Postmenopausal Early Breast Cancer Patients Research Articles

Do obese women benefit less from adjuvant endocrine therapy with aromatase inhibitors? Preliminary analysis on the association of BMI and aromatase inhibitor plasma levels.

e11118 Background: The efficacy of adjuvant endocrine treatment with aromatase inhibitors (AI), inhibiting the conversion of androgens to estrogen in adipose tissue, might depend on the volume of adipose tissue. The scientific community recently even has discussed to recommend an increase of the AI dose for obese women. However, little evidence is available regarding the potential interactions among adjuvant antihormonal treatment and obesity. We aimed at investigating the association of BMI and anastrozole plasma levels adjusted for age. Methods: We prospectively included 114 postmenopausal early breast cancer patients undergoing aromatase inhibitor treatment with anastrozole at one of their regular after-care check-ups. Sociodemographic and clinical data as well as data on weight and size for the calculation of BMI were comprehensively assessed. Blood samples were collected within the routine blood collection and measurement of aromatase inhibitor plasma levels were performed by liquid chromatography–tandem mass spectrometry. The association of anastrozole plasma levels, BMI and age was analyzed using linear regression analysis. Results: We analyzed data of 109 postmenopausal patients. Non-adherent patients (n=5, no AI plasma concentration) were excluded from the analysis. 2.1% patients were underweight (defined BMI<19.5), 47.4% (defined BMI 20-25.5) had normal weight and 50.5 (defined BMI>25.5) patients were obese. Mean patient age was 64.7 (SD 8.6) years. Regression analysis revealed that age (t=2.850, p=0.005) was a stronger predictor of higher AI plasma level than BMI. Other variables had no impact on AI blood level. Conclusions: In this study, BMI did not serve as a predictor for anastrozole plasma concentrations. Analysis proved older age to be highly predictive of increased AI plasma levels. According to these finding, it is unclear whether AI dose recommendations have to be adjusted for obesity. However, the subject of age in terms of AI metabolization has to be enhanced. Further research in that matter is mandatory to clarify results on the association of obesity and AI therapy efficacy.

Effects of Exemestane, Anastrozole and Tamoxifen on Bone Mineral Density and Bone Turnover Markers in Postmenopausal Early Breast Cancer Patients: Results of N-SAS BC 04, the TEAM Japan Substudy

Background: Use of aromatase inhibitors in women with postmenopausal breast cancer accompanies risks of bone loss. We evaluated changes in bone mineral density (BMD) and bone turnover markers in patients treated with exemestane, anastrozole or tamoxifen for hormone-sensitive postmenopausal early breast cancer. Patients and Methods: Sixty-eight patients enrolled in the Tamoxifen Exemestane Adjuvant Multinational Japan bone substudy were randomly assigned to receive tamoxifen, exemestane or anastrozole. During a 2-year study period, lumbar spine BMD was measured using dual-energy X-ray absorptiometry, and urinary type I collagen cross-linked N-telopeptide (NTX) and serum bone-specific alkaline phosphatase (BAP) were also measured. Results: BMD at 2 years of treatment was higher in tamoxifen patients compared with exemestane and anastrozole patients; however, the intergroup difference was not significant (p = 0.2521 and p = 0.0753, respectively). BMD was higher in exemestane patients compared with anastrozole patients; however, the intergroup difference was not significant (p = 0.7059 and p = 0.8134, respectively). NTX and BAP were significantly lower in tamoxifen patients compared with exemestane and anastrozole patients at 1 and 2 years of treatment (p < 0.05). Conclusion: Tamoxifen may provide better bone protection compared with exemestane or anastrozole. The effect of exemestane and anastrozole on bone loss may be comparable in Japanese postmenopausal women.

Abstract P3-10-33: Mammostrat® as an Immunohistochemical Multigene Assay for Prediction of Early Relapse Risk in Postmenopausal Early Breast Cancer: Preliminary Data of the TEAM Pathology Study

Abstract Background: Postmenopausal early breast cancer patients, treated with endocrine therapy, have approximately 90% five year disease free survival (DFS). However, for patients at higher risk of relapse, additional adjuvant chemotherapy may be indicated. The challenge is to prospectively identify such patients. The Mammostrat test uses five immunohistochemical markers to stratify patients on tamoxifen (T) therapy into various risk groups potentially guiding treatment choices. We tested the efficacy of this panel in the TEAM trial (exemestane (E) versus T→E) to determine the relevance in patients treated with an AI. Patients &amp; Methods: Pathology blocks from 4598 TEAM patients were collected and tissue microarrays constructed. The cohort overall was 47% node positive, and 36% also received adjuvant chemotherapy. Samples were stained, using triplicate 0.6mm2 TMA cores, and positivity for p53, HTF9C, CEACAM5, NDRG1, SLC7A5 assessed. Each case was assigned a Mammostrat risk score and analysed for disease free survival (DFS) by marker positivity and risk score. Results: Preliminary results on the UK TEAM cohort (1059 cases) showed 18.9% stained positive for p53 (184/972), 21.3% for NRDG1 (204/956), 26.4% for SLC7A (253/957), 21.9% for HTF9C (220/1004), 18.3% for CEACAM5 (185/1009). Complete data was available for 919 cases including patients treated with chemotherapy, with 447 (49%) designated low risk, 213 (23%) medium and 259 (28%) high risk. In univariate analysis, Mammostrat scores were prognostic (p=0.02), with 5 year DFS (see comment above) results being 86.9±1.7%, 80.1±3.0% and 80.8±2.6% for patients with low, medium and high Mammostrat scores respectively. Analyses on the entire TEAM pathology cohort are ongoing, and further data with sufficient power to evaluate the impact of Mammostrat in multivariate regression analyses will be presented. Conclusion: Preliminary analysis of the impact of the Mammostrat score in both tamoxifen and exemestane treated patients suggests it retains its prognostic value in this context. Further analysis with the power to evaluate the impact of Mammostrat in multivariate regression analyses will be presented. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-33.

Abstract P4-09-02: Prognostic and Predictive Value of Centrally Reviewed Ki67 Labeling Index in Postmenopausal Women with Endocrine-Responsive Breast Cancer: Results from Austrian Breast and Colorectal Cancer Study Group Trial 8

Abstract Purpose: The aim of the present study was to assess the prognostic and predictive value of Ki67 labeling index in postmenopausal hormone receptor-positive early breast cancer patients who were treated with adjuvant tamoxifen or anastrozole after tamoxifen. Patients and Methods: We determined the expression of Ki67 by immunohistochemistry on whole tissue sections of breast carcinoma patients who had been enrolled in Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 8 and received tamoxifen for 5 years or tamoxifen for 2 years followed by anastrozole for 3 years. Ki67 labeling index was evaluated as continuous variable or dichotomized at 10%. Distant recurrence and death were analyzed using Cox models adjusted for clinical and pathological factors. Results: High Ki67 labeling index was observed in 394 of 1587 (23%) tumors and was associated with poor outcome. Patients with high Ki67 labeling index had a significantly shorter distant recurrence-free survival (adjusted hazard ratio [HR] for distant recurrence 2.16, 95% confidence interval [CI] 1.43-3.25, P &amp;lt; 0.001) and overall survival (adjusted HR for death 1.77, 95% CI 1.30-2.42, P &amp;lt; 0.001) as compared to patients with low Ki67 labeling index. No interaction between Ki67 labeling index and treatment was observed (P = 0.84). Conclusion: High Ki67 labeling index is an independent poor prognostic factor for distant recurrence and death in postmenopausal women with early-stage, hormone receptor-positive breast cancer but is not predictive for outcome of adjuvant treatment with either tamoxifen or tamoxifen followed by anastrozole. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-09-02.

Abstract P4-09-08: PTEN Protein Expression in Postmenopausal Steroid Receptor Positive Early Breast Cancer Patients Treated with Adjuvant Tamoxifen

Abstract Background: Since one of possible causes of resistance to antiestrogen therapy in SR+BC patients is an alteration of PTEN (Phosphatase and Tensin homolog deleted on chromosome 10) signaling pathways, the aim of this study was to determine the PTEN protein expression in postmenopaual patients with steroid receptor (SR)+ breast cancer (BC) treated with adjuvant tamoxifen, to investigate the association of PTEN protein expression with tumor histology, size and grade, estrogen receptor (ER), progesteron receptor (PR) and human epidermal growth receptor 2 (HER2) statuses and disease outcome, as well. Patients and methods: This was a retrospective analysis of 78 postmenopausal SR+BC patients treated for stage I/II with adjuvant tamoxifen. PTEN protein expression and ER, PR and HER2 status were determined using immunohistochemistry method. Results: The distribution of PTEN protein expression according to tumor histology was as follows: PTEN+ status in 27/43 (62,8%) patients with ductal and in 26/35 (74,3%) patients with lobular carcinomas and PTEN-status in 16/43 (37,2%) patients with ductal and in 9/35 (25,7%) patients with lobular carcinomas. Disease relapse was observed in 38/78 pateints: 14/53 (26.4%) of PTEN+BC subgroup and 24/25 (96%) of PTEN-BC subgroup. There were no significant association between PTEN protein expression and tumor histology, size and grade, and ER, PR and HER2 expression, as well. Patients with PTEN-BC had significantly shorter disease-free interval and overall survival (for both Log rank test, P&amp;lt;0.01) compared to PTEN+BC pateints. Conclusion: Our results suggest that PTEN protein expression might be of prognostic significance in postmenopausal SR+ BC patients treated with ajduvant Tamoxifen. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-09-08.

The mammalian target of rapamycin inhibitor everolimus (RAD001) in early breast cancer: results of a pre-operative study

mTOR plays a key role in tumor cell cycle control, proliferation, and survival. RAD001 (everolimus) is a novel macrolide that inhibits mTOR and thus downstream signaling pathways. 31 post-menopausal women with early breast cancer were given 5mg RAD001 once daily for 14days prior to surgery. Biopsies were taken at diagnosis and at surgery (post 14days of treatment) and assessed for immunohistochemical changes in proliferation (Ki67), apoptosis (active caspase-3), p-AKT (s473), p-S6 (s235/236 and s240/244), p-mTOR (s2448), ER, and PR. Five patients did not complete the 2-week treatment period due to adverse events. All adverse events were grade 1 or 2 (NCIC-CTC scale). RAD001 treatment significantly decreased proliferation (geometric mean reduction 74% from baseline (p=0.019)), particularly in HER-2 positive tumors. High Ki67 pre-treatment correlated with reduction in Ki67, an increase in apoptosis, a reduction in p-AKT (cytoplasmic) and reduction in p-mTOR following treatment. Nuclear expression of p-AKT was significantly reduced with treatment. Tumors that had a reduction in Ki67 with treatment exhibited a significant reduction in cytoplasmic p-AKT. p-S6 staining was significantly reduced independently of Ki67 (p<0.001 for two sites of phosphorylation). RAD001 5mg/daily is safe and tolerable in postmenopausal early breast cancer patients and inhibits the mTOR pathway and its downstream effectors, significantly reducing tumor cell proliferation. Tumors with high Ki67, high p-AKT, and HER-2 positivity may be more responsive to mTOR inhibition with RAD001. This is the first study to report results of RAD001 5mg as a single agent in early breast cancer.

Maintenance of physical activity and body weight in relation to subsequent quality of life in postmenopausal breast cancer patients

Background: We prospectively examined the association between physical activity, body weight and quality of life in Dutch postmenopausal early breast cancer patients treated with adjuvant endocrine therapy.Patients and methods: In this side study of a large clinical trial, lifestyle and quality-of-life questionnaires were filled out 1 and 2 years after the start of endocrine therapy (T1 and T2, respectively) and included a pre-diagnosis lifestyle assessment (T0). A total of 435 breast cancer patients returned both questionnaires.Results: Individuals with a physical activity level above the median who maintained this level from T0 to T1 reported the best global quality of life and physical functioning and the least fatigue at T2, as compared with individuals with low levels of physical activity which further decreased after diagnosis (difference of +16, +14, and -22 points on a 0–100 quality-of-life scale, respectively; P < 0.01). Overweight or obese women who gained body weight after diagnosis reported worst quality of life and most fatigue as compared with women who maintained a stable body weight (difference of -8, -10 and +2 points, respectively; P < 0.01).Conclusion: Maintaining high pre-diagnosis physical activity levels and a healthy body weight is associated with better quality of life after breast cancer.

DEVA: Randomized trial of sequential epirubicin and docetaxel versus epirubicin alone in node-positive postmenopausal early breast cancer (EBC) patients.

536 Background: This group previously showed that fractionated epirubicin (EPI) alone is an active, well tolerated adjuvant regimen in postmenopausal women (Wils, JCO, 1999). DEVA evaluated the efficacy and toxicity of incorporating docetaxel (DOC) to create a sequential anthracycline-taxane regimen. Methods: Following complete tumour excision, postmenopausal women with node-positive EBC were randomised to either EPI 50 mg/m2 d1 and 8 every 4 weeks for 6 cycles, or EPI-DOC 3 cycles EPI (as above) then 3 cycles of docetaxel 100 mg/m2 d1 every 3 weeks. Patients with ER positive EBC also received endocrine therapy for 5 years. Disease-free survival (DFS) (local and distant relapse, 2nd primary breast cancer, intercurrent death) and overall survival (OS) were evaluated. Results: From 1997 to 2005, 803 patients at 36 centres entered DEVA (EPI n = 397, EPI-DOC n = 406). 198 DFS events have been reported (EPI-DOC n = 84 EPI n = 114); median follow-up 64.7 months (IQR 45.2-84.4 months). 5-year DFS rates were EPI-DOC 79.5% (CI 75.2-83.8) and EPI 72.7% (CI 68.0-77.3) with evidence of improvement in DFS with EPI-DOC (HR = 0.68; 95% CI 0.52-0.91; p = 0.008). Adjustment for factors known to affect prognosis (ER status, grade, tumour size, extent of node involvement) slightly increased size of DFS effect (HR = 0.58; 95% CI 0.43-0.79) with no evidence of a differential effect within the subgroups. 127 patients have died (EPI-DOC 52, EPI 75) with a reduction in deaths with EPI-DOC (HR = 0.66; CI 0.46-0.94; p = 0.02). 5-year OS rates were EPI-DOC 88.9 (CI 85.5-92.2) and EPI 81.8 (CI 77.7-85.9). 20 patients (EPI-DOC n = 7 EPI n = 13) died with no evidence of breast cancer relapse; 6 were due to cardiac disease (EPI-DOC n = 1 EPI n = 5). From cycles 4-6 onwards, with exception of nausea/vomiting (p = 0.003), EPI-DOC was more toxic than EPI including infection (p = 0.001), febrile neutropenia, myalgia, peripheral neuropathy, oedema, skin and nail abnormalities, and stomatitis (all p < 0.001). Conclusions: These mature results suggest, within a relatively small trial, that substitution of docetaxel for epirubicin for the last three cycles of chemotherapy results in improved outcome in postmenopausal, node-positive EBC patients. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis Pfizer, sanofi-aventis Pfizer

369 The effect of exemestane and anastrozole on bone mineral density and bone turnover markers in postmenopausal early breast cancer patients: final results of 3 years after randomization of N-SAS (national surgical adjuvant study) BC04, the TEAM Japan sub-study

369 The effect of exemestane and anastrozole on bone mineral density and bone turnover markers in postmenopausal early breast cancer patients: final results of 3 years after randomization of N-SAS (national surgical adjuvant study) BC04, the TEAM Japan sub-study

5139 Patterns of care in postmenopausal early breast cancer patients participating in the TEAM (Tamoxifen Exemestane Adjuvant Multinational) study: variations in locoregional therapy between different countries

5139 Patterns of care in postmenopausal early breast cancer patients participating in the TEAM (Tamoxifen Exemestane Adjuvant Multinational) study: variations in locoregional therapy between different countries

Plasma levels of estrone sulfate (ES) in postmenopausal women with breast cancer (BC) during letrozole (L) treatment: Association with single nucleotide polymorphisms (SNPs) of CYP19A1

555 Background: The CYP19A1 gene encodes aromatase, a key enzyme for estrogen biosynthesis. We investigated the association between four CYP19A1 SNPs, affecting different circulating estrogen levels (rs10046 C&gt;T, rs4646 G&gt;T, rs749292 C&gt;T, rs727479 T&gt;G), and suppression of plasma ES levels induced by 6 weeks (time needed to reach L steady-state concentrations) of L (25 mg/d). Methods: Patients were enrolled into a prospective, italian multi-centre trial (GIM5) testing the correlation of CYP19A1 SNPs with the efficacy of L adjuvant therapy, after 5 years of tamoxifen, in postmenopausal early BC patients. Blood samples for hormone measurements were obtained immediately before starting L (baseline) and following 6 wks of treatment. SNPs were identified from DNA obtained from peripheral blood cells by Hexaprimer Amplification Refractory Mutation System PCR (H-ARMS-PCR). Plasma ES levels were evaluated by Radio Immuno Assay (RIA). Results: SNPs and hormone levels were evaluated in at least 129 patients. SNPs of CYP19A1 were associated with different baseline plasma ES levels. Mean inhibition of aromatase activity induced by L ranges from 71% to 79%, as a function of the SNPs. After 6 weeks of L no difference in ES levels was observed between patients with different SNPs (Table). Conclusions: L therapy induces a higher aromatase suppression in patients with SNPs associated with higher baseline plasma ES levels. The difference in ES levels associated with genetic variation at the CYP19A1 locus disappeared after L therapy. [Table: see text] [Table: see text]

Endocrine effects of adjuvant letrozole versus tamoxifen in hormone responsive postmenopausal early breast cancer patients: results from the HOBOE randomized trial.

Abstract Abstract #1150 Purpose. We compared the endocrine effects of 6 and 12 months of adjuvant letrozole versus tamoxifen in postmenopausal patients with hormone responsive early breast cancer, within an ongoing phase 3 trial (HOrmonal adjuvant treatment BOne Effects – HOBOE, ClinicalTrial.gov id: NCT00412022).&amp;#x2028; Patients and Methods. Patients were randomised to receive tamoxifen or letrozole ± zoledronate. Serum values of 17-b-estradiol, FSH, LH, testosterone, dehydroepiandrosterone-solphate, progesterone, and cortisol were measured at baseline, after 6 and 12 months of treatment. For each hormone, baseline, 6 and 12-month values were compared between treatment groups, by the exact Wilcoxon-Mann-Whitney test.&amp;#x2028; Results. At December 31, 2006, 157 postmenopausal patients had been enrolled into the study; baseline data were available for 139 patients (88.5%), 43 assigned to tamoxifen and 96 assigned to letrozole. Median age was 61 and 62 years in the two groups, respectively. Baseline values were similar between the two groups for all hormones. At 6 and 12 months, levels of 17-b-estradiol were significantly lower with letrozole as compared with tamoxifen (p=0.0003 and p&amp;lt;0.0001, respectively). Patients treated with letrozole also showed higher levels of progesterone and testosterone at 6 (p=0.001 and p=0.01, respectively) and 12 months (p=0.004 and p=0.02, respectively) than those treated with tamoxifen. FSH and LH were lower (all p&amp;lt;0.0001 for both hormones), while cortisol was higher (p=0.003 at 6 and 0.001 at 12 months) with tamoxifen than with letrozole.&amp;#x2028; Conclusion. To our knowledge, this is the first study reporting on endocrine effects of letrozole as adjuvant treatment of postmenopausal early breast cancer and allowing a prospective comparison with tamoxifen. Adjuvant letrozole and tamoxifen result in significantly distinct endocrine effects. Such differences can explain the higher efficacy of letrozole as compared to tamoxifen. Long-term impact needs to be studied. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1150.

Quality of life in relation to hormonal treatment of postmenopausal women in the Dutch Tamoxifen Exemestane Adjuvant Multicentre (TEAM) trial.

Abstract Abstract #21 Background In the last decade, use of adjuvant hormonal treatment increased as well as its duration. Aromatase inhibitors are associated with a minimal increase of disease free survival compared to tamoxifen. Both therapies are associated with different side effects which can affect quality of life (QoL). Therefore, it is necessary to compare the QoL of patients using these therapies. We compared the QoL of women participating in the Dutch Tamoxifen Exemestane Adjuvant Multicentre (TEAM) Trial.&amp;#x2028; Patients and Methods The Dutch TEAM trial included 2754 postmenopausal early breast cancer patients who were randomised between five years of exemestane or 2.5-3 years of tamoxifen followed by 2.5-2 years of exemestane. A total of 742 patients were invited onto the QoL subprotocol. At one (T1) and two (T2) years after start of hormonal treatment, patients were ask to fill in questionnaires. This questionnaire contains the European Organisation for Research and Treatment of Cancer (EORTC) QLQ C30 and the EORTC BR23 questionnaires, supplemented with Functional Assessment of Cancer Therapy - Endocrine Subscale (FACT-ES) questions covering endocrine symptoms. The endpoint was the difference in QoL between patients receiving tamoxifen or exemestane.&amp;#x2028; Results Questionnaires were completed by 543 patients at T1 and 83% of these returned the questionnaire of T2. There were no significant differences in physical functioning, role functioning, cognitive functioning, emotional functioning, body image, breast symptoms, arm symptoms and endocrine symptoms between both treatment groups at T1 nor at T2. Patients receiving exemestane had significantly less sexual enjoyment (difference of 9 points on a 0-100 scale; p=0.004) and more insomnia (difference of 8 points; p=0.005) compared to patients receiving tamoxifen at T1. At T2, there was no statistically significant difference in sexual enjoyment (difference of 4 points; p=0.287). However, patients receiving exemestane reported significantly worse sexual functioning (difference of 5 points; p=0.020) and still more insomnia (difference of 8 points; p=0.004).&amp;#x2028; Conclusion Patients using exemestane reported less sexual enjoyment and more sexual functional problems than patients using tamoxifen. This may be explained by the fact that specific side effects of exemestane (e.g. vaginal dryness) can cause less sexual enjoyment which can result in a decreased sexual functioning. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 21.

Concurrent or Sequential Adjuvant Hormonoradiotherapy after Conservative Surgery for Early-stage Breast Cancer: Clinical Results of the CO-HO-RT Phase II Randomized Trial

We recently showed in an aromatase-gene transfected breast cancer cell line, a radiosensitizing effect of letrozole. We then conducted a multicentric phase II randomized trial evaluating adjuvant concomitant radiotherapy and letrozole with radiotherapy followed by letrozole in postmenopausal early breast-cancer patients (CO-HO-RT trial).

Meta-analysis of trials comparing anastrozole and tamoxifen for adjuvant treatment of postmenopausal women with early breast cancer.

ObjectiveIt was aimed to review the literature and make a meta-analysis of the trials on both upfront, switching, and sequencing anastrozole in the adjuvant treatment of early breast cancer.MethodsThe PubMed, ClinicalTrials.gov and Cochrane databases were systematically reviewed for randomized-controlled trials comparing anastrozole with tamoxifen in the adjuvant treatment of early breast cancer.ResultsThe combined hazard rate of 4 trials for event-free survival (EFS) was 0.77 (95%CI: 0.70–0.85) (P < 0.0001) for patients treated with anastrozole compared with tamoxifen. In the second analysis in which only ITA, ABCSG 8, and ARNO 95 trials were included and ATAC (upfront trial) was excluded, combined hazard rate for EFS was 0.64 (95%CI: 0.52–0.79) (P < 0.0001). In the third analysis including hazard rate for recurrence-free survival (excluding non-disease related deaths) of estrogen receptor-positive patients for ATAC trial and hazard rate for EFS of all patients for the rest of the trials, combined hazard rate was 0.73 (95%CI: 0.65–0.81) (P < 0.0001).ConclusionAnastrozole appears to have superior efficacy than tamoxifen in the adjuvant hormonal treatment of early breast cancer. Until further clinical evidence comes up, aromatase inhibitors should be the initial hormonal therapy in postmenopausal early breast cancer patients and switching should only be considered for patients who are currently receiving tamoxifen.

Concurrent or sequential adjuvant hormonoradiotherapy after conservative surgery for early stage breast cancer: First results of the CO-HO-RT phase II randomized trial

556 Background: We recently showed in an aromatase-gene transfected breast cancer cell line, a radiosensitizing effect of letrozole. We then conducted a multicentric phase II randomized trial evaluating adjuvant concomitant radiotherapy and letrozole with radiotherapy followed by letrozole in postmenopausal early breast cancer patients (CO-HO-RT trial). Methods: Postmenopausal pts with early stage breast cancer were randomized after conservative surgery to either: A) concurrent RT-LET (LET started 3 weeks before the first day of RT) or B) sequential RT-LET (LET started 3 weeks after the end of RT). Whole breast RT was delivered to a total dose of 50 Gy ± a 10–16 Gy boost. Pts were stratified by center, adjuvant chemotherapy (ACT), boost, CD8 radiation-induced apoptosis. Primary endpoint was radiation-induced acute and late skin toxicity. Skin toxicities were evaluated by two different clinicians at each medical visit (CTCAE v3.0). Lung CT-scan and functional pulmonary tests were performed regularly. Quali...

Anastrozole is cost-effective vs tamoxifen as initial adjuvant therapy in early breast cancer: Canadian perspectives on the ATAC completed-treatment analysis

To conduct an economic analysis comparing tamoxifen and anastrozole (Arimidex) in the adjuvant treatment of hormone receptor-positive (HR+), post-menopausal early breast cancer patients. An economic model examined typical patients (64 years of age, HR+, 64% node negative) from the Arimidex, tamoxifen alone, or in combination (ATAC) trial over a lifetime horizon. Rates of events were derived from ATAC trial results. Post-trial event rates were drawn from the literature for tamoxifen; event rates for anastrozole were modified by the relative risks observed in the ATAC trial. Resource utilization was drawn from Statistics Canada's Population Health Model for breast cancer, supplemented by an expert panel. A public health care system perspective, 2004 Canadian prices and a 5% discount rate were employed. Anastrozole-taking patients incurred additional hormonal treatment costs compared to tamoxifen-taking patients (incremental lifetime cost, 6,974 Canadian dollars per patient), partially offset by reduced downstream recurrences of breast cancer (1,143 Canadian dollars lifetime savings per patient) for a net incremental cost of 5,796 Canadian dollars per patient on anastrozole. The anastrozole-treated patients were projected to experience a 5.6% absolute risk reduction of first breast cancer recurrence and a 2.8% absolute risk reduction in breast cancer death. This corresponded to 30,000 Canadian dollars per life year gained and 28,000 Canadian dollars per quality-adjusted life year gained (95% confidence interval, 17,428 to 54,605 Canadian dollars). The results were affected by the duration and extent of anastrozole benefit under sensitivity analysis but remained cost-effective. Compared to tamoxifen, anastrozole therapy is effective and cost-effective as initial adjuvant therapy in post-menopausal, HR+ early breast cancer patients.

Need for Weight Management among Postmenopausal Early Breast Cancer Patients Receiving Adjuvant Endocrine Therapy

Increasingly effective adjuvant therapies mean that the prognosis for postmenopausal women with breast cancer has never been better. Weight problems are common among breast cancer patients and worsen due to the impact of diagnosis and treatment. Recent studies have linked excess weight with the risk of recurrence of breast cancer among premenopausal women. While general obesity (body mass index) does not appear to influence the already much improved prognosis for postmenopausal women, there is some evidence that limiting central obesity and improving insulin resistance may improve survival. The focus of attention for postmenopausal breast cancer survivors is also shifting to consider the mortality and morbidity from other weight-related cancers and noncancer causes, such as cardiovascular disease, making weight control a potentially important adjunct to endocrine therapy. This paper outlines the rationale and optimal design for effective weight management strategies among postmenopausal breast cancer patients receiving endocrine therapy.

The Effect of Exemestane on the Lipidemic Profile of Postmenopausal Early Breast Cancer Patients: Preliminary Results of the TEAM Greek Sub-study

Long-term endocrine therapy for breast cancer may have clinical implications as drugs that potentially alter the lipid profile may increase the risk of developing cardiovascular disease. In this study, a companion sub-protocol to the TEAM (Tamoxifen and Exemestane Adjuvant Multicenter) International trial, we compared the effect of the steroidal aromatase inactivator exemestane on the lipid profile of postmenopausal women with early breast cancer in the adjuvant setting to that of tamoxifen. In this open-label, randomized, parallel group study, 176 postmenopausal patients with estrogen and/or progesterone receptor positive early breast cancer were randomized to either adjuvant exemestane (25 mg/day; n = 90) or tamoxifen (20 mg/day; n = 86). Assessments of total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and serum triglycerides (TRG) were performed at baseline and every 3 months for the first 12 months. Serum triglyceride levels were consistently increased above baseline throughout the study in the tamoxifen arm, while there was a trend towards reduction in the exemestane arm. There was also an overall trend for tamoxifen to decrease the levels of LDL throughout the study period. Exemestane did not demonstrate any other significant change in HDL levels; however, there was a consistent trend for a reduction in total cholesterol in both treatment arms. The atherogenic risk determined by the TC:HDL ratio remained stable in both arms throughout the treatment period. Exemestane appears to have a neutral effect on total cholesterol and HDL levels. Unlike tamoxifen's positive effect on LDL levels, exemestane does not significantly alter LDL levels. Tamoxifen on the other hand increases triglyceride levels, while exemestane results in a beneficial reduction in TRG levels. These data offer additional information with regard to the safety and tolerability of exemestane in postmenopausal breast cancer patients and support further investigation of its potential usefulness in the adjuvant setting.

Estrogens and bone metabolism in postmenopausal women with early breast cancer at low risk treated with exemestane: a randomized placebo-controlled study

531 Background: Estrogens (Es) reduction in menopause increases osteoporosis and fractures risk. Aromatase inhibitors are being introduced for treating postmenopausal early breast cancer (EBC). Exemestane (E, Aromasin®), a steroidal aromatase inactivator, inhibits peripheral aromatase by 98%, markedly reducing Es. We report the effect of E on Es and bone metabolism in postmenopausal EBC patients (pts). Methods: We conducted a randomized, double blind study of E vs. placebo (P) on bone metabolism, endocrinological and metabolic parameters in postmenopausal pT1N0 or T2N0 (with no other risk factors) or ductal carcinoma in situ (DCIS) pts. ER and/or PgR+ve or unknown pts with bone mineral density (BMD) within 2 SD of the mean for 65-year (yr) women, were randomized to E 25 mg or P p.o. daily for 2 yrs, with a 1-yr follow-up. Primary objective was non-inferiority on BMD. Planned sample size was 128 BMD-evaluable pts. Estradiol (E2), estrone (E1), bone alkaline phosphatase (ALP), PINP, osteocalcin (OC), serum CTX (s-CTX), urinary CTX (u-CTX) and NTX (u-NTX) were evaluated at baseline (BS), 6, 12 and 24 months (mos). Results: 147 pts have been enrolled, 73 E and 74 P. Median age: 61 yrs (E) and 60 yrs (P). Median time from menopause: 9.7 yrs E, 8.0 yrs P. ER and/or PgR: +ve 130 pts, unknown 17 (15 with DCIS). E was well tolerated, 70% of pts had drug-related events on E, 73% on P. Nine pts withdrew on E and 3 on P for adverse events. Three withdrew consent on E and 2 on P. The % change from baseline on Es and bone metabolism markers are described in the Table. Conclusions: E induces a marked Es suppression coupled with an increase in bone resorption (CTX, NTX), and even more in bone formation (ALP, PINP, OC). This indicates an increase of bone remodeling, although no major effect is observed on bone mineral density (Lonning ASCO 2004, submitted). Correlation analyses are ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Italia S.p.A. Pfizer Co. Pfizer Co.