disease associated with DCIS lesions with different phenotypes were compared using a chi square test. Multivariate logistic regression was used to evaluate the relationship between phenotype and invasion adjusting for patient age, lesion size, nuclear grade, and the presence of comedo necrosis.  Results: One hundred and seven patients were included in the analysis. Luminal A was the most common phenotype and accounted for 59% of lesions (63/107). Associated invasive disease was identified in 6 patients with such lesions (10%). The HER-2/neu positive phenotype accounted for 21% of lesions (23/107). Invasive disease was identified in 8 patients with such lesions (35%). Seventeen patients had luminal B DCIS (16%) and 8 of these patients had associated invasive disease (47%). Basal-like lesions were uncommon; only four patients with such lesions were identified. The rates of invasion differed significantly between groups (overall rxc chi square p=0.002). By univariate analysis, the rates of invasion associated with luminal B and HER-2/neu positive phenotypes were significantly higher than the rate of invasion associated with the luminal A phenotype (p<0.001 and p=0.005, respectively). Luminal B DCIS was significantly associated with invasive disease after multivariate adjustment (OR=11.1 p <0.001).  Discussion: Invasive foci are more commonly associated with HER-2/neu over-expressing DCIS phenotypes. Moreover, co-expression of HER-2/neu and ER in DCIS lesions is an independent predictor for the presence of associated invasive disease. Novel therapies targeting HER-2/neu in addition to anti-estrogen therapies may, therefore, play a role in breast cancer prevention.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1161.
Results of the first planned analysis of the TEAM (tamoxifen exemestane adjuvant multinational) prospective randomized phase III trial in hormone sensitive postmenopausal early breast cancer.
Authors: Jones SE , Seynaeve C , Hasenburg A , Rae D , Vannetzel J , Paridaens R , Markopoulos C , Hozumi Y , Putter H , Hille E , Kieback D , Asmar L , Smeets J , Urbanski R , Bartlett JM , van de Velde CJ
Published: December 2010

Abstract #15

Background: Exemestane (E) is a steroidal aromatase inactivator, which has been demonstrated to be more effective than tamoxifen (T) in metastatic breast cancer (BC). The role of E in adjuvant therapy has been established after 2 to 3 years of T compared to 5 years of T in the Intergroup Exemestane Study (Lancet 2007; 369: 599-70). One objective of the TEAM study was to evaluate E compared to T as initial adjuvant endocrine therapy.  Methods: Using common criteria, eligible postmenopausal patients in 9 countries with invasive ER+ and/or PR+ early BC, were prospectively randomized to either open-label E 25 mg/day or T 20 mg/day. All patients had completed primary therapy of surgery and chemotherapy if indicated. All data were collected and analyzed by the Central Data Center in Leiden, The Netherlands. The trial was initiated in 2001 with a primary endpoint of DFS between T and E. In 2004, based on results of the IES, TEAM was modified such that all patients on T were switched to E at 2.5-3 years. The modified design includes 2 primary endpoints: DFS of T versus E followed up to 2.75 years, and DFS of E for 5 years versus T switched to E treated for a total of 5 years. The present analysis focuses on the first primary endpoint: DFS for T compared to E at 2.75 years with censoring of events after 2.75 years. Log rank test with a 2-sided significance level of 2.98% stratified by country and factors nested in protocols will be utilized.  Results: Between January 2001 and January 2006, 9775 women were randomized to T or E of which 9300 will be followed for 2.75 years by October 2008: 99% were ER and/or /PgR+, 50% were node negative, 44% underwent mastectomy, 68% received radiotherapy, and 36% chemotherapy. There have been 693 DFS events (locoregional or distant recurrence, second breast cancers, or death without recurrence) by April 2008 within 2.75 years of randomization. In accordance with the statistical analysis plan, the first planned analysis will be based on 723 events or 9300 patients with at least 2.75 years follow-up. We will present a detailed analysis of the first primary endpoint of DFS between T and E at 2.75 years at the 2008 SABCS. The TEAM study represents the largest of the 3 major trials to compare efficacy of an aromatase inhibitor/inactivator versus tamoxifen as initial endocrine therapy.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 15.
Preclinical modeling of endocrine response: a combination therapy approach with the ERβ agonist, diarryl propionitrile and letrozole restores sensitivity to letrozole-resistant breast cancer cells.
Authors: Nair HB , Jayarajan R , Saha SR , Veerapaneni P , Santhamma B , Kirma NB , Perla RP , Joseph AK , Evans DB , Brodie AH , Tekmal RR
Published: December 2010

Abstract #17

The majority of breast cancer patients are postmenopausal women with estrogen receptor-positive (ER+) tumors. Approximately 66% of breast carcinomas contain aromatase. Aromatase inhibitors are proving to be more effective than tamoxifen in the treatment of postmenopausal women with ER+ breast cancer. However, the development of resistance to treatment is a concern. The transition of the ER+ tumors from a responsive to unresponsive state is associated with different molecular pathways. We have therefore investigated the properties of resistance that develops in response to the aromatase inhibitor letrozole in the preclinical MCF-7-aromatase xenograft animal model following long-term treatment with letrozole by using the derived letrozole-resistant MCF-7-aromatase LTLTca breast cancer cells. The combination treatment of letrozole and the ERβ agonist diarryl propionitrile (DPN) restored sensitivity to letrozole in the letrozole-resistant LTLTca cells. Studies from our group using this postmenopausal breast cancer preclinical model clearly showed the therapeutic advantage of the ERβ agonist in overcoming unresponsiveness to letrozole. A 67% reduction in tumour size was observed in the group of animals bearing the letrozole-resistant LTLTca tumors that received the combination of letrozole and DPN. A novel delivery method using letrozole-DPN nanoparticles showed enhanced sensitivity (∼80%) to the combination nanoparticles. Letrozole was found to be relatively ineffective in these animals with only a 36% reduction in tumor size with tumors having a mean tumor weight of 0.95g by the end of four weeks of treatment. Biochemical analysis showed a reduction in the tumor aromatase enzyme levels in mice treated with letrozole + DPN when compared to letrozole alone. QRT-PCR as well as protein analysis studies of the letrozole-resistant LTLTca tumors showed a decrease in P27 levels and elevated expression levels of HER-2. Expression levels of cyclin D1 and the ERα to ERb ratio was higher in the untreated letrozole-resistant tumors compared to tumors that responded to the combination therapy. These findings provide further support for the development and testing of novel therapeutic approaches for selective regulation of ER-dependent (ERα and β) actions. Combination treatments involving agents that modulate ERβ activity may provide therapeutic advantage in the treatment, for overcoming resistance to estrogen-ablation and prevention of breast cancer.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 17.
ER-α36, a variant of ER-α, is the estrogen receptor that mediates mitogenic estrogen signaling in breast cancer cells.
Authors: Ding L , Zhang X , Wang Z
Published: December 2010

Abstract #18

The role of endogenous estrogens in breast cancer etiology has been well established. Dysregulated estrogen signaling increases the rate of cell proliferation and thus the risk of breast cancer. However, despite widespread agreement that estrogens are involved in breast cancer etiology, the molecular mechanisms of estrogen action, especially those by which estrogen signaling stimulates mammary tumorigenesis and breast cancer progression have not been well established.  Recently, we have identified and cloned a 36-kDa novel isoform of estrogen receptor α (ER-α36) that is generated from a promoter located in the first intron of the original 66-kDa ER-α (ER-α66) gene. The ER-α36 differs from the ER-α66 by lacking both transcriptional activation domains (AF-1 and AF-2) but retains the DNA-binding, dimerization and most of the ligand-binding domains. ER-α36 is mainly expressed on the plasma membrane and mediates membrane-initiated estrogen signaling that activates the MAPK/ERK pathway and stimulates cell proliferation. ER-α36 inhibits the genomic estrogen signaling mediated by the AF1 and AF2 domains of ER-α66 and ligand-dependent and -independent transactivation activities of ER-β. We designed and constructed shRNA expression vectors to express shRNAs specific for ER-α36 or ER-α66. We found that ER-positive breast cancer cells MCF7 and T47D expressing ER-α36 shRNA that successfully knockdown about 90% ER-α36 expression failed to respond to estrogen stimulation. However, estrogen strongly stimulated cell growth in MCF7 and T47D cells with ER-α66 knockdown. We found that some estrogen responsive genes such as c-Myc, CyclinD1 and progesterone receptor (PR) were induced through the extra-nuclear estrogen signaling pathway while pS2 was induced by the nuclear pathway. Our results for the first time demonstrated that ER-α36, not the original ER-α36 is the estrogen receptor that actually mediates estrogen-stimulated cell proliferation in breast cancer cells.  Among 800 cases of human breast cancer specimens examined, ER-α36 is expressed in most of the breast cancer specimens, and even in 40% of ER-negative breast cancer cases that lack expression of ER-α66. In addition, ER-α36 expressing patients responded poorly to anti-estrogen Tamoxifen treatment. In vitro study revealed that breast cancer cells that highly express ER-α36 exhibited estrogen hypersensitivity and Tamoxifen resistance, consistent with the clinical evidence that breast cancers expressing ER-α36 exhibit higher degree of malignancy and poorer survival rate.  Taken together, our results demonstrated that ER-α36 is a novel player in mitogenic estrogen signaling that plays an important role in estrogen stimulated mammary carcinogenesis.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 18.
Accuracy of breast ultrasound BI-RADS classification and final pathological assessment of breast lesions submitted to core biopsy or fine needle aspiration of a breast diagnostic referral center in South Brazil.
Authors: Duarte Filho D , Zignani JM , Zignani PM , Teixeira RM , Biesdorf M , Viegas JP , Ribeiro R , Alexandretti M , Weber B , Tadvald M , Graudenz MS , Caleffi M
Published: December 2010

Abstract #2002

Background: Breast cancer (BC) is the leading cancer related mortality in women from 40-69 years old in Brazil. In the current year, about 49,400 women are expected to be diagnosed with BC, 4,880 of these in the state of Rio Grande do Sul. Until preventive strategies can be implemented, or better therapies developed, BC mortality reduction can only come from improvement in detection. Radiologists involved in breast imaging should ensure that they have the necessary skills to carry out core biopsy (CB) and/or fine-needle aspiration (FNA) under all forms of image guidance. This quality control is crucial in countries of limited resources, where the costs generated by benign breast biopsies affect the whole public health system. This paper aims to provide a quality parameter on best practice for diagnostic interventional breast procedures and standards.  Methods: 1,071 consecutive women with breast imaging (BI) abnormalities referred to the BI Center of the Moinhos de Vento Hospital for ultrasound (Us) guided breast CB or FNA between Oct/2003 and Oct/2007 were eligible. All patients in the study population underwent clinical and radiological examination. CB was performed by Us-guided automated gun method. The pathology reports were performed by 2 independent pathologists. All breast findings were classified according to the Us BIRADS system and were correlated to pathology results. An Us BIRADS 4 or 5 was considered a positive test. Sensitivity (Sen), specificity (Spe), predictive positive value (PPV), predictive negative value (PNV) and accuracy (Acc) were calculated.  Results: Patient medium age was 45.5y (13-92y). Correlation results are summarized on table 1. In this sample, 88.7% of BC were ductal invasive carcinoma, 4.6% lobular invasive carcinoma, 1.2% ductal carcinoma in situ, 1.2% undifferentiated neoplasia, and 4.3% were other types of neoplasia. Sen of 93.3% (CI 87.7%-96.5%), Spe of 95% (93.3%-96.2%), PPV of 75.2% (68.3%Â81.1%), PNV of 98.8% (97.8%-99.4%) and an Acc of 94.7% were observed.   Discussion: Us BIRADS classification allows an adjusted standardization of radiologists images interpretation, reproducing the correlation between this and the pathology. Periodic performance audit is the most meaningful way to demonstrate the success or failure in detecting otherwise occult BC, the ultimate indicator of BI performance. Radiologists involved in BI in our center have the requirements to carry out CB and/or FNA under Us image guidance, once the observed results are in accordance with the ACR Practice Guideline, published in 2005.   

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2002.
Fine tuning of the Van Nuys prognostic index (VNPI) 2003 by using genomic grade index (GGI): a new tool for ductal carcinoma in situ (DCIS).
Authors: Altintas S , Toussaint J , Lambein K , Huizing M , Durbeque V , Larsimont D , Van Marck E , Vermorken J , Tjalma W , Sotiriou C
Published: December 2010

Abstract #2020

Introduction: DCIS is a heterogeneous malignant condition of the breast with no standard of care. The updated VNPI 2003 is a practical tool in treatment decision making. Recently, the introduction of GGI has been shown to be one of the most important prognostic indicators in invasive breast cancer. A GGI based on the expression of 4 genes using RT-PCR was developed and validated in invasive BC. The aim of this study was to assess its prognostic value in DCIS.  Methods: Real Time Polymerase Chain Reaction-GGI (RT-PCR-GGI) was applied on a DCIS population. Patients were assigned into 3 subgroups according to VNPI [low risk (score 4-6), intermediate risk (score 7-9) and high risk (score 10-12)] based on nuclear grade ± necrosis, tumor size, margin width and age. The prognostic performance of GGI was assessed by replacing pathologically determined nuclear grade by GGI: VNPI-GGI. Disease free survival (DFS) was calculated by Kaplan-Meier survival plots with log-rank significance  Results: A total of 90 patients with DCIS were analyzed. The number of recurrences per VNPI subgroup was 1/15 in subgroup 1, 5/53 in subgroup 2 and 6/22 in subgroup 3. Ten out of these 12 patients showed invasive recurrence. No statistical significance was reached (log rank 0.349; HR 3.69 [95% 0.620-21.923], p= 0.151). However, application of VNPI-GGI identified three distinct subgroups with statistically different DFS (HR = 8.887 [95% CI: 1.2–65.7], p= 0.03). Interestingly, when the VNPI-GGI was applied on the patients with low histological grade, 25% were redistributed to the high-risk group (p = 0.008). Of note, when PCR-GGI was applied to the recurrent cases (N= 12), the genomic grade status was preserved from DCIS to the recurrence disease in 83% of them.  Conclusions: RT-PCR-GGI incorporated into the VNPI improved its prognostic value for DCIS. This method has the potential to provide a powerful tool in DCIS management. Further validation is planned in a prospective trial with a larger patient population.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2020.