bluuebunny/crossref_metadata_2025_split huggingface dataset:
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
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.&#x2028; 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.&#x2028; 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.&#x2028; 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
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.&#x2028; 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 (&lt;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.&#x2028; 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 &lt;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).&#x2028; 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
Abstract #1137
Aim: To investigate the management of bone health in postmenopausal women with early breast cancer (BCA) scheduled to receive anastrozole.&#x2028; 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 &lt;-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 &lt;-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.&#x2028; 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&lt;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.&#x2028; 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.&#x2028; &#x2028;
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
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
Abstract #1152
Background:&#x2028; 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.&#x2028; Patients and Methods:&#x2028; 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&#x2028; · 12 weeks of L followed by 12 weeks of A (L→A) or&#x2028; · 12 weeks of A followed by 12 weeks of L (A→L).&#x2028; 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.&#x2028; · 29 had no prior tamoxifen and&#x2028; · 27 had received tamoxifen.&#x2028; The following lipoproteins were measured:&#x2028; - Triglyceride - HDL&#x2028; - Cholesterol - ApoA1&#x2028; - ApoB&#x2028; - Cholesterol&#x2028; - cLDL&#x2028; HDL and ApoA1 are cardioprotective whereas ↑ levels of the others are associated with an ↑ risk of coronary artery disease.&#x2028; Results:&#x2028; (Expressed as absolute changes +/- 95% CI)&#x2028; Patients who stopped tamoxifen &gt;12 weeks prior to trial entry were considered tamoxifen free. Patients who had stopped tamoxifen &lt;12 weeks prior to trial entry were considered to have tamoxifen in their system at trial entry.&#x2028; A vs L: &#x2028; There were no significant differences detected between A and L.&#x2028; A vs L in tamoxifen vs no tamoxifen groups:&#x2028; 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.&#x2028; 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.&#x2028; 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.&#x2028; There were no significant changes for any other variables measured.&#x2028; Conclusions:&#x2028; There were no significant differences between letrozole and anastrozole in their effects on lipids.&#x2028; 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
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.&#x2028; 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.&#x2028; 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&lt;0.001 and p=0.005, respectively). Luminal B DCIS was significantly associated with invasive disease after multivariate adjustment (OR=11.1 p &lt;0.001).&#x2028; 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
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.&#x2028; 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.&#x2028; 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
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.